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Overview of hereditary neuropathies

Overview of hereditary neuropathies
Author:
Peter B Kang, MD, FAAP, FAAN
Section Editors:
Jeremy M Shefner, MD, PhD
Douglas R Nordli, Jr, MD
Deputy Editor:
Richard P Goddeau, Jr, DO, FAHA
Literature review current through: Oct 2022. | This topic last updated: Jul 30, 2021.

INTRODUCTION — The hereditary peripheral neuropathies have been classified based upon clinical characteristics, mode of inheritance, electrophysiologic features, metabolic defect, and subsequently upon specific genetic loci. The primary hereditary neuropathies predominantly or exclusively affect peripheral nerves and produce symptoms of peripheral nerve dysfunction. Other hereditary neuropathies affect both the central and peripheral nervous systems and, in some cases, other organs; in such patients, symptoms related to the peripheral neuropathy may be overshadowed by other manifestations of the disease.

This topic will provide an overview of the hereditary neuropathies. Detailed discussions are found separately. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis" and "Hereditary sensory and autonomic neuropathies" and "Neuropathies associated with hereditary disorders".)

CLASSIFICATION — Historically, the primary hereditary neuropathies were designated by eponyms that had the connotation of specific clinical features (eg, Charcot-Marie-Tooth [CMT] disease or Dejerine-Sottas disease). However, phenotypic variability resulted in substantial diagnostic confusion. What became known as the Dyck classification was proposed in 1968, based upon clinical and electrophysiologic features [1], and the inherited neuropathies with primarily motor and sensory manifestations became known as the hereditary motor sensory neuropathies (HMSNs). However, the popularity of the CMT eponym for the HMSNs has had a resurgence since the 1990s, especially as a more comprehensive classification tree based on associated genes has been built upon the original broad CMT categories that were based largely on inheritance patterns and neurophysiology.

Many of the primary hereditary neuropathies are divided into motor-sensory (CMT) and sensory-autonomic neuropathies.

The motor-sensory category was subdivided into types 1 through 7 and the sensory neuropathies into types 1 through 5. Many of these types were further divided into subcategories.

Additional primary inherited neuropathies not included in this classification include hereditary neuropathy with pressure palsy, hereditary brachial plexopathy, and giant axonal neuropathy. The molecular defects in many of the inherited neuropathies have been identified.

The accelerating pace of genetic discoveries has identified a broadening phenotypic spectrum associated with specific genetic pathogenic variants and revealed an increasing degree of genetic heterogeneity and clinical overlap among the major categories of inherited neuropathies [2,3]. As an example, a pathogenic variant in the KIF5A gene can cause either an isolated axonal neuropathy (CMT2) phenotype or a type of hereditary spastic paraplegia (HSP) characterized by leg spasticity and weakness due to upper motor neuron involvement and often associated with an axonal neuropathy [2,4]. (See "Hereditary spastic paraplegia", section on 'Autosomal dominant HSP'.)

As genetic discoveries continue to unfold, traditional classifications of hereditary neurologic diseases are likely to be superseded by classifications based primarily upon the underlying genetic cause.

CHARCOT-MARIE-TOOTH DISEASE — Charcot-Marie-Tooth (CMT) disease is reviewed here briefly and discussed in detail elsewhere. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)

CMT is really a spectrum of disorders caused by specific pathogenic variants in genes that are typically expressed in myelin and/or axons. The vast majority of CMT cases are associated with pathogenic variants in one of four genes: PMP22, MPZ, GJB1, and MFN2 [5]. The clinical expression of these conditions is often affected by "gene dosage imbalance" caused by DNA duplications or deletions, as is the case in the most common form of CMT (ie, CMT1A caused by PMP22 gene duplications). The association of different pathogenic variants within the same gene with various clinical phenotypes is a common finding in the HMSN/CMT group of peripheral neuropathies. This variability suggests that these disorders represent a spectrum of related phenotypes caused by an underlying defect in peripheral nervous system myelination and/or axonal function.

