Inherited Neuropathies

CMT (HMSN)

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

5. Genetic testing

Medications to avoid in CMT:

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.

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

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

Rare Hereditary Neuropathies

Hereditary disorders of lipid metabolism

Hereditary Ataxia with neuropathy

Porphyria

Others

Famililal transthyretrin amyloidosis

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

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 

Patient exam (PND and FAP stage)

Inotersen (Tegsedi) 

Vutrisiran 

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.

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: 

Concept to consider before treating

Treatment threshold in TTR mutations:

There are a few concepts  before treating TTR patients.

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)

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:

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

Fabry’s disease

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:

Leukoencephalopathies with associated neuropathy:

Metachromatic leukodystrophy

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.  

Hereditary spastic paraparesis (HSP):


Tangier’s disease

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. 

Refsum’s disease

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

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

Friedreich's Ataxia can cause a sensory polyneuropathy

Ataxia-telangiectasia: AR, defect in DNA repair

Genetic Conditions Associated with Ataxia, Neuropathy, and Retinitis Pigmentosa

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.