Introduction

Hereditary neuropathies are groups of genetically and phenotypically heterogeneous neuropathies with varying degrees of motor and sensory manifestations. The most common group of heredofamilial neuropathies is Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathies. The global prevalence of CMT is estimated to range from 10 to 30 per 100,000 people, making it the most common inherited neuromuscular condition.1 A 2021 study suggests a rising trend in prevalence compared with earlier studies

Classification of CMT

Hereditary neuropathy phenotypes were initially defined based on their clinical features, specifically the degree of motor versus sensory involvement.CMT is the most common phenotype, affecting both sensory and motor modalities.

Conventionally, autosomal dominant CMT is categorized into two major groups based on neurophysiology: primarily demyelinating features (CMT type 1 [CMT1]) and primarily axonal features (CMT2). Autosomal recessive inheritance is categorized as CMT4. Less common CMT types, such as CMT3 and CMT5 through CMT7, are now referred to by gene type. 

Magy and colleagues proposed naming subtypes by electrophysiologic features, inheritance pattern, and for more than one-half of the patients with a clinical diagnosis of CMT, a genetic cause is confirmed. Five subtypes account for 90% of the diagnoses:

1. CMT1A due to PMP22 duplication

2. CMT1X due to GJB1 variations

3. CMT2A due to MFN2 variations

4. CMT1B due to MPZ variations

5. Hereditary neuropathy with liability to pressure palsies (HNPP) due to PMP22 deletion.

cont_2023_09_28_peripheralnerve_2023-56_sdc2.pdf 

Distal hereditary motor neuropathies present with muscle weakness and atrophy without prominent sensory deficits. Compared with more common motor neuron disorders such as sporadic or genetic (SOD1, C9orf72) amyotrophic lateral sclerosis (ALS), distal hereditary motor neuropathies manifest with predominantly symmetric distal weakness greater than proximal weakness and with less prominent upper motor neuron involvement. Hereditary sensory and autonomic neuropathies (HSAN) have more prominent sensory and autonomic involvement with a relatively broad spectrum of motor involvement. There are also overlap syndromes with both central and peripheral nervous system manifestations, such as the spinocerebellar ataxias and hereditary spastic paraplegias.

Core Clinical Features in Hereditary Neuropathies

One should suspect hereditary neuropathies in patients with chronic distal-predominant motor or sensory deficits, diminished reflexes, and foot deformity, particularly when there is a family history of neuropathy. Depending on the clinical presentation and family history, clinicians can perform further evaluations, including electrodiagnostic evaluation and genetic testing, to characterize the hereditary process.

CMT is a chronic, slowly progressive generalized length-dependent symmetric polyneuropathy with predominantly distal motor weakness and atrophy more than distal sensory loss. A hallmark clinical feature of CMT is the distinct foot morphology characterized by pes cavus and hammer toes that result from chronic atrophy of the intrinsic foot muscles. High arches accompanied by an inward turning of the heel is referred to as a cavovarus deformity. Similar foot deformities may also occur in the setting of acquired chronic neuropathies and central processes such as cerebral palsy.

The age of symptom onset varies from early childhood through late adulthood. In general, autosomal recessive CMT manifests early, from birth through childhood. Patients with dominant forms of CMT generally present later; patients with CMT1 typically develop weakness in childhood through early adulthood, whereas patients with CMT2 may have early-adult–onset or late-adult–onset symptoms. In all forms of CMT, the age of presentation for neurologic care is often many years after symptom onset. Most patients have difficulty walking due to distal and proximal lower extremity weakness and sensory ataxia. They often require assistance with ambulation, ranging from shoe inserts and orthotics to unilateral or bilateral walking aids and wheelchairs. 

Certain hereditary neuropathies, mainly autosomal recessive forms, may have a more rapidly progressive course. These cases may mimic acquired neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), especially in pediatric populations. Some hereditary neuropathies are associated with other symptoms or systemic involvement (eg, optic neuropathy in association with certain MFN2 variations, nephropathy in patients with INF2 variations, and central nervous system.

involvement in some GJB1 variations). Hearing loss is fairly common in most types of CMT. Respiratory or bulbar symptoms may rarely occur in some subtypes.

• Charcot-Marie-Tooth (CMT) is the most common hereditary neuropathy and is usually characterized by distal motor loss greater than sensory loss, areflexia,and foot deformity.

• In general, autosomal recessive CMT manifests early, from birth through childhood.

• Patients with CMT1 typically develop weakness in childhood through early adulthood, whereas patients with CMT2 may have early-adult–onset or late-adult–onset symptoms

Diagnostic approach

Once there is a clinical suspicion for a hereditary neuropathy, additional testing to further characterize and subtype the neuropathy. Electrophysiology is typically the first step in the diagnostic classification to confirm the presence of a neuropathy and subtype it. However, genetic testing may be performed before electrodiagnostic testing in scenarios with a clear family history or a characteristic phenotype. In these cases, electrodiagnosis is often considered if the genetic testing is inconclusive.

Ancillary Testing

Electrodiagnostic testing can help confirm and characterize an underlying polyneuropathy and guide further evaluation. It can differentiate between distal myopathies and sensorimotor, sensory, or motor neuropathies. Additionally, electrodiagnostic testing will determine if the polyneuropathy is primarily demyelinating or axonal. Specific electrodiagnostic features may also be seen in the context of certain neuropathy subtypes. For example, prolonged distal motor latencies and conduction block at sites prone to nerve compression is a distinct pattern seen in HNPP.

Clinicians are increasingly using ultrasonography as a diagnostic tool to assess neuropathies. Nerve cross-sectional areas are often enlarged in proximal and distal sites in common hereditary demyelinating neuropathies. Children have smaller nerve cross-sectional areas, but compared with age-matched controls, pediatric patients with CMT1A demonstrate nerve enlargement. Ultrasonography may be a useful screening tool in the pediatric population and in situations where electrodiagnostic testing is not feasible. Clinicians rarely perform a nerve biopsy in the diagnostic evaluation of hereditary neuropathy. If performed, it is typically used to exclude alternative diagnoses such as vasculitis or infiltrative processessssss

Genetic Testing

Following a thorough evaluation of family history, the ordering clinician should have a thoughtful and informed discussion with the patient regarding the reasons for undergoing genetic testing. In most cases, disease-modifying therapy is not available; however, there are other compelling reasons for the patient to understand a potential genetic etiology. A more specific diagnosis may inform prognosis or allow for screening of anticipated symptoms. The results of the genetic test may impact family planning.When alternative acquired neuropathies, such as immune-mediated disorders, are being considered, a confirmed genetic diagnosis would spare the patient further unnecessary interventions and ineffective therapy. Clinicians should also discuss the sensitivity of genetic testing because negative testing does not exclude the possibility of a hereditary neuropathy.

The specific testing approach may vary depending on the clinical context. Single-gene testing of PMP22 that looks for deletions causing HNPP or duplications associated with CMT1A may be appropriate in the correct clinical context where the patient’s personal history, examination, family history, and electrodiagnostic testing strongly suggest one of these two disorders. Clinicians may use targeted-panel tests for more than 200 known neuropathy genes when the specific subtype is uncertain. If the genetic cause is not identified through the  bove methods, clinicians can consider more comprehensive genomic testing, either whole-exome sequencing or whole-genome sequencing. This approach allows for a nontargeted evaluation of the patient’s genes. These tests may be particularly helpful in cases where the peripheral neuropathy phenotype is unclear or when there may be an overlapping syndrome. 

Comprehensive genomic testing is most useful when analyzed with parental samples. In the case of a family with multiple affected individuals, sequencing of the affected and unaffected family members may yield a novel variant or gene. Whole-exome sequencing may miss large deletions, duplications (eg, PMP22 duplication for CMT1A), intronic variants, and trinucleotide repeats. Genetic counselors should be engaged early on due to the complexities of genetic testing and interpretation. In younger children with a family history where electrodiagnostic testing is not feasible, it may be appropriate to start with genetic testing.

Pediatric Considerations

One-third of patients with CMT present in infancy or childhood. Early-onset severe CMT forms were initially referred to as congenital hypomyelinating neuropathy (neonatal onset) or Dejerine-Sottas syndrome (infantile onset). In the earliest-onset and most severe cases, neonates are hypotonic with global weakness and areflexia and have early swallowing and respiratory dysfunction. As in adults, the initial step in diagnosis is a thorough clinical and family history and neurologic examination. In infants and toddlers with a more insidious onset, early signs of neuropathy may include toe walking and delayed motor development, particularly in the setting of normal cognitive and language development. Often, affected children are described as clumsy and fall frequently. Patients may have an upper extremity postural tremor. In some cases of childhood-onset CMT, the weakness may not be apparent until the teenage or early-adult years, but other signs of CMT, such as the typical foot morphology and frequent ankle sprains, may be present earlier. 

Accurate assessment of proximal and distal weakness in pediatric patients relies heavily on an indirect assessment of patients’ gait and motor function. Muscle stretch reflexes may still be present in many children with CMT. Similarly, the sensory examination may be normal or unreliable. Therefore, brief neurophysiologic testing has diagnostic value, especially in demyelinating neuropathies after 2 years of age, when peripheral myelination is almost within the adult normative range. For example, variations in MPZ, PMP22, and EGR2 are most common when motor velocities are very slow (<15 meters per second). 

Management in affected children is mainly supportive. In young children, age-appropriate activities such as outdoor play, swimming, and dance may be more feasible and appropriate than physical therapy or a specific exercise routine. Early intervention programs and focused functional occupational and physical therapy are important to help children and families build compensatory habits that improve gait and function and reduce the risk of injuries. Ground reaction ankle-foot orthoses can help improve gait efficiency and reduce fall risk. Additionally, some patients might consider nighttime bracing to provide passive stretch and help prevent early contractures. Orthopedic care should be part of a multidisciplinary approach to management. Triple arthrodesis, or surgical fusion of the subtalar, talonavicular, and calcaneocuboid joints in the feet, is not recommended for children. 

Demyelinating CMT

CMT1 is distinguished from other forms of CMT by the electrophysiologic findings of motor nerve conduction velocities less than 38 meters per second in the upper extremity. CMT1A is the most common form of CMT, accounting for 37% of all CMT and 55% of genetically confirmed CMT. CMT1A is an autosomal dominant disorder primarily caused by a 1.5-Mb duplication on chromosome 17p11.2,which leads to a three-copy duplication of the PMP22 gene. PMP22 encodes peripheral myelin protein 22, a structural protein in the myelin sheath. CMT1A is the prototypical CMT phenotype with onset in the first two decades of life. Early symptoms are often falling or tripping and footdrop. Foot deformity with pes cavus and hammer toes is a distinctive feature, occurring in up to 90% of patients. The foot morphology often precedes clinically apparent weakness, and these patients are frequently first evaluated by orthopedists. Their legs may appear tapered due to atrophy and can be described as having an “inverted champagne bottle” or “stork leg” appearance. Affected patients occasionally have proximal weakness, particularly of knee extension. As the disease progresses, patients may become aware of intrinsic hand weakness and atrophy. Areflexia, particularly in the lower extremities, is common but not universal. Sensory loss affects both small and large fibers with a stocking-glove distribution. Pain and fatigue are also common symptoms and can significantly impact patients’ quality of life.

There are some atypical presentations of CMT1A, such as hypotonia in infants or late-adult–onset CMT1A. There are small case series of additional features such as sensorineural hearing deficits and vestibular impairment. Auditory dysfunction may be of particular concern in pediatric patients, given the potential impact on speech and language development. Respiration is largely unaffected; however, some patients may have phrenic nerve involvement that leads to hypoventilation. There also appears to be an increased prevalence of obstructive sleep apnea in patients with CMT1 (37%), although the causal relationship is unclear. While not a common or prominent manifestation, there are some case reports of patients with CMT1A exhibiting central nervous system involvement, such as demyelinating lesions, decreased white matter volume on imaging, or cognitive disorders.

CMT1B is caused by heterozygous variations in MPZ, which encodes a transmembrane protein involved in the adhesion of myelin layers around nerve axons. Typically CMT1B is clinically and electrophysiologically similar to CMT1A; however, MPZ variations can also cause an intermediate phenotype or a later-onset axonal CMT (CMT2J).  Additional CMT1 subtypes are autosomal dominant and include CMT1C caused by LITAF variations. CMT1D caused by EGR2 variations, CMT1E caused by point variations in PMP22, CMT1F caused by NEFL variations, and CMT1G caused by PMP22 variations.

