Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies - CAM 299HB
Description
The inherited peripheral neuropathies are a heterogeneous group of diseases that may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner. The inherited peripheral neuropathies can be divided into hereditary motor and sensory neuropathies (such as Charcot-Marie-Tooth disease), hereditary neuropathy with liability to pressure palsies, hereditary sensory and autonomic neuropathies, and other miscellaneous types (e.g., hereditary brachial plexopathy, giant axonal neuropathy). In addition to clinical presentation, nerve conduction studies, and family history, genetic testing can be used to diagnose specific inherited peripheral neuropathies (Kang, 2023a).
When pursuing genetic testing for inherited peripheral neuropathies, genetic counseling is strongly recommended.
Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.
- For individuals with clinical features of Charcot-Marie-Tooth (CMTA) disease, but for whom a definitive diagnosis cannot be made without genetic testing, genetic testing for PMP22 deletions/duplication, GJB1 mutations, and/or MFN2 mutations is considered MEDICALLY NECESSARY.
- For individuals with clinical features of CMT disease who have tested negative for common deleterious variants (PMP22 deletions/duplication; GJB1 or MFN2 mutations), single gene or multi-gene panel testing for CMT disease risk genes is considered MEDICALLY NECESSARY.
- For asymptomatic individuals who have a close blood relative (see Note 1) with a known deleterious mutation in a CMT gene, genetic testing for the known familial mutation is considered MEDICALLY NECESSARY.
- For individuals who are clinically suspected of having hereditary neuropathy with liability to pressure palsies (HNPP), but for whom a definitive diagnosis cannot be made without genetic testing, genetic testing for PMP22 deletions and duplications is considered MEDICALLY NECESSARY.
- For individuals who are clinically suspected of having hereditary motor neuropathy (HMN), but for whom a definitive diagnosis cannot be made without genetic testing, genetic testing for BSCL2 mutations is considered MEDICALLY NECESSARY.
NOTES:
Note 1: Close blood relatives include 1st-degree relatives (e.g., parents, siblings, and children), 2nd-degree relatives (e.g., grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings), and 3rd-degree relatives (great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins).
Note 2: For 2 or more gene tests being run on the same platform, please refer to CAM 235 Laboratory Guideline Policy.
Rationale
Peripheral neuropathies encompass the set of disorders that primarily lead to peripheral nerve dysfunction. Symptoms typically include weakness of muscles at extremities, spine curvature, and loss of sensation at extremities (Kang, 2024c; UpToDate, 2024). Neuropathies may be caused by a variety of different factors, such as metabolic issues (including Fabry disease, Niemann-Pick disease, et al.) or present as a secondary symptom to another condition (such as Tangier disease) (Kang, 2024c).
Charcot-Marie-Tooth (CMTA) disease, also known as hereditary motor sensory neuropathy, is a group of progressive disorders that affect the peripheral nerves. CMT is caused by a mutation in one of several myelin genes that result in defects in myelin structure, maintenance, or function within peripheral nerves. Charcot-Marie-Tooth disease is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people in the United States (Kang, 2024a).
Symptoms
The neuropathy of CMT affects both motor and sensory nerves. Symptoms usually start in childhood and have a gradual progression. The severity of symptoms varies greatly among individuals and even among family members with the disease and gene mutation (Bird, 2023; NINDS, 2007, 2023). Typical symptoms include the following:
- “Weakness or paralysis of the foot and lower leg muscles, which can cause difficulty lifting the foot (foot drop)
- A high-stepped gait with frequent tripping or falling
- Balance problems
- Foot deformities, such as high arches and curled toes (hammertoes)
- Lower legs may take on an "inverted champagne bottle" shape due to the loss of muscle bulk
- Reduced ability to feel heat, cold, and touch
- Weakness and atrophy may occur in the hands, causing difficulty with fine motor skills
- Decreased sense of vibration and position (proprioception)
- Curvature of the spine (scoliosis)
- Hip displacement
- Contractures (chronic shortening of muscles or tendons around joints)
- Muscle cramping
- Nerve pain” (NINDS, 2023)
Pain can range from mild to severe, and some people may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Some people living with CMT experience tremor, and vision and hearing can also be affected. In rare cases, breathing difficulties may occur if the nerves that control the muscles of the diaphragm are affected (NINDS, 2023).
Causes
CMT is caused by mutations in genes that produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. Although different proteins are abnormal in different forms of CMT disease, all mutations affect the normal function of the peripheral nerves. There is little correlation between the genotype and phenotype of CMT; it is common to see differing mutations result in various clinical phenotypes all within the same gene (Kang, 2024a).