CMT has been classified as types 1 through 7 and consists of at least 30 disorders that are distinguished by clinical, neurophysiologic, and genetic factors. The majority of cases fall within type 1 (autosomal dominant inheritance, demyelinating physiology) and type 2 (autosomal dominant inheritance, axonal physiology), with an estimated prevalence of 40 per 100,000. Common features include both motor and sensory nerve manifestations with distal leg weakness, foot deformities (pes cavus, hammer toes), and sensory deficits (table 1).

A unique feature observed in some patients with X-linked CMT type 1 (CMTX1) involves transient episodes of dysarthria, ataxia, hemiparesis, or tetraparesis, associated with similarly transient white matter lesions in the brain [6]. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'CMTX1'.)

Hereditary neuropathy with liability to pressure palsy — Hereditary neuropathy with liability to pressure palsy (HNPP, tomaculous neuropathy) is a recurrent, episodic demyelinating neuropathy (table 2) associated with PMP22 deletions and single nucleotide variants (SNVs) that is allelic to Charcot-Marie-Tooth disease type 1A (CMT1A). (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'Hereditary neuropathy with liability to pressure palsy'.)

Affected patients typically present with isolated nerve palsies with localization in areas frequently affected by compression or trauma. The most frequently affected nerves include the axillary, median, radial, ulnar, peroneal, or brachial plexus nerves. Other findings include cranial nerve involvement, nerve deafness, and scoliosis.

Symptoms first appear in the second decade in most patients, but they can occur in younger children or be delayed into the third decade. Single nerve palsies typically appear sequentially, resolving in days to months, and may be associated with persistent motor deficits in the same or in another distribution.

HNPP is an autosomal dominant disorder. In approximately 80 percent of HNPP cases, there is a 1.5 Mb deletion in chromosome 17p11.2 that results in reduced expression of the PMP22 gene. The deletion corresponds to the duplicated region of PMP22 present in CMT1A (see "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'CMT1A'). Approximately 20 percent of patients with HNPP have SNVs or small deletions in the PMP22 gene, and sporadic cases with de novo deletions have been described.

HEREDITARY BRACHIAL PLEXOPATHY — Hereditary brachial plexopathy (MIM 162100), also known as hereditary neuralgic amyotrophy (HNA), is reviewed here briefly and discussed in detail separately. (See "Brachial plexus syndromes", section on 'Hereditary brachial plexopathy'.)

Hereditary brachial plexopathy is a rare autosomal dominant disorder characterized by recurrent, painful brachial plexopathies. The condition is caused by pathogenic variants in the SEPT9 gene. Hereditary brachial plexopathy is distinct from hereditary neuropathy with predisposition to pressure palsies (HNPP) discussed above (table 2). Childhood onset of hereditary brachial plexopathy is not unusual. Many patients exhibit a relapsing-remitting course characterized by attacks that resolve spontaneously, either completely or incompletely, leaving additive residual weakness. The disorder can also follow a progressive pattern. Physical exertion and pregnancy are reported triggering events.

Attacks are heralded by pain and paresthesias, followed by paresis of the shoulder and arm. While any nerve in the brachial plexus can be involved, injury to the upper part of the brachial plexus is most frequent. Characteristic somatic features of hereditary brachial plexopathy include short stature, hypotelorism, a small face, unusual skin folds, and creases on the neck.

HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES — Hereditary sensory and autonomic neuropathies (HSANs) are discussed here briefly and reviewed in detail elsewhere. (See "Hereditary sensory and autonomic neuropathies".)

The HSANs occur much less frequently than do the primary hereditary motor sensory neuropathies. The major feature of these conditions is loss of large myelinated and unmyelinated fibers. They have been categorized into types 1 through 8, though there are multiple subtypes for some of these, leading to a total of at least 15 associated genes [7]. Some children do not fit well into the classification scheme (table 3). The five classic types are as follows:

HSAN type 1 is the most common form of HSAN and is inherited as an autosomal dominant disorder in most cases. It is characterized by degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness. Bone necrosis and spontaneous distal amputation can occur. Symptoms may begin in early childhood but can be delayed until the third decade. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN1'.)