CIDP is often on the differential diagnosis for CMT1. A retrospective study of patients with CIDP found that 3.2% of CIDP diagnoses were instead genetically confirmed CMT. The misdiagnosed group had a younger age of onset, more prominent distal atrophy at presentation, and lack of response to immunotherapy. Electrophysiology can be helpful to distinguish between acquired versus hereditary forms of demyelinating polyneuropathy. However, this approach has pitfalls because some CMT subtypes (eg, GJB1, FIG4, PCK2) can have features of acquired demyelination such as conduction block and temporal dispersion.

Axonal CMT

About 30% of genetically confirmed CMT cases are axonal, although the majority of axonal CMT cases are not genetically confirmed; the yield for genetic testing for a patient with axonal neuropathy is around 20%. Clinically, axonal and demyelinating CMT present similarly, although there are generally more patients with a later onset of axonal neuropathy. In axonal CMT, nerve conduction studies demonstrate low-amplitude motor and sensory responses with relatively preserved conduction velocities. Genes that cause CMT play a role in a range of functions in the neuron, axon, Schwann cell, and myelin. These functions include nuclear envelope processing, organelle functions, mRNA processing, membrane excitability, cytoskeletal structure, and transport.

Axonal CMTs are genetically heterogeneous. Variations can be autosomal dominant or recessive. There are more than 30 genes known to cause CMT2. These CMT2 subtypes were originally named with alphabetical letters; however, there are now more genes than letters, which has prompted a shift toward gene-centered nomenclature.

MFN2-related CMT (CMT2A) is the most common autosomal dominant CMT2 subtype accounting for 3% to 4% of all CMT and 7% to 12% of genetically confirmed cases, although it can also rarely be autosomal recessive. Mitofusin 2 plays a role in mitochondrial fusion and fission and axonal transport. Earlier symptom onset often correlates with more severe disease progression and a higher likelihood of wheelchair dependence in the future. As with other CMT subtypes, distal motor weakness is common alongside sensory loss. Compared with other CMT subtypes, progression may appearmore rapid in some patients. In addition to the neuropathy, certain MFN2 variations have been associated with optic atrophy, hearing loss, vocal cord paralysis, diaphragmatic weakness with hypoventilation, signs of upper motor neuron dysfunction, and cognitive impairment. White matter abnormalities have also been described but are not a hallmark of the disease.

Sorbitol dehydrogenase deficiency (SORD-CMT) is a recently discovered autosomal recessive axonal neuropathy with distinctive early plantar flexion weakness.

Autosomal Recessive CMTs

An autosomal recessive inheritance pattern, whether demyelinating or axonal, accounts for less than 10%of CMT. Autosomal recessive CMT is called CMT4, is generally demyelinating, and has 11 gene subtypes (CMT4A-4J). Axonal autosomal recessive CMT forms are often grouped under CMT2. Autosomal recessive CMT usually has an earlier age of onset (infancy and childhood) and a more progressive course. In addition to the characteristic distal weakness, patients also have proximal weakness, which may lead to a loss of ambulation. For example, CMT4A caused by biallelic GDAP1 variations presents in early childhood with distal weakness and sensory deficits that rapidly progress. The neuropathy appears mostly demyelinating but may also have mixed electrophysiologic features.

One of the recently described types of autosomal recessive CMT is caused by biallelic SORD variations. These patients have a motor-predominant axonal neuropathy (CMT2) or exclusively motor neuropathy that typically begins during adolescence or early adulthood, progresses slowly, and is rarely severe  In a distinctive feature of this neuropathy, plantar flexion appears more affected than dorsiflexion. SORD-CMT is likely one of the more common hereditary neuropathies based on a high allele frequency. SORD variations lead to the reduced enzymatic activity of sorbitol dehydrogenase (SORD), which is involved in the oxidation of sorbitol to fructose. A postulated pathomechanism is the toxic accumulation of sorbitol thus, a clinical trial is currently studying the effects of reducing sorbitol by using an aldolase receptor inhibitor.

Another newly reported form of autosomal recessive CMT has been identified and is caused by variations in the mitochondrial gene PCK2. The phenotype is a demyelinating neuropathy, with some features of acquired demyelination such as temporal dispersion and conduction block. Patients experience abnormal gait and weakness. Mouse models of the disease manifest a similar neuropathy phenotype.

X-linked CMT

X-linked CMT both dominant and recessive, accounts for between 10% to 15% of CMT. CMTX1, an X-linked dominant condition, is the second most common CMT after CMT1A. CMTX1 can occur in both males and females, but males are more severely affected. CMTX1 is caused by variations in GJB1, which encodes connexin 32, a gap junction protein that is highly expressed in Schwann cells and oligodendrocytes. Clinically, these patients have typical distal weakness and atrophy with foot deformity and onset in adolescence. These patients often have prominent thenar muscle weakness and atrophy. Certain variations in GJB1 are associated with recurrent transient neurologic symptoms and reversible white matter lesions. These “acute stroke–like” or “acute disseminated encephalomyelitis–like” episodes present with dysarthria, dysphagia, or limb weakness in more than 90% of cases, but they can manifest with aphasia, ataxia, diplopia, vertigo, altered mental status, and other symptoms. In some cases, these attacks are the presenting symptom before the neuropathy is apparent. Imaging performed during these episodes usually shows white matter T2 hyperintensities with or without diffusion restriction, often symmetrically in the centrum semiovale and corpus callosum. In most cases, these episodes resolve within hours or weeks, although there are reports of persistent symptoms. Similarly, the imaging findings also typically resolve. A recent systematic review of published CMTX1 cases found that 83% of patients had a recurrent episode. These episodes are postulated to be caused by dysfunction in oligodendrocytes, which also express connexin 32. Although patients are often treated with steroids because of the “acute disseminated encephalomyelitis (ADEM)–like” appearance of these white matter lesions, there is no pathophysiologic evidence supporting a mechanism of acute inflammation or data supporting the efficacy of steroids.

HNPP 

Hereditary Neuropathy with liability to Pressure Palsies has a distinct phenotype of episodic, multifocal mononeuropathies typically at common sites of compression. Most cases are secondary to a dominantly inherited deletion or sequence variation of PMP22 at chromosome 17p11.2, the same gene that is duplicated in CMT1A. The prevalence range is estimated between 7.3 and 15 per 100,000 people, making it one of the more common hereditary neuropathies. Age of onset is typically in adolescence or early adulthood, but it can present at any time. Family history of an HNPP phenotype is often present.

Patients typically present with recurrent episodes of painless focal motor and sensory symptoms. There is often a history of minor compression of the affected nerve and therefore, these mononeuropathies are typically thought to be acquired in isolation. It is only when multiple episodes occur that clinicians consider the possibility of HNPP. The most common nerves affected are the peroneal (30% to 48%) and ulnar (21% to 28%) nerves, although HNPP can affect any peripheral nerve. Brachial plexopathy occurs in approximately one-third of patients and is more common in women. Cranial neuropathies are rare. The symptoms and deficits from the acute attacks typically resolve within a few weeks, but residual deficits can occur.

In one study, persistent motor deficits of MRC 3/5 or less at 3 months were observed in 15% of patients. Patients can present with symptoms of a more generalized chronic neuropathy on examination, such as absent ankle jerks and pes cavus. Less commonly, patients with PMP22 deletions will present with the typical CMT phenotype of slowly progressive distal weakness and atrophy. There are some patients who are asymptomatic or paucisymptomatic throughout life and who may have a family member with a more typical presentation.

Nerve conduction studies in patients with HNPP show focal slowing at the compression site, sometimes with a conduction block. In addition, there may be evidence of more generalized demyelination with prolonged distal motor latencies and mildly slowed motor conduction velocities. Sensory nerve action potentials may be low amplitude with prolonged distal latencies. These electrodiagnostic features are often found in affected but asymptomatic or paucisymptomatic individuals. Nerve biopsies are rarely performed but may show tomacula, which is a pathologic term describing multiple irregular myelin layers resulting in a segment of “sausage-like” hypertrophic myelin.

Ultrasonography in HNPP can show enlarged cross-sectional areas at common entrapment sites, such as the ulnar nerve at the elbow, and some studies have shown enlargement at nonentrapment sites.

Symptomatic management includes avoidance of nerve compression to help prevent episodic neuropathies. For example, these authors recommend avoiding activities like prolonged sitting, leg crossing, and leaning on one’s wrist or elbows. Clinicians should make patients aware that rapid weight loss can lead to nerve compression. Clinicians often pursue surgical decompression, particularly before diagnosing HNPP, but there is no systematic evidence to support its benefit or potential harm.

The differential diagnosis of HNPP includes acquired demyelinating and multifocal neuropathies. The first few episodes of focal neuropathy are typically indistinguishable from common compression neuropathies.When episodes become recurrent, the differential diagnosis broadens to include multifocal neuropathies related to diabetes or vasculitis. Prominent pain, an associated rash, multiorgan manifestations, elevated inflammatory markers, and a more rapid and progressive disease course should prompt consideration of a vasculitic process. Inflammatory neuropathies such as typical CIDP, CIDP variants like multifocal CIDP (previously referred to as multifocal acquired demyelinating sensory and motor neuropathy), and multifocal motor neuropathy can also mimic HNPP.

When brachial plexopathy is a manifestation of HNPP, neuralgic amyotrophy is the primary alternative consideration and can be acquired (Parsonage-Turner syndrome) or hereditary due to SEPTIN9 (previously known as SEPT9) variations. Clinicians may consider CMT and other hereditary neuropathies when the episodic history is less prominent. Compared with patients with HNPP, patients with CMT1A have more severe distal weakness, atrophy, and slower nerve conduction velocities.

CMT (HMSN)

• • Inherited neuropathies, specifically Charcot-Marie-Tooth (CMT) disease, play a significant role in previously undiagnosed cases of peripheral neuropathy seen in large neuromuscular centers, accounting for up to 50% of such cases. CMT encompasses various subtypes that are classified based on factors such as nerve conduction velocities, presumed pathology (demyelinating or axonal), mode of inheritance (autosomal dominant, autosomal recessive, or X-linked), age of onset (infancy or childhood/adulthood), and the specific mutated gene.

  • CMT1 represents dominantly inherited myelinopathies, with median nerve conduction velocities (NCV) typically below 38 m/s. CMTX refers to X-linked inheritance, while CMT2 encompasses dominantly inherited axonopathies with median NCV above 38 m/s. Both CMT1 and CMT2 are associated with decreased SNAPs (sensory nerve action potentials) and CMAPs (compound muscle action potentials). Intermediate NCV ranging from 35 m/s to 45 m/s has been linked to a specific set of genes, including CX32, DNM2, YARS, MPZ, IFN2, and GNB4.

  • CMT4, on the other hand, represents autosomal recessive inherited neuropathies, involving both axonal and demyelinating forms. CMT IA is the most common form of CMT, accounting for 55% to 80% of all CMT cases. It is caused by a duplication mutation of the PMP-22 gene located on chromosome 17 (17p11.2-12), resulting in an increased expression of PMP-22 protein. PMP-22 is critical for the compaction and structural integrity of peripheral nerve myelin, as well as proper axonal development. It accounts for 2-5% of myelin protein and is implicated in 75% of all CMT1 cases, making it the most common inherited demyelinating neuropathy.

  • CMT1A is usually inherited in an autosomal dominant manner, although rare cases of autosomal recessive, X-linked, and de novo mutations have been reported. It is as a result of duplication of PMP22 gene.  Approximately 10% of CMT1A patients present with denovo mutations, which are believed to arise due to unequal crossover during meiosis and are paternally inherited. Nerve conduction studies (NCS) in CMT1A typically reveal "demyelinating" features.

    • Clinical manifestations :

      • Onset: Present during first to third decade of life, although, some remain asymptomatic until later in life.

      • Normal initial developmental milestones followed by slowly progressive distal leg weakness.

      • Predilection for anterior compartment , fibular nerve  innervated muscles, and intrinsic muscles of the feet resulting in a muscle imbalance that produces bony changes of pes cavus (high arches and hammertoes; later inverted champagne bottle).  Eventually the nerves to the calves degenerate and the ability to plantar flex the feet is lost. 

