Clinical and genetic spectrum of an orphan disease MPAN: a series with new variants and a novel phenotype

Abstract

Introduction. Pathogenic variations in C19orf12 are responsible for two allelic diseases: mitochondrial membrane protein-associated neurodegeneration (MPAN); and spastic paraplegia type 43 (SPG43). MPAN is an orphan disease, which presents with spasticity, dystonia, peripheral nerve involvement, and dementia. The pattern of iron accumulation on brain MRI may be a clue for the diagnosis of MPAN. SPG43, on the other hand, is characterised by progressive lower limb spasticity without brain iron accumulation. We here present clinical and genetic findings of MPAN patients with potentially pathogenic C19orf12 variants. Materials and methods.Patients from 13 different families having progressive motor symptoms with irritative pyramidal signs and brain iron accumulation were screened for C19orf12 gene variants. results. C19orf12 screening identified seven variants associated with MPAN in eight patients from seven families. We associated two pathogenic variants (c.24G > C; p.(Lys8Asn) and c.194G > A; p.(Gly65Glu)) with the MPAN phenotype for the first time. We also provided a genetic diagnosis for a patient with an atypical MPAN presentation. The variant c.32C > T; p.(Thr11Met), common to Turkish adult-onset MPAN patients, was also detected in two unrelated late-onset MPAN patients.conclusions. Genetic analysis along with thorough clinical analysis supported by radiological findings will aid the differential diagnosis of MPAN within the neurodegeneration with brain iron accumulation spectrum as well as other disorders including hereditary spastic paraplegia. Dystonia and parkinsonism may not be the leading clinical findings in MPAN patients, as these are absent in the atypical case. Finally, we emphasise that the existence of frameshifting variants may bias the age of onset toward childhood.

Exploring the Genetic and Genomic Connection Underlying Neurodegeneration with Brain Iron Accumulation and the Risk for Parkinson’s Disease

“…In the literature, this variant has been seen in compound heterozygosity in patients with the MPAN NBIA phenotype. 50,51,52 Lastly, we found the p.P60L mutation at statistical significance present in one UKB case and absent in controls. The carrier under study was a female PD patient with an age at inclusion of 66 and no other notable C19orf12 mutations.…”

Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease

“…In addition, another two patients were reported to have this phenotype; one carrying the compound heterozygous mutations p.G65V and p.P60L and the other carrying a homozygous p.G65V variant 39 . The p.K142E variant, present it our data, has been seen in compound heterozygosity in patients with the MPAN NBIA phenotype [40][41][42] . Lastly, we found the p.P60L mutation at statistical significance present in one UKB case and absent in controls.…”

Complex dystonias: an update on diagnosis and care

“…NBIAs are an expanding group of progressive diseases characterized by abnormal accumulation of iron in the brain, particularly the basal ganglia, caused by different mutations with different modes of inheritance (see Table 2; Akcakaya et al 2019;Mari et al 2018;Rattay et al 2019;Haack et al 2012;Marchi et al 2019) leading to neurodegeneration. Most patients present with movement disorders, particularly dystonia and parkinsonism.…”