Pattern of Inheritance
The pattern of inheritance varies with the type of CMT disease. CMT1, most cases of CMT2, and most intermediate forms are inherited in an autosomal dominant pattern. CMT4, a few CMT2 subtypes, and some intermediate forms are inherited in an autosomal recessive pattern. CMTX is inherited in an X-linked pattern. Some cases of CMT disease result from a new mutation and occur in people with no history of the disorder in their family. In rare cases the gene mutation causing CMT disease is a new mutation which occurs spontaneously in the individual's genetic material and has not been passed down through the family (Kang, 2024a).
CMT1
Charcot-Marie-Tooth disease type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and are usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop (Bird, 2023). The six subtypes of CMT1 shown in Table 1 are clinically indistinguishable and are designated solely on molecular findings (Saporta et al., 2011)
Table 1: Molecular Genetics of CMT1 (Saporta et al., 2011)
Locus Name |
Proportion of CMT1 (excluding CMTX) |
Gene |
Protein Product |
CMT1A |
70% – 80% |
PMP22 |
Peripheral myelin protein 22 |
CMT1B |
10% – 12% |
MPZ |
Myelin protein P0 |
CMT1C |
~1% |
LITAF |
Lipopolysaccharide-induced tumor necrosis factor-alpha factor |
CMT1D |
Unknown |
EGR2 |
Early growth response protein 2 |
CMT1E |
~1% |
PMP22 |
Peripheral myelin protein 22 (sequence changes) |
CMT1F/2E |
Unknown |
NEFL |
Neurofilament light polypeptide |
Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant disease that results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP-22). Overexpression of this gene causes the structure and function of the myelin sheath to be abnormal. A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP-22 genes. In this case, abnormally low levels of the PMP-22 gene result in episodic, recurrent demyelinating neuropathy (NINDS, 2007, 2023).
Charcot-Marie-Tooth disease type 1B (CMT1B) is an autosomal dominant disease caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (P0), which is another critical component of the myelin sheath. Most of these mutations are point mutations. As a result of abnormalities in P0, CMT1B produces symptoms similar to those found in CMT1A (NINDS, 2007, 2023).
Other less common causes genetic causes of CMT1 result from mutations within LITAF, EGR2, PMP22, and NEFL genes, respectively (NINDS, 2023).
CMT2
Charcot-Marie-Tooth disease type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy. Axonal peripheral neuropathy shows extensive clinical overlap with CMT1 (Bird, 2023). In general, individuals with CMT2 tend to be less disabled and have less sensory loss than individuals with CMT1 (Bird, 2023). It is less common than CMT1. CMT2A, the most common axonal form of CMT, is caused by mutations in Mitofusin 2, a protein associated with mitochondrial fusion. Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1. Additionally, symptoms for CMT2 may have vocal cord or phrenic nerve involvement, causing speech or respiratory problems (NINDS, 2023).
Table 2: Molecular Genetics of CMT2 (Anthony Antonellis, 2018; Bird, 2023; Peter De Jonghe, 2011; Schindler, 2014; Züchner, 2013)
Locus |
Proportion of CMT |
Gene / Chromosome Locus |
Protein Product |
CMT2A1 |
Unknown |
KIF1B |
Kinesin-like protein KIF1B |
CMT2A21 |
20% |
MFN2 |
Mitofusin-2 |
CMT2B |
Unknown |
RAB7A |
Ras-related protein Rab-7 |
CMT2B1 |
Unknown |
LMNA |
Lamin A/C |
CMT2B2 |
Unknown |
MED25 |
Mediator of RNA polymerase II transcription subunit 25 |
CMT2C2 |
Unknown |
TRPV4 |
Transient receptor potential cation channel subfamily V member 4 |
CMT2D3 |
3% |
GARS |
Glycyl-tRNA synthetase |
CMT2E/1F4 |
4% |
NEFL |
Neurofilament light polypeptide |
CMT2F |
Unknown |
HSPB1 |
Heat-shock protein beta-1 |
CMT2G |
Unknown |
12q12-q13 |
Unknown |
CMT2H/2K |
5% |
GDAP1 |
Ganglioside-induced differentiation-associated protein-1 |
CMT2I/2J |
Unknown |
MPZ |
Myelin protein P0 |
CMT2L |
Unknown |
HSPB8 |
Heat-shock protein beta-8 |
CMT2N |
Unknown |
AARS |
Alanine--tRNA ligase, cytoplasmic |
CMT2O |
Unknown |
DYNC1H1 |
Cytoplasmic dynein 1 heavy chain 1 |
CMT2P |
Unknown |
LRSAM1 |
E3 ubiquitin-protein ligase LRSAM1 |
CMT2S |
Unknown |
IGHMBP2 |
DNA-binding protein SMUBP-2 |
CMT2T |
Unknown |
DNAJB2 |
DnaJ homolog subfamily B member 2 |
CMT2U |
Unknown |
MARS |
Methionine--tRNA ligase, cytoplasmic |
CMT3
Dejerine-Sottas disease (CMT3), is a severe demyelinating neuropathy that begins in infancy. Infants have severe muscle atrophy, weakness, and sensory problems. This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively (NINDS, 2023).
