Charcot-Marie-Tooth Disorders and Other Hereditary Neuropathies (continued)

Adrenoteukodystrophy and adrenomyeloneuropathy are X-linked disorders characterized by cerebellar ataxia, corticospinal tract degeneration, dementia, and slowing of NCV indicative of peripheral demyelinating neuropathy (43-45). Affected patients show increased levels of serum C24 and C26 saturated very-long-chain fatty acids due to a defect in fatty acid acyl-coenzyme A synthetase encoded at Xq2g. AbetalipopToteinemia is a childhood cerebral demyelinating disorder resulting from vitamin E deficiency; however, the neuropathy is more axonal than demyelinating (46). There is more than one genetic type of Pelizaeus-Merzbacher disease, another rare X-linked leukodystrophy (47). In one family so studied, female carriers were identified by electrophysiologic studies (48), and the relationship was suggested for a PLP (proteolipid protein) gene dosage effect in the X chromosome, homologous to that of the PMP22 gene in CMT1A for chromosome 17 (49). Krabbe's disease (50), Fabry's disease (51), giant axonal neuropathy (52,53), and Cockayne's syndrome (54,55) can have slow NCV indicating peripheral nerve involvement, as do patients with olivopontocerebellar degeneration, now termed spinocerebellar atrophy (SCA) (56), and others with myotonic muscular dystrophy (57), the latter of which maps to chromosome 19ql3 (57). The several types of SCA are separable by clinical and genetic differences (14,58,59). A rare neuropathy described in association with Joseph-Machado degenerative disease involves anterior horn cells (60,61).

The five subtypes of FAP demonstrate extensive genetic and therefore phenotypic diversity. Affected patients generally show late-age onset, slow progression, autonomic involvement, fasciculation in wasted muscles, and, in some, carpal tunnel syndrome (62-64). The most common gene defect resides on chromosome 18 at q11.2 and q12.1, in the gene for prealbumin transthyretin in Portuguese-Cypriot patients (37,65). The gene defect in Iowa patients, FAP type IV, maps to chromosome 11 at q23-qter and is associated with apolipoprotein Al. Finnish, FAP type V, patients have a gene defect on chromosome 9 at q33 with abnormal production of gelsoline (38,66,67). Suspicion of FAP is an indication for nerve and muscle biopsy that should include immunofluoresence for amyloid apple-green birefringence (63,68).

CHARCOT-MARIE-TOOTH DISEASE AND RELATED DISORDERS

The incidence of 42 per 100,000 persons for the CMT disorders may be an underestimate if based on conventional clinical and electrophysiologic studies. When cases of HNPP and asymptomatic family members are included using sensitive nerve conduction studies and special sensory recording studies, the incidence doubles (2,4,5,14,69).

Our understanding of CMT has evolved over the past century. Charcot and Marie (70) favored an SMA 'oasis, but Tooth (71) likened it to neuropathy. The acquired limb deformities include clubbed foot, talipes equina varus, pes cavus, flat feet, hammer toes, foot drop, and claw hand (Fig. 1).These lead to the characteristic gait disorder associated with foot slapping, unsteadiness, and frequent falls. The least manifestation, pes cavus, is found in patients with forme ftuste who can also have NCV as slow as those with more severe clinical involvement (16,17,72-74). Stork-leg deformity describes the marked atrophic appearance of the lower leg beginning in the thigh, giving rise to the appearance of an inverted champagne bottle, Stork legs and clubbed feet are also found in patients with Friedrich's ataxia (FA) (75) or SCA1, which may resemble CMT in appearance. The gene for FA is located on chromosome 9 at q2l (76) . Pes cavus and talipes equina varus by themselves do not indicate CMT because they are also a feature of anti-MAG, diabetic, amyloid neuropathy, myotonic muscular dystrophy, Welander's disease, scapuloperoneal syndrome, Duchenne muscular dystrophy, spastic paraplegia, and the nonneurologic disorder, idiopathic familial talipes equina varus (2,77). About one third of family propositi show additional features of CMT sufficient to warrant additional clinical subgroups (6). Patients with neuronal or CMT2C can have a hoarse voice due to vocal cord paresis (78). Others have proximal weakness of an SMA type with depressed or absent tendon reflexes and pes cavus. A recently examined patient with CMT2C in addition had bulbar palsy.

