Niemann-Pick’s disease type B and brain iron accumulation

Background: Niemann-Pick’s type B (NP-B) disease is a rare, autosomal recessive visceral storage disorder related to a lysosomal accumulation of sphingomyelin, which is caused by mutations in the sphingomyelinase gene, SMPD1 . Case report: We present a boy who had normal early development, but from one year of age, he showed progressive manifestations of hepatosplenomegaly, somatomotor retardation and cardiopulmonary dysfunction. The activity of the sphingomyelinase enzyme was very low in his fibroblasts. He died at 17 years of age from cardio-respiratory insufficiency. Gross pathology and histology of the internal organs were compatible with Niemann-Pick’s disease. His brain and spinal cord displayed no signs of storage disease, confirming the subtype of NP-B. Unexpectedly, however, significant accumulation of iron was seen in the substantia nigra, subthalamic nuclei, putamen, globus pallidus and some cortical regions accompanied by axonal spheroids. Brain iron accumulation is the hallmark of a disease group termed neurodegeneration with brain iron accumulation (NBIA). Sequencing of the known NBIA disease genes was unsuccessful in the proband’s DNA isolated from formalin-fixed, paraffin-embedded blocks, but both asymptomatic parents were heterozygous carriers of the same c19orf12 deletion. Conclusions: This case initially raised the question as to whether two rare autosomal recessive disorders, NP-B and a subtype of NBIA could have co-occurred in our patient, or the lipid dysmetabolism due to sphingomyelinase deficiency caused secondary brain iron accumulation. Genetic analyses in the parents suggested the former possibility by identifying a c19orf12 gene deletion known to underlie in homozygous state Mitochondrial Membrane Protein Associated Neurodegeneration.