Hereditary Polyneuropathies

Published on 03/03/2015 by admin

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71 Hereditary Polyneuropathies

Monique M. Ryan

Clinical Vignette

A 15-year-old boy presents with frequent tripping and exercise intolerance. He falls frequently and tires easily. He was born at term after an uncomplicated pregnancy. His early developmental milestones were normal until he walked late, at 20 months of age. On examination, he has mild wasting of the distal lower extremities without contractures. He walks well on his toes but cannot walk on his heels. There is mild weakness of ankle dorsiflexion and eversion. The ankle jerks are absent even with reinforcement, but other reflexes are preserved. Sensation is intact. There is no family history of neuromuscular disorders, but on examination his father has high-arched feet with distal weakness and generalized areflexia. Neurophysiologic testing of the patient and his father reveals marked slowing of motor nerve conduction, of the order of 18 m/s, with absent sensory responses. Genetic testing is positive for a duplication of the PMP22 gene on chromosome 17, confirming the clinical diagnosis of Charcot–Marie–Tooth disease type 1A.

The hereditary motor and sensory neuropathies (HMSNs) account for approximately 40% of chronic neuropathies. There are now more than 40 known genes or loci for the various forms of HMSN, which are collectively known as Charcot–Marie–Tooth disease (CMT). About 1 in 2500 persons is affected by CMT. New genes or loci for CMT subtypes are identified very frequently. Less common inherited polyneuropathies are those associated with systemic genetic disorders and inborn errors of metabolism (Table 71-1). Advances in genetic characterization of the inherited neuropathies have afforded greater insight into their biologic basis, and there is increasing interest in therapeutic strategies for these disorders, which can cause lifelong morbidity related to weakness, sensory loss, and orthopedic complications.

Table 71-1 Classification of Inherited Polyneuropathies

	Inheritance	Neurophysiology
Hereditary motor and sensory neuropathy type 1	Autosomal dominant	Demyelinating
Hereditary motor and sensory neuropathy type 2	Autosomal dominant Autosomal recessive	Axonal
Hereditary motor and sensory neuropathy type 3	Autosomal/de novo dominant	Demyelinating
Hereditary motor and sensory neuropathy type 4	Autosomal recessive	Demyelinating
Intermediate CMT	Autosomal dominant	Mixed
X-linked CMT	X-linked dominant, X-linked recessive	Mixed
Hereditary sensory and autonomic neuropathies	Autosomal recessive	Axonal
Hereditary motor neuropathies	Autosomal dominant	Axonal
Hereditary neuropathy with liability to pressure palsies	Autosomal dominant	Demyelinating
Other Inherited Neuropathies
Hereditary neuralgic amyotrophy	Autosomal dominant	Axonal
Familial amyloid polyneuropathy	Autosomal dominant	Axonal
Giant axonal neuropathy	Autosomal recessive	Axonal
Infantile neuroaxonal dystrophy	Autosomal recessive	Axonal
Andermann syndrome	Autosomal recessive	Axonal
Neuropathies Associated with Inborn Errors of Metabolism
Lipid Disorders
Cerebrotendinous xanthomatosis	Autosomal recessive	Mixed
Abetalipoproteinemia, hypolipoproteinemia	Autosomal recessive	Demyelinating
Ataxia with vitamin E deficiency	Autosomal recessive	Demyelinating
Peroxisomal Disorders
Refsum disease	Autosomal recessive	Demyelinating
Adrenomyeloneuropathy	X-linked	Axonal
Mitochondrial Cytopathies
NARP	Autosomal recessive	Mixed
MNGIE	Autosomal recessive	Mixed
Leigh disease	Autosomal recessive	Mixed
Lysosomal Enzyme Diseases
Globoid cell leukodystrophy	Autosomal recessive	Demyelinating
Metachromatic leukodystrophy	Autosomal recessive	Demyelinating
Fabry disease	X-linked	Axonal
Tyrosinemia type 1	Autosomal recessive	Axonal
Sphingomyelin Lipidoses
Niemann–Pick disease type C	Autosomal recessive	Demyelinating
Farber disease	Autosomal recessive	Demyelinating
Porphyrias
Acute intermittent porphyria	Autosomal dominant	Axonal
Hereditary coproporphyria	Autosomal dominant	Axonal
Variegate porphyria	Autosomal dominant	Axonal
Disorders with Defective DNA Synthesis or Repair
Ataxia telangiectasia	Autosomal recessive	Axonal
Cockayne syndrome	Autosomal recessive	Demyelinating
Neuropathies Associated with Spinocerebellar Ataxias
Friedreich ataxia, other SCAs	Autosomal recessive	Axonal
Neuroacanthocytosis	Autosomal recessive	Axonal

MNGIE, mitochondrial neurogastrointestinal encephalopathy; NARP, neuropathy, ataxia, and retinitis pigmentosa; SCA, spinocerebellar ataxia.

Etiology and Pathogenesis

Charcot–Marie–Tooth disease is commonly divided—on the basis of inheritance, neurophysiologic findings, and histopathology—into demyelinating forms (including dominantly inherited subtypes, CMT1 and CMT3, and autosomal recessive forms, CMT4) and axonal neuropathies (CMT2, which can have either dominant or recessive inheritance). Other forms of CMT include hereditary sensory and autonomic neuropathy (HSAN), which has prominent sensory and autonomic features, and distal hereditary motor neuropathy (dHMN), which has pure motor findings with no clinical or neurophysiologic evidence of sensory deficits.

Regardless of their genetic basis, the final common pathway of all neurologic deficits in the inherited neuropathies is length-dependent axonal degeneration, which accounts for the clinical findings common to many forms of CMT. Neurophysiologic studies variably demonstrate changes of demyelination, axon loss, or a combination of these findings.

