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Clinical Genetics 1985: 28: 15 1-1 56

Duchenne-like muscular dystrophy in two sisters with normal karyotypes: evidence

for autosomal recessive inheritance HANNU SOMER,' ARJA VOUTILAINEN,' SAKARI KNUUTILA,~ ILKKA KAITILA,2.3 JUHANI RAPOLA? AND

HANNU LEINONEN4

Departments of 'Neurology, ZMedical Genetics, 'Children's Hospital, and 4The First Department of Medicine, University of Helsinki, Finland

Two sisters, products of a consanguineous marriage (with a total of 12 children) showed muscle weakness at ages 7 and 6 yrs, respectively. The symptoms progressed rapidly and the patients were confined to wheelchairs at ages of 12 and I 1 yrs, respectively. They had mild facial weakness and pseudohypertrophy of the calves, but neither cardiomyopathy nor mental retardation. Serum CK activities exceeded upper normal limit by 70 to 85-fold. Muscle biopsies were compatible with muscular dystrophy. Both girls had a normal karyotype. The healthy mother had mild CK elevations in two out of three occasions, but the muscle biopsy was normal. Three out of the six unaffected sibs had mild CK elevations. The findings support the concept of severe progressive muscular dystrophy with autosomal recessive inheritance. The condition is clinically indistinguishable from Duchenne muscular dystrophy.

Received 13 January, accepted j o r publication 14 M a y 1985

Key words: Creatine kinase; genetic counselling; hereditary diseases; karyotyping; muscular dystrophy.

Duchenne muscular dystrophy is an X- linked recessive disease with a fairly uni- form clinical picture (Walton & Gardner- Medwin 1981). Duchenne's original ma- terial (1868), however, consisted of l l boys and 2 girls. Severe muscular dystrophy in girls has subsequently remained a matter of controversy. Penn et al. (1970) reviewed the matter very carefully and found 104 such cases, but considered them either atypical of Duchenne dystrophy, or found the clinical and cytogenetic data insufficient for pro- per judgment. Balanced X-autosome translocations were then described in seven girls with Duchenne-like muscular dystrophy providing a new explanation for the cause (Canki et al. 1979, Lindenbaum et al. 1979,

Greenstein et al. 1980, Jacobs et al. 1981, Zatz et al. 1981, Emanuel et al. 1983, Verell- en-Dumoulin et al. 1984).

We now report on a clinical follow-up of two sisters whose clinical picture is like Duchenne muscular dystrophy. The results of the cytogenetic studies were normal. The family history suggests autosomal recessive inheritance.

Case Reports

First Patient The patient (T.N., IV-10) was the product of a consanguineous marriage, the parents being first cousins. They had 12 children in common (Fig. 1). The pregnancy and

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Fig. 1. Pedigree of the family. Arrow indicates the propositus

delivery were uneventful. She walked at age 15 months, but she never learned to run and disliked play with physical activity. From age 2 she had relapsing urinary tract infec- tions. When entering elementary school at age 7 she was unable to climb up-stairs.

Clinical examination at age 9 revealed a shy and reserved girl with normal intelligence on neuropsychological testing. Her face had a slight myopathic expression. Shoulder girdle and pectoralis muscles were slightly atrophic, while calf muscles showed pseudohypertrophy (Fig. 2). She had both proximal and distal muscle weakness in her extremities. Deep tendon reflexes were diminished and the Gower’s sign was positive. The EEG showed mild nonspecific

Fig. 2. The first patient (IV-10) at age 9 showing myopathic expression on the face, muscular atrophy on the shoulder girdle region and pseudohypertrophy of the calves.

