Neuropathies, Inherited

Key Features

• 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

Clinical Findings

• 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

Diagnosis

• 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 ...