The female carrier of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy is an X-linked recessive disorder, affecting only males and transmitted by females, who have a 50% risk of an affected son or a carrier daughter. The incidence has been estimated at between one in 3000 and one in 5000 male births, but not all the mothers of affected infants are carriers; a substantial proportion of cases will represent new mutations. According to Haldane, the mutation rate for a potentially lethal X-linked condition in which the biological fitness (fertility) of affected males is practically zero would be one-third. Estimates based on population studies have produced a similarly high figure. If, then, one-third of the mothers of affected infants are not carriers the investigation of the carrier state and genetic counselling are vitally important for the families concerned. The first essential step in genetic counselling must always be to verify the diagnosis in the index case. Next, a detailed family tree should be constructed before investigation of the possible carrier is begun. A genetically definite or obligate carrier is a woman with an affected son and an additional affected male relative; all other female relatives are possible carriers. The creatine kinase test is the most reliable for detecting carriers. The serum activity of the enzyme is grossly raised in patients with Duchenne dystrophy and raised to a mild-to-moderate extent in some but not all female carriers of the gene. Several studies have shown the proportion of genetically obligate carriers with definitely raised creatine kinase activities to be about two-thirds. Since creatine kinase activity is normal in about a third of definite carriers it clearly does not exclude the carrier state. An accurate estimate of the statistical risk that a woman with a normal creatine kinase activity is a carrier can be made from the actual activity of the creatine kinase, on the basis of the distribution curves in normal controls and in obligate carriers and the application of Bayesian theory, which takes account both of the antecedent family history and of the creatine kinase activity of the person at risk and of other female relatives. Followup studies of families counselled in this way have verified the validity of this approach. The creatine kinase activity can be spuriously high after vigorous exercise and it drops during pregnancy. Genetic counselling requires the combined skills of the physician and the laboratory and is best undertaken in specialised centres; random counselling based on isolated results of estimation of creatine kinase can have disastrous consequences. Other biochemical tests have been tried in the detection of carriers. Some, such as that based on raised serum activity of pyruvate kinase, are at least potentially practicable, though having little or no advantage over creatine kinase. On clinical examination several features may be found in carriers, ranging from prominence of the calves (often unilateral) through muscle cramps or minimal weakness to overt muscle wasting and weakness. The overtly weak heterozygote with the Duchenne gene may on rare occasions manifest the actual disease owing to a concomitant chromosomal abnormality such as (presumptive) Turner's syndrome (XO), XO/XX mosaicism, a structurally abnormal X chromosome, or a translocation with partial deletion of the X chromosome. Such women must also be distinguished from those with autosomal recessive limb girdle dystrophy. A further three carriers of Duchenne muscular dystrophy with overt clinical weakness, high creatine kinase activities, electrocardiographic abnormalities, and histological changes have recently been reported from Japan. Only one was a genetically definite carrier (with two affected sons and an affected brother); the other two were mothers of isolated cases.