Neuropathies, Inherited

Charcot-Marie-Tooth disease (HMSN type I, II)

• Usually an autosomal dominant mode of inheritance

• Occasional cases occur on a sporadic, recessive, or X-linked basis

Dejerine-Sottas disease (HMSN type III)

• May occur on a sporadic, autosomal dominant or, less commonly, autosomal recessive basis

Friedreich ataxia

• Only known autosomal recessive trinucleotide repeat disease

• Caused by expansion of a poly-GAA locus in the gene for frataxin on chromosome 9, leading to symptoms in childhood or early adult life

Refsum disease (HMSN type IV)

• Autosomal recessive disorder

• Due to a disturbance in phytanic acid metabolism

Porphyria

• Peripheral nerve involvement may occur during acute attacks in both variegate porphyria and acute intermittent porphyria

Familial amyloid polyneuropathy

• The polyneuropathy is axonal, and likely results from amyloid deposition within the peripheral nerves due to mutations in the genes encoding transthyretin, apolipoprotein A1, or gelsolin

Charcot-Marie-Tooth disease (HMSN type I, II)

• Foot deformities or gait disturbances in childhood or early adult life

• Slow progression leads to typical features of polyneuropathy

  • Distal weakness and wasting that begin in the legs

  • A variable amount of distal sensory loss

  • Depressed or absent tendon reflexes

• Tremor is a conspicuous feature in some instances

Dejerine-Sottas disease (HMSN type III)

• Onset in infancy or childhood

• Progressive motor and sensory polyneuropathy with weakness, ataxia, sensory loss, and depressed or absent tendon reflexes

• Peripheral nerves may be palpably enlarged and are characterized pathologically by segmental demyelination, Schwann cell hyperplasia, and thin myelin sheaths

Friedreich ataxia

• Gait becomes ataxic

• Hands become clumsy

• Other signs of cerebellar dysfunction develop accompanied by weakness of the legs and extensor plantar responses

• Involvement of peripheral sensory fibers leads to sensory disturbances in the limbs and depressed tendon reflexes

• Bilateral pes cavus

Refsum disease (HMSN type IV)

• Pigmentary retinal degeneration is accompanied by progressive sensorimotor polyneuropathy and cerebellar signs

• Auditory dysfunction, cardiomyopathy, and cutaneous manifestations may also occur

Porphyria

• Motor symptoms usually occur first

• Weakness is often most marked proximally and in the upper limbs rather than the lower

• Sensory symptoms and signs may be proximal or distal in distribution

• Autonomic involvement is sometimes pronounced

Familial amyloid polyneuropathy

• Sensory and autonomic symptoms are especially conspicuous

• Distal wasting and weakness occur later

• Transthyretin amyloidosis is the most common form and is associated with cardiomyopathy, nephropathy, leptomeningeal involvement, and vitreous opacity

Nerve conduction velocity and electromyography studies

Sural nerve and/or muscle biopsy

• Charcot-Marie-Tooth disease (HMSN type I, II)

  • In HMSN type I

    • Reduction in motor and sensory conduction velocity is marked

  • In HMSN type II

    • Motor conduction velocity is normal or only slightly reduced

    • Sensory nerve action potentials may be absent

    • Signs of chronic partial denervation are found in affected muscles

    • Predominant pathologic change is axonal loss rather than segmental demyelination

  • Dejerine-Sottas disease (HMSN type III)

    • Conduction is slowed

    • Sensory action potentials may be unrecordable

  • Friedreich ataxia

    • Marked loss of cells in the posterior root ganglia and degeneration of peripheral sensory fibers

    • Changes are conspicuous in the posterior and lateral columns of the spinal cord

    • Conduction velocity in motor fibers is normal or only mildly reduced

    • Sensory action potentials are small or absent

  • Refsum disease (HMSN type IV)

    • Motor and sensory conduction velocities are reduced, often markedly

    • There may be electromyographic evidence of denervation in affected muscles

  • Porphyria

Electrophysiologic findings are in keeping with the results of neuropathologic studies, suggesting that the neuropathy is axonal in type

Dysesthesic neuropathic pain, if present, can be treated with gabapentin, tricyclic antidepressants (low dose), pregabalin and duloxetine (see Neuropathies, Peripheral)

Charcot-Marie-Tooth disease (HMSN type I, II)

• No known curative measures

• Orthopedic surgery or equipment (such as braces or orthopedic shoes) may help affected patients to walk

• Physical and occupational therapy may to help preserve muscle strength and improve independence

Dejerine-Sottas disease (HMSN type III)

• No known curative measures

• Current therapies are limited to symptomatic relief

• Many patients continue to lead active lives

Friedreich ataxia

• No known curative measures

• Treatment of symptoms and accompanying complications can help affected individuals to preserve function and independence

• Foot deformities and scoliosis can be corrected with braces or orthopedic surgery

Refsum disease (HMSN type IV)

• Dietary restriction of phytanic acid and its precursors

• Plasmapheresis to reduce stored phytanic acid may help at initiation of treatment

Porphyria

• Hematin (4 mg/kg intravenously over 15 minutes once or twice daily)

• A high-carbohydrate diet and, in severe cases, intravenous glucose or levulose

• Propranolol (up to 100 mg orally every 4 hours) may control tachycardia and hypertension in acute attacks

Familial amyloid polyneuropathy

• Liver transplantation

• Patisiran, 0.3 mg/kg up to 30 mg intravenously once every 3 weeks

• Inotersen, 284 mg subcutaneously weekly

• Tafamidis

  • Helps transthyretin amyloid cardiomyopathy

  • May slow the progression of the neuropathy