Early-onset parkinsonism caused by alpha-synuclein gene triplication: Clinical and genetic findings in a novel family

Introduction: Triplications of SNCA, the gene encoding for α-synuclein, cause a very rare Mendelian form of early-onset parkinsonism combined with cognitive and autonomic dysfunctions. Only six families with SNCA triplications have been described so far, limiting our knowledge of the associated phenotype. In this study, we report clinical and genetic findings in a new Italian family with SNCA triplication. Methods: The patients' phenotype was assessed by neurological examination, neuropsychological tests, and brain imaging (MRI and SPECT-DaTSCAN). For the genetic investigation, we used three independent techniques: genome-wide SNP microarrays, fluorescence in situ hybridization (FISH), and multiplex ligation-dependent probe amplification (MLPA). Results: Genetic studies documented the presence of four copies of the SNCA gene in the affected family members. FISH experiments and the segregation in the family were consistent with a heterozygous triplication of the SNCA locus. The patients carrying the SNCA triplication developed early-onset parkinsonism combined with depression, behavior disturbances, sleep disorders, and cognitive decline; marked autonomic dysfunctions were not observed. Brain imaging revealed fronto-parietal atrophy and a severe striatal dopaminergic deficit. Conclusion: The identification of this novel family contributes to the genetic and clinical characterization of this rare form. Our data reinforce the view that SNCA triplications cause early-onset parkinsonism, with prominent non-motor features

Manganese transport disorder: Novel SLC30A10

Background: SLC30A10 mutations cause an autosornal recessive disorder, characterized by hyperrnanganesaennia, polycythennia, early-onset dystonia, paraparesis, or late-onset parkinsonism, and chronic liver disease. This is the first identified inborn error of Mn metabolism in humans, reported in 10 families thus far. Methods: Methods for this study consisted of clinical examination, neuroimaging studies (MRI), serum dosages, and SLC30A10 genetic analysis. Results: We describe early disease manifestations (including videos) in 5 previously unreported Indian children, carrying novel homozygous SLC30A10 mutations. Gait and speech disturbances, falls, dystonias, and central hypotonia were the presenting neurological features, starting within the first 5 years of life. All children also had severe hypermanganesemia, polycythennia, variable degree of liver disease, and marked brain MRI Ti hyperintensities. Conclusions: Our findings expand the mutational and clinical spectra of this recently recognized disorder. An early diagnosis is warranted, because treatment with manganese-chelating agents, iron supplementation, or their combination might improve symptoms and prevent progression of this otherwise potentially fatal disease. (C) 2015 International Parkinson and Movement Disorder Societ

Manganese Transport Disorder: Novel SLC30A10 Mutations and Early Phenotypes

Background: SLC30A10 mutations cause an autosornal recessive disorder, characterized by hyperrnanganesaennia, polycythennia, early-onset dystonia, paraparesis, or late-onset parkinsonism, and chronic liver disease. This is the first identified inborn error of Mn metabolism in humans, reported in 10 families thus far. Methods: Methods for this study consisted of clinical examination, neuroimaging studies (MRI), serum dosages, and SLC30A10 genetic analysis. Results: We describe early disease manifestations (including videos) in 5 previously unreported Indian children, carrying novel homozygous SLC30A10 mutations. Gait and speech disturbances, falls, dystonias, and central hypotonia were the presenting neurological features, starting within the first 5 years of life. All children also had severe hypermanganesemia, polycythennia, variable degree of liver disease, and marked brain MRI Ti hyperintensities. Conclusions: Our findings expand the mutational and clinical spectra of this recently recognized disorder. An early diagnosis is warranted, because treatment with manganese-chelating agents, iron supplementation, or their combination might improve symptoms and prevent progression of this otherwise potentially fatal disease. (C) 2015 International Parkinson and Movement Disorder Societ

DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease

ObjectiveDNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age<11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within approximate to 10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD). MethodsThe DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies. ResultsWe identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD. InterpretationOur findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis. Ann Neurol 2016;79:244-25

The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN

Introduction: Mutations in the C19orf12 gene cause mitochondrial membrane protein associated neurodegeneration (MPAN), an autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA). A limited number of patients with C19orf12 mutations, particularly those with adult onset of symptoms, have been reported

Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency

BackgroundECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh-like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations. MethodsClinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed. ResultsThe first sibling is 17 years old and presents with generalized dystonia and severe bilateral pallidal MRI lesions after 1 episode of infantile subacute metabolic encephalopathy (Leigh-like syndrome). In contrast, the younger sibling (15 years old) only suffers from paroxysmal exercise-induced dystonia and has very mild pallidal MRI abnormalities. Both patients carry compound heterozygous ECHS1 mutations: c.232G>T (predicted protein effect: p.Glu78Ter) and c.518C>T (p.Ala173Val). Linkage analysis, exome sequencing, cosegregation, expression studies, and metabolite profiling support the pathogenicity of these mutations. Expression studies in patients' fibroblasts showed mitochondrial localization and severely reduced levels of ECHS1 protein. Increased urinary S-(2-carboxypropyl)cysteine and N-acetyl-S-(2-carboxypropyl)cysteine levels, proposed metabolic markers of this disorder, were documented in both siblings. Sequencing ECHS1 in 30 unrelated patients with paroxysmal dyskinesias revealed no further mutations. ConclusionsThe phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. (c) 2016 International Parkinson and Movement Disorder Societ