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Charcot-Marie-Tooth Hereditary Neuropathy Overview

[CMT]

Summary

Disease characteristics. Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy. The affected individual typically has distal muscle weakness and atrophy often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet.

Diagnosis/testing. The genetic neuropathies need to be distinguished from the many causes of acquired (non-genetic) neuropathies. Clinical diagnosis is based on family history and characteristic findings on physical examination, EMG/NCV testing, and occasionally sural nerve biopsy. At least 40 different genes/loci are associated with CMT. Molecular genetic testing is available on a clinical basis for some types of CMT.

Management.  Treatment of manifestations: management by a multidisciplinary team of neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists; special shoes and/or ankle/foot orthoses (AFOs) to correct foot drop and aid walking; gripping exercises for hand weakness; orthopedic surgery as needed for severe pes cavus deformity and hip dysplasia; acetaminophen or nonsteroidal anti-inflammatory agents for musculoskeletal pain; tricyclic antidepressants, carbamazepine or gabafpentin for neuropathic pain. Prevention of secondary complications: daily heel cord stretching exercises. Agents/circumstances to avoid: drugs and medications such as vincristine, taxol, cisplatin, isoniazid, and nitrofurantoin that are known to cause nerve damage; obesity as it makes walking more difficult.

Genetic counseling. CMT hereditary neuropathy syndrome can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of  inheritance in each family, and results of molecular genetic testing. Prenatal  testing for pregnancies at increased risk is possible for some types of CMT if the disease-causing mutation(s) in the family is/are known.

Definition

Clinical Manifestations

Charcot-Marie-Tooth (CMT) hereditary neuropathy (also called hereditary motor/sensory neuropathy [HMSN]) results from involvement of peripheral nerves that can affect the motor system and/or the sensory system. Individuals with CMT experience symmetric, slowly progressive distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands. Pes cavus foot deformity is common.

Although usually described as "painless," the neuropathy of CMT can be painful [Carter et al 1998].

Other findings can include hearing loss and hip dysplasia, which may be an under-recognized manifestation of CMT [McGann & Gurd 2002].

Establishing the Diagnosis of CMT

Progressive weakness of the distal muscles in the feet and/or hands is evident on medical history.

Individuals with typical CMT have high-arched feet, weak ankle dorsiflexion, thin distal muscles, depressed tendon reflexes, and distal sensory loss.

Electrophysiologic studies (electromyography [EMG] and nerve conduction velocity [NCV]), when carefully done, are almost always abnormal [Carter et al 2004 ; Pareyson, Scaioli et al 2006].

Sural nerve biopsy is not routinely performed, but is occasionally helpful in establishing the diagnosis of CMT hereditary neuropathy because relatively characteristic lesions are found in CMT1 , leprosy, vasculitis, and amyloid neuropathy [Schroder 2006].

Differential Diagnosis of CMT

Causes of acquired peripheral neuropathy include alcoholism, vitamin B12 deficiency, thyroid disease, diabetes mellitus, HIV infection, vasculitis, leprosy, neurosyphilis, amyloid deposition associated with chronic inflammation, occult neoplasm, heavy metal intoxication, and inflammatory and immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP).

Blindness, seizures, dementia, and mental retardation are not part of the CMT hereditary neuropathy phenotype and suggest a different diagnosis.

Autosomal dominant disorders with neuropathy

• Familial brachial plexus neuropathy (hereditary neuralgic amyotrophy).  Affected individuals have sudden onset of pain and weakness in the shoulder or upper arm associated with distal and/or proximal weakness and atrophy of the upper extremity. Associated sensory loss may occur. Onset frequently occurs in childhood but can occur at any age. Partial or full recovery is typical. The syndrome may recur in the same or opposite limb and occasionally in the lower extremity. In some families, associated clinical features include short stature, ocular hypotelorism, cleft palate, epicanthal folds, facial asymmetry, and partial syndactyly [Jeannet et al 2001]. Mutations in the SEPT9 gene are causative [Kuhlenbaumer et al 2005].

• Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by the acute onset of recurrent, painless, focal sensorimotor neuropathy in a single nerve [Kumar et al 2002]. Deletion of one PMP22 gene is causative.

