Rapid disease progression in adult‐onset mitochondrial membrane protein‐associated neurodegeneration

Abstract

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive degeneration of the central nervous system and high basal ganglia iron deposition. The list of identified causative genes for NBIA syndromes continues to expand and includes one autosomal dominant, one X-linked, and a number of recessive forms. Mitochondrial membrane protein-associated neurodegeneration is a recently described NBIA syndrome caused by C19orf12 mutations. In this study, we report two consanguineous families with a homozygous C19orf12 p.Thr11Met mutation. Our patients presented at a later age and had more rapid disease progression, leading to early death in two, than those previously reported. We conclude that C19orf12 mutation is associated with wide phenotypic heterogeneity, and that further research is needed to examine the role of C19orf12 in NBIA and related diseases and to elucidate its protein function as well as other factors that may affect disease progression and expression.

Analysis of the C19orf12 and WDR45 genes in patients with neurodegeneration with brain iron accumulation

“…The Thr11Met mutation has been described in a number of publications [5,10,12,13,15]. Both patients carrying this mutation in homozygous state in the present investigation (MPAN-1 and MPAN-2) were from consanguineous Turkish families.…”

“…Two patients (MPAN-1 and MPAN-2) showed the homozygous mutation c.C32T (p.Thr11Met) which only affects the longer transcript variant of C19orf12 and has been reported repeatedly [5,10,12,13]. Both affected subjects were from consanguineous Turkish families, but, to our knowledge, were not related to each other.…”

Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN)

“…Until now, 67 MPAN patients have been described in the literature (Deschauer et al, 2012;Dezfouli et al, 2013;Dogu et al, 2012;Goldman et al, 2013;Hartig et al, 2011;Hogarth et al, 2013;Panteghini et al, 2012;Schottmann, Stenzel, Lutzkendorf, Schuelke, & Knierim, 2013;Schulte et al, 2013). A compilation of all these cases shows that MPAN leads to a distinctive phenotype with prominent pyramidal and extrapyramidal signs, cognitive decline, neuropsychiatric abnormalities, optic atrophy, and motor axonal neuropathy (Table 3.1).…”

“…In addition to iron accumulation, generalized brain atrophy and/or cerebellar atrophy is found in a fraction of MPAN patients. Compilation of patients from references (Deschauer et al, 2012;Dezfouli et al, 2013;Dogu et al, 2012;Goldman et al, 2013;Hartig et al, 2011;Hogarth et al, 2013;Panteghini et al, 2012;Schottmann et al, 2013;Schulte et al, 2013).…”

“…Haplotype analysis suggests that the 11 bp deletion derives from a common founder at least 50-100 generations ago (Hartig et al, 2011). The second frequent mutation is the p.Thr11Met mutation, which was found in eight families from Turkey, Iran, Poland, and Russia with German origin (Deschauer et al, 2012;Dezfouli et al, 2013;Dogu et al, 2012;Hartig et al, 2011;Schulte et al, 2013). Seven further mutations were identified in two or more families.…”