Patients with CMT are more sensitive to neurotoxic drugs and chemicals and can develop worsening of sensory function and walking ability.The CMT Association has published a list of these proscribed substances (79). Pregnancy and parturition can precipitate clinical worsening (2,80). Some affected patients may, for example, require a cane, crutches, or even a wheelchair postpartum due to interim worsening.

Primary complaints in the arms are infrequent (6,7), but atrophy and weakness of intrinsic hand muscles are an invariable finding on examination even when they are not apparent to the patient. Pain, paresthesia, numbness, dysesthesia, and burning sensations appear in late stages (3). Glove-and-stocking or distal vibratory loss occurs in most patients. In HNPP, the sensory loss is asymmetric, corresponding to individually affected nerves. Patients with CMT3 can have prominent sensory involvement leading to foot ulcers and osteomyelitis at sites of deformity. The fingers in such patients may be whittled away in a Motvan hand appearance or demonstrate the hypertrophic changes of the "main succulent." Proprioceptive defects also occur in FA (75) and in others with hereditary sensory and autonomic neuropathies (HSAN) (81), sometimes accompanied by autonomic vascular alterations. Myotonic Dystrophy may mimic the appearance of CMT in the legs (82).

Parents, siblings, and children should be included in the clinical evaluation of an index case. Hypertrophic supraclavicular, posterior and greater auricular, ulnar, superficial radial, and peroneal sensory nerves are frequently palpable or visible in CMT1 and -3 (30,31,83); the latter has a tapir face appearance (2,3 1). Scoliosis is sometimes found in CMT but more often in FA. Patients with CNS involvement can have normal or brisk reflexes and elicitable Babinski signs (2,82,84). Ocular involvement with optic atrophy and retinitis pigmentosa can occur in CMT (85) but is more common in FA (75,85), Refsum's disease, and abetalipoproteinemia (46). The association of optic atrophy and retinitis pigmentosa should lead to consideration of an underlying mitochondrial disorder (39). Cerebellar and extrapyramidal involvement should lead to consideration of SCA (56), Joseph's disease (60), and adrenomyeloneuropathy (44). Childhood axonal involvement should lead to careful consideration of CMT2C with vocal cord paralysis (78) but can also occur in Fabry's disease (51,87), giant axonal neuropathy (52,53), CMT3 (30,31,86,88), Krabbe disease's (50), and Cockayne's syndrome (54,55). One third of patients have an essential or familial tremor (89). Roussy and Levy (90) believed that the syndrome of CMT associated with tremor was a distinct entity, but most now consider it a variant of CMT1 (91,92). The differentiation of CMT1 from CMT2 is usually not clinically possible. In general, CMT1 has palpable hypertrophic nerves (2,84,93), and CMT2 has a later onset of disease typically in the second decade and is clinically less severe (17). Newborns with CMT3 may be hypotonic at birth and demonstrate severe generalized weakness, sensory loss, and hypertrophic nerves. A Tunisian autosomal recessive variant of CMT4 is even more severe (86) because of rapid advancement of muscular weakness in childhood, and severe gait disability often culminates in the need for a wheelchair (94). In addition, in CMT4 there is pes cavus, scoliosis, and slowing of NCV in the range found in CMT1 and CMT3.

