Hereditary Sensory and Motor Neuropathies

In general, the hereditary sensory and motor neuropathies are peripheral neuropathies that affect either autonomic nerves, sensory nerves, motor fibers, or a combination thereof. The molecular genetics of these disorders is being ardently pursued and the mechanisms underlying them are rapidly being unraveled. However, to date there is overlapping terminology used when they are described (i..Ta.bie 36z8 ). This discussion is organized according to the classification that is emerging based on genetics (..iT§ble.36:9 ). CMT is the most common hereditary sensory and motor neuropathy, and CMT type 1A is the most common form of CMT, accounting for more than 50 percent of all cases of CMT.

Pathogenesis and Pathophysiology. Pathological changes seen in CMT include loss of myelinated fibers and sclerosis in the posterior column of the spinal cord, particularly in the fasciculus gracilis in its upper regions. Peripheral nerves show fewer myelin sheaths, with the extent of the decrease correlating with the severity of clinical disease. There is also an increase in transverse fascicular area, especially in the auricular and sural nerves. Onion bulbs, made up of circumferentially directed Schwann cells and their processes, can be seen at myelinated internodes, demyelinated internodes, or former sites of myelinated fibers.

There has been considerable controversy over the years whether the primary defect in CMT originates in the neuron and its axon or in the Schwann cell. The histopathological changes seen emphasize demyelination, whereas the clinical picture of muscle weakness and atrophy is evidence





HSMN 111

Particular Characteristics

Hypertrophic demyelinating neuropathy

Axonal neuropathy with normal or near normal nerve conduction Velocities

Severe hypertrophic demyelinating neuropathy with onset in infancy



Mode of Inheritance

Gene Gene Locus




Duplication (or rarely, point mutation) at 17pll.2-12




Deletion at 17pll.2


Dejerine-Sottas syndrome A


Point mutation at 17pll.2


Dejerine-Sottas syndrome B


Point mutation at lq22.3

Myelin protein zero (PO)
















X-linked CMT



Connexin 32













AD autosomal dominant AR autosomal recessive CMT, Charcot-Mane-Tooth disease; HNPP, hereditars neuropathy with liability to pressure palsies; PO, myelin protein zero; PMP, peripheral myelin protein.

of muscle denervation and axonal loss and of axons with calibers reduced out of proportion to the extant of myelin loss. pel

The gene defects and their products associated with the CMTs are beginning to clear this up. Peripheral myelin protein 22, which has been implicated in several of the CMTs (see T.a.bIe,3§..-9 ), is present as a protein in all myelinated fibers of the peripheral nervous system and is localized to compact myelin. Studies in the trembler mouse, which also has a gene defect in peripheral myelin protein 22, indicate that Schwann cells can modulate axon caliber, neurofilament phosphorylation, and neurofilament density within the axoplasm. Therefore, abnormal expression of peripheral myelin protein 22 could account for both the neuronal and Schwann cell alterations seen in CMT. y

Myelin protein zero (P0) is the major component of peripheral nervous system myelin. It is an integral membrane glycoprotein, and its expression is confined to myelinated Schwann cells. A major role of the P0 extracellular domain is compaction of peripheral myelin, while the cytoplasmic domain is thought to interact with a component of the opposing membrane of the compact myelin, holding these membranes together. [bq]

Connexin 32 is a gap junction protein. Before its identification as a gene for X-linked CMT (CMT X), it was not known there were gap junctions in human peripheral nerve. It has now been detected at the nodes of Ranvier and the Schmidt-Lanterman incisures, which may mean it forms intracellular gap junctions between the folds in Schwann cell cytoplasm.^

Epidemiology and Risk Factors. The hereditary sensory and motor neuropathies occur worldwide, with an estimated prevalence ranging from 4.7 to 36 per 100,000, and an approximate incidence of 1 in 25,000 persons. Autosomal dominant, autosomal recessive, and X-linked dominant and recessive inheritance patterns have been

reported. Tablei...3.6.-9. identifies the known genetic loci and known gene products.