      • Difficulty in clearance of foot when walking, scuffing of forefoot when walking on uneven terrain, difficulty running, frequent sprains of the ankles, stumbling and slapping of the feet (steppage gait) are noted by the parents of young children.

      • Mild (often asymptomatic) sensory loss.   Although people with CMT1 usually do not complain of sensory loss, reduced sensation to all modalities is apparent on examination.

      • Areflexia (which more commonly occurs in the CMT1 group compared to the other CMT2).

      • Also visible or palpably enlarged nerves  (posterior auricular, and elbo) due to peripheral nerve hypertrophy.

      • Approximately 1/3 of patients with CMT1 have an essential tremor (Roussy-Levy syndrome).  

      • Some individuals who are affected may develop deafness or Adie's pupils.  

      • After many years or in severe case, there is atrophy of the hand muscles (hand becomes clawed).   Wasting seldom ascends the elbows in upper extremities and the mid-thigh in lower extremities.

      • AFO frequently required by the 3rd decade.

      • Phrenic nerve involvement is some individuals can lead to respiratory weakness.

      • Rarely does nerve root hypertrophy occurs to significantly compress the spinal cord or cauda equina. 

      • One form of CMT (CMT1G ) is associated with focal segmental glomerulosclerosis. 

    • There is often a family history of neuropathy, though due to variable expression, some affected family members may only have mild features such as hammertoes and may remain undiagnosed for a large part of their life; sporadic cases without a clear family history also exist.

    • Most patients remain ambulatory throughout life and have a normal lifespan.

      • In the absence of a clear family history diagnosis of an inherited neuropathy can be challenging.

    • Lab features:

      • CSF protein may be elevated.

      • Genetic testing: PMP22, GJB1, MFN2, MPZ (more than 90% of CMT cases are associated with these four genes).

        • 1/3 of all cases do not reach a molecular diagnosis. 

      • MRI of L-S spine may show enlargement of the lumbosacral nerve roots and, in some cases, may result in spinal stenosis.

      • EDX: 

        • Demyelinating type: 

          • CV <75% of LLN.

          • Mean motor nerve conduction velocities were less than 38 m/s (median and ulnar), but in most cases the NCV are in the 20-25 m/s range.

          • At birth and infancy the NCV may be normal or minimally slowed.  However, the NCVs rapidly decline, and, by 3-5 years of age, reach their nadir and remains slow throughout the rest of patient's life.  However the CMAP amplitudes continue to diminish over time, reflecting ongoing axonal loss.  DML continue to prolong until 10 years of age, at  which time there is little further prolongation.  No conduction block or temporal dispersion.

          • Uniform slowing without CB or temporal dispersion on NCS.  However, they are reported CMT1A with non-uniform slowing and CVs over 42 m/s, mimicking an acquired neuropathy.  

          • There may be evidence of secondary axonal loss in the demyelinating forms as well, particularly in patients with long-standing disease; conduction velocities as well as CMAP and SNAP amplitudes will be reduced. 

          • SNAPs reach nadir and stay stable throughout the rest of the person's life

        • Needle EMG: positive sharp waves, fibrillation potentials along with reduced recruitment of long-duration, high-amplitude, and polyphasic MUAPs in distal legs and lesser in arms. Evidence of active denervation and reinnervation may also be found in some of the proximal muscles.

        • Evoked potentials: 

          • SSEP show slowing of central conduction.

          • VEP show slowing of the optic pathways.

      • Histopathology:

        • Usually not done as diagnosis can be made by less invasive testing (EMG and genetic testing).

        • Reduction of myelinated nerve fibers with preferential loss of the large-diameter fibers.

        • Axonal diameter is also decreased. However the G-ratio is >0.6.

          • G-ratio is the ratio of axon diameter in a myelinated nerve to the total diameter (axon and thickness of myelin surround the former). It is usually 0.6). 

          • In demyelination there is a thin (wisp) layer of myelin  around the axon.

        • Increased in density of neurofilaments within atrophic axons.

        • Recurrent demyelination and remyelination leads to reduced internode length, while Schwann cell proliferation results in formation of so-called onion bulbs.

    • DDx: distal muscular dystrophies, late forms of familial motor system disease, Friedreich ataxia. Roussy-Levy syndrome, familial polyneuropathies, CIDP, paraproteinemic neuropathies.

    • Treatment:

      • No specific treatment. Only supportive.

      • Trial (NCT02579759) using PXT3003, a combination of naltrexone, baclofen, and sorbitol.

      • MDT (Neurologist, physiatrist, PT/OT, orthopedic, RN, and genetic counselor)

      • AFO

      • Fitting shoes with springs.

      • Stabilizing ankles by arthrodeses is foot-drop is severe.

      • Tendon lengthening and transfers

      • Regular exercise, but avoiding excessive weight training

      • Screening for diseases that may exacerbate their impairment: DM, hypothyroidism, vitamin def, monoclonal gammopathies, AIDP.

  • CMT1B

    • ~20% of patients with CMT1 have CMT1B.  

    • AD

    • Point mutation of MPZ (myelin protein zero) located on chromosome 1 (1q22-23)

      • MPZ is an adhesive molecule and plays a role in compaction of peripheral nerve myelin.

    • Patients with CMT1B cluster into two distinct groups:

      • Severe, early-onset, demyelinating neuropathy with conduction velocities <15 m/s

        • Delayed motor milestones, weakness since infancy

      • Late-onset axonal neuropathy with normal or near-normal conduction velocities.

    • Associated with Adies' pupil.

    • Early areflexia, distal weakness, sensory loss

  • CMT1C

    • Rare AD, neuropathy, caused by mutations in LITAF gene (lipopolysaccharide-induced TNF-alpha factor), on chormosome 16p13.1-p12.3

      • LITAF, a.k.a SIMPLE (small integral membrane protein of the lysosome/late endosome), is expressed on Schwann cells and may play a role in protein degradation.

      • Temporal dispersion of nerve conduction and irregularity of conduction slowing have been reported in CMT1C.

  • CMT1D

    • AD.

    • Mutation in early growth response-2 protein gene (EGR2) on chromosome 10q21.1-q22.1

    • EGR2 is a transcription factor which is the Schwann cell DNA-binding protein.

    • <1% of molecular defined cases of CMT1.

  • CMT1E

    • AD.

    • Refers to kinships with CMT1 associated with deafness.

    • Allelic to CMT1A and caused by point mutations in PMP-22 gene.

  • CMT1F/2E

    • AD

    • Mutation in the neurofilament light chain gene (NEFL/NFL) located on chromosome 8p13-21

    • CMAPs low, NCV are normal to slightly slow, with some reportedly in 20s m/s.

    • The NEFL gene encodes the neurofilament light chain, which is essential for nerve cell function.  Pathogenic variants in NEFL cause Charcot-Marie-Tooth neuropathy type 2E/1F (CMT 2E/1F), progressive peripheral motor and sensory neuropathy characterized by distal lower limb paresis ranging from mild weakness to complete paralysis, decreased or absent tendon reflexes, pes cavus, and sensory symptoms; cerebellar dysfunction, tremor and hearing loss are noted in some individuals.  CMT due to pathogenic variants in NEFL is reported to have complete penetrance; however, onset of symptoms range is from infancy through the fifth decade of life.  NCV's are often reduced, consistent with demyelinating neuropathy; however, normal NCV's consistent with axonal neuropathy are also reported.  Most often NEFL related CMT is inherited in an autosomal dominant pattern; however, rarely, autosomal recessive inheritance has been reported.  Most pathogenic NEFL variants are dominantly inherited missense variants functioning through gain of function mechanism.  However, autosomal recessive inheritance has been reported in families with homozygous nonsense variant causing early onset CMT through loss of function mechanism.

  • CMT1G

    • AD, 14q32-33, IFN2, associated with focal segmental glomerulosclerosis. 

    • 1/3 have SNHL.  Intellectual disabilities and abnormalities in the white matter and ventricular dilatation on brain MRI.  

    • IFN2 (formin 2) reacts with Rho-GTPase CDC42 and myelin and lymphocyte count (MAL) and is felt to be important in the essential steps of myelination and myelin maintenance. 

  • CMTX1

    • X-linked dominant

    • 15% - 20% of CMT cases.  CMT type X is the second most common form of CMT, next to CMT type 1A.

    • In cases presenting with a classic phenotype, but which are negative for the PMP22 duplication, family history is very important.  In the absence of male to male transmission in the family, CMT1X is considered to be the most probable phenotype.

    • Males affected more severely than females. 

    • Manifest in the 1st decade of life.

    • Mutation in the gap junction protein (GJB1) gene, encoding connexin-32 gene on chromosome Xq13. 

      • Connexin is important in forming the gap junctions in myelin at the paranodal regions.

      • This gene is expressed in myelinating Schwann cells.

    • Asymmetric neuropathy, both clinically and electrophysiologically

      • May be mistaken for acquired immune-mediated neuropathy.

    • Distal muscle weakness and atrophy, distal sensory loss, and areflexia.

    • Pes cavus and hammertoes are common

    • Bilateral foot drop occurs.

    • Claw-hand deformity may occur in adult males.

    • Spasticity and pyramidal signs are also seen

    • Auditory neuropathy - deafness.

    • MR if disease is from infancy

    • Women are mildly affected

    • Primarily axonopathy with secondary demyelination

    • Rarely, stroke like sx including dysarthria, ataxia, weakness, and transient white matter hyperintensities on MRI.  Encephalopathy or stroke-like symptoms associated with altitude, dehydration, or hyperventilation have been reported as the presenting symptom of CMT type X.

  • CMTX2: Xp22.3

  • CMTX3: Unknown

  • CMTX4 (Cowchock syndrome): AIFM1

  • CMTX5: PRPS1

  • CMTX6: PDK3

  • CMT 2

    • 10%-15% of all CMT cases.

    • Axonal neuropathies, less demyelination.

    • Most are AD, but AR and X-linked forms are also present. 

    • Prevalence is half of CMT 1

    • Genetic mutation is not found in 2/3rd of CMT2 patients.

    • EDX: SNAP and CMAP amplitude are reduced.  Conduction velocity is normal or near normal >45/ms. Signs of denervation on EMG.

    • CMT2A1

      • AD, 1p36.2, KIF1B

    • CMT2A2, allelic to HMSN type-5 with optic atrophy 

      • Mutation in mitofusin-2 (MFN2), an intrinsic membrane fusion protein in mitochondria

      •  1p36.22.  AD

      • Symptom onset is commonly in early childhood, although onset has been reported well into adult life.  Rare cases of compound heterozygotes with clinically unaffected parents have been reported, consistent with an autosomal recessive inheritance pattern, but all have had onset in early childhood. De Novo mutations account for a small proportion of patients with CMT2A. Non-paternity, germ-cell mosaicism, and reduced penetrance are all possible in cases in which asymptomatic parents have not undergone genetic testing.

      • Presents later in life compared to CMT1. 

      • Severe  and most common subtype, ~1/3rd of CMT2 cases overall. 

      • Less involvement of intrinsic muscles of hand as compared to CMT1.

      • Profound atrophy and weakness of both the anterior compartments (peroneal and anterior tibial) and the posterior compartment (gastrocnemius and soleus) of the distal legs compared to CMT1.

      • Normal to increased muscle stretch reflexes.

      • 50%-70% have significant reduction in light touch, pain, joint position, and vibration sensation.

      • Pes cavus, hammertoes may be seen but are not marked as in CMT1.

      • Large majority of patients are not ambulating by 20 years of age.

      • Optic atrophy, hearing loss, pyramidal tract, and subcortical white matter abnormalities on brain MRI is sometimes seen in CMT2A2

    • CMT2B (HSAN I): 

      • AD

      • 3q13-q22

      • Most reported cases are from North Africa and Middle East where consanguineous marriages are not uncommon.

      • Severe mutilating neuropathic ulceration, mostly in feet and similar to a HSAN1.

      • RAB7A

    • CMT2B1

      • Allelic to LGMD1B

      • LMNA

      • AR, 1q21.2

      • North Africa and then Middle Eastern cultures.

      • Onset Is between ages of 6 to 27 years.  Course of neuropathy varies ranging from rapidly progressive with severe distal and proximal weakness of the hands and legs evolving in a few years to mild weakness. 2 decades after symptom onset. 

