This page copies a pamphlet produced by Athena Diagnostics. Last updated: 4/13/1995.
Athena Diagnostics
CMT Type 1A DNA Test
Athena Diagnostics, formerly Genica Pharmaceuticals Corporation, is located at Four Biotech Park, 377 Plantation Street, Worchester, MA 01605. They can be reached by calling 1-800-394-4493.
Table of Contents
Clinical Guidelines for the use of Charcot-Marie-Tooth Type 1A DNA Test
In response to the neurology community's request for clinical guidelines and up-to-date educational information on innovative diagnostic testing services offered by Athena Diagnostics (Formerly Genica Pharmaceuticals Corporation), we have recently premiered a service entitled NeuroSynopsis.
The enclosed information on the recognition of clinical criteria and appropriateness of ordering the CMT1A DNA test was compiled by a group of leading experts in the fields of neurology and genetics. In summary: CMT1A DNA testing is a valuable adjunct to the work-up of any patient with a chronic idiopathic demyelinating polyneuropathy.
The CMT1A DNA test detects the chromosome 17 duplication associated with CMT type 1A.
Charcot-Marie-Tooth (CMT) polyneuropathy syndrome, or the primary Hereditary Motor and Sensory Neuropathies (HMSN I, II, and III) are a genetically and clinically heterogeneous group of disorders of the peripheral nerves characterized by insidious onset and slowly progressive weakness of the distal muscles with mild sensory impairment. The clinical manifestations can vary considerably in severity and age of onset, although patients typically present in late childhood or early adulthood.[1,2,3] The clinical features may be so mild that they may be undetectable by patients, their families and physicians.
The molecular test for CMT1A is designed to assist in the diagnosis of any patient who has chronic idiopathic peripheral neuropathy, regardless of whether there is a family history. All patients at risk for CMT, that is, those who have one affected parent or sibling, should be tested. Asymptomatic, at-risk patients with normal neurologic examination may have the CMT1A duplication, along with slowed nerve conduction studies.
- Evidence of chronic demyelinating polyneuropathy of unknown origin
- Symmetrically-decreased nerve conductivity velicity (NCV<40m/sec)
- Patient with slowly progressive distal muscle atrophy and weakness, often with gait disturbance and deformity of feet and hands
- Patients with positive family history (one affected parent or sibling) of Charcot-Marie-Tooth Disease
A positive CMT1A DNA Test is indicated by the presence of a 500kb CMT1A duplication specific junction fragment, and is diagnostic for Charcot-Marie-Tooth 1A.[4] No false positive occurrences have been identified. A positive result has important applications in genetic counselling of patients and their families.
A negative CMT1A Test is indicated by the absence of the CMT1A duplication specific junction fragment. The CMT1A duplication has been identified in 70-90% of patients with clinical CMT1.[4-8] Point mutations in the peripheral myelin protein gene, PMP22, have recently been identified in some CMT1A patients who do not exhibit the duplication.[9] A negative result therefore does not rule out diagnosis of Charcot-Marie-Tooth Disease.
- CMT is the most common inherited peripheral neuropathy, and with an estimated prevalence of 1:2500, it is one of the most common genetic disorders.[3]
- In a large majority of CMT1 pedigrees, the mode of inheritance is autosomal dominant; however, there are pedigrees which exhibit X-linked inheritance and rarer ones exhibiting autosomal recessive inheritance. In addition, sporadic cases occur.
- In the majority of autosomal dominant CMT1 families (85%), the disease locus is linked to markers on the proximal short arm of chromosome 17. Patients demonstrating mutations in this region are classified as CMT type 1A.[4]
- A 1.5 million base pair tandem DNA duplication in 17p11.2 has been identified in 70-90% of CMT1A patients.[4]
- In addition to familial cases, frequent de novo CMT1A mutations have also been described, 90% of which are due to the CMT1A duplication.[8]
- The PMP22 gene, which encodes a peripheral nerve myelin protein, has recently been mapped within the CMT1A duplication. The overexpression of this gene is thought to be the cause of clinical and electrophysiological phenotype of CMT1A.[9]
In the large population of CMT1 patients, the following clinical symptoms were reported:[1]
- Distal muscle atrophy and weakness
- 76% reported loss of balance
- 73% demonstrated gait disturbance
- 66% demonstrated foot deformity
- 62% had frequent muscle cramps
- 60% reported decreased exercise tolerance
- 59% had reduced use and deformity of hands
- Sensory loss
- 85% demonstrated absent or decreased reflexes
- 67% reported cold hands and/or feet
- 41% reported numbness of hands and/or feet
- In addition, 65% reported family history
- Symmetrically-decreased nerve conductivity velocity (NCV<40m/sec)
- Nerve hypertrophy with onion bulb formation on sural nerve biopsy
- EMG findings consistent with chronic denervation
Athena Diagnostics is pleased to provide you with the information contained within. The use of this information remains the sole responsibility of the physician; all diagnostic test findings should be considered within the context of clinical findings.
We hope you have found this service useful. If you have any technical inquires, product ideas, or requests for future NeuroSynopsis issues please contact Athena Diagnostics at 1-800-394-4493. As always, we look forward to serving your neurological diagnostic needs.
- Lupski JR, Garcia CA, Parry G, Patel P: Charcot-Marie-Tooth polyneuropathy syndrome: Clinical electrophysiological and genetic aspects. In Appel S. (ed) Current Neurology Vol 11 Chicago, Mosby Yearbook 1991; pp. 1-25.
- Dyck PJ, Chance PF, Lebo RV, Carney JA: Hereditary motor and sensory neuropathies. In Peripheral Neuropathiy, Third Edition, PJ Dyck, PK Thomas, JW Griffin, PA Low and JF Podulso. (eds) Philadelphia: WB Saunders 1992; pp. 1094-1136.
- Skre H: Genetic and clinical aspects of Charcot-Marie-Tooth disease. Clin Genet 1974; 3; 6: 98-118.
- Lupski JR, Montes de Oca-Luna R, Slaugenhaupt S, et al: DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 1991; 66:219-232.
- Lupski JR: An inherited DNA rearrangement and gene dosage effect are responsible for the most common autosomal dominant peripheral neuropathy: Charcot-Marie-Tooth disease type 1A. Clin Res 1992; 40:645-652.
- Wise CA, Garcia CA, Davis S, et al: Molecular analysis of unrelated Charcot-Marie-Tooth disease patients suggest a high frequency of the CMT 1A duplication. Amer J Hum Genetics, 1993; 53:853-863.
- Raeymaekers P, Timerman V, Nelis E, et al: Estimation of the size of the chromosome 17p11.2 duplication in Charcot-Marie-Tooth neuropathy type 1A (CMT1A). J Med GENET 1992; 29:5-11.
- Hoogendijk JE, Hensel GW, Gabreel-Festen AAWM, et al: De novo mutation in heritary motor and sensory neuropathy type 1. Lancet 1992; 339:1081-1082.
- Roa BB, Garcia CA, Suter U, et al: Charcot-Marie-Tooth Disease type 1A associated with de novo point mutation in the PMP22 gene. N Engl J Med, 1992; 329:96-101.