• Amyloid neuropathies, including transthyretin-associated amyloidosis , result in progressive accumulation of amyloid protein in peripheral nerves [Lynch & Chance 1997].

Autosomal recessive disorders with neuropathy

• Refsum disease

• Metachromatic leukodystrophy

• Krabbe disease

X-linked recessive disorders with neuropathy

• Adrenomyeloneuropathy

• Pelizaeus-Merzbacher disease

• Lowe syndrome

Hereditary ataxias with neuropathy.  Friedreich ataxia may present with sensory loss, depressed tendon reflexes, and high-arched feet.

Other hereditary ataxias sometimes have an associated peripheral neuropathy (see Ataxia Overview).

Hereditary motor neuropathies (HMN) are associated with distal weakness without sensory loss [Irobi et al 2004 , Auer-Grumbach et al 2005].

CMT syndrome with spasticity.  Some individuals with distal muscle atrophy and weakness may have signs of spasticity with brisk tendon reflexes and/or Babinski responses. This set of findings has been called HMSN V and sometimes overlaps with hereditary motor neuropathy (HMN).

One type is associated with mutations in BSCL2 (see BSCL2-Related Neurologic Disorders) and another with mutations in SPG20, the gene encoding spartin (see Troyer Syndrome .

See also Hereditary Spastic Paraplegia Overview .

Hereditary sensory neuropathies (HSN).  Several autosomal dominant axonal neuropathies have primarily sensory symptoms (one family is described as having "burning feet syndrome" [Stogbauer et al 1999]), and are classified as hereditary sensory neuropathies (HSNs) [Auer-Grumbach et al 2003]. Distal weakness may also occur.

Distal myopathies.  See Table 1 .

Mitochondrial disorders associated with peripheral neuropathy

• NARP (neuropathy, ataxia, and retinitis pigmentosa): A mitochondrial disorder caused by mutations in mitochondrial DNA (mtDNA)

• MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) [Said et al 2005].

Prevalence

Charcot-Marie-Tooth (CMT) hereditary neuropathy is the most common genetic cause of neuropathy. Prevalence is about 1:3,300.

Approximately 20% of all individuals presenting to neuromuscular clinics with a chronic peripheral neuropathy have CMT1A.

Causes

Single-Gene Causes

The classification used in this GeneReview is based on inheritance patterns and molecular genetics (see Table 2). However, classification is especially difficult when different mutations in a single gene are associated with both autosomal dominant and autosomal recessive inheritance, and/or both axonal and demyelinating neuropathy.

Vance (2000) suggested a similar classification system that differs slightly, with CMT3 referring to axonal presentations that are autosomal recessive and CMT4 referring to demyelinating presentations that are autosomal recessive.

Other valid classification systems may emphasize electrophysiologic characteristics such as nerve conduction velocities or pathologic findings.

The molecular genetics of CMT has been reviewed by Carter et al (2004), Kleopa & Scherer (2006), Houlden & Reilly (2006), and Nicholson (2006), and the molecular pathogenesis has been reviewed by Zuchner & Vance (2006) and Bernard et al (2006).

Charcot Marie Tooth Type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity (typically 5-30 meters per second; normal: >40-45 m/s). It is usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually become symptomatic between ages five and 25 years. Fewer than 5% of individuals become wheelchair dependent. Life span is not shortened.

The six subtypes of CMT1 are clinically indistinguishable and are designated solely on molecular findings [Saifi et al 2003] (Table 3).

Table 3. CMT1: Molecular Genetics

Locus Name	Proportion of CMT1	Gene Symbol	Protein Product	Test Availability
CMT1A	70%-80%	PMP22	Peripheral myelin protein 22	Clinical
CMT1B	5%-10%	MPZ	Myelin P0 protein	Clinical
CMT1C	Unknown	LITAF	Lipopolysaccharide-induced tumor necrosis factor-alpha factor	Clinical
CMT1D	Unknown	EGR2	Early growth response protein 2	Clinical
CMT1E	Unknown	PMP22	Peripheral myelin protein 22	Clinical
CMT1F/2E	Unknown	NEFL	Neurofilament light polypeptide	Clinical

Charcot Marie Tooth Type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy. Nerve conduction velocities are usually within the normal range; however, occasionally they fall in the low-normal or mildly abnormal range (35-48 m/s). Peripheral nerves are not enlarged or hypertrophic.

