Nihan Hande Akçakaya1, Garen Haryanyan2, Sevcan Mercan2, Nejla Sozer3, Asuman Ali4, Temel Tombul5, Ugur Ozbek6, Sibel Aylin Uğur İşeri2, Zuhal Yapıcı7. 1. Council of Forensic Medicine, Kımız sokak no:1 Bahçelievler, 34034 Istanbul, Turkey. nhakcakaya@gmail.com. 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.
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.
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.
Entities:
Keywords:
C19orf12; HSP; MPAN; SPG43; iron accumulation; spastic paraplegia