CMT4
Charcot-Marie-Tooth disease type 4 (CMT4) comprises several different subtypes of autosomal recessive demyelinating motor and sensory axonal neuropathies. Each neuropathy subtype is caused by a different genetic mutation, may affect a particular ethnic population, and produces distinct physiologic or clinical characteristics. Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. Several genes have been identified as causing CMT4, including GDAP1 (CMT4A), MTMR13 (CMT4B1), MTMR2 (CMT4B2), SH3TC2 (CMT4C), NDG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FDG4 (CMT4H), and FIG4 (CMT4J) (Kang, 2024a; NINDS, 2007, 2023).
Table 3: Molecular Genetics of CMT4 (Bird, 2017; Delague, 2013; Hamid Azzedine, 2015; Li, 2013)
Locus Name |
Proportion of CMT4 |
Gene |
Protein Product |
CMT4A1 |
Unknown |
GDAP1 |
Ganglioside-induced differentiation-associated protein 1 |
CMT4B1 |
MTMR2 |
Myotubularin-related protein 2 |
|
CMT4B2 |
SBF2 |
Myotubularin-related protein 13 |
|
CMT4C2 |
SH3TC2 |
SH3 domain and tetratricopeptide repeats-containing protein 2 |
|
CMT4D |
NDRG1 |
Protein NDRG1 |
|
CMT4E |
EGR2 |
Early growth response protein 2 |
|
CMT4F |
PRX |
Periaxin |
|
CMT4H3 |
FGD4 |
FYVE, RhoGEF and PH domain-containing protein 4 |
|
CMT4J4 |
FIG4 |
Phosphatidylinositol 3, 5 biphosphate |
CMTX
CMTX is caused by a point mutation in the connexin-32 gene on the X chromosome. The connexin-32 protein is expressed in Schwann cells, which wrap around nerve axons and make up a single segment of the myelin sheath (NINDS, 2007, 2023). CMTX type 1 is characterized by a moderate to severe motor and sensory neuropathy. Hearing loss and central nervous system symptoms may also occur in certain affected families (Abrams, 2020).
Table 4: Molecular Genetics of CMTX (Bird, 2023; Kim, 2013)
Disease Name |
Proportion of X-Linked CMT |
Gene / Chromosome Locus |
Protein Product |
CMTX11 |
90% |
GJB1 |
Gap junction beta-1 protein (connexin 32) |
CMTX22 |
Unknown |
Xp22.2 |
|
CMTX31 |
|
Not applicable |
|
CMTX41 |
AIFM1 |
Apoptosis-inducing factor 1 |
|
CMTX52 |
PRPS1 |
Ribose-phosphate pyrophosphokinase 1 |
|
CMTX61 |
PDK3 |
Pyruvate dehydrogenase kinase isoform 3 |
Hereditary Brachial Plexopathy (Hereditary Neuralgic Amyotrophy)
This condition is primarily characterized by painful injuries to the brachial plexus nerves as well as episodic weakness of the shoulder and arm. Other symptoms such as winging of the scapula, short stature, neck folds, small face, and hypotelorism may be present. Nerve conduction velocity is typically normal, and the histopathology of this condition is non-specific. The septin 9 gene (SEPT9) on chromosome 17 has been associated with this condition (Bromberg, 2023).
Giant Axonal Neuropathy
This condition is characterized by disorganization of cytoskeletal intermediate filaments stemming from a mutated form of gigaxonin. Patients with this disorder often have a signature physical appearance; red and kinked hair, high foreheads, long eyelashes, and pale complexions are all hallmarks of this condition. The central nervous system may be affected as well with cerebellar dysfunction, spasticity, and potentially intellectual disability as possible symptoms. Nerve biopsy may show axonal loss or another axonal dysfunction. This diagnosis is confirmed by testing of the GAN gene (Kang, 2024c).
Hereditary Sensory and Autonomic Neuropathies (HSANs)
This subsection of disorders primarily encompasses non-motor neuropathies and are characterized by major loss of myelinated and unmyelinated fibers. These conditions are not as common as hereditary motor neuropathies and primarily present with sensory dysfunction, although motor functions may be affected. There are five main types of HSAN, each caused by different genes. Genes are associated as shown below (Eichler, 2024):
Disease Name (subtype) |
Gene(s) or Locus |
Examples of symptoms |
HSAN1 (A) |
SPTLC1 |
Distal sensory loss, distal muscle wasting |
HSAN1 (B) |
3p24-p22 |
Axonal neuropathy with distal sensory impairment |
HSAN1 (C) |
SPTLC2 |
Distal sensory loss, distal muscle wasting |
HSAN1 (D) |
ATL1 |
Distal sensory loss, distal muscle wasting |
HSAN1 (E) |
DNMT1 |
Hearing loss, progressive dementia |
HSAN1 (F) |
ATL3 |
|