CMT2 shows extensive clinical overlap with CMT1; however, in general, individuals with CMT2 tend to be less disabled and have less sensory loss than individuals with CMT1. A threshold of 38 m/s for median motor nerve conduction is often used clinically to distinguish CMT1 from CMT2.

CMTX1 may present with a relatively axonal form of CMT that may be confused with CMT2.

The fifteen subtypes of CMT2 are similar clinically and are distinguished by molecular genetic findings (Table 4).

Table 4. CMT2: Molecular Genetics Locus Name Proportion of CMT2 Gene Symbol Chromosomal Locus  1 Protein Product Test Availability CMT2A1 Unknown  2 KIF1B Kinesin-like protein KIF1B Clinical CMT2A2 MFN2 Mitofusin-2 Clinical CMT2B RAB7 Ras-related protein Rab-7 Clinical CMT2B1 LMNA Lamin A/C Clinical CMT2B2 Unknown 19q13.3 Unknown Research only CMT2C Unknown 12q23-q24 Unknown CMT2D GARS Glycyl-tRNA synthetase Clinical CMT2E/1F NEFL 8p21 Neurofilament light polypeptide Clinical CMT2F HSPB1 Heat-shock protein beta-1 Clinical CMT2G Unknown 12q12-q13 Unknown Research only CMT2H Unknown CMT2I MPZ Myelin P0 protein Clinical CMT2J Clinical CMT2K GDAP1 Ganglioside-induced differentiation-associated protein-1 Clinical CMT2L HSPB8 Heat-shock protein beta-8 Clinical

1.  Chromosomal locus included only when gene is unknown 2. The frequencies of the various types of CMT2 are unknown and no single type is known to predominate [Timmerman et al 1996 , Saifi et al 2003].

Autosomal Dominant Intermediate CMT

Autosomal dominant intermediate CMT (DI-CMT) (Table 5) is characterized by a relatively typical CMT phenotype with clinical and pathologic evidence of both abnormal myelin and axonopathy. Nerve conduction velocities (NCVs) overlap those observed in CMT1 and CMT2 [Nicholson & Myers 2006]. Motor NCVs usually range between 25 and 50 m/sec.

Charcot-Marie-Tooth type 4 (CMT4) is a group of progressive motor and sensory axonal and demyelinating neuropathies. It is distinguished from other forms of CMT by autosomal recessive inheritance (see Table 6). Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity.

Note: The term Dejerine-Sottas syndrome (DSS) was originally described as a severe demyelinating neuropathy of infancy and childhood associated with very slow NCV, elevated CSF protein, marked clinical weakness, and hypertrophic nerves with onion bulb formation. Inheritance of DSS was assumed to be autosomal recessive. Subsequently, individuals with this clinical diagnosis have had various types of autosomal recessive CMT (CMT4) and have been heterozygous for point mutations in genes associated with CMT1 including: PMP22 (CMT1A), MPZ (CMT1B), and EGR2 (CMT1D) [Boerkoel, Takashima, Bacino et al 2001 ; Boerkoel, Takashima, Stankiewicz et al 2001].

Although the term DSS is still sometimes used to indicate a clinical phenotype, it does not imply an inheritance pattern or a specific genetic defect [Parman et al 2004].

Table 6. CMT 4: Molecular Genetics Locus Name Proportion of CMT4 Gene Symbol Protein Product Test Availability CMT4A Unknown GDAP1 Ganglioside-induced differentiation-associated protein 1 Clinical CMT4B1 MTMR2 Myotubularin- related protein 2 Research only CMT4B2 SBF2 Myotubularin-related protein 13 CMT4C SH3TC2 SH3 domain and tetratricopeptide repeats-containing protein 2 CMT4D NDRG1 Protein NDRG1 Clinical CMT4E  1 EGR2 Early growth response protein 2 Clinical CMT4F  1 PRX Periaxin Clinical

1. Tentative name

X-Linked CMT

Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is characterized by a moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families (see Table 7).