The symptoms in HSAN type 2 are caused also by loss of pain, temperature, pressure and touch sensation with large and small fiber sensory involvement. Fractures and recurrent infections of the digits occur in early childhood, and mutilation of the fingers and toes occurs as the disease progresses. A stable, nonprogressive congenital form also has been recognized. HSAN2 is inherited in a recessive manner. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN2'.)

HSAN type 3 is more commonly known as Riley-Day syndrome or familial dysautonomia. This recessive disorder is a progressive sensorimotor neuropathy, but sympathetic autonomic dysfunction is responsible for most clinical manifestations. Neuropathic symptoms include loss of reflexes, hypotonia, and decreased perception of pain and temperature. Sympathetic symptoms include orthostatic hypotension, swallowing dysfunction, gastrointestinal motility dysfunction, bladder dysfunction, decreased or absent tearing, pupil dilation, decreased sweating (leading to defective temperature dysregulation), and blotchy skin. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN3 (Familial dysautonomia)'.)

HSAN type 4, also called congenital insensitivity to pain with anhidrosis (CIPA), is an autosomal recessive disorder. Symptoms begin early in infancy and prominent features include profound loss of pain sensitivity, leading to injuries, self-mutilation, and osteomyelitis, episodic hyperthermia that can be associated with seizures, and mild to moderate intellectual disability. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN4'.)

Patients with HSAN type 5 disease have loss of pain and temperature sensation, but other sensation is preserved. It is an autosomal recessive disorder. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN5'.)

GIANT AXONAL NEUROPATHY — Giant axonal neuropathy (GAN; also called giant axonal neurodegeneration) is a severe neurodegenerative disorder of the peripheral and central nervous system that becomes clinically apparent in early childhood [8,9]. It is transmitted as an autosomal recessive trait [10]. The disease locus maps to 16q24.1 [11], and the mutated GAN gene encodes for a cytoskeletal protein called gigaxonin [12]. Abnormal gigaxonin is presumed to be responsible for the generalized disorganization of cytoskeletal intermediate filaments [12-15].

Affected children present with a gait disturbance and frequent falls caused by muscle weakness and ataxia [9]. There is a mixed motor sensory polyneuropathy with associated predominantly distal limb weakness [16,17]. A characteristic physical appearance is a hallmark of the disorder. The hair tends to be red and tightly curled, the forehead high, the complexion pale, and eyelashes long. Manifestations of central nervous system involvement include cerebellar dysfunction (eg, ataxia, dysmetria, oculomotor apraxia, and nystagmus), spasticity, and optic atrophy [18,19]. Intellectual disability occurs in some cases. Progressive gait deterioration occurs, with death usually by the third decade, most often due to respiratory failure [9]. A milder form of the disease resembling Charcot-Marie-Tooth disease has also been described [20].

Nerve conduction studies are consistent with an axonal neuropathy. Electroencephalograms, visual evoked potentials, and somatosensory evoked responses may be abnormal [9,19]. In some cases, brain magnetic resonance imaging (MRI) is normal [9], while in other cases MRI demonstrates subcortical, periventricular and cerebellar white matter lesions [16].

The diagnosis is suggested by findings on nerve biopsy and confirmed by genetic testing for pathogenic variants in the GAN gene [9]. Nerve biopsy shows axonal loss and distortion of fibers by giant axonal swellings filled with densely packed bundles of neurofilaments [14,21,22]. Similar filaments are seen in other tissues such as Schwann cells, fibroblasts, and vascular endothelium, findings that are consistent with a defect in intermediate filament organization [14]. Neuropathologic findings include degeneration of central tracts [9]. Cerebral white matter shows leukoencephalopathy, and the cerebellum and optic tracts show atrophy with gliosis.