D U C H E N N E - L I K E D Y S T R O P H Y I N T W O S I S T E R S 153

Fig. 3. Muscle biopsy from the first patient at age 9 shows great variation of the fiber diameters, internal nuclei, increase of endomysial connective tissue and “split” fibers. H 8. E x 280.

changes. The ECG revealed a marginally reduced P-Q interval with no delta wave. The R/S amplitude ratio was normal in lead VI and no pathologic Q waves were seen in left unilateral limb leads. The serum CK activity was 3540 U/L (normal up to 50 U/ L), and serum aldolase activity was 20 U/L (normal up to 3.1 U/L). The EMG showed a myopathic pattern. Muscle biopsy obtained from the right femoral quadriceps muscle revealed increase of both peri- and endomysial connective tissue and fat. The diameter of the muscle fibers varied from slightly hy- pertrophic (over 60 pm) to severely atrophic. Single and multiple internal nuclei and “splitting” of the muscle fibers were common (Fig. 3). Active cell necrosis was not found, but occasional regenerative fibers were seen. Special stainings for NADH-te- trazolium reductase, ATP-ase, PAS and fat did not reveal changes suggesting specific

or metabolic myopathies. The histological picture was compatible with muscular dystrophy.

At age 10 she was unable to get up from a chair or to lift her extremities against grav- ity. Muscle weakness progressed rapidly with evolving lordosis and scoliosis. She was confined to a wheelchair at age 12. At age 15 she had contractures and active move- ment in the finger muscles only. Cardiolog- ical examinations at age 19 included clinical examination, ECG, M-mode and 2- dimensional echocardiography with normal results.

Second Patient The patient (I.N., IV-12) is the proband’s younger sister (Fig. 1). Pregnancy and delivery were uneventful. Like her older sister, she also suffered from urinary tract infec- tions. The mother does not recall the age

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I.N. learned to walk. Neurological examination at age 6 revealed difficulty in getting up from the floor, mild muscle weakness in the shoulder girdle muscles and pseudohypertrophy of the calves. Serum CK activity was 4200 U/L, aldolase was 41 U/L. The EMG was myopathic and muscle biopsy revealed profound changes compatible with muscular dystrophy. Her intelligence and the EEG examination were normal. The clinical course progressed as with her older sister, except that she was confined to a wheelchair already at age 11 after a bone fracture in the ankle. Muscle biopsy, re- peated at age 16, contained almost exclus- ively fat and connective tissue. Cardiolog- ical examination, using the same methods as with the proband, was normal at age 16.

Cy togene t ic SE udies Karyotypes were studied on both girls with high resolution banding technique on pro- metaphase chromosomes. The karyotype was considered normal at the level of about 550 bands per haploid set.

Family Studies Both parents come from a large family (Fig. 1). The father, who refused to be examined clinically, has twelve healthy sibs. The mother has three healthy brothers. Two out of her five sisters died of febrile convulsions, one is crippledfrom infancy because of tu- berculous meningitis. The patient's ten sibs (Fig. 1) are all healthy; the youngest one is now 18. The sibs have nine healthy children altogether.

The mother, now aged 60, does not exhi- bit any muscle weakness, muscle atrophy or pseudohypertrophy. Cardiological studies using the same methods as with her daugh- ters were normal. Muscle biopsy was also interpreted as normal. Serum CK activity has been measured on three occasions with two marginally elevated results (Table 1). Enzyme activity was measured also in six

Table 1

Serum CK activity among patients and family members

1973 1983

IV-10 (First patient) 3540 - IV-12 (Second patient) 4200 - 111-13 (father) - - 111-14 (mother) 4038 201 IV-1-3,9 - -

IV-4 82 - IV-5 51 - IV-6 53 - IV-7 74 - IV-8 204 - IV-11 36 -

Serum CK activity was measured in 1973 at 25°C with normal values: 0-50 UIL. In 1983 the enzyme activity was measured at 37'C, with normal values up to 150 UIL.

out of the ten unaffected sibs. One of them was within normal range, two were mar- ginal and three showed abnormal values. The mean CK activity among these six sibs was 83 U/L.

Discussion

Several explanations can be offered for the Duchenne-like muscular dystrophy in girls. Many of the earlier cases (Penn et al. 1970) were found in genetic field studies and diseases like spinal atrophy or polymyositis cannot be reliably excluded. A whole spec- trum of metabolic or congenital myopathies has subsequently been described, some of them remarkably resembling Duchenne dystrophy (Donner et al. 1975, DiMauro 1979).

