open access

Vol 53, No 6 (2019)
Research Paper
Submitted: 2019-06-13
Accepted: 2019-09-30
Published online: 2019-12-05
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Clinical and genetic spectrum of an orphan disease MPAN: a series with new variants and a novel phenotype

Nihan Hande Akçakaya1, Garen Haryanyan2, Sevcan Mercan2, Nejla Sozer3, Asuman Ali4, Temel Tombul5, Ugur Ozbek6, Sibel Aylin Uğur İşeri2, Zuhal Yapıcı7
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Pubmed: 31804703
·
Neurol Neurochir Pol 2019;53(6):476-483.
Affiliations
  1. Council of Forensic Medicine, Kımız sokak no:1 Bahçelievler, 34034 Istanbul, Türkiye
  2. Department of genetics, Institute of Aziz Sancar Experimental Medicine (ASDETAE), Istanbul University
  3. Department of Neurology, Dr. Sadi Konuk Training and Research Hospital, Health Sciences University Istanbul, Turkey
  4. Department of Neurology, Yuksek Ihtisas Training and Research Hospital, Health Sciences University, Bursa, Turkey
  5. Department of Neurology, Yuzuncu Yil Faculty of Medicine, Yuzuncu Yil University, Van, Turkey
  6. Department of Medical Genetics, Acibadem Faculty of Medicine, Acibadem University, Istanbul, Turkey
  7. Department of child neurology, Istanbul University

open access

Vol 53, No 6 (2019)
Research papers
Submitted: 2019-06-13
Accepted: 2019-09-30
Published online: 2019-12-05

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.

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.

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Keywords

MPAN, C19orf12, SPG43, iron accumulation, spastic paraplegia, HSP

About this article
Title

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

Journal

Neurologia i Neurochirurgia Polska

Issue

Vol 53, No 6 (2019)

Article type

Research Paper

Pages

476-483

Published online

2019-12-05

Page views

1966

Article views/downloads

580

DOI

10.5603/PJNNS.a2019.0062

Pubmed

31804703

Bibliographic record

Neurol Neurochir Pol 2019;53(6):476-483.

Keywords

MPAN
C19orf12
SPG43
iron accumulation
spastic paraplegia
HSP

Authors

Nihan Hande Akçakaya
Garen Haryanyan
Sevcan Mercan
Nejla Sozer
Asuman Ali
Temel Tombul
Ugur Ozbek
Sibel Aylin Uğur İşeri
Zuhal Yapıcı

References (14)
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