297 early presentation of autosomal dominant emery-dreifuss muscular dystrophy

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Page 1: 297 Early presentation of autosomal dominant Emery-Dreifuss muscular dystrophy

Abstracts All7

single-base shift in exon 3 of PMP22 was found. No mutation was found in two cases with the special morphology of unstable, outfolding myelin sheath.

In conclusion, mutations in PO or rarely PMP22 were found in 66% of non-duplicated familial CMTla cases, a figure which warrants the molecular study in those families for which a genetic counselling comes under discussion. The low frequency of mutations found in sporadic cases suggest that many of them involve other myelin genes, perhaps in a recessive mechanism.

297 Early presentation of autosomal dominant Emery-Dreifuss muscular dystrophy E MERCURI,’ A Y MANZUR,’ H JUNCBLUTH,’ G BONNE,’ A MUCHIR,2 C SEWRY,‘” K SCHWARTZ,’ V DUBOWITZ,’ F MUNTONI’ ‘Department of Paediatrics, Imperial College School of Medicine, Hammersmith Hospital, London, UK; ‘INSERM UR 153, GH Pitie-Sa’lpetri&e, Paris, France; 3MRIC Biochemistry Group North East Wales Institute Plas Coch, Wrexham, Wales, UK

The gene responsible for the autosomal dominant form of Emery-Dreifuss muscular dystrophy (EMD2) has been recently identified. This gene encodes for the nuclear envelope proteins, lamins A and C, and is located on chromosome lqll-q23. Affected members of EMD2 show early contractures in the elbows and Achilles tendon, rigidity of the spine and a typical distribution of muscle atrophy which involves the biceps and the triceps in the upper l imbs and the calf muscles. As in the X- linked form of Emery-Dreifuss, the onset of weakness and atrophy generally occurs in the second decade of life while the cardiac involvement occurs at a later stage (3rd-4th decade). Individuals with exclusive cardiac involvement have also been found to carry mutations in this gene.

We report two children with an unusually early presentation by 2 years of age showing a severe phenotype. One of the children is now 4 years old and has rigidity of the lumbar spine, scapular winging and scapuloperoneal muscle wasting. He also showed Achilles tendon (TA) contractures and foot drop which required TA release and tibialis anterior transfer. The other boy is now 12 years old but he lost ambulation at the age of 7. In both children serum creatine kinase was elevated and a muscle biopsy showed a dystrophic pattern. Dystrophin and emerin were normal and genetic analysis demonstrated a de nave mutation of the lamin A/C gene on chromosome lq, suggesting a diagnosis of autosomal dominant Emery-Dreifuss muscular dystro- phy. Our case suggests that early presentation can also occur in the EMD2 and that a negative family history does not exclude the diagnosis, as a high incidence of de no~o events has been reported for this gene. Genetic analysis of the LMNA gene is the only accurate way of diagnosing this condition whose full spectrum of severity is only starting to be revealed.

298 Mutations in the lamin a2 chain gene in children with merosin-deficient CMD and cortical dysplasia E MERCURI, I NAOM, M KING,’ C SEWRY, V DUBOWITZ, F MUNTONI Neuromuscular Unit, Department of Paediatrics, Imperial College School of Medicine, Hammersmith Hospital, London, UK; ‘Department of Paediatric Neurology, Temple Street Hospital, Dublin, Ireland

Merosin-deficient congenital muscular dystrophy (CMD) is a severe congenital myopathy that accounts for about 40% of CMD children. Diffuse white matter changes on brain MRI is invariably present after 6 months of age. In rare instances, children with merosin-deficiency also have structural abnormalities, such as cerebellar hypo- plasia and/or neuronal migration disorder affecting the occipital cortex. Since only a minority of children with merosin-deficient CMD have these associated structural brain defects, the question of whether these children have either unusual mutations in the laminin a2 (LAMAZ) chain gene, or a separate genetic form of CMD has been raised in the past. We report on three children with cortical dysplasia and merosin-deficiency in whom genetic analysis confirmed the primary role of the LAMA gene on chromosome 6q2.

One of the three children had a more severe phenotype with moderate-to-severe mental retardation and epi- lepsy. The other two had clinical signs which were otherwise indistinguishable from classical merosin-defi- cient CMD. In the first case merosin was severely reduced in the muscle biopsy; in the other two cases (siblings) there was no protein expression.

Genetic analysis of the LAMA gene in case 1 showed a point mutation G-tA in exon 2 at position 306. This missense mutation resulted in a change of cysteine into tyrosine. Single-strand conformational polymorphism (SSCP) analysis suggested that the second mutation is in exon 56 and is still being characterized. Haplotype analysis of the two siblings (case 2 and 3) showed a similar homozygous pattern for the chromosome 6q2 markers, suggesting linkage to the LAMA locus. An abnormal conformer was obtained using SSCP analysis in exon 30 and is being characterized.

In conclusion, our results show that merosin-deficient CMD with cortical dysplasia is due to a primary involvement of the LAh4A2 chain gene on chromosome 6q2. The mutations found in these children were located in exons similar to those reported in children without neuronal migration disorder. The reason for the co- existence of a structural brain defect in these four children is therefore still not known. However, our results suggest an important role for the laminin st2 chain gene in brain development.