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.)

Table C22-1 Classification of Hereditary Neuropathies Associated With Specific Metabolic Defects

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)