The overall clinical picture in these two girls is compatible with severe progressive muscular dystrophy. Controversy arises as to what subtitle should be used. The distri- bution of muscle weakness and the rate of progression fits best to the Duchenne form. Muscle symptoms were not observed quite as early as usual, but considering the large

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size of the family it may very well have been due to the astuteness of the parents. Cardiomyopathy and mental retardation were both absent, but neither one is neces- sary for the diagnosis. Had these girls been boys and the marriage nonconsanguineous, most clinicians would undoubtably have called their disease Duchenne dystrophy.

Chromosomal aberrations may explain some cases of female Duchenne dystrophy since both the 45,X (Ferrier et al. 1965) and the 45,X/46,XX/47,XXX mosaicisms (Jal- bert et al. 1966), as well as X-autosome translocations (Canki et al. 1979, Linden- baum et al. 1979, Greenstein et a]. 1980, Jacobs et al. 1981, Zatzet al. 1981, Emanuel et al. 1983, Verellen-Dumoulin et al. 1984) have been reported in girls. The explanation in X-autosome translocations probably is that the normal X-chromosome is late rep- licating and presumably inactive in all or most cells (Wyss et al. 1982, Verellen-Du- moulin et al. 1984). No structural abnor- malities were, however, detected in our patients. Heterozygote manifestation is a possibility, since about 8 % of Duchenne carriers do show a progressive myopathy (Moser & Emery 1974). In some cases the clinical picture may be very severe (Gomez et al. 1977, Meola et al. 1981, Olson & Fenichel 1982), apparently because of non- random inactivation of the normal X-chromosome. Heterozygote manifestation ap- pears unlikely with this family history.

Severe muscular dystrophy in two sisters in a consanguineous marriage suggests a childhood form of muscular dystrophy with autosomal recessive inheritance. Some pre- vious studies (Penn et al. 1970) contain cases from consanguineous marriages and they may very well have represented the same entity. This form has recently been found to be prevalent in Sudan (Salih et al. 1983) and in Tunisia (Hamida et al. 1983), and the gene, although rare, may be relatively widespread. Gardner-Medwin & Johnston

(1 984) recently studied the clinical features of 12 girls with severe muscular dystrophy found in England. Their cases lacked both mental retardation and cardiomyopathy, and progressed at a slightly slower rate than Duchenne dystrophy. There was, however, no reliable clinical method to distinguish between these two entities at an early stage of the disease. This is unfortunate in terms of genetic counselling, and has an impact on research directed towards the basic ab- normality in Duchenne dystrophy as well. Occasionally these studies may suggest the existence of biochemical subtypes (Sa- maha & Congredo 1977). Such divergent results need not be artefactual but may be due to some of the cases representing the autosomal recessive form.

References

Canki, N., B. Dutrillaux & I. Tivadar (1979). Dystrophie musculaire de Duchenne chez une petite fille porteuse d’une translocation t(X;3)(p21;q13) de novo. Ann. GCnet. 22, 35-39.

DiMauro, S. (1979). Metabolic myopathies. In Handbook of Clinical Neurology. P. J. Vinken & G. W. Bruven (eds.) Amsterdam. North-Hol- land Pubiishing Company Vol. 41, pp. 175-234.

Donner, M., J. Rapola & H. Somer (1975). Con- genital muscular dystrophy: a clinico-patho- logical and follow-up study of 15 patients. Ne- uropadiatrie 6, 239-258.

Duchenne, G. B. ( 1 868). Recherches sur la para- lysie musculaire pseudohypertrophique on pa- ralysie myo-sclerosique. Arch. G h Mkd. ll ,

868. Emanuel, B. S., E. H. Zackai & S. H. Tucker

(1983). Further evidence for Xp21 location of Duchenne muscular dystrophy (DMD) locus: X;9 translocation in a female with DMD. J. Med. Genet. 20, 461463.

Ferrier, P., F. Bamatter & D. Klein (1965). Muscu- lar dystrophy (Duchenne) in a girl with Tur- ner’s syndrome. J . Med. Genet. 2, 3846.

