Neurodegeneration with Brain Iron Accumulation

Testing NBIA genes: analysis of genetic heterogeneity and validation of mitochondrial markers

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare brain diseases, genetically as well as phenotypically heterogeneous. The department of medical genetics in the University Hospital of Bordeaux is an expert center involved in the clinical and molecular diagnosis of these pathologies.The diagnosis is suspected on brain MRI which shows abnormal depositsof iron in the basal ganglia, and is confirmed by genetic testing. Ten individualized forms are now described but overlaps exist between the clinical presentations. In addition interpretation of sequencing data may be difficult due to variants of unknown signification.

Approximately half of the clinically relevant cases with iron deposits on brain MRI remain without any molecular deleterious alteration. In order to achieve a more efficient molecular diagnosis we address two main purposes: more exhaustivity in genetic testing with new candidate genes and the development of functional studies to explore the consequences of unknown variants.

At present, four pathways are involved in the pathophysiology of NBIA: iron and lipids metabolism, mitochondrial energetic sand autophagy. The link between iron overload and neurodegeneration is still unclear but accumulating data show that a mitochondrial dysfunction is involved as a cause or a consequence of iron excess.A gene panel including 11new NBIA genes is tested to identify variants in patients without molecular diagnosis.

This screening will be followed by whole exome sequencing in a sub group of patients allowing a trio strategy to identify new genes.We currently study the mitochondrial anomalies in the most frequent forms: MPAN(gene C19 or f12), PKAN (gene PANK2) and BPAN(gene WDR45)to define the biological markers pertinent to confirm the pathogenicity of unknown variants. The study is initiated with patient’s fibroblasts and will continue with neuronal IPScto validate these markers. In addition aPANK2 yeast model has been engineered by CRISPR-Cas9 and will be used to test therapeutic molecules.

Contributing Members

Patricia Fergelot [PH]
Isabelle Coupry [CR1 INSERM]
Christelle Durand [IH]
Christophe Hubert [IE UB]
Cyril Goizet [PU-PH]

National and International Collaborations

UMR 5095 IBGC Bordeaux. Équipe Génétique Moléculaire des Systèmes Mitochondriaux

Filières nationales maladies rares DéfiScience

Brain-Team