Hereditary neuropathies and amyloid neuropathies together account for a substantial proportion of chronic neuropathies, particularly when the syndrome doesn’t fit a typical acquired pattern. Modern molecular genetics has identified hundreds of genes that cause hereditary neuropathy (Charcot-Marie-Tooth disease and its variants), and amyloid neuropathies are now treatable with disease-modifying therapy that has transformed prognosis. Recognition of these diseases requires careful clinical evaluation, family history, electrodiagnostic studies, nerve biopsy in selected cases, and increasingly molecular testing. This page covers hereditary and amyloid neuropathies.

Charcot-Marie-Tooth Disease (CMT)

The most common hereditary neuropathy, affecting ~1 in 2,500. Genetically heterogeneous (>100 genes); divided by phenotype into demyelinating (CMT1, CMT4), axonal (CMT2), intermediate, and other forms.

CMT1 (Autosomal Dominant Demyelinating)

  • CMT1A: PMP22 duplication (most common); ~70% of CMT1.
  • CMT1B: MPZ mutations.
  • CMT1C: LITAF mutations.
  • CMT1D: EGR2 mutations.

Clinical Features

  • Childhood/adolescent onset.
  • Distal weakness; foot drop common.
  • Pes cavus (high-arched feet); hammer toes.
  • Stocking-glove sensory loss.
  • Reduced or absent reflexes.
  • Slowly progressive.

Pathology

  • Demyelinating pattern: segmental demyelination, remyelination.
  • Hypertrophic onion bulbs: characteristic; concentric Schwann cell processes.
  • Reduced number of large myelinated fibers.
  • Slow conduction velocities (< 38 m/s upper extremity).

Treatment

  • Supportive: orthotics, physical therapy.
  • Investigational: gene therapy approaches in development for CMT1A.

CMT2 (Autosomal Dominant Axonal)

  • Many genes: MFN2 (most common), MPZ, NEFL, AARS, GARS, others.
  • Often later onset than CMT1.
  • Normal or mildly reduced conduction velocities.
  • Distal weakness + sensory loss.
  • Pathology: axonal pattern.

CMTX (X-Linked)

  • GJB1 (connexin-32) mutations most common.
  • X-linked dominant; men more severely affected.
  • Demyelinating or intermediate pattern.
  • Sometimes with CNS features (transient brain MRI changes).

CMT4 (Autosomal Recessive)

  • Severe, early-onset.
  • Multiple genes (GDAP1, MTMR2, NDRG1, others).
  • Demyelinating predominantly.

Intermediate Forms

Mixed axonal-demyelinating; various genes (CMTDI, CMTRI subtypes).

HNPP (Hereditary Neuropathy with Liability to Pressure Palsies)

  • PMP22 deletion (opposite of CMT1A duplication).
  • Autosomal dominant.
  • Recurrent transient mononeuropathies at sites of compression (ulnar at elbow, peroneal at fibular head, median at wrist).
  • Mild background polyneuropathy.
  • Pathology: “tomacula” — focal sausage-shaped thickenings of myelin on teased fibers; characteristic.

Refsum Disease

  • PHYH or PEX7 mutations.
  • Defective phytanic acid metabolism.
  • Cerebellar ataxia + retinitis pigmentosa + neuropathy + hearing loss + ichthyosis + cardiomyopathy.
  • Treatment: dietary phytanic acid restriction; plasmapheresis acute.

Hereditary Sensory and Autonomic Neuropathies (HSAN)

  • HSAN I-VII; predominantly sensory + autonomic.
  • HSAN I (autosomal dominant): adult-onset sensory loss + sensorimotor; SPTLC1 mutations.
  • HSAN III (Riley-Day, familial dysautonomia): autosomal recessive; severe autonomic dysfunction; IKBKAP mutations.
  • HSAN IV (congenital insensitivity to pain with anhidrosis): NTRK1 mutations.
  • HSAN V (congenital insensitivity to pain): NGF mutations.

Amyloid Neuropathies

Classification

  • AL amyloidosis (immunoglobulin light chain): plasma cell dyscrasia (myeloma, MGUS, Waldenström); systemic; cardiac involvement common.
  • ATTR amyloidosis (transthyretin):
    • Hereditary ATTR (hATTR): TTR gene mutations; autosomal dominant; sensorimotor + autonomic + cardiac.
    • Wild-type ATTR (wtATTR, senile systemic amyloidosis): elderly men; cardiac predominant; some neuropathy.
  • AA amyloidosis: secondary to chronic inflammation (rheumatoid, infections); rare nerve involvement.
  • Other rare types: ApoA1, gelsolin, lysozyme.

Clinical Features of hATTR

  • Adult-onset progressive sensorimotor + autonomic neuropathy.
  • Cardiomyopathy (restrictive, arrhythmias).
  • GI dysmotility, alternating diarrhea/constipation.
  • Orthostatic hypotension.
  • Erectile dysfunction.
  • Carpal tunnel syndrome (early manifestation in some).
  • Vitreous opacities, glaucoma.
  • Specific TTR mutations have characteristic phenotypes (e.g., Val30Met, Val122Ile in African-American populations).

Pathology

  • Congo red apple-green birefringence: definitive for amyloid.
  • Endoneurial and perivascular amyloid deposits.
  • Predominantly axonal degeneration with small fiber loss.
  • Mass spectrometric typing: identifies which amyloid (AL, ATTR, etc.) — critical for treatment decisions.

