1/6. Clinical findings and biochemical and molecular analysis of four patients with holocarboxylase synthetase deficiency.Holocarboxylase synthetase (HLCS) deficiency (HLCSD) is a rare autosomal recessive disorder of biotin metabolism. HLCS catalyzes the biotinylation of the four human biotin-dependent carboxylases. Using the newly available human genomic sequence, we report the map of HLCS genomic structure and the predicted exon/intron boundaries. Moreover, the molecular studies of four patients (two Italians, one Iranian, and one Australian) affected by HLCS deficiency are here reported. The clinical findings, the age of onset, and response to biotin treatment differed between our patients. The diagnosis was made by organic acid analysis and confirmed by enzymatic analysis in three patients. Six mutations in the HLCS gene were identified, including two novel (N511K and G582R) and four known missense mutations (L216R, R508W, V550M, and G581S). Five of the mutations are localized within the HLCS biotin-binding domain, whereas the L216R amino acid change is located in the N-terminal region outside of the putative biotin-binding domain. This mutation, previously reported in a heterozygous state, was detected for the first time in a patient with homozygous status. The patient's severe clinical phenotype and partial responsiveness to biotin support a genotype-phenotype correlation through the involvement of residues of the N-terminal region in a substrate specificity recognition or regulation of the HLCS enzyme.- - - - - - - - - - ranking = 1keywords = deficiency (Clic here for more details about this article) |
2/6. A genomic approach to mutation analysis of holocarboxylase synthetase gene in three Chinese patients with late-onset holocarboxylase synthetase deficiency.OBJECTIVE: multiple carboxylase deficiency (MCD, MIM:253270) is a common organic aciduria and caused by deficiency of either biotinidase or holocarboxylase synthetase (HLCS; EC 6.3.4.10). patients commonly present during early infancy with acute metabolic derangements and severe metabolic acidosis. Recently, a late onset form of HLCS deficiency was also described. The different phenotypes (early and late presenting) may be related to a spectrum of mutations in HLCS gene. Applications of mutation analysis in HLCS had been limited previously by the requirement of cDNA from living tissue for study. We described here a genomic approach for molecular diagnosis of HLCS deficiency which we have used to detect mutations in Chinese patients who had the late-onset form of HLCS deficiency. In addition, a fibroblast cell line with MCD from Coriell Cell repositories was also studied. DESIGN AND methods: Three Chinese patients with late onset HLCS deficiency were studied. The genomic sequence of HLCS was retrieved and newly designed primers were used to cover all coding sequences of the gene. PCR products were analyzed by direct sequencing. population allelic frequencies of mutations detected were determined by genotyping of control samples by restriction fragment length polymorphism. RESULTS: We found a recurrent mutation, R508W, in the three unrelated Chinese patients. Two were homozygous for this mutation. The other patient was a compound heterozygote of R508W and a novel mutation, D634N. The results suggest that R508W may be an important and relatively prevalent disease-causing mutation in Chinese MCD patients. A fibroblast cell-line from an African patient revealed an additional novel mutation, R565X and a known mutation, V550M. CONCLUSION: R508W is a recurrent mutation in Chinese MCD patients which is associated with the late onset phenotype. This new genomic approach for mutation analysis of HLCS gene provides new opportunities in studies of MCD.- - - - - - - - - - ranking = 24.698845863533keywords = carboxylase deficiency, deficiency (Clic here for more details about this article) |
3/6. Partial response to biotin therapy in a patient with holocarboxylase synthetase deficiency: clinical, biochemical, and molecular genetic aspects.We report the clinical course and biochemical findings of a 10-year-old, mentally retarded girl with late-onset holocarboxylase synthetase (HCS, gene symbol HLCS) deficiency and only partial response to biotin. On treatment, even with an unusually high dose of 200mg/day, activities of the biotin-dependent mitochondrial carboxylases in lymphocytes remained below 50% of the mean control values. Not only urinary 3-hydroxyisovaleric acid excretion has been persistently elevated, but also plasma and, with even higher concentrations, cerebrospinal fluid 3-hydroxyisovaleric acid have not normalized. The unusual and insufficient response of this patient to biotin treatment can be explained by the effect of the combination of the common HLCS allele IVS10 5 g>a on one chromosome and a truncating mutation on the other. This case illustrates mechanisms involved in the genotype-phenotype correlation that unequivocally exists in HCS deficiency.- - - - - - - - - - ranking = 1keywords = deficiency (Clic here for more details about this article) |
4/6. Severe holocarboxylase synthetase deficiency with incomplete biotin responsiveness resulting in antenatal insult in samoan neonates.We describe 7 Polynesian babies with a unique severe form of holocarboxylase synthetase deficiency characterized by antenatal growth retardation, subependymal cysts, only partial response to biotin, and a poor outcome.- - - - - - - - - - ranking = 0.83333333333333keywords = deficiency (Clic here for more details about this article) |
5/6. First prenatal molecular diagnosis in a family with holocarboxylase synthetase deficiency.OBJECTIVES: We report on the first prenatal molecular diagnosis of holocarboxylase synthetase (HLCS) deficiency in the fourth pregnancy of an at-risk family. This disorder is a rare autosomal recessive inborn error of metabolism, leading to a multiple carboxylase defect (MCD). HLCSD diagnosis was performed postmortem in the proband on dna from autoptic biological material. Molecular analysis of the proband's entire HLCS gene by direct sequencing identified the R508W amino acid change, at the homozygous status. methods: Fetal dna was isolated from chorionic villus sampling at 11 weeks of gestation. Direct sequencing of exon 6 of the fetal HLCS gene was performed. RESULTS: The R508W mutation was identified in the fetal dna at the homozygous level. The genetic lesion was confirmed on abortive tissue. CONCLUSION: Molecular diagnosis has several advantages over enzymatic activity assay of carboxylases in chorionic villi or amniocytes. It can be performed earlier, is faster, and the response time is shorter.- - - - - - - - - - ranking = 0.83333333333333keywords = deficiency (Clic here for more details about this article) |
6/6. holocarboxylase synthetase deficiency presenting as ichthyosis.holocarboxylase synthetase deficiency is a rare autosomal recessive disorder of biotin metabolism. Clinical manifestations usually present within the first few days of life and include severe acidosis, feeding difficulties, breathing abnormalities, vomiting, seizures, progressive loss of consciousness, coma, and death. skin findings, when present, usually develop within the first weeks of life and are described as an erythroderma-like dermatitis involving the eyebrows, eyelashes, and scalp. We were asked to consult on a newborn with a collodion membrane and severe metabolic acidosis who was eventually diagnosed with holocarboxylase synthetase deficiency and ichthyosis. The diagnosis of holocarboxylase synthetase deficiency might be considered in a newborn with collodion membrane, ichthyosis, and acidosis.- - - - - - - - - - ranking = 1.1666666666667keywords = deficiency (Clic here for more details about this article) |