Duchenne-like muscular dystrophy in two sisters with normal karyotypes: evidence for autosomal recessive inheritance

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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 retar- dation. 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 clini- cal and cytogenetic data insufficient for pro- per judgment. Balanced X-autosome trans- locations 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 152 I II m 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 intelli- gence 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 weak- ness in her extremities. Deep tendon reflexes were diminished and the Gowers sign was positive. The EEG showed mild nonspecific Fig. 2. The first patient (IV-10) at age 9 showing myopa- thic 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 endomy- sial connective tissue and fat. The diameter of the muscle fibers varied from slightly hy- pertrophic (over 60 pm) to severely atro- phic. Single and multiple internal nuclei and splitting of the muscle fibers were com- mon (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 dys- trophy. 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 cli- nical examination, ECG, M-mode and 2- dimensional echocardiography with normal results. Second Patient The patient (I.N., IV-12) is the probands younger sister (Fig. 1). Pregnancy and deliv- ery were uneventful. Like her older sister, she also suffered from urinary tract infec- tions. The mother does not recall the age 154 S O M E R E T A L . I.N. learned to walk. Neurological examin- ation at age 6 revealed difficulty in getting up from the floor, mild muscle weakness in the shoulder girdle muscles and pseudohy- pertrophy 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 mo- ther 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 25C 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 dis- eases 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 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 155 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 pa- tients. 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-chro- mosome. 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 dune 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- ners 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) translo- cation in a girl with Duchenne muscular dys- trophy. 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). 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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 translo- cation involving Xp21 and non-random inacti- vation 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 chromo- some: 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


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