    • CMT2B2

      • AD, 19q13, MED25

    • CMT2C is an autosomal dominant neuropathy caused by a mutation of TRPV4 (transient receptor potential cation channel, subfamily V, member 4 gene) on 12q23-24, TRPV4 cation channels are involved in the transduction of many sensory stimuli.  TRPV4 is a Ca++ permeable, nonselective cation channel with multiple functions including regulation of systemic osmotic pressure.  CMT2C may be associated with vocal cord paralysis and breathing difficulties due to weakness of the diaphragmatic and intercostal muscles. Laryngeal weakness is more often insidious in onset and presents as progressive hoarseness.  Phrenic nerve is involved leading to decreased ventilatory function and orthopnea.  Patient require tracheal assisted mechanical ventilation (TAMV).  Severe atrophy of distal lungs most common.  Proximal limb weakness can occur.  There is mild sensory loss.  Reflexes are diminished.  Press cavus is uncommon. 

    • Nerve conduction studies show reduced CMAP amplitudes, normal to borderline slowed motor conduction velocities (36-60 m/s).  SNAPs can be normal, decreased, or absent based on the age of the patient.  EMG shows predominantly chronic neurogenic changes in distal muscles.

    • CMT2CC (NEFH) causes a progressive non-length-dependent, motor-predominant phenotype

    • CMT2D neuropathy is associated with a phenotype that is predominantly motor and unique in that the hands are affected early in the disease course, often before lower extremity involvement. This neuropathy is caused by mutations in the glycyl-tRNA synthetase gene, GARS.  It is allelic to distal SMA5.  AD, 7p14

      • FDI atrophy is appreciable.  Onset of weakness usually in the late teens (12 to 36 years).  Neuropathy has a slowly progressive course.  Distal sensory loss and areflexia is common.  Pes cavus, hammertoes and scoliosis may be present.  

    • CMT2E/1F: NEFL (allelic to CMT1F)

      • AD, 8p21

      • It is a rare neuropathy and is usually manifested in the second or third decade of life with progressive distal leg weakness.  Some patients develop deafness.  Sensory loss, past cavus, and areflexia are also often appreciated on examination.

      • The neurofilament light chain (NF-L) is a major constituent of intermediate filaments and plays a pivotal function in the assembly and maintenance of axonal cytoskeleton. Mutations in the NF-L gene (NEFL) cause autosomal dominant neuropathies that are classified either as axonal Charcot-Marie-Tooth (CMT) type 2E (CMT2E) or demyelinating CMT type 1F (CMT1F). 

    • CMT2F is caused by mutation in the heat-shock protein-1 gene located on chromosome 7q11-q21. HSPB1

      • AD,  7q11-q21, HSPB1

      • It is reported in a Russian family with symmetric weakness and atrophy of the distal legs greater than the arms, with onset age 15 to 25 years.

    • CMT2G: 12q12-q13, AD

      • CMT2G, described in a large Spanish kinship with typical CMT2 phenotype, with age at onset being 9-76 (mean 29) years.  Most patients developed symptoms in the second decade of life.

    • CMT2H/2K: GDAP1.  Allelic to CMT2K and CMT4A, AD, 8q21.3, GDAP1

      • Affected individuals may have vocal cord paralysis.  They can have axonal or demyelinating abnormalities on NCS.

    • CMT2I and CMT2J: MPZ.  Allelic to CMT1B, AD, 1q22.

      • CMT2I is associated with late onset axonal neuropathy, Adie's pupil, and hearing loss.  It is caused by mutations in MPZ that are more typically associated with demyelinating neurophysiology such as CMT1B

      • CMT 2J, a late onset neuropathy (usually fifth or sixth decade) associated with a hearing loss or pupillary abnormalities (Addie's pupil), is also alleilic to CMT1B and caused by mutations and MPZ.

    • CMT2K: It is due to GDAP1 (ganglioside-induced differentiation-associated protein) mutation of chromosome 8q21.11 and has several phenotypes.  Allelic to CMT2H and CMT4A. 

      • Axonal, recessive

      • Axonal dominant

      • Recessive, intermediate A (CMT RIA). Presents in childhood with gait imbalance and causes distal sensory loss and proximal and distal weakness.  NCS shows mixed demyelinating and axonal features. Nerve pathology showed mixed axonal and demyelinating features. 

    • CMT2L: HSPB8.  AD.  Allelic to distal hereditary motor neuropathy type 2, 12q24.

      • CMT2L was reported in a large Chinese family.  Also the disease was between 15 and 33 years of age with symmetric weakness of the distal lower limbs, mild to moderate sensory impairment including pain and touch, and absent muscle stretch reflexes.

    • CMT2M:  AD, 19p13.2, DYN2

      • CMT2M is more commonly classified as dominant intermediate CMT type B (CMTDIB) because nerve conduction velocities are usually in the intermediate range.  It is allelic to a formal centronuclear myopathy.

    • CMT2N: AD, 16q22.1,  AARS

      • CMT2N is associated with an age of onset ranging from early childhood to his sixth decade of variable severity.  Sensorineuroal hearing loss may be seen in some individuals.  Nerve conduction velocities are in the intermediate range.

    • CMT2O: AD, 14q32.31, DYNC1H1

      • CMT2O presents in childhood with delayed motor milestones and abnormal gait.  Some affected individuals have paresthesias year and neuropathic pain, while some have learning disabilities.

    • CMT2P:  AD/AR, 9q33, LRSAM1

      • CMT2P is associated with a relatively mild, very slowly progressive axonal neuropathy with age of onset in the second or third decade of life.

    • CMT2X: X-linked, Xp22.11, PDGK3

    • CMT2X: X-linked, Xq22.3, PRPS1

    • CMT2Z:  MORC2.  Autosomal dominant.  Associated with developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy. 

    • CMT2T (MME) causes autosomal recessive, axonal forms of CMT encodes a metalloprotease called neprilysin. Case report.

  • Intermediate forms:  Intermediately slowed nerve conduction velocities (25 m/s to 38 m/s)

    • Myelinopathy and axonal forms. 

    • DI-CMTA (CMT2GG): AD, 10q24.32, GBF1

    • DI-CMTB: AD, 19p12-p13.2 DNM2

    • DI-CMTC: AR, 1p34-p35, YARS 

    • RI-CMT: AR,  1p36.31, PLEKHG5

  • Slowest forms: 10 m/s or less NCVs.

    • CMT3: Dejerine-Sottas disease, congenital hypomyelinating neuropathy):   It is a historical term used to denote a severe demyelinating neuropathy in children.  Formerly considered a distinct entity with autosomal recessive inheritance, genetic analysis has demonstrated that Dejerine-Sottas is a syndrome caused by either recessive inheritance or de novo mutations with autosomal dominant inheritance.  The recessive forms are now incorporated into the CMT4 group, but the de novo AD mutations are on the same genes implicated for CMT1 (PMP22, MPZ, EGR2), but with the genetic defect resulting in a much more severe demyelinating neuropathy.

    • The classic phenotype in Dejerine-Sottas disease describes a hypotonic infant with areflexia and hypertrophic nerves; NCS with CV around 12 m/s to 6 m/s. 

    • AD, 17p11.2, PMP22

    • AD, 1q21-23, MPZ

    • AR, 10q21.1-22.1, ERG2

    • AR, 19q13, PRX

    • CMT4E (congenital hypomyelinating neuropathy): AR, probably includes PMP22, MPZ, and EGR2

  • CMT4

    • CMT4A. GDAP 1 mutation in 8q12-21.1, AR, allelic to CMT2K and CMT2H

      • GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy typically affects the lower extremities earlier and more severely than the upper extremities. Autosomal recessive inheritance.

      • As the neuropathy progresses, the distal upper extremities also become severely affected. 

      • Proximal muscles can also become weak. 

      • Age at onset ranges from infancy to early childhood. 

      • In most cases, disease progression causes disabilities within the first or second decade of life.  At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. 

      • The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. 

      • Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.

      • Symptoms and signs:

        • Early onset of peripheral neuropathy, presenting especially with foot deformities, muscle wasting, and involvement of the sensory nerves resulting in decreased appreciation of touch, pain, and vibration. Proximal weakness usually comes later.

        • Disability within the first and second decade of life consisting of foot deformity, difficulty walking and claw hand deformity.

        • Vocal cord paresis manifest as a hoarse voice.

        • Mild to moderate scoliosis.

        • Occasional involvement of cranial nerves sometimes resulting in facial weakness.

    • CMT4B1: AR, 11q23,  MTMR2

    • CMT4B2: AR, 11p15.4, SBF2

    • CMT4B3: AR. 22q13.33, SBF1

    • CMT4C: AR, 5q23-3, SH3TC2

    • CMT4D (HMSN-Lom): AR, 8q24,  NDRG1

    • CMT4E (congenital hypomyelinating neuropathy): AR, probably includes PMP22, MPZ, and EGR2

    • CMT4F: AR, 19q13.1-13.3, PRX

    • CMT4G (CMT Russe type): AR, 10q23.2, HK1

    • CMT4H: AR, 12q12-q13,  FGD4

    • CMT4J: AR, 6q21,  FIG4

      • Sensory motor demyelinating polyneuropathy. 

      • Non-uniform slowing of CV, CB, temporal dispersion on NCS, which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination is usually the cause. There was associated Schwann cell dedifferentiation and macrophages in spinal roots where nerve blood barriers are weak. 

  • HNPP (Hereditary neuropathy with liability to pressure palsies - a.k.a. Tomaculous neuropathy)

    • AD. Predominantly demyelinating hereditary neuropathy.

    • Allelic with CMT1A.

    • 3rd most common type of CMT

    • Deletion  mutation of a copy of PMP22 on chromosome 17, resulting in loss of function of PMP22 protein

      • PMP22 protein is reduced to half number of normal (from 2 to 1).

    • Age of onset 20-30 years of age.  Some may manifest earlier, while others remain asymptomatic their entire life. 

    • Recurrent attacks of mononeuropathy (single or multiple) that are characteristically brought on by mild pressure, like wearing a backpack, leaning on the elbows, crossing one's legs for even a short time.

      • Common affected nerves: median nerve at wrist, ulnar nerve at elbow, radial nerve at arm, and fibular nerve at head of fibula. 

      • The brachial plexus may be involved following excessive overhead activity (basketball), carrying a heavy rucksack or backpack. 

      • Usually resolve, but takes several weeks or months.

      • Patients with HNPP, as the name implies, often present with entrapment neuropathies and typically present with one of the more common nerve entrapment syndromes—carpal tunnel syndrome, ulnar neuropathy at the elbow, radial neuropathy at the spiral groove, or peroneal neuropathy at the fibular neck.  Most often, there is no obvious precipitating cause, or the amount of compression resulting in the entrapment is minimal.

    • Some may manifest with a progressive, relapsing, generalized, and symmetric sensorimotor peripheral neuropathy that resembles CMT or even CIDP. 

    • Painless numbness and weakness in the distribution of a single nerve, although multiple neuropathies including cranial neuropathies can occur. 

    • Exam shows pes-cavus, hammer toes, palpable nerves and Tinel's sign at entrapment sites for median (wrist) and ulnar (elbow).  There is a decrease to all sensory modalities, particularly large fiber functions.  

    • There is slowly progressive demyelinating sensorimotor neuropathy. Not all cases show areflexia and most show hyporeflexia or even normal reflexes.

    • Patients may show progessive or relapsing, generalized, symmetric pattern sensorimotor PN resembling CMT or even CIDP

    • Sausage-like changes (tomaculi) are seen in myelin (focal myelin thickening) in teased nerve preparations.

    • Association and overlap syndromes: Smith Magenis Syndrome.  Picture of physical characteristics

    • Pathogenesis: 

      • De novo deletions are usually paternally inherited and arise due to unequal crossing over during the illnesses, while rare de-novo mutations or of female origin and the result of intra-chromosomal rearrangements.

      • Normal expression of PMP 22 appears to be important for proper axonal development.  Nerve biopsies demonstrate an under expression of PMP22 mRNA and the protein and inversely correlate with the mean diameter of the excellence and clinical severity.

    • EDX: 

      • Although the clinical sx and signs are typically focal, NCS often reveals diffuse abnormalities. 

      • Sensory and motor nerve conduction studies usually demonstrate moderately prolonged distal latencies and slightly slow nerve conduction velocities with normal reduced amplitudes.  