Diagnosis

  • Clinical features + family history (hATTR).
  • Serum and urine immunofixation, free light chains (for AL).
  • Genetic testing for TTR mutations.
  • Tissue diagnosis: nerve biopsy, fat pad biopsy, rectal biopsy, salivary gland biopsy.
  • Cardiac imaging: echo, MRI, technetium pyrophosphate scan for ATTR.

Treatment of hATTR

  • Patisiran (siRNA against TTR mRNA): approved 2018; transformative.
  • Vutrisiran (siRNA, subcutaneous): approved 2022; less frequent dosing.
  • Inotersen (antisense oligonucleotide): approved 2018.
  • Eplontersen (antisense oligonucleotide): approved 2023.
  • Tafamidis: TTR stabilizer; approved for ATTR cardiomyopathy.
  • Acoramidis: TTR stabilizer; approved 2024.
  • Liver transplantation (historical; less common with new therapies).

Other Hereditary Neuropathies

  • Hereditary motor neuropathies (HMN): pure motor; multiple genes.
  • Distal hereditary motor neuropathies (dHMN): distal weakness; HSPB1, BSCL2, GARS, others.
  • Familial brachial plexus neuropathy: hereditary neuralgic amyotrophy; SEPT9 mutations.
  • Hereditary spastic paraplegia with neuropathy: various genes; SPG7, SPG11, others.
  • Adrenomyeloneuropathy: X-linked; ABCD1; spastic paraparesis + adrenal insufficiency + neuropathy.

Diagnostic Approach to Suspected Hereditary Neuropathy

  1. Family history (often non-trivial — many CMT patients don’t know).
  2. Clinical examination: distribution, age of onset, foot deformity, hearing, vision.
  3. EMG/NCS: demyelinating vs axonal; symmetric vs asymmetric.
  4. Targeted genetic testing based on phenotype.
  5. NGS gene panels: efficient for inherited neuropathies.
  6. Nerve biopsy in selected cases (when genetics negative, or for confirmation).

🔍 Did You Know?

The 2018 approvals of patisiran and inotersen for hereditary transthyretin amyloidosis transformed one of the most devastating progressive neurologic diseases into a treatable condition. Before these therapies, hATTR amyloidosis produced relentless progression: sensorimotor and autonomic neuropathy worsening over years, cardiomyopathy progressing to heart failure, GI dysmotility, and death typically within 10-15 years of onset. Liver transplantation was the only intervention that could halt progression — by removing the major source of mutant transthyretin — but was offered only to selected younger patients. The RNAi (patisiran) and antisense oligonucleotide (inotersen) therapies suppress TTR production in the liver by ~80%, dramatically reducing the amyloidogenic protein. The APOLLO trial (2018) showed substantial reduction in neuropathy progression with patisiran, and the NEURO-TTR trial showed similar benefit with inotersen. Subsequent approvals (vutrisiran 2022, eplontersen 2023) have offered alternatives with better dosing schedules. The story illustrates a powerful principle: knockdown therapies for monogenic diseases can be transformative, and the molecular target (mRNA encoding the disease protein) is accessible with modern RNA technology. The therapeutic revolution in hATTR is extending to other neurodegenerative diseases — SOD1-ALS (tofersen 2023), Huntington (in trials), and others — where antisense oligonucleotides or RNAi can suppress the disease-causing protein. The lesson generalizes: genetic neurologic diseases are increasingly drug-targetable, and precise molecular diagnosis is the prerequisite for therapy. The nerve biopsy with Congo red staining and mass spectrometric typing of amyloid, once a research-oriented procedure, is now a critical decision point for life-changing treatment.

Pitfalls and Pearls

  • CMT1A: PMP22 duplication; demyelinating; most common CMT.
  • CMT2: axonal; MFN2 most common; later onset.
  • CMTX: GJB1; X-linked; intermediate.
  • HNPP: PMP22 deletion; recurrent pressure palsies; tomacula on biopsy.
  • Hypertrophic onion bulbs: CMT1, CMT4.
  • Tomacula: HNPP.
  • Refsum disease: PHYH; phytanic acid; dietary restriction.
  • HSAN III (Riley-Day): severe autonomic dysfunction in Ashkenazi Jewish children.
  • HSAN IV/V: congenital insensitivity to pain.
  • hATTR amyloidosis: TTR mutations; sensorimotor + autonomic + cardiac.
  • Congo red apple-green birefringence + mass spec ATTR: hATTR diagnosis.
  • Patisiran, vutrisiran, inotersen, eplontersen: TTR knockdown therapies for hATTR.
  • Tafamidis, acoramidis: TTR stabilizers.
  • AL amyloidosis: plasma cell dyscrasia; serum/urine immunofixation + free light chains.
  • Carpal tunnel syndrome bilateral in older patient: consider amyloid (especially ATTR-cardiomyopathy).
  • Pes cavus + foot drop + family history: think CMT; genetic testing.

References

  1. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8(7):654-667.
  2. Adams D, Suhr OB, Hund E, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. 2016;29(Suppl 1):S14-S26.
  3. Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21.
  4. Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2023;30(1):1-9.
  5. Vallat JM, Mathis S, Magy L. Charcot-Marie-Tooth disease: history of the eponym and an update of its clinical features. Eur J Neurol. 2019;26(5):665-672.
  6. Auer-Grumbach M. Hereditary sensory and autonomic neuropathies. Handb Clin Neurol. 2013;115:893-906.