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Inclusions of intermediate filaments are found in a number of neurodegenerative diseases. Using whole exome sequencing, linkage analysis and proteomics, Wong and Chiu et al. identify a new familial neurodegenerative disease with intermediate filament inclusions, linked to a mutation in the gene encoding the PKA type I-beta regulatory subunit, PRKAR1B.Pathological accumulation of intermediate filaments can be observed in neurodegenerative disorders, such as Alzheimer's disease, frontotemporal dementia and Parkinson's disease, and is also characteristic of neuronal intermediate filament inclusion disease. Intermediate filaments type IV include three neurofilament proteins (light, medium and heavy molecular weight neurofilament subunits) and alpha-internexin. The phosphorylation of intermediate filament proteins contributes to axonal growth, and is regulated by protein kinase A. Here we describe a family with a novel late-onset neurodegenerative disorder presenting with dementia and/or parkinsonism in 12 affected individuals. The disorder is characterized by a unique neuropathological phenotype displaying abundant neuronal inclusions by haematoxylin and eosin staining throughout the brain with immunoreactivity for intermediate filaments. Combining linkage analysis, exome sequencing and proteomics analysis, we identified a heterozygous c.149T > G (p.Leu50Arg) missense mutation in the gene encoding the protein kinase A type I-beta regulatory subunit (PRKAR1B). The pathogenicity of the mutation is supported by segregation in the family, absence in variant databases, and the specific accumulation of PRKAR1B in the inclusions in our cases associated with a specific biochemical pattern of PRKAR1B. Screening of PRKAR1B in 138 patients with Parkinson's disease and 56 patients with frontotemporal dementia did not identify additional novel pathogenic mutations. Our findings link a pathogenic PRKAR1B mutation to a novel hereditary neurodegenerative disorder and suggest an altered protein kinase A function through a reduced binding of the regulatory subunit to the A-kinase anchoring protein and the catalytic subunit of protein kinase A, which might result in subcellular dislocalization of the catalytic subunit and hyperphosphorylation of intermediate filaments.

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 Society

LRRK2 mutations can cause familial and sporadic Parkinson's disease (PD) with Lewy-body pathology at post-mortem. Studies of olfaction in LRRK2 are sparse and incongruent. We applied a previously validated translation of the 16 item smell identification test from Sniffin' Sticks (SS-16) to 14 parkinsonian carriers of heterozygous G2019S LRRK2 mutation and compared with 106 PD patients and 118 healthy controls. The mean SS-16 score in LRRK2 was higher than in PD (p < 0.001, 95% CI for beta = -4.7 to -1.7) and lower than in controls (p = 0.007, 95% CI for beta = +0.6 to +3.6). In the LRRK2 group, subjects with low scores had significantly more dyskinesia. They also had younger age of onset, longer disease duration, and reported less frequently a family history of PD, but none of these other differences reached significance. Odor identification is diminished in LRRK2 parkinsonism but not to the same extent as in idiopathic PD. (C) 2010 Movement Disorder Society

To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD).We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA.A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state.We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.