      • Slowing of nerve conduction velocities, conduction block, and temporal dispersion are accentuated across typical sites of entrapment or compression (carpal tunnel, Cubital tunnel, Guyon's canal, and across the fibular head) and can also be demonstrated across sites of compression.  In addition the also appears to be a distal accentuation of nerve conduction slowing, irrespective of possible compression.  However, this length dependent slowing has not been appreciated by all.  Nerve conduction studies may also be abnormal and asymptomatic family members who carries a mutation.

      • Suspect HNPP in a patient who may have minor symptoms, but with EMG/NCS alarmingly abnormal (slow CV, CB)

    • Histopathology

      • Tomaculae

https://www.cmtausa.org/

https://www.ncbi.nlm.nih.gov/books/NBK1392/

https://www.hnf-cure.org/

https://medlineplus.gov/genetics/condition/hereditary-neuropathy-with-liability-to-pressure-pa

Approach to CMT Diagnosis (phenotypic and neurophysiological association) in CMT phenotype:

1. History 

   1. 3 types of presentation

      • Normal motor milestones > slowly progressive symmetrical distal leg weakness with sensory loss (1st to 3rd decade) > foot drop and hand weakness

      • Early onset: Delayed walking >15 months, toe walking and clumsiness

      • Adult onset: ~40 years with variable progression of disease.

   2. Family history to help determine the mode of inheritance

      • 3 generation or more pedigree

      • Early deaths, any family member who became wheelchair bound at an early age, family member who had problems walking, using braces.

      • Consanguinity

      • Caution: de novo mutation are common.

2. Physical exam

   1. Clinical phenotype

      • Pes cavus, hammer toes

3. Labs to rule out other neuropathies

4. EMG/NCV

• • First, a clinical classification that includes EDX (neurophysiological pattern) studies should be performed to determine whether the neuropathy is primarily demyelinating or primarily axonal in type. 

  • EDX studies are sometimes problematic in children, some physicians may opt to proceed directly to genetic testing of symptomatic children suspected of having CMT. 

  • The ulnar motor conduction velocity  across the forearm is tested (preferred).

  • Test for mutation and PMP22, MPZ, GJB1, and MFN 2.  This will cover approximately 92% of CMT patients.

  • Classical CMT phenotype with nerve conduction velocities between 16 and 35 m/s, initially should be screened for PMP22 duplications as this is the most common mutation.  If this is negative then patient should next be screened for GJB1 mutations (CMT1X).  Only if these targets are negative, screening for point mutation in PMP22, LITAF/SIMPLE, and EGR2.

  • Those with severely slow nerve conduction velocities of 15 m/s or less and with history of beginning to walk after 15 months of age (late walkers) should have testing for both PMP22 duplications and MPZ mutations.  If there is history that the patient walked before 15 months of age, test for PMP22 duplication.  If there is no PMP22 duplication or MPZ mutations, sequence PMP 22.

  • Individuals with intermediate nerve conduction velocities between 35 and 45 m/s usually have CMT1X or CMT1B.  For patients with no male to male transmission, intermediate conductions, and the classical phenotype, screen first for GJB1 mutations.  Alternatively, if there is a male to male transmission, patient should be further screened for DNM2 mutations as seen in CMT1B.  Since no patient with CMTIA has intermediate conduction velocities, there is no need for testing for PMP 22 duplication.  If testing for MPZ and GJB1 is negative, patient should be screened for mutations in the less common dominant intermediate forms of CMT including DNM2 (DI-CMT B) and YARS (DI-CMTC).   DYN2 mutation should also be considered for patients with cataracts and neutropenia.

  • In severe childhood onset CMT2 screening should begin with testing for MFN2 as this is the most common cause of CMT2.  If this is negative testing for MPZ and GJB1 would be reasonable.  Sequencing MPZ and GJB1 also would be the initial genes to screen for late onset CMT2; if there was a male to male transmission in the pedigree only MPZ screening is necessary.

  • As whole exome and whole genome sequencing becomes more widely available and cheaper, the strategies may change.  The downside of exome sequencing is that only exons are sequenced so mutations in promoter regions are intron segments important for RNA splicing may be missed this technique may be particularly useful in identifying novel CMT associated genes, particularly in CMT2 in which only about 30% of cases can be genotypes at present.

5. Genetic testing

• PMP22 duplication: CMT1A

• MPZ: CMT1B

• PMP22 seq: CMT1E

• PMP22 deletion: HNPP

• GJB1 (CX32): CMTX1

• MFN2: CMT2A2A and CMT2A2B

• KIF1B: CMT2A1

• LITAF: CMT1C

• EGR2: CMT1D

• NFEL: CMT2E

• GDAP1: CMT2K

• GARS: CMT2D

cont_2023_09_28_peripheralnerve_2023-56_sdc2.pdf 

Medications to avoid in CMT:

• Definite High Risk (including asymptomatic CMT)

  • Vinca alkaloids (Vincristine) 

  • Taxols (paclitaxel, docetaxel, cabazitaxel)

• Moderate to Significant Risk:  Amiodarone (Cordarone), Arsenic Trioxide (Trisenox),

  • Bortezomib (Velcade), Brentuximab Vedotin(Adcetris), Cetuximab (Erbitux), Cisplatin & Oxaliplatin, Colchicine (extended use), Dapsone, Didanosine (ddI, Videx) 

  • Dichloroacetate, Disulfiram (Antabuse) , Eribulin (Halaven) , Fluoroquinolones , Gold salts , Ipilimumab (Yervoy), 

  • Ixabepilone (Ixempra), Leflunomide (Arava), Lenalidomide (Revlimid), Metronidazole/Misonidazole (extended use), Nitrofurantoin (Macrodantin, Furadantin, Macrobid), Nitrous oxide (inhalation abuse or Vitamin B12 deficiency), Nivolumab (Opdivo), Pembrolizumab (Keytruda), 

  • Perhexiline (not used in U.S.), Pomalidomide (Pomalyst) , Pyridoxine (Although megadoses [10 times or more the RDA] of Vitamin B6 may be harmful, high intakes of vitamin B6 from food sources have not been reported to cause adverse effects.) 

  • Stavudine (d4T, Zerit), Suramin, Thalidomide, Zalcitabine (ddC, Hivid), 

• Uncertain or Minor Risk: 5-Flurouracil,  Adriamycin, Almitrine (not in U.S.), Chloroquine, Cytarabine (high dose), Ethambutol, Etoposide (VP-16), Gemcitabine, Griseofulvin, Hexamethylmelamine, Hydralazine, Ifosphamide, Infliximab, Isoniazid (INH), Lansoprazole (Prevacid), Mefloquine, Omeprazole,  (Prilosec), Penicillamine, Phenytoin (Dilantin), Podophyllin resin,  Sertraline (Zoloft), Statins, Tacrolimus (FK506, ProGraf), Zimeldine (not in U.S.),  a-Interferon. 

• Negligible or Doubtful Risk: Allopurinol, Amitriptyline, Chloramphenicol, Chlorprothixene, Cimetidine, Clioquinil, Clofibrate, Cyclosporin A, Enalapril, Gluthethimide, Lithium, Phenelzine, Propafenone, Sulfonamides, Sulphasalzine, 

• A Note about Alcohol: Alcohol was removed from the neurotoxic drug list in July 2004. While people with CMT generally suffer no ill effects from the moderate consumption of alcohol, they should be particularly mindful of the fact that alcohol affects balance and coordination, and that overconsumption of alcohol is generally not recommend under any circumstances. If you have questions about alcohol and your health, consult your physician.

Pregnancy and CMT1A:  Some patients experience worsening of neuropathy symptoms during pregnancy but it is difficult to predict with certainty if this is will occur in any individual patient.

CIDP  and CMT: CIDP is probably more common in CMT patients, and there is a suggestion that CMT may alter the antigenicity of the myelin.  A similar argument is made for the inflammatory component of Duchenne muscular dystrophy (DMD) and hence a justification for steroid therapy. 

Genetic Information Non‐discrimination Act (GINA) provides protections against discrimination on the basis of genetic information in health insurance and employment.  It does not apply to life insurance, disability insurance, or long-term care insurance. GINA applies to genetic information alone (e.g. results of genetic testing or family history) and not to manifestations of disease. GINA’s employment provisions generally do not apply to employers with fewer than 15 employees.

Pain in CMT.  The distribution and character of pain in CMT reflect a multitude of clinical consequences, including musculoskeletal pain in the back and joints, radicular pain, tingling/shooting pain, muscle cramps and painful calluses.

HSAN or HSN 

Hereditary sensory and autonomic neuropathies predominantly involve myelinated and unmyelinated sensory nerves but also affect motor nerves.

• HSAN I: 

  • HSAN I is a slowly progressive neurological disorder characterized by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset.

  • It is the most common form of HSAN presenting in adulthood with predominantly loss of pain and temperature sensation, lancinating pain, and variable motor involvement, yet vibration sense is preserved.

  • Also known as: HSN, CMT2B

  • SPTLC1 or serine palmitoyltransferase long-chain base subunit 1

    • SPTCL1 gene encodes for serine palmitoyltransferase, which is the first and rate limiting step in the synthesis of sphingolipids. 

    • Misense mutations in SPTCL1 gene yield atypical deoxysphingolipids (1-deoxy-sphinganine, and 1-deoxymethyl-sphinganine) which are neurotoxic.

  • SPTLC2 or serine palmitoyltransferase long-chain base subunit 2 are found to cause late onset HSAN1, onset after age 50 years, biopsy confirmed SFN in patient with progressive distal sensory impairment.  Small nerve fibers are affected early  in the course of the dsiease, progressing to development of motor involvement without autonomic involvement. 

  • RAB7A, also allelic to LGMD1B.

  • ATL1 and DNMT1.

  • Clinical features:

    • Impaired sensation sense mainly distributed to the distal parts of the upper and lower limbs.  

    • Variable distal muscle weakness and wasting

    • Chronic skin ulcers are characteristic. 

    • Autonomic features (usually sweating disturbances) are invariably observed.

    • Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy (Charcot's joint)  which may even necessitate amputations. 

    • Some patients suffer from severe pain attacks. 

    • Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. 

    • Diagnosis is based on the clinical observation and is supported by a family history. 

  • EDx: Axonal sensory > motor.  Demyelinating range in DML can be seen.  Sensory and motor neuropathy predominantly affecting the lower limbs.

  • DDx:  HSAN II, III, IV, and V, especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumours like amelanotic melanoma.

• The congenital and early onset forms of HSAN (HSN) are subcategorised as subtypes HSAN II – V and are transmitted by an autosomal recessive trait

• HSAN II

  • Also known as congenital sensory neuropathy. 

  • WNK1 or WNK lysine deficient protein kinase 1, RETREG1, and KIF1A have been associated with HSAN II.

  • AR, early onset or sporadic disorder. 

  • Clinical features:

    • Sensory loss (touch, pain, temperature, proprioception) leading to self-mutilation of fingers and toes.

    • Lack of fungiform papillae.

    • Patient usually have recurrent infections. 

  • EDx: Axonal. Absent SNAPs.

• HSAN III

  • Also known as Riley-Day syndrome or familial dysautonomia is an autosomal recessive disorder. 

  • HSAN III is caused by homozygous mutations in the ELP1 gene, which encodes elongator complex protein 1 (ELP1, also known as IκB kinase complex–associated protein) 

  • ELP1 (formely called: IKBKAP) or inhibitor of kappa light polypeptide gene enhancer in B cells, kinsase complex-associated protein gene.  It is limited to children of Ashkenazi Jewish descent.v  The incidence of familial dysautonomia is 1 in 3700 live births among Ashkenazi Jews, and the carrier frequency is 1 in 32 individuals.

  • It affects the development and survival of sensory, sympathetic, and some parasympathetic neurons, leading to reduction in neurons in sympathetic ganglia, intermedio-lateral gray columns, dorsal root ganglia, and spinal cord.

  • Clinical features:

    • Impaired mechanosensory and chemosensory neuronal development results in baroreflex and chemoreflex dysfunction, leading to orthostatic hypotension, paroxysmal hypertension, and abnormal control of cardiovascular function and ventilatory responses to hypoxia and hypercapnia. Other clinical manifestations include absence of tears, hypoactive corneal reflexes, and absence of lingual fungiform papillae.  Poor sucking and feeding, esophageal reflux with vomiting and aspiration, and swallowing dyscoordination may be the first clinical manifestations.

    • Reduced pain and temperature sensation, absent deep tendon reflexes, and gait ataxia. 

