NeuroCAST - Sessions

Athena's New CMT Type 2 Assays
Charcot-Marie-Tooth disease (CMT) is the most commonly inherited form of peripheral neuropathy with an overall prevalence in the general population of 30 per 100,000.¹ It is characterized by symmetrical, progressive weakness, atrophy of the distal muscles, and mild sensory loss.² The disease is divided into two subcategories: CMT type 1 (CMT1) or myelinopathies, and CMT type 2 (CMT2) or axonopathies. CMT1 is typically the demyelinating form of the disease and presents with slow nerve conduction velocities (NCVs). It is caused by mutations in myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), connexin32 (Cx32), and early growth response gene 2 (EGR2). By contrast, CMT2 is an axonal peripheral neuropathy. NCVs are typically normal or near-normal and EMG testing demonstrates positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses.¹

CMT2 is usually inherited in an autosomal dominant fashion (meaning there is a 50% chance that the children of an individual with a CMT mutation will be affected with the disorder). CMT2E is currently the only genetically identified form of primary axonopathy (CMT2) and results from a missense mutation (a mutation that causes substitution of one amino acid for another, resulting in a different sequence) in the neurofilament light gene (NF-L, NEFL) on chromosome 8p21.³

Because of overlapping clinical symptoms with other inherited peripheral neuropathies, CMT may be challenging to diagnose. In fact, CMT2 may be difficult to distinguish from other forms of CMT, such as CMT1, CMTX, and chronic idiopathic axonal neuropathy.¹ For example, the CMT2 phenotype of mildly slowed NCVs can be caused by a mutation in MPZ, which typically causes CMT1B. Additional confusion among HMSNs can be caused by the CMT2 phenotype seen in families with CMTX, where no male-to-male-transmission is observed. Electrophysiologically, the nerve conduction studies of CMT2 and CMTX are typically normal compared to slow NCVs in CMT1, a demyelinating neuropathy.⁴ Therefore, an overlap in symptoms between CMT2 and CMTX can result in a challenging diagnosis, especially when the phenotypes and electrophysiological findings can be so similar. A genetic test can help clarify the diagnosis and provide the most accurate information about a patient's CMT type.

Two leading CMT research groups have generously contributed case studies of families with CMT2 caused by the neurofilament light gene mutation. These families demonstrate the clinical presentation and genotype of CMT2.

The overlapping symptoms seen in patients with peripheral neuropathies (see chart below) can make definitive identification of the disorder's etiology difficult. Molecular diagnostic assays for CMT1 and CMT2 can: help confirm a suspected clinical diagnosis, help in assigning risks for developing the disease or passing on the abnormal gene to family members, enable appropriate genetic counseling, and lead to more informed patient management. CMT experts emphasize:

Our data suggest that patients and families that are diagnosed as CMT1 should also be screened for mutations in the NF-L [NEFL] gene once mutations in the CMT1 genes have been excluded.³

		Your understanding of the disease or condition
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