Prenatal diagnosis of BMD in Morocco: Evolution and limits

Prenatal Diagnosis of BMD in Morocco: Evolution and Limits

Khalil Hamzi

Afaf Ben Itto

Mohammed Itri

Sellama Nadifi

Received: 10 August 2013 / Accepted: 25 August 2013 / Published online: 8 September 2013

#Springer Science+Business Media New York 2013

Abstract The muscular dystrophy is a group of inherited disorders characterized in the most of cases by progressive muscle weakness. The best known are X-linked disorder Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). BMD is a milder form of the disease with a later age of onset and a slower clinical progression. The DMD gene, located on Xp21, is the largest human gene in the human genome (2.3 Mb). DMD gene consists of 79 exons and codes for dystrophin protein. A 9-year-old boy, who experienced symptoms of the disease, was admitted to the Casablanca University Children’s Hospital. The patient, with no known family history of significant muscle disease, was first exam- ined at 4 years of age because of walking difficulties and a limited hands force. Blood tests revealed elevated serum levels of creatine kinase (7.60 U/L). The electromyogram showed myopathic changes, consisting of polyphasic poten- tials, and the muscular biopsy revealed dystrophic aspect.

Analysis of the dystrophin-encoding gene by PCR deletion analysis of the dystrophin gene was performed by multiplex PCR primer sets of Chamberlain and Beggs. The analysis showed a deletion of exons 45 to 49. Mother genetic testing showed the heterozygosis deletion.

Keywords Prenatal diagnosis . Becker muscular dystrophy . Legal framework

Dear Editor,

The muscular dystrophy is a group of inherited disorders characterized in the most of cases by progressive muscle weakness. The best known are X-linked disorder Duchenne

muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). BMD is a milder form of the disease with a later age of onset and a slower clinical progression. The DMD gene, located on Xp21, is the largest human gene in the human genome (2.3 Mb) (Koening et al.

of 79 exons and codes for dystrophin protein (Forrest et al.

1988). Sixty-five percent of DMD/BMD cases are caused by

partial gene deletions (60 %) or by duplications (5 %) of different sizes that are preferentially clustered in two major hotspots of mutation, exons 3

7 and exons 44

55. Point mutations and small deletion/insertion account for the other cases (35 %) (Den Dunnen et al.

tween DMD and BMD can be explained by the reading frame hypothesis that mutations which disrupt the reading frame, causing a premature termination and loss of dystrophin, are leading to a severe phenotype (Duchenne disease) and that mutations which retain the reading frame generate a shortened protein; the dystrophin may still have been limited to almost normal function, leading to a milder phenotype (Becker dis- ease) (Hu et al.

In our communication, we report the case of a pregnant mother of a 9-year-old boy with BMD (Fig.

positive for DMD gene deletion, she is asking for genetic counseling and prenatal testing for BMD. In this case, we are confronted to two difficulties: prenatal molecular testing and legal position.

Case Report

A 9-year-old boy, who experienced symptoms of the disease, was admitted to the Casablanca University Children

s Hospi- tal. The patient, with no known family history of significant muscle disease, was first examined at 4 years of age because of walking difficulties and a limited hands force. Blood tests revealed elevated serum levels of creatine kinase (7.60 U/L).

The electromyogram showed myopathic changes, consisting of polyphasic potentials, and the muscular biopsy revealed

:

Laboratory of Human Genetics, Faculty of Medicine, University Hospital, Casablanca, Morocco

e-mail: [email protected] A. B. Itto

:

Pediatrics Department, University Hospital, Casablanca, Morocco J Mol Neurosci (2014) 52:459–460

DOI 10.1007/s12031-013-0106-5

dystrophic aspect. Analysis of the dystrophin-encoding gene by PCR deletion analysis of the dystrophin gene was performed by multiplex PCR primer sets of Chamberlain and Beggs. The analysis showed a deletion of exons 45 to 49. Mother genetic testing showed the heterozygosis deletion.

We received the couple for a prenatal diagnosis; an amnio- centesis was done, and the molecular testing by MLPA meth- od gave the following three informations:

1.

Microsatellite testing showed that the fetus is a boy.

2.

Quantitative testing showed the presence of exons 45 to 49 deletion.

3.

However, microsatellite testing showed the presence of some maternal cells in amniotic sample.

On the basis of those informations, we provide accurate counseling for the family. In front of variable and heteroge- neous features of Becker muscular dystrophy, the absence of legal directives on prenatal testing and pregnancy interruption, it was impossible to have a medical decision. In Morocco, consanguinity presents 35 % in population with an important concentration of genetics and inherited diseases, especially

autosomal recessive diseases (Jalal et al.

is no legal framework governing the prenatal testing practice.

Aside from a risk of the mother

s life, the pregnancy interrup- tion is punishable by law. However, prenatal testing requests growths every day, and we think that it is the time to establish a National Bioethics Committee, which will consider the organization techniques and structures authorized to perform prenatal testing. The objective of this study is to report diffi- culties and limits of prenatal testing, therapeutics decisions in the absence of a legal framework, and also, the difficulties of genetic counseling in front of variable and heterogeneous features of genetic diseases.

References

Den Dunnen JT, Grootscholten PM, Bakker E et al (1989) Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications. Am J Hum Genet 45(6):835–847

Forrest SM, Cross GS, Flint T, Speer A, Robson KJH, Davies KE (1988) Further studies of gene deletions that cause Duchenne and Becker muscular dystrophies. Genomics 2(2):109–114

Hu X, Burghes AH, Ray PN, Thompson MW, Murphy EG, Worton RG (1988) Partial gene duplication in Duchenne and Becker muscular dystrophies. J Med Genet 25(6):369–376

Jalal T, Abd Errazzak K, Abd El-Majid S, Abd El-Aziz C (2007) Study of consanguinity in Moroccan population. Influence on the profile of health. Antropo 15:1–11

Koening M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM (1987) Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50(3):

509–517 Fig. 1 The pedigree presenting the family of A.H

460 J Mol Neurosci (2014) 52:459–460