Clinical Presentation

CMT generally first manifests in the first decade but progresses slowly, presenting in childhood or early adulthood with an abnormal gait or pes cavus. Less commonly, CMT presents in infancy with hypotonia and delayed motor milestones, or in late adulthood. The cardinal features of the genetic polyneuropathies are distal muscle wasting and weakness, loss of the deep tendon reflexes, and impaired distal sensation. The gait is high-stepping because of foot drop. Nerve hypertrophy may be palpable in the neck or at the elbow (Fig. 71-1) or nerve enlargement may be seen on magnetic resonance imaging (MRI) (Fig. 71-2).

Figure 71-1 Findings in Charcot–Marie–Tooth Disease.

Figure 71-2 MRI Findings in Charcot–Marie–Tooth Disease, with Normal Comparison.

Orthopedic deformities develop in at least two thirds of CMT patients. The most common finding is pes cavus, caused by imbalance between the muscles of the posterior and anterior compartments of the leg. With time, foot deformities become fixed and can cause pain, pressure areas, and stress fractures. Scoliosis and developmental hip dysplasia are less common complications of CMT.

The clinical evaluation should include inquiry as to the family history. Consanguinity suggests a possible recessive inheritance, whereas male-to-male transmission excludes an X-linked condition.

Differential Diagnosis

A hereditary neuropathy is suggested by a long, slowly progressive course, clinical findings such as pes cavus (which suggests long-standing weakness), and relatively prominent motor deficits without positive sensory phenomena. Acquired neuropathies have a shorter time course, are more likely to be associated with painful sensory phenomena, and may be associated with systemic symptoms or signs.

Diagnostic Approach

Careful clinical evaluation is very important. Often no family history can be obtained, either because a case is sporadic, or because less severely affected relatives have not been diagnosed. Clinical examination and targeted neurophysiologic and genetic testing may reveal relatives to be also affected by hereditary neuropathies.

In patients with suspected neuropathies, the initial investigation will generally be nerve conduction studies and electromyography (Fig. 71-3). CMT is classified as demyelinating if the median nerve motor conduction velocity (MCV) is less than 38 m/s, or axonal (CMT2) if the median MCV is more than 38 m/s. Axonal (neuronal) neuropathies are also associated with low-amplitude sensory and motor responses. Intermediate forms of CMT have median MCVs in the 25–45 m/s range. In the hereditary demyelinating neuropathies, neurophysiologic abnormalities are generally homogeneous, with uniform slowing of motor and sensory nerve conduction. In contrast, the acquired demyelinating neuropathies (such as Guillain–Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy) are characterized by patchy involvement of peripheral nerves with focal slowing, conduction block, and dispersion of motor responses (Fig. 71-4).

Figure 71-3 Classification of Charcot–Marie–Tooth Disease.

Figure 71-4 Neurophysiologic and Pathologic Findings in Charcot–Marie–Tooth Type IA.

CMT can be inherited in an autosomal dominant, autosomal recessive, or X-linked fashion. Many “sporadic” patients have (new) heterozygous mutations in a gene for an autosomal dominant form of CMT. Others have autosomal recessive CMT. In Western populations, about 90% of cases of CMT are either autosomal dominant or X-linked. Recessive CMT is more frequent in populations in which consanguinity is common.

Genetic testing is available for the more common forms of CMT, but for less common phenotypes is often performed only on a research basis. Specific genetic diagnoses enable evaluation of relatives, prognostication and prediction of recurrence risk, and antenatal testing. Classification and clinical assessment are complicated by the fact that a single phenotype is often caused by different genes, and that mutations in a gene may present with a variety of phenotypes (see Fig. 71-3).

Testing for neuropathies associated with inborn errors of metabolism is based on the clinical and neurophysiologic phenotype. Careful attention needs to be paid to other clinical findings that may guide diagnosis, such as cognitive deficits, vision or hearing loss, evidence of other organ dysfunction, and abnormalities on neuroimaging and biochemical investigations.

Classification of Cmt

CMT Type 1

Autosomal dominant demyelinating CMT—CMT type 1—is the most common form of CMT in most populations. Five genes for CMT1 are known (Table 71-2). Most patients present with the “classical” CMT phenotype in the first two decades of life, with a steppage gait, frequent falls, and development of pes cavus. Distal sensory loss is generally mild. There is marked slowing of motor conduction (<38 m/s), and sensory nerve action potentials (SNAPs) are generally lost. Nerve biopsy is usually not required for diagnosis, but if performed shows a hypertrophic demyelinating neuropathy with onion bulb formation. The most common form, CMT1A, is caused by duplications in the peripheral myelin protein 22 gene on chromosome 17. Deletions in the same gene cause hereditary neuropathy with liability to pressure palsies (HNPP), which presents with recurrent mononeuropathies after minor compressive stresses. Other forms of CMT1 are very uncommon. Genes implicated in CMT type 1 can also cause Déjerine–Sottas syndrome, a severe demyelinating neuropathy that presents before the age of 2 years.

Table 71-2 Dominant Demyelinating Forms of CMT (CMT type 1)

CMT Type 2

Axonal forms of CMT—CMT type 2—are relatively uncommon and can be difficult to distinguish from sporadic axonal neuropathies. CMT2 has been linked to at least 13 loci and 10 genes (Table 71-3). The most common form, CMT2A, is caused by mutations in the gene for a mitochondrial fusion protein, mitofusin 2 (MFN2). Mutations in MFN2 can cause the classic CMT phenotype or can be associated with early-onset severe weakness, long-tract signs, and/or optic atrophy. Other forms of type 2 CMT may be associated with prominent sensory loss and a mutilating arthropathy, early involvement of the distal upper extremities, and pyramidal signs.

Table 71-3 Dominant Axonal Forms of CMT (CMT type 2)