Classification

Hereditary neuropathies are a heterogeneous group of peripheral nerve disorders (Figure C22-2). Some have a known metabolic basis and potential therapies (Table C22-1). The hereditary neuropathies that are not based on known specific metabolic defect are classified into three clinical groups: (1) hereditary motor and sensory neuropathies (HMSNs); (2) hereditary sensory and autonomic neuropathies (HSANs); and (3) hereditary motor neuropathies (HMNs).

Figure C22-2 Classification of hereditary neuropathies.

(Adapted, with revisions, from Thomas PK. Classification and electrodiagnosis of hereditary neuropathies. In: Brown WF, Bolton CF, eds. Clinical electromyography, 2nd ed. Boston, MA: Butterworth-Heinemann, 1993, pp. 391–425.)

The hereditary motor and sensory neuropathies (HMSNs) were classified by Dyck and Lambert into three predominant types (1) HMSN I, a demyelinating type; (2) HMSN II, a neuronal (axonal) type; and (3) HMSN III (Dejerine-Sottas disease), a severe demyelinating neuropathy of infancy and early childhood. HMSN I and II are characterized by skeletal deformities (pes cavus, hammer toes, scoliosis), insidious onset of distal lower more than upper extremities weakness, atrophy and sensory loss, and reduced or absent deep tendon reflexes. Based on clinical examination, these disorders are difficult to distinguish from each other because of similar phenotypes. With the recent influence of chromosomal linkage and gene identification, the term Charcot-Marie-Tooth disease (CMT) reemerged which created some confusion in the nomenclature and classifications of these disorders.

Charcot-Marie-Tooth disease (CMT) is subdivided into six major types with some but not perfect correlation to the HMSN classification (Table C22-2). CMT1 and CMT2 are interchangeable with HMSN I and HMSN II. The name Dejerine-Sottas syndrome (DSS, Dejerine-Sottas disease) is preserved and is the same condition as HMSN III. The term CMT3 is not commonly used since the genes involved with DSS are the same as CMT1. CMT4 is a new designation for a group of autosomal recessive CMT and should not be confused with HMSN IV which is Refsum disease. CMTX is an X-linked disorder and hereditary neuropathy with liability to pressure palsy (HNPP) is a distinct disorder characterized by recurrent mononeuropathies.

Table C22-2 Charcot-Marie-Tooth Disease (CMT, Hereditary Motor and Sensory Neuropathy, HMSN) Subtypes, Its Variants and Their Genetic Causes

* Duplication (98%) and point mutation (2%).

† Deletion (80%) and point mutation (20%).

The hereditary sensory and autonomic neuropathies (HSANs) are very rare and familial neuropathies with selective involvement of the primary sensory, with or without the autonomic, fibers. They should be distinguished from inherited disorders that affect large primary afferent neurons (spinocerebellar degeneration). They are currently subdivided into five types, based on mode of inheritance, natural history, electrophysiologic characteristics and histopatologic findings (Table C22-3).

Table C22-3 Hereditary Sensory and Autonomic Neuropathy (HSAN)

The hereditary motor neuropathies (HMNs) are loosely subdivided into proximal and distal (Table C22-4). The proximal HMNs are better known as spinal muscular atrophies (SMAs). These are among the most common autosomal recessive disorders in childhood affecting 1/10 000 live births with carrier frequency of 1/50. Spinal muscular atrophy is caused by a deficiency of the ubiquitous survival motor neuron (SMN) protein, which is encoded by the SMN genes, SMN1 and SMN2, on chromosome 5q. The distal HMNs are a genetically and clinically heterogeneous group of disorders that are also known as spinal CMT because of their overlap with CMT. They are characterized by distal weakness with or without foot deformities, but without sensory or autonomic involvement. Sensory nerve action potentials are normal while the motor NCSs reveal low-amplitude CMAPs with normal or borderline velocities, consistent with motor axonopathy. The inheritance of HMNs is either dominant or recessive. Only few have been mapped to a chromosome or have a defined gene mutation.

Table C22-4 Hereditary Motor Neuropathy (HMN)

Clinical Features and Genetics

Electrodiagnostic studies have proven to be the most important distinguishing test. CMT1, is also known as HMSN I or the demyelinating form of CMT, is a predominantly demyelinating polyneuropathy that is characterized by prominent uniform slowing of motor conduction velocities, with relative preservation of CMAP amplitudes. CMT2, also known as HMSN II or the neuronal form of CMT, is a predominantly axonal polyneuropathy that can be distinguished by normal or near-normal motor distal latencies and conduction velocities and decreased CMAP amplitudes. CMTX is an X-linked disorder characterized by intermediate slowing of conduction velocities, placing this disorder in the midst between CMT1 and CMT2.

