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By Thomas D. Bird, MD
Editor’s Note: The molecular genetic revolution is having a major impact on the practice of neurology. This phenomenon is especially evident in the area of genetic testing for inherited diseases of the nervous system. Last year, Neurology Alert published a review of clinically available direct DNA tests for hereditary neurological diseases (see Neurology Alert January 2000 Supplement). The review listed more than 100 such disorders for which a direct DNA test is now commercially available. This review should be of considerable benefit to the busy practicing neurologist who needs quick information concerning the availability of genetic diagnostic testing for the differential diagnosis of specific patients. Metabolic and other nonDNA tests were not listed in the review, but further information about all types of genetic tests can be found at www.genetests.org. This website provides names and phone numbers of laboratories performing genetic testing as well as research laboratories that may be performing additional tests on a noncommercial (research) basis. A complementary website (www. geneclinics.org) provides clinical information and guidelines for interpreting and using DNA tests for many of the disorders listed in the table. This is a rapidly expanding field and several new tests have become available in the past year. We will briefly review them here.
A wide range of hereditary peripheral neuropathies present as the Charcot-Marie Tooth (CMT) Syndrome with chronic, progressive, distal weakness, and sensory loss associated with depressed tendon reflexes. The conditions may be demyelinating or axonal (CMT Type 1 and Type 2, respectively). The most common form is demyelinating (CMT1A) and caused by duplication of the peripheral myelin protein 22 (PMP 22) gene. Other types with available DNA tests include hereditary neuropathy with liability to pressure palsy (HNPP), mutations in the myelin PO (MPZ) gene, and X-linked forms with mutations in the connexin 32 gene. Rare causes are point mutations in the PMP 22 gene or the Early Growth Response 2 (EGR2) gene. DNA tests for all these are now available.
The autosomal dominant hereditary ataxias are referred to as Spinocerebellar Ataxias (SCA). At least 14 different subtypes have been defined on the basis of unique chromosomal loci. DNA-based tests have been previously available for SCA-1,2,3,6,7. Testing is now available for SCA-8 and SCA-10. SCA-8 is associated with a CTG repeat expansion (rather than CAG) and a relatively pure cerebellar atrophy syndrome. Testing for SCA-8 is associated with a CTG repeat expansion (rather than CAG) and a relatively pure cerebellar atrophy syndrome. Testing for SCA-8 is controversial because of decreased penetrance and because it remains unclear what is the frequency of the CTG expansion in the normal population. Positive tests for SCA-8 should be discussed with an expert in the field. SCA-10 is a dominant ataxia that is associated with seizures and is most often found in Mexican populations. SCA-10 is unique in being a penta-nucleotide repeat (ATTCT). A DNA-test for Friedreich Ataxia, the most common autosomal recessive type, is also available.
Creutzfeldt-Jacob (CJD) disease is usually sporadic and not genetic. However, a few rare families with this phenotype have a variety of mutations in the prion gene and a screening for such DNA mutations is now clinically available. The genetic prion syndromes include typical CJD (with rigidity, myoclonus, and dementia), or may be associated with ataxia (Gerstmann-Straussler-Scheinker, GSS), or may present with familial fatal insomnia (FFI).
Rett Syndrome is an X-linked neurodevelopmental disorder affecting almost exclusively girls. It is associated with autistic features, loss of speech, microcephaly, seizures, and stereotypic hand movements. DNA-based testing can now identify a variety of mutations in the methyl CPG binding protein 2 (MECPT2) on the long arm of the X chromosome.
Additional information about the diseases can be found at www.ncbi.nlm.nih.gov/omim. Families with these disorders often require professional genetic counseling. —TDB
(Dr. Bird is Professor, Neurology, and Medical Genetics/Geriatric Researcher, University of Washington-VA Medical Center, Seattle, Washington.)
1. Bird TD. Risks and benefits of DNA testing for neurogenetic disorders. Semin Neurol 1999;19:253-259.