Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability

Balicza, Péter; Bencsik, Renáta; Lengyel, András; Gál, Anikó; Grosz, Zoltán; Csabán, Dóra; Rudas, Gábor; Danics, Krisztina; Kovács, Gábor G.; Molnár, Mária Judit

doi:10.1212/nxg.0000000000000515

Cited by 11 publications

(15 citation statements)

References 16 publications

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“…Apart from the unusually late age of onset, the presentation of the disease was consistent with the phenotypes of previous patients carrying p.Val691del or p.Thr319Met, and also with what is known about adult‐onset PLA2G6 ‐related parkinsonism in general. PLA2G6 ‐associated hippocampal changes have been previously described in number of previous studies 28 . In this study, MRI of one proband but not the other showed hippocampal expansion.…”

Section: Discussionsupporting

confidence: 64%

PLA2G6‐associated late‐onset parkinsonism in a Sudanese family

Bakhit

Tesson

Ibrahim

et al. 2023

Ann Clin Transl Neurol

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Introduction The phospholipase A2 group VI gene (PLA2G6) encodes an enzyme that catalyzes the hydrolytic release of fatty acids from phospholipids. Four neurological disorders with infantile, juvenile, or early adult‐onset are associated with PLA2G6 genetic alterations, namely infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia‐parkinsonism (DP), and autosomal recessive early‐onset parkinsonism (AREP). Few studies in Africa reported PLA2G6‐associated disorders and none with parkinsonism of late adult onset. Material and Methods The patients were clinically assessed following UK Brain Bank diagnostic criteria and International Parkinson and Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS‐UPDRS). Brain MRI without contrast was performed. Genetic testing was done using a custom‐made Twist panel, screening 34 known genes, 27 risk factors, and 8 candidate genes associated with parkinsonism. Filtered variants were PCR‐amplified and validated using Sanger sequencing and also tested in additional family members to study their segregation. Result Two siblings born to consanguineous parents developed parkinsonism at the age of 58 and 60 years, respectively. MRI showed an enlarged right hippocampus in patient 2, but no overt abnormalities indicative of INAD or iron deposits. We found two heterozygous variants in PLA2G6, an in‐frame deletion NM_003560:c.2070_2072del (p.Val691del) and a missense variant NM_003560:c.956C>T (p.Thr319Met). Both variants were classified as pathogenic. Conclusion This is the first case in which PLA2G6 is associated with late‐onset parkinsonism. Functional analysis is needed to confirm the dual effect of both variants on the structure and function of iPLA2β.

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Section: Discussionsupporting

confidence: 64%

PLA2G6‐associated late‐onset parkinsonism in a Sudanese family

Bakhit

Tesson

Ibrahim

et al. 2023

Ann Clin Transl Neurol

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“…Recently, an in vivo study on zebrafish embryos found that depletion of dynactin 1 was not adequate to cause the death of motor neurons but contributed to the pathogenesis of ALS [45]. Furthermore, oligogenic and polygenic factors have been implied to play an important role in the variable expressivity of monogenic disorders [46,47]. It is hypothesized that the phenotype variability of the same DCTN1 mutation carriers may be partially accounted for by oligogenic or polygenic background.…”

Section: Discussionmentioning

confidence: 99%

Clinical, pathological and genetic characteristics of Perry disease—new cases and literature review

Dulski

Cerquera-Cleves

Milanowski

et al. 2021

Euro J of Neurology

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Background and purpose: Perry disease (or Perry syndrome) is an autosomal dominant neurodegenerative disorder characterized by parkinsonism, neuropsychiatric symptoms, central hypoventilation, weight loss and distinct TDP-43 pathology. It is caused by mutations of the DCTN1 gene encoding an essential component of axonal transport. The objectives were to provide the current state of knowledge on clinical, pathological and genetic aspects of Perry disease, as well as practical suggestions for the management of the disease. Methods: Data on new patients from New Zealand, Poland and Colombia were collected, including autopsy report. Also all of the published papers since the original work by Perry in 1975 were gathered and analyzed.Results: Parkinsonism was symmetrical, progressed rapidly and was poorly responsive to L-Dopa; nonetheless, a trial with high doses of L-Dopa is warranted. Depression was severe, associated with suicidal ideations, and benefited from antidepressants and L-Dopa. Respiratory symptoms were the leading cause of death, and artificial ventilation or a diaphragm pacemaker prolonged survival. Weight loss occurred in most patients and was of multifactorial etiology. Autonomic dysfunction was frequent but underdiagnosed.There was a clinical overlap with other neurodegenerative disorders. An autopsy showed distinctive pallidonigral degeneration with TDP-43 pathology. Genetic testing provided evidence of a common founder for two families. There was striking phenotypic variability in DCTN1-related disorders. It is hypothesized that oligogenic or polygenic inheritance is at play.

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“…22 unrelated AD-MPAN families, 11,12 only nine variants are supported by strong evidences of pathogenicity: six identified in sporadic cases, 5,8,1,2,5 and three in families. 5,10 Additional eight sporadic cases with unavailable parental DNA were described. 5 In the other patients carrying a heterozygous variant, a second hidden variant in C19orf12 or the involvement of another yet unknown NBIA gene has been suspected.…”

Section: Discussionmentioning

confidence: 99%

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

Angelini,

Durand,

Fergelot

et al. 2023

Movement Disorders

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BackgroundMitochondrial membrane protein‐associated neurodegeneration (MPAN) is caused by mutations in the C19orf12 gene. MPAN typically appears in the first two decades of life and presents with progressive dystonia‐parkinsonism, lower motor neuron signs, optic atrophy, and abnormal iron deposits predominantly in the basal ganglia. MPAN, initially considered as a strictly autosomal recessive disease (AR), turned out to be also dominantly inherited (AD).ObjectivesOur aim was to better characterize the clinical, molecular, and functional spectra associated with such dominant pathogenic heterozygous C19orf12 variants.MethodsWe collected clinical, imaging, and molecular information of eight individuals from four AD‐MPAN families and obtained brain neuropathology results for one. Functional studies, focused on energy and iron metabolism, were conducted on fibroblasts from AD‐MPAN patients, AR‐MPAN patients, and controls.ResultsWe identified four heterozygous C19orf12 variants in eight AD‐MPAN patients. Two of them carrying the familial variant in mosaic displayed an atypical late‐onset phenotype. Fibroblasts from AD‐MPAN showed more severe alterations of iron storage metabolism and autophagy compared to AR‐MPAN cells.ConclusionOur data add strong evidence of the realness of AD‐MPAN with identification of novel monoallelic C19orf12 variants, including at the mosaic state. This has implications in diagnosis procedures. We also expand the phenotypic spectrum of MPAN to late onset atypical presentations. Finally, we demonstrate for the first time more drastic abnormalities of iron metabolism and autophagy in AD‐MPAN than in AR‐MPAN. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability

Cited by 11 publications

References 16 publications

PLA2G6‐associated late‐onset parkinsonism in a Sudanese family

PLA2G6‐associated late‐onset parkinsonism in a Sudanese family

Clinical, pathological and genetic characteristics of Perry disease—new cases and literature review

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

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