Charcot-Marie-Tooth Disease 1 (CMT1, HMSN I)

Hereditary motor and sensory neuropathy I (HMSN I, CMT1) is the prototype of all inherited neuropathies. It is an autosomal-dominant disorder with complete penetrance and with a marked interfamily and intrafamily clinical phenotypic variability. The age of symptom onset varies from birth through the forties. Many adult patients can trace, in retrospect, their symptoms before the age of 20. These childhood or adolescence manifestations may include incoordination, frequent ankle or foot trauma, or poor athletic ability. The disorder is a slowly progressive, distal, symmetrical, motor more than sensory, peripheral polyneuropathy. The most common presenting symptoms are related to muscle weakness, muscle atrophy, or foot deformity (pes cavus, hammer toes, pes equinovarus, or pes planus). Many patients undergo surgical correction of foot deformity before correct diagnosis. Sometimes, the diagnosis is made during EDX studies for other, unrelated symptoms, or it may occur as part of an evaluation of family members. There is poor correlation in CMT1 between the clinical findings and conduction velocities.

Common findings on examination include distal muscle weakness, atrophy, distal areflexia, pes cavus, and hammer toes (Figure C22-3). The atrophy is predominant in the foot but may extend into the distal legs, resulting in an “inverted champagne bottle” appearance to the leg, and into the hands, resulting in “claw hands.” Although most patients do not complain of positive sensory symptoms, there is distal loss of all sensory modalities. Pain, other than that related to foot deformity and callus formation, is rare. Scoliosis is present in a minority of patients. Enlarged and palpable peripheral nerves may be identified in some patients with HMSN I. Late in the disease, steppage gait and claw hands are common. Although the disorder is frequently disabling, the life expectancy of patients with the disease is normal.

Figure C22-3 Classic foot deformity (pes cavus and hammer toes) of a 25-year-old woman with CMT1A (A). Her 35-year-old sister, who was asymptomatic, had milder foot deformities and marked slowing of conduction velocities (B).

Molecular and genetic studies have further subdivided CMT1 into four subtypes, with no definitive phenotypic characteristics that could accurately distinguish among them. These are named 1A, 1B, 1C, and 1D (see Table C22-2). CMT1A is the most common inherited neuropathy. Most patients have a tandem duplication of a 1.5 Mb region, which contains the peripheral myelin protein-22 (PMP22) gene, on chromosome 17p11.2p12. Duplication of PMP22 gene leads to overexpression (increased dosage) of the peripheral myelin protein. Occasional patients have point mutations of the PMP22 gene complex. CMT1B is associated with mutations of the myelin protein zero (MPZ) gene located on chromosome 1q22-23. The exact function of PMP22 and MPZ is not well understood, but both proteins are integral parts that likely play a major role in myelin compaction. CMT1C and CMT1D have been mapped to chromosome 16p and 10q with gene loci, named LITAF and EGR2, respectively.

Electrodiagnosis

Electrodiagnostic (EDX) examination provides important information for the clinician suspecting a diffuse peripheral polyneuropathy or hereditary neuropathy.

In dying-back axonal peripheral polyneuropathy, the amplitudes of the CMAPs are diminished with stimulation at any site along the nerve without conduction blocks or significant temporal dispersion; however, the conduction velocities are normal or only slightly reduced (values usually are more than 80% of the lower limits of normal). By contrast, slowing of conduction velocities is pronounced in demyelinating polyneuropathy; values usually are less than 60% of the lower limits of normal, and there is relative preservation of CMAP amplitudes. When evoked, the sensory distal latencies and conduction velocities parallel the motor latencies and velocities. Conduction velocity values of the sural sensory nerve are less than 60% of the lower limits of normal in HMSN I, and are either normal or greater than 80% of the lower limits of normal in HMSN II.

Table C22-5 Electrophysiologic Characteristics of Demyelinating Polyneuropathy

CIDP = chronic inflammatory demyelinating polyneuropathy; CMT1 = Charcot-Marie-Tooth disease 1.

In summary, hereditary demyelinating neuropathy are characterized by diffuse, uniform, and symmetrical slowing, without conduction block or temporal dispersion. Common causes of hereditary demyelinating peripheral neuropathy with uniform slowing are shown in Table C22-6.

Table C22-6 Hereditary Demyelinating Peripheral Neuropathy Associated With Prominent and Uniform Slowing of Conduction Velocities

* Often associated with multifocal slowing and/or conduction block at common entrapment sites.

Figure C22-4 A practical work-up for patients with hereditary motor and sensory neuropathies (HMSN) using forearm motor conduction velocities as a guide to ordering the appropriate commercially available genetic test.

In general, needle EMG in patients with CMT shows no specific abnormalities; results are similar in both types of the disease. Because of the slow tempo of the disease, needle EMG often reveals signs of chronic partial denervation with reinnervation. Long-duration, high-amplitude MUAPs are present bilaterally, and there is reduced recruitment of MUAPs, particularly in the distal muscles of the lower and upper limbs. Fibrillation and, less commonly, fasciculation potentials are relatively inconspicuous and are identified mainly in distal muscles. Although fibrillation potentials are more common in CMT2 (neuronal form) than CMT1 (demyelinating form), this finding does not allow differentiation of these two disorders.