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.
CMT is the most common genetic neuromuscular disorder, with a prevalence ranging from 1 in 1,213 to 2,500 individuals. It is characterized by genetic transmission, complete symmetry in terms of involvement, slow progression, and a disproportionate loss of myelin compared to axons. More than 70 distinct genes have been associated with at least one of the CMT phenotypes, including HMSN (Hereditary Motor and Sensory Neuropathy), HSAN (Hereditary Sensory and Autonomic Neuropathy), and dHMN (Distal Hereditary Motor Neuropathy). There is a significant overlap between specific genes and phenotypes in CMT.
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.
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.
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
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.ncbi.nlm.nih.gov/books/NBK1392/
https://medlineplus.gov/genetics/condition/hereditary-neuropathy-with-liability-to-pressure-pa
Approach to CMT Diagnosis (phenotypic and neurophysiological association) in CMT phenotype:
History
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.
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.
Physical exam
Clinical phenotype
Pes cavus, hammer toes
Labs to rule out other neuropathies
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
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.
Hereditary sensory and autonomic neuropathies predominantly involve myelinated and unmyelinated sensory nerves but also affect motor nerves.
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
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.
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
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.
HNA (hereditary neuralgic amyotrophy), AD, 17q24, SEPT9
HMSN-P, AD, 3q13-q14, TFG
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
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).
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.
Patient exam (PND and FAP stage)
Inotersen (Tegsedi)
Vutrisiran (Amvuttra)
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.
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)
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:
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).
Since amyloid fibrils can deposit in multiple organs, multidisciplinary care is a requisite.
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.
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.
Cardiac magnetic resonance imaging can help differentiate amyloidosis from other infiltrative diseases. Findings include extracellular volume expansion and diffuse late gadolinium enhancement.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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/
AR, chrom 22, lysosomal storage disease caused by mutations in the arylsulfatase A (ARSA) resulting in accumulation of sulfatides in cells that produce myelin (oligodendrocytes: CNS, and Schwann cells: PNS). It is a lysosomal storage disorder.
Late infantile: Most patients manifest this form. Normal development followed by regression. Loss of speech, progressive weakness, gait disturbances, hypertonicity > rigidity. Children become quadriparetic, spastic, and cortically blind and often develop seizures. On exam there is generalized weakness, hypotonia, hyporeflexia, and extensor plantar responses. Most children die within 5-6 years after onset of symptoms.
Juvenile onset is seen later in childhood or adolescence and is associated with clinical features similar to the late infantile form of the disease.
Adult onset patients develop slowly progressive dementia, psychosis, spasticity, ataxia, extrapyramidal signs visual impairment, and incontinence in the 3rd or 4th decade of life.
Labs: decreased arylsulfatase (ARSA) in urine, blood, cultured fibroblasts. Genetic confirmation ARSA or PSAP (prosaposin) genes. Prenatal diagnosis by amniocentesis. CSF protein is markedly elevated: 100-300 mg/dL.
EDX: CMAPs amplitudes are reduced, prolonged DML, slow CV (10-20 m/s in legs and 20-40 m/s in arms). No CB, but occasionally temporal dispersion may be seen. SNAPs are absent or reduced in amplitude, prolonged latencies and slow CVs.
Evoked potentials: VEP, BAEP, SSEPs are delayed.
MRI of brain demonstrates increased signal on T2WI in the subcortical white matter.
Histopathology: Characteristic abnormality is accumulation of metachromatically staining inclusions in the cytoplasm of Schwann cells. On EM, these inclusions appear as lamellated bodies within Schwann cells.
Krabbe’s Disease (Globoid cell leukodystrophy): AR, chromosome 14, deficiency of enzyme galactocerebroside β-galactosidase > toxic accumulation of galactocerebroside and psychosine in the white matter of CNS and PNS, leading to degeneration of oligodendroglia and Schwann cells, respectively. It is a lysosomal storage disorder. It is a myelinopathy and affects both CNS and PNS. It is caused by mutations in the beta-galactosidase gene (GALC) located on 14q24.3-q32.1. Beta-galactosidase enzyme metabolizes galactocerebroside to ceramide and galactose as well as catalyze the hydrolysis of psychosine.
Infantile onset: Most cases manifest between 3-8 months of age. Affected infants often appear normal at birth but later become irritabile and appear to be sensitive to various stimuli which may provoke opisthotonous. The develop feeding difficulties, recurrent vomiting, GTC seizures. Progressive weakness, spasticity, blindness, deafness ensues. MSR are hyperactive but later become hypoactive as concurrent polyneuropathy worsens. Plantar responses are extensors. Death by age 2 years.
Late onset: 10% to 15%. Slow progression after late onset, presenting with spastic paraparesis or hemiparesis, cerebellar ataxia, cortical blindness and optic atrophy, dementia; pes-cavus and scoliosis may be seen.
EDx: Uniformly demyelinating PN. CMAP amplitudes reduced, moderately prolonged DML, slow CV, and delayed or absent F-waves. Absent or reduced SNAP amplitudes, prolonged latencies and slow CV.
Labs: Decreased beta-galactosidase enzyme activity in leukocytes or cultured fibroblasts. CSF protein elevation in 50% of cases.
MRI of brain shows evidence of demyelination involving corticospinal tracts and optic radiations as well as demyelination or atrophy of the posterior part of corpus callosum.
Nerve biopsies show loss of myelinated fibers and segmental demyelination or hypomyelination, and macrophages filled with galactocerebroside. The abnormal inclusions in macrophages stain with PAS (glycogen), faintly with Sudan black (lipid) and with acid phosphatase (suggesting that these are within lysosomes). Unlike MLD, the inclusions in Krabbe disease are not metachromatic.
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.
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.
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
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
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
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.