Neurodegeneration with brain iron accumulation: Characterization of clinical, radiological, and genetic features of pediatric patients from Southern India

Bhardwaj, Neerja; Gowda, Vykuntaraju K; Saini, Jitendra; Sardesai, Ashwin Vivek; Santhoshkumar, Rashmi; Mahadevan, Anita

doi:10.1016/j.braindev.2021.06.010

Cited by 6 publications

(2 citation statements)

References 31 publications

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“…Indeed, according to such criteria, this variant is classified as a VUS, applying PM1 (mutational hot spot) and PM2 (absence in controls) at the supporting level. Upon discovering a positive family history and reexamining clinical and imaging data, we were able to manually flag two additional criteria at the supporting level, namely, PP1 (cosegregation into multiple family members) and PP4 (highly specific phenotype), yet, to strictly adhere to current guidelines, 8 we did not flag PP5 (reliable source reports the variant as pathogenic), although the same variant had formerly been reported in three unrelated patients with features in the spectrum of PLA2G6‐associated neurodegeneration 14‐17 . Thus, despite that this homozygous variant clearly appears as causative of the early‐onset dystonia‐parkinsonism phenotype shown by the patient, ACMG criteria still do not reach the sufficient strength to unequivocally classify the variant as pathogenic/likely pathogenic.…”

Section: Discussionmentioning

confidence: 99%

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study

Di Fonzo,

Percetti,

Monfrini

et al. 2023

Movement Disorders

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Background and ObjectiveEarly‐onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next‐generation sequencing (NGS) of PD‐associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far.MethodsWe retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD‐related genes, as well as PD‐multiplex ligation‐dependent probe amplification in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report, and final interpretation (positive/negative/inconclusive). Patients were further stratified based on age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD‐associated GBA1 variants were considered diagnostic.ResultsIn 186 of 648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18 of 186 (10%) patients, with 5 shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive.ConclusionsThis study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS‐multigene panels, with relevant implications for counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionmentioning

confidence: 99%

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study

Di Fonzo,

Percetti,

Monfrini

et al. 2023

Movement Disorders

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“…1,5,12 As highlighted in this case report, the application of next-generation sequencing (NGS) tests will improve diagnostic accuracy. 17 The differential diagnoses with similar clinical phenotype include multiple system atrophy, Machado Joseph's disease, Parkinson's plus syndrome and Wilson's disease. 1,13,18 We present here an adult Turkish patient with MPAN and a novel (c.101C>T;p.Ala34Val) disease-causing variant in the C19orf12 gene.…”

Section: Discussionmentioning

confidence: 99%

A novel p.Ala34Val variant in C19orf12 is associated with neurodegeneration with brain iron accumulation

Kocaaga¹,

Uslu²

2022

NeuroAsia

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Loss-of-function mutations in the C19orf12 gene may lead to mitochondrial membrane protein- associated neurodegeneration (MPAN), which is a subtype of neurodegeneration with brain iron accumulation disorders. It is manifest with juvenile-onset spastic paraparesis, dystonia, dysphagia, optic atrophy, decreased cognitive functions, and neuropsychiatric symptoms. Large amounts of iron are accumulated in the globus pallidus and substantia nigra pars reticulata due to abnormal brain iron metabolism. We report a novel C19orf12 (c.101C>T;p.Ala34Val) homozygous mutation in a Turkish man who presented with postural instability, slow gait and anxiety. Neuroimaging showed mild iron deposition in the basal ganglia and cortical atrophy. These results are consistent with the MPAN. This report demonstrates the importance of testing patients with spastic paraplegia, parkinsonism, motor axonal neuropathy, difficulty walking or dysarthria for MPAN.

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Neurodegeneration with brain iron accumulation: a case series highlighting phenotypic and genotypic diversity in 20 Indian families

et al. 2023

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Neurodegeneration with brain iron accumulation: Characterization of clinical, radiological, and genetic features of pediatric patients from Southern India

Cited by 6 publications

References 31 publications

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study

A novel p.Ala34Val variant in C19orf12 is associated with neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation: a case series highlighting phenotypic and genotypic diversity in 20 Indian families

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