Clinical Features and Associated Disorders. Although there is wide intrafamilial variability in phenotype, it is generally accepted that clinical presentation of CMT 1A and 1B are similar, although they are distinguishable, and CMT 1A may have a milder clinical course than 1B. Age of onset ranges from childhood to early adulthood, with symmetrical insidious weakness and atrophy of the intrinsic foot and peroneal muscles occurring first, associated with varus deformity of the feet and a steppage gait. Calf, intrinsic hand, and thigh muscles may be involved later ( F.!g 36z8 ). Atrophy tends to occur at the distal ends of the gastrocnemius, soleus, and quadriceps muscles. Cramps and fasciculations are often reported after exercise. Stretch reflexes disappear first in the gastrocnemius and soleus, then the quadriceps, and finally the arms.

Although patients generally do not report sensory disturbances, a careful examination reveals abnormalities in all modalities. Pes cavus and hammer toes are present in up to two thirds of patients. Decreased skin temperature over the distal leg is common, and decreased sweating has been reported. Enlargement and hardening of nerves, particularly those between the shoulder and elbow, have been observed in up to one fourth of patients.

Hereditary neuropathy with liability to pressure palsies, also called tomaculous neuropathy, is a syndrome characterized by a tendency toward the development of recurring sensory and motor nerve palsies brought on by mild pressure

Figure 36-8 Patient with Charcot-Marie-Tooth disease showing marked wasting of calf muscles and intrinsic foot muscl(From Dubowitz V: Muscle Disorders in Childhood. London, W.B. Saunders, 1995.)

or trauma to a particular peripheral nerve bundle. An insult from which a normal person would quickly recover results in residual nerve damage that may take days or even months to resolve. Some of these patients go on to develop CMT, whereas other family members may have only the CMT phenotype.

Dejerine-Sottas syndrome, sometimes called progressive hypertrophic neuropathy, is a more severe form of peroneal muscular atrophy with presentation in infancy of progressive generalized muscle weakness, severe sensory loss, limb ataxia, and marked hypertrophy of peripheral nerves. Both dominant and recessive inheritance patterns have been reported. Molecular genetic studies indicate that Dejerine-Sottas syndrome is a variation of CMT with a generally more malignant phenotype.

About 10 percent of cases of CMT are X-linked, in which primarily male family members are affected through maternal transmission. Again there is intrafamilial variation in severity, but generally, onset occurs in childhood, with slowly progressive distal weakness and sensory disturbance that tends to be more severe than that seen in CMT 1. Carrier females may have mild, variable clinical disease.

In Roussy-Levy syndrome, peroneal muscular atrophy is associated with essential tremor. The gene locus has not been identified. y

Differential Diagnosis and Evaluation. Other mixed polyneuropathies of nutritional, infectious, toxic, autoimmune, and vasculitic origin should be considered. Both axonal and demyelinating neuropathies need to be included in the differential diagnosis. At present, genetic confirmation of this disorder is available only for CMT 1A, hereditary neuropathy with liability to pressure palsies, Dejerine-Sottas syndrome, and X-linked CMT. CK is normal. On EMG, nerve conduction velocities are slowed in peripheral nerves. The extent of velocity reduction is no longer an accepted criterion for diagnosing the type of CMT. On nerve biopsy, there is a moderate increase in epineurium and perineurium and a variable decrease in the number of myelinated fibers that correlates with the severity of disease. Onion bulb formation is visible around myelinated and demyelinated internodes. y

Management.There is no cure or effective treatment for these disorders. Physical therapy, occupational therapy, and orthotic devices can help maintain optimal function. Genetic counseling is an obvious and important component of care for these patients.

Prognosis and Future Perspectives.Although large studies are not available, several series conclude that life expectancy is not reduced in CMT1 and that generally those with CMT type 1A remain ambulatory throughout their lives. A 20-year follow-up study of a family with CMT type 1B demonstrated that patients remained ambulatory with a normal lifespan. Autopsy studies included a 92-year-old family member. y

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