    • Episodic dysautonomic crises triggered by physical and emotional stress.

      • Impaired mechanosensory and chemosensory neuronal development results in baroreflex and chemoreflex dysfunction, leading to orthostatic hypotension, paroxysmal hypertension, and abnormal control of cardiovascular function and ventilatory responses to hypoxia and hypercapnia. 

    • A characteristic facial expression may develop over time that appears to be due to the effects of facial tone on bone development. The facies appear more similar with advancing age and there is a curious flattening of the upper lip that is most obvious when smiling.  Other common physical characteristics are due to orthopedic problems such as severe kyphoscoliosis and short stature.

  • EDx: Axonal sensory > motor.   Unmyelinated and small myelinated neurons are affected, resulting in decreased sensory, sympathetic, and parasympathetic neurons. 

  • Absent or reduced IENFD on skin biopsy (lenght-dependent). 

  • Absence of overflow emotional tears

  • Clinical Criteria for HSAN III:

    • Absent lingual fungiform papillae

    • Depressed patellar reflexes

    • Lack of an axon flare following intradermal histamine

    • Documentation of Ashkenazi Jewish extraction

• HSAN IV

  • Also known as congenital insensitivity to pain with anhidrosis [CIPA] or hereditary sensory neuropathy with anhidrosis) is the second most common HSAN.  This autosomal recessive disorder manifests in the first months of life.  Features include insensitivity to pain, anhidrosis, episodes of unexplained fever, and intellectual and motor developmental delay.  Missense, nonsense, frameshift, and splice-site loss-of-function mutations in the NTRK1 (TRKA) gene are associated with this disorder.  In humans, this gene encodes a high affinity tyrosine kinase receptor for nerve growth factor (NGF).  HSAN V is caused by a homozygous missense or frame shift mutation in NGF, which encodes β-NGF.  The clinical presentation is characterized by loss of pain perception and consequent acral ulceration, painless fractures, and other trophic injuries.

  • Clinical features:

    • Infancy

    • Mild to moderate developmental delay

    • Profound insensitivity to pain leading to mutilation of digits, face, and mouth regions.

    • Tongue papillae is present and tearing is preserved (distinguishing feature from HSAN III)

    • Histamine test evokes a wheal, but no axon flare response. Sympathetic skin response is absent. Pilocarpine does not induce sweating.

    • Risk of death is secondary to overheating.

  • EDx: usually normal. Axonal sensory > motor.  Demyelinating range in DML can be seen. 

• HSAN V

  • NTRK1 or neurotrophic receptor tyrosine kinase 1 

  • NGF or nerve growth factor 

  • Congenital insensitivity to pain with anhidrosis

  • Severe loss of deep pain perception, painless fractures, joint deformities, and normal intellingence. 

  • AR

  • Clinical features: same as HSAN IV, but milder.

  • EDx: Axonal sensory > motor.  Demyelinating range in DML can be seen. 

DYSTONIN; DST

Congenital myopathy 29 with contractures (Lethal Congenital Contracture Syndrome 12)

Autosomal Recessive Epidermolysis Bullosa Simplex 3

Neuropathy, hereditary sensory and autonomic, type VI

A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN6 is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection. 

Hereditary Sensory And Autonomic Neuropathy Type VI

In 3 members of an Italian family with an adult form of hereditary sensory and autonomic neuropathy type VI (HSAN6; 614653), Fortugno et al. (2019) identified novel compound heterozygous mutations in the DST gene: a nonsense mutation (K4330X; 113810.0004) and a missense mutation (A203E; 113810.0005) affecting a highly conserved residue in an isoform-specific N-terminal region of the dystonin protein. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Patient cells demonstrated defects in actin cytoskeleton organization and delayed cell adhesion, spreading, and migration, and the A203E missense mutation was shown to disrupt dystonin binding to actin. Affected individuals were seen in their fifties to seventies with ulcerations of the feet, painless fractures, amputations of the toes, and joint deformities. The authors proposed that homozygous truncating mutations result in a severe disorder with congenital defects and early lethality, whereas compound heterozygosity for a truncating and a missense mutation partially maintains dystonin protein expression and function and thus causes neuropathy that is compatible with an adult onset of disease. 

In 3 adult brothers, born to healthy nonconsanguineous Italian parents, with HSAN-VI, Manganelli et al. (2017) identified compound heterozygosity for 2 mutations in the DST gene (113810.0008-113810.0009) affecting only neuronal isoform-a2. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. Levels of the DST protein were absent or very low in neurons derived from induced pluripotent stem cells of the patients. 

In a 17-year-old Italian girl, born of unrelated parents, with HSAN6, Cappuccio et al. (2017) identified compound heterozygous mutations in the DST gene: a nonsense mutation (R1296X; 113810.0010) and a missense mutation (H269R; 113810.0011). The mutations, which were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. The mutations were not found in the ExAC database. The H269R mutation in exon 7 affected only the neuronal isoform of DST (isoform-a), whereas the R1296X mutation in exon 29 affected both the neuronal and skin (isoform-e) isoforms. The patient had clinical features of HSAN6, consistent with both mutations affecting the neuronal isoform. She also had some skin blistering and peeling suggestive of EBS3 which may have been related to haploinsufficiency for isoform-e, although these may have been a secondary result of peripheral neuropathy. Functional studies of the variants and studies of patient cells were not performed.

HNA (hereditary neuralgic amyotrophy), AD, 17q24, SEPT9

HMSN-P, AD, 3q13-q14, TFG

Rare Hereditary Neuropathies

Hereditary disorders of lipid metabolism

• Metachromatic leukodystrophy

• Krabbe disease (globoid cell leukodystrophy)

• Fabry disease

• Adrenoleukodystrophy / adrenomyeloneuropathy

• Refsum disease

• Tangier disease

• Cerebrotendinous xanthomatosis 

Hereditary Ataxia with neuropathy

• Friedreich ataxia

• Vit E deficiency

• SCA

• Abetalipoproteinemia (Bassen-Kornzweig disease)

• Ataxia-telangiectasia

• Oculomotor apraxia type 1

• Oculomotor apraxia type 2

• Cockayne syndrome

Porphyria

• AIP

• HC

• VP

Others

• GAN

• Polyglucosan body neuropathy

• Familial amyloid polyneuropathy

Famililal transthyretrin amyloidosis

Transthyretin (TTR) gene encodes one of the three prealbumins, which include alpha-1-antitrypsin, transthyretin and orosomucoid. The encoded protein, transthyretin, is a homo-tetrameric carrier protein, which transports thyroid hormones in the plasma and cerebrospinal fluid. It is also involved in the transport of retinol (vitamin A) in the plasma by associating with retinol-binding protein. The protein may also be involved in other intracellular processes including proteolysis, nerve regeneration, autophagy and glucose homeostasis. Mutations in this gene are associated with amyloid deposition, predominantly affecting peripheral nerves or the heart, while a small percentage of the gene mutations are non-amyloidogenic. The mutations are implicated in the etiology of several diseases, including amyloidotic polyneuropathy, euthyroid hyperthyroxinaemia, amyloidotic vitreous opacities, cardiomyopathy, oculoleptomeningeal amyloidosis, meningocerebrovascular amyloidosis and carpal tunnel syndrome 

Transthyretin (TTR) is a type of protein made up of 127 amino acids. It is called a transport protein, because it carries both thyroxine (T4) and retinol-binding protein bound to retinol, which is how its name is derived: trans- (transport), thyr- (thyroxine), retin (retinol). Transthyretin is found in the serum and cerebrospinal fluid and circulates as a hometramer, which is a protein complex made up of four identical subunits which are associated but not covalently bound. 

Familial transthyretrin amyloidosis Clinical features of hereditary transthyretin (ATTR) amyloidosis can include peripheral sensorimotor neuropathy and autonomic neuropathy, as well as non-neuropathic changes (cardiomyopathy, nephropathy, vitreous opacities, and CNS amyloidosis) 

There are 4 types

• • TTR Tranthyretrin amyloidosis

  • Familial amyloid polyneuropathy type I (Portuguese-Swedish-Japanese type): Young patient, severe painful neuropathy, dysautonomia, CHF, CKD - in context of painful peripheral neuropathy = think FAP, type-1.

    • Autosomal dominant

    • Early sx: 

      • Slow progressive sensorimotor polyneuropathy of the legs, followed by motor neuropathy within a few years. 

      • The initial signs of this sensory neuropathy are paresthesias (sense of burning, shooting pain) and hypesthesias of the feet. 

      • Temperature and pain sensation are impaired earlier than vibration and position sensation. By the time sensory neuropathy progresses to the level of the knees, the hands have usually become affected. 

      • In the full-blown stage of the disease, sensory loss, muscle atrophy, and weakness of the extremities show a glove and stocking distribution. Foot drop, wrist drop, and disability of the hands and fingers are common symptoms of motor neuropathy.

      • Carpal tunnel syndrome: familial.

      • Autonomic dysfunction: Constipation/ diarrhea, impotence, orthostatic hypotension, gastroparesis, anhidrosis, urinary retention and incontinence. 

    • Late sx:

      • Cardiac conduction block

      • Cardiomyopathy

      • Vitreous opacities

      • Nephropathy

Patisiran, a small interfering RNA delivered as an IV infusion every 3 weeks

Inotersen, an antisense oligonucleotide administered subcutaneously 3 times a week on alternate days in the first week and then once weekly for 64 weeks, have received regulatory approval by the US Food and Drug Administration (FDA).

Vutrisiran (AMVUTTRA)

ONPATTRO® (patisiran) FAP and PND Handout (onpattrohcp.com) 

Eplontersen https://www.wainuahcp.com/

Patisiran, lipid complex, (ONPATTRO) is 0.3 mg/kg every 3 weeks by intravenous infusion. For patients weighing 100 kg or more, the recommended dosage is 30 mg.  Premedicate with a corticosteroid, acetaminophen, and antihistamines.  Filter and dilute prior to administration.  Infuse over approximately 80 minutes 

• Check prealbumin (TTR) levels.

• Check vitamin A levels. 

• Vitamin A RDA 

Patient exam (PND and FAP stage)

Inotersen (Tegsedi) 

Vutrisiran (Amvuttra)

https://vyndamax.pfizerpro.com/

eplontersen  (Wainua)

Tafamidis, a transthyretin stabilizer, is a pharmacologic chaperone of transthyretin that prevents tetramer dissociation into monomers, which is the rate-limiting step in amyloid fibril formation.

Acromadis: Attruby™ ATTR-CM Treatment - Clinical Information For HCPs 

Diflunisal

Orthotopic liver transplantation (OTLX) halts the progression of peripheral and/or autonomic neuropathy; OTLX is recommended in individuals younger than age 60 years with: 

• • (1) disease duration less than five years, 

  • (2) polyneuropathy restricted to the lower extremities or with autonomic neuropathy alone, and 

  • (3) no significant cardiac or renal dysfunction.

Concept to consider before treating

Treatment threshold in TTR mutations:

There are a few concepts  before treating TTR patients.

• There is no indication to treat asymptomatic patients yet. 

• Treatment is for length-dependent peripheral neuropathy so CTS alone is insufficient either.

• To initiate treatment we require a patient to have symptoms of a PN,  Signs on exam and one positive confirmatory test (EMG, Skin biopsy, autonomic reflex screen etc.). If so, we treat as we don't want to wait until the patient accumulates a lot of damage.

• Tissue diagnosis is required in most patients, not necessarily from nerve.  You may make an exception with very straightforward cases with other family members with the exact phenotype.

• In cases with alternative etiologies suspected, you can intervene on them and re-evalute in about 6 months.  None of these common etiologies (diabetes, or B12 deficiency) would progress as fast as amyloid does.

There is no data for any of the  above 4 medicines for asymptomatic TTR mutations and considering that these are not 100% penetrant diseases and vary from mutation to mutation and even with the same mutation in different regions of the world, is not clearly beneficial.

I tend to treat the majority of patients with symptoms of neuropathy, even when mild with objective evidence of neuropathy, including reduced epidermal nerve fiber density.  There is data from meeting abstracts for both of the RNA silencing drugs, that patients have better outcomes, with earlier treatment, which I think is true for most neuropathies.

