ABSTRACT
Although ribosomes are ubiquitous 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-coding 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.
Subject(s)
Cerebral Small Vessel Diseases/genetics , Leukoencephalopathies/genetics , Mutation , RNA, Small Nucleolar/genetics , Adolescent , Adult , Calcinosis/genetics , Calcinosis/pathology , Cell Line , Cerebral Small Vessel Diseases/pathology , Child , Child, Preschool , Chromosomes, Human, Pair 17 , Cohort Studies , Cysts/genetics , Cysts/pathology , Exome , Female , Genetic Linkage , Genome, Human , Humans , Infant , Leukoencephalopathies/pathology , Male , Middle Aged , Sequence Analysis, DNA , Young AdultABSTRACT
BACKGROUND AND STUDY AIMS: Detailed data on long-term effectiveness of various drug therapies in Wilson's disease (WD) are lacking. Therefore, we retrospectively reviewed our patient cohort treated with D-penicillamine. PATIENTS AND METHODS: This study reports on the clinical presentation, the diagnostic evaluation, and the disease course in 24 WD patients treated long-term (15+/-12 years, between 1969 and 2009) with D-penicillamine. RESULTS: The overall survival in our cohort was 91.6%. Twenty-two of 24 patients had liver disease at presentation, 17 of 24 patients (71%) had cirrhosis, 11 of whom had complications of cirrhosis. Six of 11 of these patients showed hepatological improvement (five of six) or stabilization (one of six), three of 11 were transplanted, one of 11 died, one of 11 discontinued follow-up. In the six of 17 cirrhotic patients without complications, improvement (four of six) or stabilization (two of six) occurred. Of all other patients (seven of 24), five of seven showed improvement (three of five) or stabilization (two of five), hepatological deterioration occurred only in one patient due to poor therapy compliance and one of seven discontinued follow-up. Neuropsychiatric symptoms were present in 13 of 24 at presentation and resolved in one of 13, decreased in seven of 13, stabilized in four of 13 and worsened in one of 13 patients (due to poor compliance). In general, we observed a favorable hepatological and neurological evolution with D-penicillamine. CONCLUSION: Despite the presence of liver disease or neuropsychiatric symptoms at baseline in all but one of the patients, we report beneficial results on liver and neurological disease after very long-term treatment with D-penicillamine, thereby adding to its reputation as 'first-line' therapy in WD.