Four other forms of hereditary neuropathy have been linked to the X chromosome. None of the genes has been identified. Associated findings are [Huttner et al 2006]:

• CMTX2. Mental retardation [Ionasescu et al 1991 , Ionasescu et al 1992]
• CMTX3. Spasticity and pyramidal tract signs [Ionasescu et al 1991 , Ionasescu et al 1992 , Huttner et al 2006]
• CMTX4 (Cowchock syndrome). Deafness and mental retardation [Cowchock et al 1985 , Priest et al 1995]
• CMTX5. Deafness and optic neuropathy [Kim et al 2005]

Table 7. CMTX: Molecular Genetics Disease Name Proportion of X-Linked CMT Gene Symbol Chromosomal Locus  1 Protein Product Test Availability CMTX1 90% GJB1 Gap junction beta-1 protein (connexin 32) Clinical CMTX2 Unknown Xp22.2 Research only CMTX3 Xq26 CMTX4/Cowchock syndrome Xq24-q26.1 CMTX5 Xq21.3-q24

1. Chromosomal locus included only when gene is unknown

Evaluation Strategy

Establishing the specific cause of Charcot-Marie-Tooth (CMT) hereditary neuropathy for a given individual involves a medical history, physical examination, neurologic examination, and nerve conduction and EMG testing, as well as a detailed family history and the use of molecular genetic testing when available.

Family history.  A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or through review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Individuals with CMT may have a negative family history for many reasons, including mild subclinical expression in other family members, autosomal recessive inheritance, or a de novo (new) mutation for a dominant gene.

• About one-third of individuals with identifiable point mutations in PMP22, GJB1, or MPZ causing the CMT hereditary neuropathy phenotype have de novo mutations, and thus present as simplex cases (i.e., a single occurrence in a family) [Boerkoel et al 2002].
• PMP22 duplications (which are much more common than point mutations) occur as de novo mutations in about 10%-20% of people with CMT1 [Blair et al 1996 , Bort et al 1997].

Physical examination.  In individuals who have no family history of neuropathy, the first step is to exclude acquired causes of neuropathy by standard neurologic evaluation (see Differential Diagnosis).

Distal weakness, sensory loss, depressed tendon reflexes, and foot deformity are commonly (but not always) present.

In CMT1, the most common CMT subtype, NCVs are very slow and peripheral nerves may be palpably enlarged. This is not true of CMT2 or CMTX.

Molecular genetic testing.  Molecular genetic testing is presently available on a clinical basis for mutations in numerous genes associated with similar phenotypes. (see Table 3 , Table 4 , Table 5 , Table 6 , Table 7). Note: Failure to identify a disease-causing mutation in a proband does not rule out a diagnosis of CMT since undetected mutations in other genes may be causative.

The following testing strategy may provide the most efficient and cost-effective approach to testing [Saifi et al 2003 , Klein & Dyck 2005 , Szigeti et al 2006]. However, it should be noted that some clinical laboratories may group tests into 'panels', which may be less expensive than sequential testing of individual genes if more than two or three genes are analyzed.

Positive family history

• In families with at least two-generation involvement, known male-to-male transmission, and slow NCV, testing for the PMP22 duplication (CMT1A) should be obtained first, and then, if normal, followed by testing of MPZ (CMT1B).
• In families with at least two-generation involvement and slow NCV, but without male-to-male transmission, molecular genetic testing of PMP22 (CMT1A), MPZ (CMT1B), LITAF (CMT1C), and GJB1 (CMTX) should be performed sequentially.
• In families with probable X-linked inheritance of the CMT phenotype, molecular genetic testing of GJB1 (CMTX) is appropriate to confirm the diagnosis.
• In individuals with the CMT2 phenotype, MFN2 can be tested first followed by testing of MPZ and GJB1.
• Families with early-onset CMT in which only sibs are affected may have autosomal recessive CMT and can be tested for mutations in GDAP1, EGR2, and PDX.

Negative family history

• Molecular genetic testing of PMP22dup (CMT1A), MPZ (CMT1B), and GJB1 (CMTX) should all be performed on males and females who have no family history of neuropathy because de novo duplications of the 17p11 region occur often, giving rise to CMT1A, and because females who have a GJB1 mutation causing CMTX1 may be asymptomatic.
• Early-onset severe CMT may be caused by point mutations in PMP22 (CMT1A),