Limitations of Testing

The clinician must recognize that the sensitivity of genetic testing varies among clinical conditions and apply


Disorders of carbohydrate metabolism

Myophosphorylase deficiency (McArdle's disease; type V glycogenosis)

Phosphofructokinase deficiency (Tarui's disease; type VII glycogenosis)

Phosphoglycerate kinase deficiency (type IX glycogenosis)

Phosphoglycerate mutase deficiency (type X glycogenosis)

Lactate dehydrogenase deficiency

Phosphorylase b kinase deficiency

Disorders of lipid metabolism

Carnitine palmitoyl transferase deficiency

Long-chain acyl-coenzyme A dehydrogenase deficiency

Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency

Defects of the respiratory chain

Defects of complex I, complex III, and complex IV

Coenzyme Q10 deficiencv


Myoadenylate deaminase deficiency X-linked myopathy with abnormal dystrophin Idiopathic

Modified from Rifai Z, Griggs RC: Metabolic myopathies. In Samuels MA, Feske S, Mesulam MM, et al (eds): Office Practice of Neurology, New York, Churchill Livingstone, 1996, pp 600-604.

testing methods in the appropriate context. The molecular test for Huntington's disease is very sensitive and specific, but other clinical conditions exist in which adult-onset chorea may be present. As an example, dentatorubropallidoluysian atrophy (see ChaipteL35 - also has an autosomal dominant pattern of inheritance but is caused by triplet repeat expansion of a gene distinct from that causing Huntington's disease. The diagnosis of neurofibromatosis 1 is best established clinically, because the search for gene mutations is currently too laborious to be practical in most cases. Whereas the premature protein truncation test is the most sensitive molecular test for this disease, it detects abnormalities in only about 70 percent of affected individuals.

In disorders in which the gene product, generally a protein, is functionally well-characterized, it is usually more effective to screen for the presence of abnormalities by functional testing. For example, the lysosomal storage diseases are caused by defective enzymes that can be directly assayed. Thus, the most effective screening test is a direct assay of enzyme function or of substrates or breakdown products of the enzyme in question in serum, urine, or skin fibroblasts. Genetic diagnosis of mitochondrial disorders is complicated because the diseases result from mitochondrial DNA mutations that are not reflected in the genomic DNA and the proportion of mutant mitochondria can vary tremendously from tissue to tissue (see Chapte,L31 _.

For diseases caused by mutations of the nuclear genome, it is generally sufficient to analyze DNA extracted from periopheral blood leukocytes. Genomic DNA can be isolated from other tissues as well. When PCR analysis is performed, it is sometimes possible to extract sufficient DNA from archived paraffin-embedded or formalin-fixed tissue. For the molecular diagnosis of mitochondrial diseases, however, it is sometimes necessary to test an affected tissue, such as muscle, because the distribution of normal and mutant mitochondria in an individual may be very heterogeneous, such that the blood mitochondria may be normal, whereas the tissue mitochondria are abormal.

In the setting of genetic testing, in which molecular test results not only provide diagnostic information but also may predict the onset of disease, the clinician must advise patients of the potential implications of obtaining genetic information as it relates to their health and economic and social well-being, as well as that of their relatives. Adverse genetic risk information could potentially affect an individual's employment and insurance status. Confidentiality must be maintained according to the patient's wishes in all situations. Counseling must be included as part of any genetic testing program and should include discussions with geneticists or genetic counselors as well as psychiatrists or psychologists in specific disorders for which predictive testing is possible.


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