In the fully developed state, HNPP is indistinguishable from CMT1 (95) and shares a common locus on chromosome 17 (96). Onset is usually in the second or third decade with episodes of multiple or recurrent mononeuropathies at sites prone to compression. Recovery from an episode may be complete, but subsequent ones have significant residua and coalescence of lesions leading to the appearance of generalized demyelinating neuropathy in the legs. The most common involved nerves are the ulnar at the elbow, peroneal at the fibular head, radial at the humeral spiral groove, median at the wrist, and involvement of the brachial and lumbar plexuses. Swollen demyelinated areas or tomaculi are composed of redundant myelin loops and reduplicated internodal myelin segments. The intermittent nature of HNPP can lead to an erroneous diagnosis of CIDP or conduction block neuropathy (23,24). Brachial plexus involvement in HNPP differs from neuralgic amyotrophy, brachial neuritis, and true familial brachial plexus neuropathy, respectively, by the absence of pain and dysmorphic features (97-99).

LABORATORY STUDIES

Electrodiagnostic studies are important in all patients with CMT (2,3,34,100,101) because it distinguishes the demyelinating and axonal forms and effectively screens index cases and minimally affected family members or those with forme fruste such as pes cavus deformity (2-4). The electrophysiologic features of CMT and other genetic neuropathies include uniform slowing of NCV along segments, proximal and distal (102); absence of motor conduction block or significant temporal dispersion (22,102); and with the exception of HNPP that resembles anti-MAG paraproteinemic neuropathy, proportionate prolongation of distal latencies for the degree of slowing of NCV (35,36). CMAP and SNAP amplitudes correlate with the severity of clinical involvement, especially with slow progression over many years. Special stimulation and recording techniques using high voltage, near-nerve percutaneous electrodes, proximal stimulation, and various late responses such as the H reflex and F response are helpful to show the essential characteristics of CMT, especially the uniformity of slowing.

Nerve biopsy indicates the degree of neuropathy and reveals morphologically specific alterations, including demyelination, remyelination, and onion bulb formation (6,93). The latter are visible by light and electron microscopy as concentrically laminated Schwann cell processes in cotyledon layers (8,103). They are seen in CMT1, CMT3, and CMT4 and occasionally in CIDP (22), hypothyroid neuropathy (6,82), sensory neuropathy and multiple endocrine neoplasia (104), and in HNPP with tomaculi (95,105).

Serum for very-long-chain fatty acids, in addition, are useful in the diagnosis of adrenormyeloneuropathy and adrenoleukodystrophy. A blood smear can be inspected for acanthocytes in the evaluation of abetalipoproteinemia (46,106); ocular and CNS involvement may be estimated by the responses obtained in electroretinography and in somatosensory evoked potentials (46). Serum lysosomal enzymes can be used to exclude hexosaminidase A deficiency and the diagnosis of GM2 gangliosidosis (107,108), especially among cases of CMT resembling SMA.

HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY

The clinical features and inheritance patterns of the HSAN are reviewed in detail elsewhere (6,7,81,88). The underlying pathologic lesion and gene products are still unknown. There is frequent association with CNS involvement, often with deformed and atrophic lower legs. Trophic lesions and ulcers of the feet result from profound sensory loss. Patients with HSAN1 are characterized by neurogenic arthropathy with recurring fractures, mutilating foot ulcers, onset in the second decade, and autosomal dominant inheritance. Affected patients typically complain of severe distal burning, aching, lancinating, and stabbing leg pains (109). Three types are congenital or recessive, including HSAN2 or Morvan syndrome with congenital insensitivity to pain (110), HSAN3 or Riley-Day syndrome with familial dysautonomia (109), HSAN4 with anhydrosis (111), and other solitary cases with insensitivity to pain. One was classified as HSAN5 because of type C fiber abnormality defined histologically by a nerve biopsy. Other cases similar to type 2 have had retinitis pigmentosa and sensory difficulty related to oral food handling (112). There is an X-linked form associated with hereditary ataxia. There are also cases defined by problems in DNA repair (113). The electrophysiologic diagnosis of HSAN has been facilitated by the four generations of computer-assisted sensory examination because it enables careful evaluation of automated sensory and autonomic parameters (114).

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FIG. 1. Pescavus foot deformity is seen in medial view of the left foot in a patient with CMT type 1A.