A De Novo case of autosomal dominant mitochondrial membrane protein‐associated neurodegeneration

Abstract

Background Mitochondrial membrane protein‐associated neurodegeneration (MPAN) is a genetic neurodegenerative condition previously thought to be inherited only in an autosomal recessive pattern through biallelic pathogenic variants in C19orf12. Recent evidence has proposed that MPAN can also follow autosomal dominant forms of inheritance. We present a case of a de novo pathogenic variant in C19orf12 identified in a female with clinical features consistent with a diagnosis of MPAN, adding further evidence that the disease can be inherited in an autosomal dominant fashion. Methods A 17‐year‐old Hispanic female was born to non‐consanguineous healthy parents. She developed progressive muscle weakness and dystonia beginning when she was 12 years old. Trio, whole‐exome sequencing with mitochondrial genome sequencing, and deletion/duplication analysis of both nuclear and mitochondrial genomes was performed in December 2019. Results Whole‐exome sequencing analysis revealed a single de novo variant in C19orf12. The specific variant is c.256C>T (p.Q86X) located in exon 3. Conclusion Our clinical report provides further clinical evidence that MPAN can be inherited in an autosomal dominant or recessive fashion. The patient's age of onset and clinical symptoms are very similar to the previous patient published with this specific variant as well as others with heterozygous pathogenic variants in C19orf12 in Gregory et al. 2019. Our case report highlights the importance of considering both autosomal dominant and autosomal recessive version of MPAN with all patients demonstrating clinical features suggestive of MPAN.

Case Report: Identification of a De novo C19orf12 Variant in a Patient With Mitochondrial Membrane Protein–Associated Neurodegeneration

“…Thus, Rickman et al (2021) considered “haploinsufficiency of isoform 3” as a potential mechanism of monoallelic MPAN, which results in a protein truncated after amino acid 75 and lacking the putative transmembrane region. Other studies subsequently confirmed an autosomal dominant mode of inheritance in MPAN ( Fraser et al, 2021 ; Rickman et al, 2021 ).…”

Autosomal Dominant MPAN: Mosaicism Expands the Clinical Spectrum to Atypical Late‐Onset Phenotypes

“…27 Although the existence of two modes of inheritance, recessive and dominant, appears now irrefutable in MPAN, no clinical differences were previously reported between them. 5,11 Our series of eight AD-MPAN patients strongly argues for this, excepted for patients with mosaicism who display later onset.…”

“…Until recently the inheritance of C19orf12 pathogenic variants was thought to be strictly autosomal recessive. 11,24 However, several recent reports paved the way for parallel existence of a dominant form (Table S2). [5][6][7][8][9][10][11][12]15,25 To date, among the 18 monoallelic candidate variants reported in FIG.…”

“…11,24 However, several recent reports paved the way for parallel existence of a dominant form (Table S2). [5][6][7][8][9][10][11][12]15,25 To date, among the 18 monoallelic candidate variants reported in FIG. 4.…”

“…Brain MRI typically shows T2‐weighted hypointensities in the globus pallidus (GP) and substantia nigra (SN). AD‐MPAN is generally considered phenotypically indistinguishable from AR‐MPAN although few cases have been reported up to now 5‐12 …”