A. Charcot-Marie-Tooth Disease (HMSN Type I, II)
There are several distinct varieties of Charcot-Marie-Tooth disease, usually with an autosomal dominant mode of inheritance, but occasional cases occur on a sporadic, recessive, or X-linked basis. Clinical presentation may be with foot deformities or gait disturbances in childhood or early adult life. Slow progression leads to the typical features of polyneuropathy, with distal weakness and wasting that begin in the legs, a variable amount of distal sensory loss, and depressed or absent tendon reflexes. Tremor is a conspicuous feature in some instances. Hereditary motor and sensory neuropathy (HMSN) type I is characterized by demyelination on electrodiagnostic studies and is usually caused by mutations in the peripheral myelin protein 22 or myelin protein zero gene. In HMSN type II, electrodiagnostic studies show axonal loss rather than demyelination; one-third of cases are due to mutations in the gene mitofusin 2.
A similar disorder may occur in patients with progressive distal spinal muscular atrophies, but there is no sensory loss; electrophysiologic investigation reveals that motor conduction velocity is normal or only slightly reduced, and nerve action potentials are normal.
B. Dejerine-Sottas Disease (HMSN Type III)
The disorder may occur on a sporadic, autosomal dominant or, less commonly, autosomal recessive basis. Onset in infancy or childhood leads to a progressive motor and sensory polyneuropathy with weakness, ataxia, sensory loss, and depressed or absent tendon reflexes. The peripheral nerves may be palpably enlarged and are characterized pathologically by segmental demyelination, Schwann cell hyperplasia, and thin myelin sheaths. Electrophysiologically, there is a slowing of conduction, and sensory action potentials may be unrecordable.
This disorder, the only known autosomal recessive trinucleotide repeat disease, is 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. The gait becomes ataxic, the hands become clumsy, and 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. There is bilateral pes cavus. Pathologically, there is a marked loss of cells in the posterior root ganglia and degeneration of peripheral sensory fibers. In the central nervous system, changes are conspicuous in the posterior and lateral columns of the cord. Electrophysiologically, conduction velocity in motor fibers is normal or only mildly reduced, but sensory action potentials are small or absent. Cardiac disease is the most common cause of death.
In the differential diagnosis for Friedreich ataxia are other spinocerebellar ataxias, a growing group of at least 30 inherited disorders, each involving a different identified gene. These heterogeneous disorders, which frequently (but not exclusively) exhibit an autosomal dominant inheritance pattern and poly-CAG expansion of the affected gene, typically cause cerebellar ataxia and varying combinations of other symptoms (such as peripheral neuropathy, ophthalmoparesis, dysarthria, and pyramidal and extrapyramidal signs).
D. Refsum Disease (HMSN Type IV)
This autosomal recessive disorder is due to a disturbance in phytanic acid metabolism. Pigmentary retinal degeneration is accompanied by progressive sensorimotor polyneuropathy and cerebellar signs. Auditory dysfunction, cardiomyopathy, and cutaneous manifestations may also occur. Motor and sensory conduction velocities are reduced, often markedly, and there may be electromyographic evidence of denervation in affected muscles. Dietary restriction of phytanic acid and its precursors may be helpful therapeutically. Plasmapheresis to reduce stored phytanic acid may help at the initiation of treatment.
Peripheral nerve involvement may occur during acute attacks in both variegate porphyria and acute intermittent porphyria. Motor symptoms usually occur first, and 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. The electrophysiologic findings are in keeping with the results of neuropathologic studies suggesting that the neuropathy is axonal in type (see Chapter 40).
F. Familial Amyloid Polyneuropathy
Sensory and autonomic symptoms are especially conspicuous, whereas distal wasting and weakness occur later. 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. Transthyretin amyloidosis is the most common; is associated with cardiomyopathy, nephropathy, leptomeningeal involvement, and vitreous opacity; and is treatable with liver transplantation, the small interfering ribonucleic acid patisiran (0.3 mg/kg up to 30 mg intravenously once every 3 weeks), or the antisense oligonucleotide inotersen (284 mg subcutaneously weekly). Tafamidis helps transthyretin amyloid cardiomyopathy and may slow the progression of the neuropathy.