American Journal of Medical Genetics 26:235-236 (1987)

Letter to the Editor: Genetic Heterogeneity in Duchenne Muscular Dystrophy

To the Editor:

The very high incidence of Duchenne muscular dystrophy (DMD) of around 240-300 X seems likely to be due to genetic heterogeneity with mutations at different closely linked loci or at different points within the same locus or region. However, whether such genetic heterogenetity is reflected clinically is a moot point. We found that in affected boys with severe mental handicap (IQ < 50) who are largely ineducable, the age at onset and of becoming confined to a wheelchair was somewhat later; the fall in serum creatine kinase levels with age less marked; and the urinary excretion of certain amino acids somewhat greater than in a group of carefully matched affected boys with normal intelligence [Emery et al, 19791. Though none of the differences between the two groups reached statistical significance, we suggested that the results might indicate that affected boys with severe mental handicap represent a small subgroup of patients genetically distinct from most other patients with the disease. We did not suggest that the presence or absence of lesser degrees of mental impairment could be a criterion for dividing patients into different groups because this is obviously not valid, and Bortolini and Zatz [1986] have misinterpreted our conclusions. These latter investigators felt their own data did not document evidence of heterogeneity. However, re-examination of their calculations indicates that boys with mental handicap (IQ < 70) did become confined to a wheelchair significantly later than boys with normal intelligence (Table I>, this parameter being a particularly reliable manifestation of the disorder.

Others have found a high concordance for intellectual function within families: in 37 of 39 families by Cohen et al 119681, in 11 of 14 families by Kozicka et al [1971], and in 16 of 22 families by Bortolini and Zatz 119861, giving an overall concordance of 85 % , despite obvious environmental influences on intelligence. We have found that whenever an index case is severely mentally hanicapped (IQ < 50) and has an affected brother, the latter is almost always severely mentally handicapped as well.

Despite these indications of genetic heterogeneity the problem is unlikely to be resolved further by simply considering clinical criteria. However, it seems clear

Received for publication May 17, 1986.

Address reprint requests to Alan Emery, Medical School, Teviot Place, Edinburgh, Scotland.

0 1987 Alan R. Liss, Inc.

236 Emery

TABLE I. Age at Becoming Confined to a Wheelchair in Patients With Normal Intelligence or With Mental Handicap

Normal intelligence Mental handicap Number Mean SD Number Mean SD Probability Reference

12 8.77 1.12 13 9.65 1.60 NS Emery et a1 119791 24 9.49 1.70 11 10.83 1.65 <0.05 Bortolini and Zatz

[ 19861

already that heterogeneity exists at the molecular level [Monaco et al, 1985; Ray et al, 19851, and in future it will be interesting to compare various clinical and biochem- ical parameters in those cases with one molecular defect (say a gene deletion) with those with a different defect.

REFERENCES Bortolini ER, Zatz M (1986): Investigation on genetic heterogeneity in Duchenne muscular dystrophy.

Am J Med Genet 24:lll-117. Cohen HJ, Molnar GE, Taft LT (1968): The genetic relationship of progressive muscular dystrophy

(Duchenne type) and mental retardation. Develop Med Child Neurol 10:754-765. Emery AEH, Skinner R, Holloway S (1979): A study of possible heterogeneity in Duchenne muscular

dystrophy. Clin Genet 15:444-449. Kozicka A, Prot J, Wasilewski R (1971): Mental retardation in patients with Duchenne progressive

muscular dystrophy. J Neurol Sci 14:209-213. Monaco AP, Bertelson CJ, Middlesworth W, Colletti C-A, Aldridge J, Fischbeek KH, Bartlett R,

Pericak-Vance MA, Roses AD, Kunkel LM (1985): Detection of deletions spanning the Duchenne muscular dystrophy locus using a tightly linked DNA segment. Nature (Lond) 316:842-845.

Ray PN, Belfall B, Duff C, Logan C, Kean V, Thompson MW, Sylvester JE, Gorski JL, Schmickel RD, Worton RG (1985): Cloning of the breakpoint of an X;21 translocation associated with Duchenne muscular dystrophy. Nature (Lond) 318:672-675.

Alan Emery Medical School, Teviot Place Edinburgh, Scotland

Edited by John M. Opitz