Brain & Development, 15 (1993) 313 315 0387-7604/93/$06.00 © 1993 Elsevier Science Publishers B.V. All rights reserved

BRADEV 00069

An unusual case of Duchenne muscular dystrophy

H a l u k T o p a l o ~ l u a, M D , Pervin Dinger b, MSc, Safiye G6~ii~ c, M D ,

Stikrtiye A y t e r b, P h D and Mera l T o p g u a, M D

Departments of aPediatrie Neurology, bMolecular Biology and Cpediatric Pathology, Hacettepe University, Children's Hospital, Ankara, Turkey

Received 30 November 1992; accepted 23 April 1993

A 10-year-old boy with Duchenne muscular dystrophy (DMD), with quite unusual clinical data, is presented. He was unable to walk until age 6, walked only for 9 months and then became wheel-chair bound. No dystrophin was present on muscle biopsy sections and a large deletion was found in the dystrophin gene. The deletion encompassed the central high frequency deletion region of the gene. Early developmental milestones may be

delayed in DMD, but patients usually start to walk around 2-3 years of age. A delay of the extent in this case is very unusual.

Key words: Duchenne muscular dystrophy; Severe

INTRODUCTION

Duchenne muscular dystrophy (DMD) is mostly caused by out-of-frame deletions in the dystrophin gene [1]. The gene is located at Xp21 and consists of at least 75 exons that encode a 14 kb transcript [2], which is translated into a 427 kDa protein named dystrophin [3]. The majority of mutations (65%) in DMD are in- tragenic deletions [4]. We report here a 10-year-old boy with DMD who did not begin walking until age 6. He had a large out-of-frame deletion (exons 45 52) in the DMD gene and absent dystrophin on biopsy sections.

CASE REPORT

This boy was the second child to a non-consangui- neous couple. There were two male maternal great cou- sins (ages 45 and 37) who had walked at 5 years of age, but supposedly are in good health now (no detailed documentation was available). Pregnancy and birth was uneventful. He was noted to be rather floppy in early infancy and his motor developmental milestones were delayed; he could hold his neck at 7 months, sat without support at 3 years and crawled at 3 9/12 years of age. His speech development was normal as he ut- tered his first two word sentences at 14 months. When

Correspondence address." Dr. H. Topalog'lu, Department of Pediatric Neurology, Hacettepe Children's Hospital, Ankara 06100, Turkey. Fax: (90) (4) 310 6262.

examined at 10 years all his growth parameters were below the 10th centile. His IQ was 73. He had general- ized muscle weakness with an overall muscle power of 3/5 according to the MRC scale. Muscles were atrophic. He could remain sitting without support but could not walk. There were bilateral contractures at the knees and Achilles tendons. His creatine kinase was elevated at 2,474 U/1 (normal < 191). Biopsy from the vastus lateralis showed a clear dystrophic pattern with endomysial fibrosis, degenerating and regenerating foci, internal nuclei and rounding of fibers. Dystro- phin immunostaining by NCL-Dys 1 and NCL-Dys 2 monoclonal antibodies (Novocastra Laboratories, Newcastle upon Tyne, UK) showed less than 3% fi- bers positively stained (Fig 1). This was consistent with DMD [5]. He was investigated using the polymerase chain reaction system with 14 different deletion-prone exon sequences of the dystrophin gene. The procedure was carried out essentially according to Chamberlain et al. [6] and Abbs et al. [7]. He lacked exons 45-52 lo- cated in the central high frequency deletion region of the gene (Fig 2), resulting in an out-of-frame deletion. The following studies were normal: blood and urine amino acid screen, thyroid function tests, blood chem- istry for liver and renal disorders, and cranial CT.

DISCUSSION

Delay in walking is commonly encountered in pa- tients with DMD, and even in the milder form Becker

Brain & Development, Vol 15, No 4, 1993 313

Fig 1. Dystrophin immunostaining by NCL-Dys l antibodies. Note the almost absent staining on the sarcolemma ot" the fibers. Quadriceps muscle.

dystrophy (BMD). In Hodgson et al.'s series of 287 patients with D M D and BMD, 41 44% of D M D and 25% of BMD cases walked after 18 months of age [8]. One particular D M D case in that series started to walk after 48 months. Our patient is unusual in that his walking was delayed until 6 years of age. He was am- bulant for only 9 months and then was wheel-chair bound. He must have had absent dystrophin from birth, but how this caused his huge delay in walking is unknown. There are multiple dystrophin isoforms pre- sent during human foetal development, but the rele-

Exon 50 (711 bp) Pm ( 5 3 5 bp) Exon 43 (357 bp) Exon 13 ( 2 3 8 bp) Exon 52 (113 bp)

MW C P

MW C P

Exon 48 (506 bp) Exon 19 ( 4 5 9 bp) Exon 44 (426 bp) Exon 51 ( 3 8 8 bp) Exon 8 ( 3 6 0 bp) Exon 45 (307 bp) Exon 4 ( 1 9 6 bp) Exon 47 (181 bp) Exon 42 ( 1 5 5 bp)

Fig 2. Five exon and nine exon multiplex amplifications. Patient lacks exons from 45 to 52. MW is QXI74 Haelll DNA.

vance of these can only be speculated upon [9]. In view of the positive family history, our patient may have a co-existent condition, so-called querry benign congeni- tal hypotonia; however, this is debatable and falls short to giving a full explanation. We think that this severe case may add new insights to our knowledge of the clinical spectrum of DMD.

ACKNOWLEDGEMENTS

We thank Meral ~)zgfiq, PhD, for helpful comments. This work has been supported by a grant from the Turkish Child Neurology Asso- ciation.

REFERENCES

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