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

Nihan Hande Akçakaya, Garen Haryanyan, Sevcan Mercan, Nejla Sozer, Asuman Ali, Temel Tombul, Ugur Ozbek, Sibel Aylin Uğur İşeri, Zuhal Yapıcı
DOI: 10.5603/PJNNS.a2019.0062
·
Pubmed: 31804703
·
Neurol Neurochir Pol 2019;53(6):476-483.

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

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)

Pages

476-483

Published online

2019-12-05

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)
  1. Hartig MB, Iuso A, Haack T, et al. Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet. 2011; 89(4): 543–550.
  2. Schottmann G, Stenzel W, Lützkendorf S, et al. A novel frameshift mutation of C19ORF12 causes NBIA4 with cerebellar atrophy and manifests with severe peripheral motor axonal neuropathy. Clin Genet. 2014; 85(3): 290–292.
  3. Deschauer M, Gaul C, Behrmann C, et al. C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis. J Neurol. 2012; 259(11): 2434–2439.
  4. Olgiati S, Doğu O, Tufekcioglu Z, et al. The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN. Parkinsonism Relat Disord. 2017; 39: 64–70.
  5. Hogarth P, Gregory A, Kruer MC, et al. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology. 2013; 80(3): 268–275.
  6. Dogu O, Krebs CE, Kaleagasi H, et al. Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration. Clin Genet. 2013; 84(4): 350–355.
  7. Horvath R, Holinski-Feder E, Neeve VCM, et al. A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy. Mov Disord. 2012; 27(6): 789–793.
  8. Skowronska M, Kmiec T, Kurkowska-Jastrzębska I, et al. Eye of the tiger sign in a 23 year patient with mitochondrial membrane protein associated neurodegeneration. J Neurol Sci. 2015; 352(1-2): 110–111.
  9. Akcakaya NH, Iseri SU, Bilir B, et al. Clinical and genetic features of PKAN patients in a tertiary centre in Turkey. Clin Neurol Neurosurg. 2017; 154: 34–42.
  10. Tschentscher A, Dekomien G, Ross S, et al. Analysis of the C19orf12 and WDR45 genes in patients with neurodegeneration with brain iron accumulation. J Neurol Sci. 2015; 349(1-2): 105–109.
  11. Illingworth MA, Meyer E, Chong WK, et al. PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease. Mol Genet Metab. 2014; 112(2): 183–189.
  12. Landouré G, Zhu PP, Lourenço CM, et al. NIH Intramural Sequencing Center. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum Mutat. 2013; 34(10): 1357–1360.
  13. Kleffner I, Wessling C, Gess B, et al. Behr syndrome with homozygous C19ORF12 mutation. J Neurol Sci. 2015; 357(1-2): 115–118.
  14. Venco P, Bonora M, Giorgi C, et al. Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca²⁺. Front Genet. 2015; 6: 185.

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