Although ribosomes are ubiquitously expressed and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein encoding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.
We investigated the genetic, phenotypic, and interferon status of 46
patients from 37 families with neurological disease due to mutations in
ADAR1. The clinicoradiological phenotype encompassed a
spectrum of Aicardi–Goutières syndrome, isolated bilateral
striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive
spastic dystonic motor disorder, and adult-onset psychological difficulties with
intracranial calcification. Homozygous missense mutations were recorded in five
families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of
23 families with compound heterozygous mutations. We also ascertained 11 cases
from nine families with a p.Gly1007Arg dominant-negative mutation, which
occurred de novo in four patients, and was inherited in three families in
association with marked phenotypic variability. In 50 of 52 samples from 34
patients, we identified a marked upregulation of type I interferon-stimulated
gene transcripts in peripheral blood, with a median interferon score of 16.99
(interquartile range [IQR]: 10.64–25.71) compared with
controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in
ADAR1 are associated with a variety of clinically distinct
neurological phenotypes presenting from early infancy to adulthood, inherited
either as an autosomal recessive or dominant trait. Testing for an interferon
signature in blood represents a useful biomarker in this context.
Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2, was seen in all twenty-seven patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.
Background
Dyskinesia is a troublesome complication of long-term dopaminergic medications in Par-kinson’s disease (PD) patients. Many factors are reported to be associated with dyskinesia in PD.
Objective
To investigate the association between sleep quality and dyskinesia in patients with PD.
Methods
Four hundred twenty-five patients with PD were enrolled in this study. Demographic information was collected. Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr (H-Y) stage scale were also performed. Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were applied to evaluate daytime sleepiness and overall nighttime sleep quality, respectively, in PD patients.
Results
Patients with dyskinesia tended to have a longer duration of disease, higher daily levodopa-equivalent dose (LED), H-Y stage, UPDRS II and PSQI score, and a higher percentage of levodopa treatment than those without dyskinesia. After adjusting for age, sex, age at onset of PD, disease duration, UPDRS I, UPDRS II, UPDRS III, cigarette smoking, use of different antiparkinsonian drugs, phenotype, daily LED, and restless leg syndrome (RLS), PSQI score was still associated with dyskinesia, with corresponding ORs 1.111 (95% CI, 1.004–1.229) as a continuous variable, and 2.469 (95% CI, 1.051–5.800) as a categorical variable, respectively. Further analysis of PSQI components showed that subjective sleep quality and sleep latency were associated with dyskinesia in PD patients.
Conclusions
Our data showed that poor nighttime sleep is positively associated with dyskinesia in PD patients. Attention to the management of nighttime sleep quality may be beneficial to dyskinesia in patients with PD.
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