Infantile neuroaxonal dystrophy: challenges for identification and new advances in prenatal diagnosis.

Infantile neuroaxonal dystrophy (INAD; OMIM #256600) is a rare disease belonging to the group of neurodegenerative disorders together with NBIA (neurodegeneration with brain iron accumulation, PANK2 gene, OMIM #234200), KARAK syndrome and Schindler disease (OMIM #609241). These diseases share the pathologic feature of axonal degeneration with distended axons throughout the central nervous system. In previous work there has been some controversy regarding whether INAD is a separate entity or is part of a spectrum of diseases with panhothenate kinase-associated neurodegeneration (PANK). Based on molecular studies of the PANK2 gene it became clear that INAD and PANK are genetically heterogeneous disorders. Recently, a gene PLA2G6, encoding a phospholipase A2, has been recognized as causing INAD. However, there is still some overlap in phenotypes resulting from deficiencies in the PLA2G6 and PANK2 genes. We present here the clinical features, diagnosis and molecular results of four patients from three unrelated families in whom a definitive diagnosis could be made by molecular analysis. In all four patients clinical data and biochemical studies were in agreement with a diagnosis of neuroaxonal dystrophy. Molecular studies of the PLA2G6 were performed to confirm this diagnosis. The two male siblings from family 1 were homozygous for a p.Val371Met substitution; there was no apparent consanguinity in this family. A healthy carrier female was born after prenatal diagnosis through chorionic villus sampling. The 2 other patients were from consanguineous parents, and were homozygous for a previously described p.Leu481Gln mutation and a frameshift mutation resulting from a 2bp duplication, respectively.