Testing of NBIA Genes: Analysis of Genetic Heterogeneity and Validation of Mitochondrial Markers for Assessing Causality of Sequence Variants.

Neurodegeneration with brain iron accumulation (NBIA) represent a group of rare neurodevelopmental diseases, genetically as well as phenotypically heterogeneous.

The diagnosis is based on brain MRI. It shows abnormal deposit of iron in the basal ganglia, especially in the globus pallidus and the substance nigra. It is also based on genetic testing. Ten individualized forms are now described. However overlaps exist between the different clinical presentations and the molecular diagnosis may be misinterpreted because of variants, named as variants of unknown signification, whom the pathogenic role is not proven. Approximately half of the clinically relevant cases with iron deposits on brain MRI remain without any molecular deleterious alteration.

Two main purposes must be addressed to get a better molecular diagnosis: on one hand reaching enough exhaustivity which may be performed with a larger gene panel and next generation sequencing; this panel will include new genes and could be enlarged as more genes are identified. On the other hand, it is now necessary to validate or infirm the deleterious consequences of variants with the help of functional studies.

Four major pathways are involved in the pathophysiology of NBIA: iron and lipids metabolisms, mitochondrial metabolism and autophagy.

Considering that biochemical mechanisms inside the mitochodrion are involved in these four pathways, the investigators performed a first test starting from patient's fibroblasts and analyzed the literature in order to define the parameters that could be pertinent as biological markers of NBIA.