by Robert E. Lovelace

Reprinted from Motor Disorders, edited by David S. Younger, MD, Chapter 16.

Peripheral neuropathy is among the most common neurologic disorders after stroke and epilepsy. Up to 20% of all neuropathies have a confirmed or suggested inherited basis (1-3). The presenting symptoms of a genetic neuropathy are found distally in the limbs due to involvement of the longest nerve fibers, often with pes cavus and club foot and later claw hand deformities (4-6). The Charcot-Marle-Tooth (CMT) disorders comprise 80 to 90% of all genetic neuropathics (7,S) and have an incidence of more than 42 per 100,000, which represents more than 250,000 cases nationwide. The terms peroneal muscular atrophy (9), hereditary motor and sensory neuropathy (HMSN), and CMT are used interchangeably for the prototypic disorder that exhibits clinical and genetic heterogeneity (IO, II).

BACKGROUND

The recent explosion in molecular genetics of the past 15 years has revolutionized our understanding and classification of the CMT disorders (Table 1), but on the whole it has not yet translated into useful therapy (12-15). The first major advance was the application of electrophysiologic studies to the nosology, with the designation of some conditions as axonal and others as demyelinating. Those with normal or slightly reduced compound muscle action potentials (CMAP) and sensory nerve action potentials (SNAP) and excessively slow nerve conduction velocity (NCV) were deemed demyelinating. Others with low-amplitude CMAP and SNAP and normal or mildly reduced NCV were deemed axonal (6,12-17). The classification of the CMT neuropathies begins with the main division of demyelinating neuropathy, termed CMT1 or HSMN 1, and the axonal type, termed CMT2, HSNN2, or "neuronal" form. Both have the same phenotypic presentation. The group of distal spinal muscular atrophies (SMA) (I 8,19) with a phenotype similar to peroneal muscular atrophy is known as the spinal type and lacks slowing of NCV or involvement of sensory fibers. Hereditary neuropathy with liability to pressure palsy (ITNPP) (14,17,20,21) shares clinical features with CMT1A, and when all such cases are ascertained, HNPP probably has a similar incidence (Gareth Parry, personal communication, 1998).

Symmetric involvement of the hands and feet is important in the general presentation of an inherited neuropathy. It may be so insidious as to be overlooked or compensated by the patient for years. Progressive deformity of the legs is related to differential muscle imbalance and sensory deprivation. Even though a delay of several years may occur, hand involvement invariably manifests itself in a similar way with profound difficulty in handling small objects such as a button or pen. This is usually associated with atrophy of intrinsic hand muscles and the lower forearms. The absence of hand involvement should cast doubt on the diagnosis of a genetic neuropathy. Patients with 14NPP present with multiple nerve lesions and prominent asymmetry reminiscent of chronic inflammatory demyelinating polyneuropathy (CIDP) (22-24).

The application of molecular genetics has more clearly defined the clinical and genetic diversity of CMT and its related disorders than ever before. Genetic investigations can be performed in utero to determine fetal involvement. Lebo et al. (25) pioneered methods of intrauterine diagnosis and described at least eight genetic abnormalities with abnormal membrane proteins. It is potentially useful in CMT syndromes, particularly CMT1A, wherein the effects of reduplications, particularly of a large segment of DNA, and increased gene dosage leads to increased clinical severity (25-28). Lupski (29) described use of genetic tests for each of the 10 different CMT syndromes, including the deletions in HNPR If all of the individually mutated amino acid deletions in the gene for peripheral myelin protein (PMP) 22, myelin protein zero (MPZ) or PO, and connexin are counted, there are altogether more than 300 genetic defects in the CMT disorders. In a given family, the clinical manifestations of CMT can vary from asymmetric or pes cav-us deformity to profound locomotor problems and limb deformity requiring Canadian crutches or a wheelchair (3,29). Slow NCV in hyperttophic nerves does not always define the dominant CMT IA phenotype because it also occurs in the recessive disorder Dejerine-Sottas disease or HMSN3, now termed CMT3 (30,31); in amyelinating neuropathy (32,33); and in CIDP (34), demyelinating neuropathy associated with antibodies to myelin-associated glycoprotein (MAG) (35), and HNPP. Unlike CMT, in both anti-MAG neuropathy and HNPP, distal motor latencies are disproportionatety long for the degree of slowing (17,36). Genetic heterogeneity in CMT may also be manifested in a single family such as when CMT types I and 2 and the spinal form are simultaneously present (10).

NON-CHARCOT-MARIE-TOOTH GENETIC NEUROPATHIES

Other hereditary neuropathies that should be considered in a given patient include those associated with the recessively inherited disorders metachromatic leukodystrophy, abetalipoproteinemia or Bassen-Kornzweig disease, and polyglucosan body disease, all typified by chemical or storage products and specific neuropathologic changes. Acute intermittent porphyria (37) and familial amyloid polyneuropathy (FAP) (38) are dominantly inherited. Acute intermittent porphyria results from deficiency of uroporphyrin-l-synthetase and porphobilinogen deaminase due to I of 18 mutations in the porphobilinogen gene (37); FAP is discussed in more detail below. Demyelinating neuropathy is occasionally associated with mitochondrial encephalomyopathy in which the mode of transmission is generally matemal; however, rare patients have demonstrated recessive and dominant Mendelian inheritance (39,40). The leukodystrophies generally present with symptoms and signs referable to the central nervous system (CNS) (2); however, abnormal nerve conduction studies with slowing of NCV indicates peripheral nervous system involvement as in childhood and adult-onset forms of metachromatic leukodystrophy (41,42).

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