History of CMT DNA Testing

[Guest guest]

(This past week someone asked when the first CMT DNA test was

offered...so here's some history on the DNA test from the former CMT

News ~ Gretchen)

A new test for CMT and a bit of history (2001)

by Ulisse, Athena Diagnostics Marketing Assistant

Athena Diagnostics offered our first CMT test in 1993. Since then,

collaboration with academic and clinical researchers has allowed Athena

to develop and commercialize a comprehensive range of genetic test for

CMT, including testing for the PMP22, EGR2, MPZ, and Connexin32 genes.

Continuing in this tradition, we are pleased to announce the recent

development of testing services for the neurofilament-light gene (NF-L)

involved in Charcot-Marie-Tooth disease type 2 (CMT2). A variety of

disease-causing mutations in the NF-L gene are associated with this

axonal form of CMT. To provide a more accurate diagnosis, Athena

sequences the entire coding region of the NF-L gene in order to detect

these mutations.(1)

Historically, Charcot-Marie-Tooth disease has been divided into two

subcategories: CMT type 1 (CMT1) and CMT type 2 (CMT2) on the basis of

nerve conduction velocities (NCV). CMT1 is typically the demyelinating

form of the disease and is characterized by a considerable decrease in

motor and sensory NCVs, with an upper limit of 38 m/s for the motor NCV

of the median nerve.2 By contrast, CMT2 is an axonal peripheral

neuropathy and is characterized by an NCV that is only slightly

decreased (>38 m/s) or even normal.(2)

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). NF-L is the first gene

discovered in CMT2. A missense mutation (a mutation that causes

substitution of one amino acid for another, resulting in a different

sequence) in the NF-L gene (NEFL) on chromosome 8p21 is linked to the

disease.(3) The NF-L gene encodes neurofilament light protein, which is

one of the three major neurofilament proteins constituents.

Neurofilaments play an important role in axonal structure.

Two leading CMT research groups studied families with CMT2 caused by

neurofilament light gene mutation. These families demonstrated the

clinical presentation and genotype of CMT2. In the first study, Irina V.

Mersiyanova et al., suggest that Gln333Pro represents a rare

disease-causing mutation, which results in the CMT2 phenotype.(4)

Timmerman, PhD, De Jonghe, MD, PhD et al. identified a

novel mutation, Pro8Arg, in a second CMT family.(5)

Because of overlapping clinical symptoms with other inherited peripheral

neuropathies, CMT may be challenging to diagnose clinically, and CMT2

may be difficult to distinguish from other forms of CMT, such as CMT1,

CMTX, and chronic idiopathic axonal neuropathy.(6) A genetic test can

help clarify a clinical diagnosis and provide the most accurate

information about an individual’s CMT type, which may help in assigning

risks for developing the disease or passing on the abnormal gene to

family members, enable appropriate genetic counseling, and lead to

better disease management. To learn more about Athena’s CMT full line of

testing, visit

www.athenadiagnostics.com/site/product_search/test_names_template.asp

References

1. Schenone, A., et al., Molecular basis of inherited neuropathies.

Current Opinion in Neurology, 1999; 12(5): 603-16.

2. Meriyanova, I.V. et al., A New Variant of Charcot-Marie-Tooth Disease

Type 2 is Probably the Result of a Mutation in the Neurofilament-Light

Gene. American Journal of Human Genetics 2000; 67:37-46.

3. DeJonghe, P. et al., Further Evidence that Neurofilament Light Chain

Gene Mutations Can Cause Charcot-Marie-Tooth Disease Type 2E. ls of

Neurology 2001; 49:245-249.

4. Case study provided courtesy of Oleg V. Evgrafov, PhD (Research

Center for Medical Genetics in Moscow, Russia and Columbia University

Genome Center in New York, NY) and Irina V. Mersiyanova, PhD (Research

Center for Medical Genetics in Moscow, Russia)

5. DeJonghe, P. et al., Further Evidence that Neurofilament Light Chain

Gene Mutations Can Cause Charcot- Marie-Tooth Disease Type 2E. ls of

Neurology 2001; 49:245-249.

6. Bird, T. Charcot-Marie-Tooth Neuropathy Type 2.

http://www.geneclinics.org/profiles/cmt2/index.html.2001