NEUROPATHIES ASSOCIATED WITH GENERALIZED DISORDERS — A number of generalized hereditary disorders are associated with neuropathy. Many of these disorders affect both the central and peripheral nervous systems and, in some cases, other organs. Symptoms related to the peripheral neuropathy may be overshadowed by other manifestations of the disease. A partial list of these disorders includes infantile neuroaxonal dystrophy, Tangier disease, abetalipoproteinemia, Refsum disease, Chediak-Higashi syndrome, and hereditary tyrosinemia.

In addition, neuropathy is associated with a number of lysosomal storage diseases (eg, Fabry disease, Krabbe disease, metachromatic leukodystrophy, Niemann-Pick disease), mitochondrial disorders (eg, Leigh syndrome, Leber hereditary optic neuropathy), and DNA repair disorders (eg, xeroderma pigmentosum, Cockayne syndrome).

The neuropathies associated with these generalized metabolic disorders are discussed separately. (See "Neuropathies associated with hereditary disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Charcot-Marie-Tooth disease (The Basics)")

SUMMARY

Charcot-Marie-Tooth disease – Charcot-Marie-Tooth disease (CMT; also known as hereditary motor and sensory neuropathy) is a spectrum of disorders caused by pathogenic variants in genes that are expressed in myelin and/or axons. The vast majority of CMT cases are associated with pathogenic variants in one of four genes: PMP22, MPZ, GJB1, and MFN2. CMT has been classified as types 1 through 7 and includes at least 30 different disorders (table 1). (See 'Charcot-Marie-Tooth disease' above.)

The most common subtypes are CMT1 and CMT2, which together are the most frequent hereditary peripheral neuropathies. Shared features of CMT1 and CMT2 include both motor and sensory nerve manifestations with distal leg weakness, foot deformities (pes cavus, hammer toes), and sensory deficits.

Hereditary neuropathy with liability to pressure palsy – Hereditary neuropathy with liability to pressure palsy (HNPP), a recurrent, episodic demyelinating neuropathy (table 2), is allelic to CMT1A. Affected patients typically present with isolated nerve palsies in areas frequently affected by compression or trauma including the axillary, median, radial, ulnar, peroneal, or brachial plexus nerves. Single nerve palsies typically appear sequentially, resolving in days to months, and may be followed by persistent motor deficits in the same or in another distribution. (See 'Hereditary neuropathy with liability to pressure palsy' above.)

Hereditary brachial plexopathy – Hereditary brachial plexopathy is a rare autosomal dominant disorder characterized by recurrent, painful brachial plexopathies (table 2). Attacks may be triggered by physical exertion and are heralded by pain and paresthesias, followed by paresis of the shoulder and arm. Many patients exhibit a relapsing-remitting course characterized by attacks that resolve spontaneously, either completely or incompletely, leaving additive residual weakness. (See 'Hereditary brachial plexopathy' above.)

Hereditary sensory autonomic neuropathies – Hereditary sensory autonomic neuropathies (HSANs) are a rare group of conditions characterized by degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness. Bone necrosis and spontaneous distal amputation can also occur. They have been categorized into types 1 through 8, although some children do not fit well into this classification (table 3). (See 'Hereditary sensory and autonomic neuropathies' above.)

Giant axonal neuropathy – Giant axonal neuropathy is a severe neurodegenerative disorder of the peripheral and central nervous system that becomes clinically apparent in early childhood. Affected children present with a gait disturbance and frequent falls caused by muscle weakness and ataxia. A characteristic physical appearance is a hallmark; the hair tends to be red and tightly curled, the forehead high, the complexion pale, and eyelashes long. Progressive gait deterioration occurs, with death usually by the third decade. (See 'Giant axonal neuropathy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert P Cruse, DO, who contributed to earlier versions of this topic review.

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