Familial amyloid polyneuropathy type II (Indiana/Swiss or Maryland/German type)

• • Early:

    • Carpal tunnel syndrome

  • Late:

    • Sensorimotor polyneuropathy of extremities

    • Autonomic dysfunction: Constipation / diarrhea, impotence

    • Cardiomyopathy

    • Vitreous opacities

    • Nephropathy

    • Familial amyloid cardiomyopathy

    • TR leptomeningeal/CNS amyloidosis

    • Familial oculoleptomeningeal amyloidosis (FOLMA)

Most patients with the p.V142I mutation were African American, whereas many with p.T80A and other rare TTR mutations were Caucasian. Family history of hATTR was more common among patients with p.T80A and other rare TTR mutations than among patients with p.V142I. Regardless of the underlying mutation variant, many hATTR patients can present with various symptoms/manifestations aside from CM, such as PN and bilateral carpal tunnel syndrome. Recognising the neurological symptoms that can occur alongside CMandperforming subsequent genetic testing facilitates diagnosis of hATTR. Early diagnosis is critical in hATTR because it is progressive and fatal, and early initiation of disease-modifying therapy is essential to optimising patient outcomes.

Scales: FAP Stage and PND scale. 

hATTR Evaluation Tools | Monitor Symptoms and Measure Progression 

https://link.springer.com/article/10.1007/s40120-020-00210-7

2023 ACC Expert Consensus on Cardiac Amyloidosis: Key Points

The following are key points to remember from a new Expert Consensus Decision Pathway document on comprehensive multidisciplinary care for the patient with cardiac amyloidosis:

1. Amyloid cardiomyopathy is caused by misfolding of (i) monoclonal immunoglobulin light chain produced in bone marrow plasma cell disorders called AL, or (ii) transthyretin (TTR) protein called ATTR. ATTR-cardiomyopathy (ATTR-CM) can occur in the context of genetically normal protein (wild type or ATTRwt-CM) or due to genetic mutations (most commonly isoleucine substitution for valine at position 122), rendering the protein abnormal (ATTRv-CM).

2. Since amyloid fibrils can deposit in multiple organs, multidisciplinary care is a requisite.

3. Cardiac clues to diagnosis of amyloidosis includes increased left ventricular hypertrophy in the absence of hypertension or valvular heart disease, heart failure symptoms, diastolic dysfunction, atrial fibrillation, conduction system disease, and elevated cardiac biomarkers. Extracardiac manifestations include carpal tunnel syndrome, spinal stenosis, hip or knee replacement, prior shoulder surgery, proteinuria, and peripheral or autonomic neuropathy causing orthostatic hypotension. Pathognomonic extracardiac findings for AL include macroglossia, periorbital purpura, and acquired factor X deficiency. Findings unique to ATTR are spontaneous biceps rupture and spinal stenosis.

4. Low voltage electrocardiography and presence of hypertrophy on echocardiography is only present in 30% of amyloid patients. Other echo findings include left ventricular hypertrophy, atrioventricular valve/right ventricular free wall/interatrial septum thickening, diastolic dysfunction, biatrial enlargement, and decreased global longitudinal strain with apical sparing.

5. Cardiac magnetic resonance imaging can help differentiate amyloidosis from other infiltrative diseases. Findings include extracellular volume expansion and diffuse late gadolinium enhancement.

6. The first step in identifying type of amyloidosis is a monoclonal protein screen involving: serum free light chain assay, serum and urine immunofixation electrophoresis. If all are negative, AL has been ruled out. If any are positive, the next step is biopsy of the involved organ with mass spectrometry to confirm AL deposition. A negative fat pad biopsy does not rule out AL or ATTR, and biopsy of the involved organ (heart or kidneys) should be considered.

7. A serum/urine protein electrophoresis should not be used to rule out monoclonal protein due to lower accuracy relative to immunofixation. In chronic kidney disease, elevated serum free light chain ratios of K/L are common but with a normal serum and urine immunofixation electrophoresis.

8. If AL has been ruled out, a technetium pyrophosphate scan can be used to diagnose ATTR-CM. Genetic testing is warranted to distinguish between ATTRwt-CM or ATTRv-CM.

9. Tafamidis is a TTR stabilizer and is the only Food and Drug Administration approved medication available for all ATTR-CM. It delays disease progression but does not result in regression, and in trials, reduced all-cause mortality and cardiovascular hospitalizations. It has minimal side effects but has a high cost, needing copay assistance programs for patients.

10. Alternatives to tafamidis include diflunisal, also a TTR stabilizer, which is less effective but significantly cheaper. It is a nonsteroidal anti-inflammatory drug and should be avoided in chronic kidney disease, decompensated heart failure, and gastrointestinal (GI) bleeding.

11. Beta-blockers should be used with caution and may worsen outcomes. Angiotensin inhibitors may be poorly tolerated due to orthostatic hypotension. Retrospective analysis of trials suggests a beneficial effect of spironolactone. There is no evidence to guide use of SGLT-2 inhibitors in amyloidosis.

12. If atrial fibrillation is present, anticoagulation is recommended regardless of CHA2DS2-VASc score, and prior to cardioversion, a transesophageal echocardiogram should always be performed regardless of anticoagulation status due to high risk for intracardiac thrombus.

13. There should be close monitoring for conduction disease and ventricular arrhythmias, both being very common in amyloid cardiomyopathy. However, defibrillators have not consistently demonstrated improved survival for amyloidosis and hence should be considered based on standard heart failure guidelines for amyloid patients.

14. If aortic stenosis is present with cardiac amyloidosis, aortic valve replacement (AVR) may help improve symptoms and referral for transcatheter AVR (TAVR) should be considered.

15. Emerging therapies not yet approved for cardiac amyloidosis include TTR silencers such as patisiran or vutisiran (approved for ATTRv polyneuropathy) and inotersen. These are currently only approved for amyloid polyneuropathy. Data on green tea derivatives are lacking and not recommended.

16. GI mucosa involvement can cause protein losing enteropathy, GI dysmotility, abdominal pain, constipation, or diarrhea and bleeding. Treatment is supportive and should include collaboration with a GI specialist.

17. Treatment for multiple myeloma with AL amyloidosis includes either high-dose melphalan with stem cell transplant daratumumab with cyclophosphamide, bortezomib, and dexamethasone. For AL-CM, a stem cell transplant followed by cardiac transplant would be ideal, but in some cases, sequential heart transplant followed by stem cell transplantation may be considered.

18. Kidney involvement is very common with AL and ATTR amyloidosis. Treatment is supportive and includes low salt diet, use of diuretics for fluid overload, and angiotensin antagonists for proteinuria.

https://www.ncbi.nlm.nih.gov/books/NBK574531/

Nomenclature:

The c.424G>A (p.V142I) alteration (also known as p.V122I) is located in coding exon 4 of the TTR gene. This alteration results from a G to A substitution at nucleotide position 424, causing the valine (V) at amino acid position 142 to be replaced by an isoleucine (I). 

Hereditary transthyretin amyloidosis val30met in the elderly | IMCRJ 

https://arci.org/

Fabry’s disease

• • X-linked recessive sphingolipidosis due to deficiency in alpha-galactosidase A caused by mutations in the GLA on Xq21-22. It is a lysosomal storage disorder. 

  • Accumulation of glycosphingolipids (globotriaosylceramide a.k.a. Gb3) in the endothelium of cerebral vessels (foamy cells) and renal glomerular arterioles leading to HTN, cardiac ischemia, renal failure, skin lesions, and strokes.  It also causes dysfunction in the corneas and peripheral nerves. 

  • Intermittent lancinating pain and dysesthesias affecting distal limbs (hand and feet) which may be triggered by fever, hot weather, or vigorous exercise

  • Autonomic dysfunction: small fiber neuropathy

    • Patients have hypohidrosis, decreased tear and saliva production, GI dysmotility (abdominal pain), and impotence.

  • Angiokeratomas over the lower half of the body; around umbilicus, groin, scrotum (bathing trunk distribution).  Tiny red angiectasia may be seen in nailbeds, oral mucosa, and conjunctiva.  

  • Cornea verticillata

  • Labs: decrease alpha-galactosidase activity in leukocytes or cultured fibroblasts.  Genetic confirmation of GLA mutation.  Prenatal diagnosis by amniocentesis. 

  • Tx: Fabrazyme infusions (biweekly) Pheytoin for pain. Renal transplant for renal failure.

Leukodystrophies 

These are disorders in which the primary or major abnormality involves myelin development (dysmyelination) or myelin degeneration (demyelination) of central nerves occurring alone or in combination with demyelinating peripheral neuropathy.  Primary myelin abnormality may cause degeneration of the long axons, manifesting clinically as the syndrome of HSP (CNS-predominant distal motor sensory axonopathy) instead of a leukodystrophy syndrome. 

Leukodystrophies have extremely variable clinical presentations, including progressive cognitive disturbance and signs of corticospinal and corticobulbar tract deficits.  Early corticobulbar tract involvement argues against disorders causing distal motor-sensory axonopathy (ie, types of HSP).  Although the complete constellation of insidiously progressive cognitive impairment, spasticity, optic neuropathy, and demyelinating peripheral neuropathy is suggestive of generalized leukodystrophy (affecting both the CNS and peripheral nervous system), often all elements of this constellation are not present.  In particular, demyelinating peripheral neuropathy, which typically accompanies childhood-onset leukodystrophies (eg, Krabbe disease and metachromatic leukodystrophy), may be absent in the rare adolescent- and adult-onset forms of these disorders.

Whereas it is not uncommon for inherited leukodystrophies to eventually cause spastic paraparesis or tetraparesis, it is much more common for inherited leukodystrophies (eg, CADASIL [cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy], adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, mitochondrial disorder [eg, DARS2 mutation], and Alexander disease) to manifest initially and predominantly with cerebral symptoms (i.e., cognitive impairment).  Notable exceptions occur when the primary myelin disturbance (eg, due to proteolipid protein [PLP1] mutation) results in progressive axon degeneration involving corticospinal tracts.  In these individuals, primary myelin impairment (ie, leukodystrophy) manifests as a myelopathy.  When cognitive disturbance is minimal or absent, leukodystrophies may be difficult to distinguish from hereditary CNS distal axonopathy (ie, HSP).  Certainly, demyelinating optic neuropathy and deafness, which are not uncommon in leukodystrophies but quite atypical of HSP, would aid the differential diagnosis.  Brain and spinal cord MRI, brainstem and visual evoked potentials, and nerve conduction studies are valuable in evaluating individuals suspected of having leukodystrophy. 

For all patients with unexplained spastic paraplegia and those with leukodystrophy check: serum vitamin B12, MMA, folate, VLCFA, lactate, pyruvate, serum copper, plasma amino acids (including homocysteine and methionine), urine amino acids, and serum cholestanol. 

Adrenoleukodystrophy/Adrenomyeloneuropathy

These are allelic peroxisomal disorders.  They are X-linked dominant disorders.  

ALD is more common and manifests in young males as progressive dementia, optic atrophy, cortical blindness, hearing loss, seizures, and spasticity.  90% of patients have adrenal insufficiency.  Onset of symptoms is usually between 4-8 years of age, and death usually occurs within 2 years of onset of symptoms.  Less commonly ALD occurs in adolescence or young adult life and progresses at a slow rate.  Affected individuals are commonly misdiagnosed with multiple sclerosis.  Later onset case manifest with psychiatric symptoms leading to misdiagnosis as schizophrenia.  

AMN phenotype is seen in 30% of cases.  It usually manifests in the 3rd to 5th decade of life.  Affected individuals develop progressive spastic paraplegia along with mild to moderate peripheral neuropathy.  MSR may be normal or reduced.  Progressive dementia develops later in the course of disease. AI is seen in 2/3rds of patients. 

In women carriers of ALD or AMN, rarely develop myelopathy later in life (~30s) and these patients often get misdiagnosed with MS or familial spastic paraparesis. 

Labs: VLCFA levels (C24, C25, and C26) are elevated in serum.  The ratio of hexacosanoic acid to docosanoic acid or erucic acid (C26:C22) and tetracosanoic acid to docosanoic acid (24:22) are increased in both ALD and AMN.  Thus, VLCFA are not useful to discriminate between ALD and AMN.  Diagnosis is confirmed by genetic testing for mutations in the peroxisomal transmembrane adenosine triphosphate-binding cassette transporter gene (ABCD1), located on Xq28.   

