Since 1980, Arnold Munnich has made every efforts to conciliate the clinical and molecular approaches of genetic diseases in children. His efforts have resulted in the founding of the Department of Genetics, Hôpital des Enfants-Malades, Paris, which brings together i) a Clinical Research INSERM unit, dedicated to the mapping and identification of genes causing developmental and neurogenetic diseases in children, ii) the Medical Genetic Clinic of Assistance Publique, Hôpitaux de Paris.
Thanks to the improvement of the human gene map, he has mapped and/or identified twenty disease causing genes, including the genes for:
- achondroplasia (1/15,000 live births, fibroblast growth factor receptor 3),
- Hirschsprung disease (1/5,000 live births, Ret oncogene),
- spinal muscular atrophy (1/6,000 live births, survival motor neuron, SMN),
- X-linked spastic paraplegia (proteolipid protein),
- Holt-Oram syndrome (brachyury),
- multiple exostosis (EXT),
- Stargardt macular dystrophy (ABCR4),
- Leber congenital amaurosis (retinal guanylate cyclase),
- Saethre-Chotzen craniosynostosis (twist),
- Pearson’s marrow pancreas syndrome (mitochondrial DNA deletion),
- the first nuclear gene for Leigh syndrome (SDH, FP),
- mental retardation (AR) : neurotrypsine,
- several nuclear genes for mitochondrial diseases (BCS1, COX10, SCO1),
- Triple A syndrome (1/50,000 live births, Aladin),
- Incontinentia pigmenti (1/5,000 live births, Nemo, with the International IP Consortium) and ectodermal dysplasia-immune deficiency (1/5,000 live births, Nemo and IkBa).
He has recently shown that Friedreich ataxia results from multiple iron-sulphur protein injury caused by iron overload in mitochondria. Based on this observation, he devised a novel therapeutic approach using short-chain quinones (Idebenone) to protect iron sulphur centers from oxidative stress. This treatment, now given to all novel cases, cures cardiomyopathy in 85% of patients. He has also identified a novel inborn error of quinone synthesis resulting in multiple respiratory chain deficiency and caused by a point mutation in a polyprenyl transferase gene. Most importantly, children are cured by oral quinone administration.
A. Munnich has fostered several research groups and young investigators that gradually took over the leadership and seniorship of their projects.
What are the benefits for the children and their families ? The mapping and identification of these genes makes carrier testing, genetic counselling and prenatal diagnosis of these conditions now feasible and allow novel therapeutic approaches. The originality of his project consists in the combination of a clinical expertise and a molecular approach of medical genetics in the unique environment of a large european pediatric hospital.