Gardner-Medwin, D. & H. M. Johnston (1984). Severe muscular dystrophy in girls. J . Neurul. Sci. 64, 79-87.

5-25, 179-209, 305-321, 421443, 552-588,

156 S O M E R E T A L .

Gomez, M. R., A. E. Engel, G. Dewald & H. A. Peterson (1977). Failure of inactivation of Duchenne dystrophy X-chromosome in one of female identical twins. Neurology 27, 537-541.

Greenstein, R. M., M. P. Reardon, T. S. Chan, A. B. Middleton, R. A. Mulivor, A. E. Gree- ne & L. L. Coriell (1980). An (X;Il) translocation in a girl with Duchenne muscular dystrophy. Cytogenet. Cell Genet. 27, 268.

Hamida, M. B., M. Fardeau & N. Attia (1983). Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle & Nerve 6, 469480.

Jacobs, P. A,, P A. Hunt, M. Mayer & R. D. Bart (I98 I). Duchenne muscular dystrophy (DMD) in a female with an Xjautosome translocation: further evidence that the DMD locus is at Xp21. Am. J . Hum. Genet. 33, 513-518.

Jalberg, P., C. Mouriquand, A. Beaudoing & M. Jaillard (1966). Myopathic progressive de type Duchenne et mosaique XOjXXjXXX: Con- siderations sur la genese de la fibre musculaire striee. Ann. G in i f . 9, 104108.

Lindenbaum, R. H., G. Clarke, C. Patel, M . Moncrieff & J . T. Hughes (1979). Muscular dystrophy in an X;I translocation female suggests that Duchenne locus is on X chromosome short arm. J . Med. Genet. 16, 389-392.

Meola, G., E. Scarpini, V. Silani & G. Scarlato (198 I) . Manifesting carrier of X-linked Duch- enne muscuar dystrophy. J . Neurol. Sci. 49, 455463.

Moser, H. & A. E. H . Emery (1974). The manifesting carrier in Duchenne muscular dystrophy. Clin. Genet. 5, 271-284.

Olson, B. J. & G. M. Fenichel(l982). Progressive muscle disease in a young woman with family history of Duchenne’s muscular dystrophy. Arch. Neurol. 39, 378-380.

Penn, A. S., R. P. Lisak & L. P. Rowland (1970).

Muscular dystrophy in young girls. Neurology

Salih, M. A. M., M. I. A. Omer, R. A. Bayoumi, 0. Karrar & M. Johnson (1983). Severe autoso- ma1 recessive muscular dystrophy in an ex- tended Sudanese kindred. Develop. Med. Child Neurol. 25, 43-52.

Samaha, F. J. & C. Z. Congredo (1977). Two biochemical types of Duchenne dystrophy: Sar- coplasmic reticulum membrane proteins. Ann. Neurol. 1, 125-130.

Verellen-Dumoulin, C., M. Freund, R. De Meyer, C. Laterre, J . Frederic, M. W. Thompson & V. D. Markovic (1984). Expression of an X-linked muscular dystrophy in a female due to translocation involving Xp21 and non-random inactivation of the normal X chromosome. Hum. Genet. 67, 115-1 19.

Walton, J. N. & D. Gardner-Medwin (1981). Pro- gressive muscular dystrophy and the myotonic disorders. In Disorders of Voluntary Muscle. 4th Edit. J. Walton (ed.) Edinburgh, Churchill Livingstone, pp. 481-524.

Wyss, D., C. D. Delozier, J . Daniel1 & E. Engel (1982). Structural anomalies of the X chromosome: personal observation and review of non- mosaic cases. Clin. Genet. 21, 145-159.

Zatz, M., A. M. Vianna-Morgante, P. Campos & A. J . Diament (1981). Translocation (X;6) in a female with Duchenne muscular dystrophy: implications for the localisation of the DMD locus. J . Med. Genet. 18, 442447.

20, 147-159.

Address:

Dr. Hannu Somer Department of’ Neurology University of Helsinki 00290 Helsinki 29 Finland