EDX: Typically normal in ALD.  In AMN there is associated sensorimotor polyneuropathy.  SNAP and CMAP amplitudes are reduced, DML is prolonged, and CV are slightly slow, suggesting an axonopathy with secondary demyelination.  SSEPs and VEPs may show evidence of central slowing. 

MRI of brain reveals confluent subcortical white matter demyelination in ALD, preferentially in the posterior parietal-occipital regions.   

Treatment:

• Treat adrenal insufficiency

• Diet low in VLCFA and supplemented by Lorenzo oil (erucic  and oleic acids) reduce the levels of VLCFAs and increase the levels of C22 in serum, fibroblasts, and liver, but these changes are not consistently noted in the brain. 

https://adrenoleukodystrophy.info/

https://adrenoleukodystrophy.info/clinical-diagnosis/diagnosis-of-ald

Hereditary spastic paraparesis (HSP):

• Hereditary spastic paraplegia (HSP) is a group of clinically and genetically diverse disorders that typically cause progressive spasticity and weakness in the lower extremities.  The usual age of onset is 20 to 40 years although it can occur at any age.  There are autosomal dominant, autosomal recessive, X-linked, and maternally inherited (mitochondrial) forms of HSP. 

• HSP symptoms begin in early childhood, gait disturbance may be nonprogressive and resemble spastic diplegic cerebral palsy. 

• HSP symptoms that begin after early childhood typically progress slowly over a number of years. 

• Neurologic examination demonstrates signs of upper motor neuron impairment as various degrees of hyperreflexia, spasticity, and weakness that are exclusively present or markedly greater in the legs than the arms.  For example, in the presence of spasticity, weakness, and grade 3 to 4 reflexes in the legs, upper extremities are typically entirely asymptomatic yet show mildly brisk deep tendon reflexes.  This is often accompanied by subtle decrease in vibration perception in the toes. 

• Numerous types of complicated HSP have neurologic involvement in addition to corticospinal tract and dorsal column disturbance. These abnormalities include, for example, peripheral neuropathy, cerebellar ataxia, cognitive impairment, dementia, and distal muscle wasting. 

• SPAST mutations are the single most common cause of dominantly inherited HSP, present in approximately 35% to 45% of such individuals with HSP.  Individuals with SPAST HSP typically manifest with a slowly progressive uncomplicated spastic paraparesis. 

• Recognizing HSP is straightforward when the patient has similarly affected first-degree relatives, neurologic involvement is limited to progressive corticospinal tract impairment (often accompanied by urinary urgency and subtle impairment of vibration perception), and other disorders are excluded by laboratory testing and neuroimaging.  Recognizing HSP is more difficult when patients have no family history (which may be the case when HSP is autosomal recessive, X-linked, or due to de novo mutation and when diverse neurologic symptoms are (or eventually become) indicative of more extensive CNS involvement.

Tangier’s disease

• • Autosomal recessive disorder with childhood onset, very rare. It is a peroxisomal disorder. 

    • Mutation in the ATP-binding-cassette subfamily A member 1 gene (ABCA1) on 9q31 that encodes ATP-binding cassette transporter, an important protein involved in regulating the intracellular transport of cholesterol.

  • Apolipoprotein A deficiency

    • Very low HDL levels, and therefore reduced ability to transport cholesterol out of tissues.

    • Accumulation of cholesterol in tissues

    • Elevated triglyceride levels.

  • Accumulation of cholesteryl esters in various tissues including tonsils, RES, cornea, GIT, Schwann cells, and bone marrow.

  • Large orange tonsils

  • Lymphadenopathy, hepatomegaly, and splenomegaly

  • Corneal infiltrates

  • Macrophages contain cholesterol esters. 

  • Vacuolation (lipid droplets) occurs in Schwann cells and RES.

  • Premature atherosclerosis occurs.

  • Sensorimotor neuropathy (relapsing) affecting predominantly with sparing of distal extremities

    • Dissociated sensory loss (loss of pain, temperature with relative preservation of posterior column modalities - vibration, proprioception, light touch, two point discrimination)

      • Loss of pain and sensation in upper limbs, similar to a pattern seen in case of syringomyelia. 

      • Starts proximally and progresses distally 

    • Tendon reflexes are depressed.

    • Cranial nerves may be involved.

  • Hand intrinsic atrophy

  • Segmental demyelination and remyelination without evidence of fiber loss, overall. 

  • Electrodiagnostic studies show both axonal and demyelinating features.

  • Tx: Low fat diet may improve the neuropathy symptoms. 

Abetalipoproteinemias

This disorder occurs as a result of mutation in microsomal triglyceride transfer protein (MTTP) causing a failure in absorption and transportation of Vit E, resulting in a sensorimotor neuropathy and signs of myelopathy, vision impairment due to retinitis pigmentosa.  As a result of fat malabsorption, patients have steatorrhea and other malabsorption syndromes. 

• • Very low triglycerides, total cholesterol, and absent beta-lipoproteins.

  • Acanthocytosis

  • Treatment with vitamin E 150 mg/kg/d and other fat-soluble vitamins

Refsum’s disease

• • Autosomal recessive peroxisomal disorder.

  • Mutations in two genes have been identified in individuals with Refsum disease: PHYH, the gene that encodes phytanoyl-CoA hydroxylase, is mutated in more than 90% of individuals; PEX7, the gene that encodes the PTS2 receptor, is mutated in fewer than 10% of individuals.

  • It is characterized by progressive distal motor and sensory impairment, ataxia of trunk and limb movements, blindness (from pigmentary degeneration of the retina), and deafness of sensorineural type. Additional clinical manifestations, of varying degree, include anosmia, pupillary abnormalities, nystagmus, ichthyosis, skeletal deformities, and a cardiomyopathy that can lead to arrhythmias, cardiac failure, and early death. 

  • The disease makes its appearance in late childhood, adolescence, or early adult life, and, untreated, progresses gradually, though with occasional remissions.

  • The biochemical abnormality is a marked increase in the serum phytanic acid, a branched 20-carbon fatty acid. Phytanic acid is present in dairy products and the meat of ungulates.  Accumulation of phytanic acid is due to the deficiency of phytanoyl CoA hydroxylase, the enzyme responsible for the first step in the catabolism of phytanic acid via alpha oxidation within the peroxisome.

  • The peripheral nervous system shows a severe demyelinating neuropathy. The nerves (including the spinal nerve roots) are considerably enlarged as compared with normal. 

  • Microscopically, there are prominent onion-bulb structures interspersed with collagen fibers, creating a striking onion-bulb pattern. There is also an increase of perineurial and interstitial connective tissue. Axons, both myelinated and unmyelinated, are decreased in numbers.

  • In the CNS, a cerebellar system degeneration is often present with neuronal loss in the inferior olivary nucleus and dentate nucleus and loss of fibers in the cerebellar peduncles. 

  • Posterior-column degeneration and loss of neurons in the gracile and cuneate nuclei have also been observed.

  • Polyneuropathy (sensorimotor, distal, and symmetrical, affecting LE > UE) plus:

    • Retinitis pigmentosa leading to night blindness

    • Cerebellar ataxia

    • Sensorineural hearing loss

    • Cardiomyopathy

    • Ichthyosis

    • Short metacarpals and metatarsals, especially 4th MT, with rest of the toes overriding. 

    • Anosmia

    • Elevated proteins in CSF (albuminocytologic dissociation)

    • Increase in blood phytanic concentration greater than 200 µmol/L. Normal level is <0.3 mg/dL.

    • May respond to dietary restriction of phytanic acid (<10 mg/d) or pheresis

    • Other biochemical findings include increased phytanic acid/pristanic acid ratio, elevated pipecolic acid concentrations (in 20% of affected individuals), and deficiency of phytanoyl-CoA hydroxylase enzyme activity or deficiency of the peroxisome-targeting signal type 2 receptor.

    • Onion-bulb formation on pathological specimen

  • Tx: Strict reduction in dietary phytanic acid, or PLEX can improve clinical manifestations. 

Giant axonal neuropathy: AR, childhood onset with gait disorder, gigaxonin mutation.

• Affects both CNS and PNS.  Neuropathy is due to defect of intermediate filament organization. 

• Onset is prior to age 7 years.  In some patients, neonatal respiratory of feeding problems occur and walking may be delayed.  In most other infants are normal until gait abnormalities become apparent by 3 years of age or sometimes later.  The gait is "clumsy." There is distal lower limb weakness, severe enough to sometimes present as foot drop.  Then neuropathy may progress and involve the upper limb which become weak.  MSR are hypoactive or absent. Large fiber sensory modalities like vibration and proprioception are predominantly affected relative to small fiber sensory modalities of pinprick or temperature.  There may be variable cranial nerve involvement with ptosis, ophthalmoplegia, facial weakness, and tongue weakness. Vocal cord paralysis and optic atrophy are rare manifestations.  CNS manifestations include UMN: extensor plantar responses, dysarthric, scanning speech (cerebellar), intention tremor, gaze evoked nystagmus, and mental retardation may be seen.  In some focal or generalized seizures may occur. 

• The single most distinctive non-neurological abnormality is tightly curled hair, which is seen in most but not all patients.  Using scanning EM, abnormal hair grooves imply a defect in keratin organization.  Pes cavus, pes planus, scoliosis, and high-arched palate may be seen.  Precocious puberty may be associated with elevated serum prolactin levels or abnormal responses to LHRH. 

• It is relentless progressive disorder.  Most patients are either confined to a wheelchair or die by the third decade. 

• CSF: protein and cell count is normal

• EDx: NCS shows absent or reduced SNAPs.  Motor NCV are normal or minimally reduced with reduced CMAP amplitudes.  Needle EMG shows psw, fibrillation potentials and reduced number of MUAP with increased amplitude and duration.   

• SSEPs, VEPs, BAER are abnormal.  EEG may show generalized spikes, sharp and slow waves, as well as focal slowing. 

• MRI brain shows diffuse demyelination, multiple foci of decreased intensity in the parieto-occipital and cerebellar regions and narrowing of corpus callosum. 

Spinocerebellar ataxias: AD, some with axonal polyneuropathy that is sensory or sensory-motor.  

• • Associated with cerebellar and brainstem dysfunction

  • Hyporeflexia, loss of vibration sensation.

  • Sensory dysfunction, UMN, and cerebellar signs

Friedreich's Ataxia can cause a sensory polyneuropathy

Ataxia-telangiectasia: AR, defect in DNA repair

Genetic Conditions Associated with Ataxia, Neuropathy, and Retinitis Pigmentosa

• NARP

  • mtDNA

  • MT-ATP6

  • Maternal

• Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC)

  • 20p11.21

  • ABHD12

  • AR

• Ataxia with isolated vitamin E deficiency

  • 8q12.3

  • TTPA

  • AR

• Refsum disease

  • 10p13

  • PHYH

  • AR

• Abetalipoproteinemia

  • 4q23

  • MTP

  • AR

• Congenital disorder of glycosylation type IA (CDG1A)

  • 16p13.2

  • PMM2

  • AR

• SCA-2

  • 12q24.12

  • SCA2

  •  AD

• PCARP

  • 1q32.2

  • FLVCR1

  • AR

CANVAS

https://www.ataxia.org/canvas/

Genetic testing 

Genetic testing is often able to establish a precise diagnosis for patients with hereditary myelopathy.  Depending on the clinical syndrome (i.e, whether cerebellar ataxia, spastic paraparesis, or cognitive impairment is the predominant symptom), the clinician may choose to either analyze a large panel of genes implicated in spinocerebellar ataxias, HSPs, leukodystrophies, or motor neuron disorders or proceed with whole-exome analysis.  Next-generation sequencing (either of gene panels or whole-exome analysis) may not sensitively detect gene copy number variation (deletion or duplication).  Chromosome microarray analysis may be useful in this regard. 

In general, genetic testing has the highest likelihood of yielding unambiguous information when a clinical diagnosis is made, and syndrome-specific candidate genes are analyzed. It is often difficult to interpret the significance of gene variations (such as those identified in whole-genome or whole-exome sequencing) that have little or no known association with the specific syndrome. It is important to note that identifying a precise genetic cause of the syndrome often does not indicate the extent and severity of the individual’s symptoms. Each of these syndromes is highly variable. Significant variation may be seen even between individuals who share exactly the same mutation. For most conditions, little is known about genotype-phenotype correlation and the contribution of modifying genes and potentially modifying environmental factors. For this reason, a cautious approach to prognosis is advised.