Including three new japanese patients we diagnosed in this study, ten japanese families. Holocarboxylase synthetase hcs deficiency is an autosomal recessive disorder in which the body is unable to covalently bind biotin to the apocarboxylases to form active holocarboxylases. Molecular analysis of holocarboxylase synthetase deficiency. A lack of holocarboxylase synthetase activity may also alter the regulation of certain genes that are important for normal development. Mutations prevent the production of or reduce the activity of the enzyme holocarboxylase synthetase hcs. Characterization of mutant holocarboxylase synthetase hcs. Holocarboxylase synthetase deficiency presenting as ichthyosis holocarboxylase synthetase deficiency presenting as ichthyosis arbuckle, h. Holocarboxylase synthetase deficiency, a biotinresponsive multiple carboxylase deficiency mcd, is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Although the two diseases differ in the age of onset. Holocarboxylase synthetase deficiency is an inherited disorder in which the body is unable to use the vitamin biotin effectively. The typical presentation described in the medical literature is of neonatal onset within hours to weeks of birth with emesis, hypotonia, lethargy, seizures, metabolic ketolactic acidosis, hyperammonemia, developmental delay, skin rash and. Apr 22, 2020 holocarboxylase synthetase deficiency. Holocarboxylase synthetase deficiency results in impaired activation of enzymes implicated in glucose, fatty acid and amino acid metabolism.
Biotinidase deficiency is caused by mutations in the btd gene 3p25 and holocarboxylase synthetase deficiency by mutations in the hlcs gene 21q22. Multiple carboxylase deficiency genetic and rare diseases. Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical. Holocarboxylase synthetase an overview sciencedirect topics. Failure to attach the biotin results in multiple carboxylase deficiency and. Holocarboxylase synthetase hlcs deficiency is an inherited disease characterized by vomiting, lethargy, developmental delays, and hypotonia when untreated. Multiple carboxylase deficiency mcd is an autosomal recessive metabolic disorder caused by defective activity of biotinidase or holocarboxylase synthetase hlcs in the biotin cycle. The neonatal form of multiple carboxylase deficiency that is caused by a defect or deficiency in holocarboxylase synthetase.
This disorder is classified as a multiple carboxylase deficiency, a group of disorders characterized by impaired activity of certain enzymes that depend on biotin. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period summary by suzuki et al. Nov 03, 2015 finally, in 1980, based on the work of saunders and coworkers, roth et al reported holocarboxylase synthetase deficiency in a subsequent sibling of their original case. Holocarboxylase synthetase deficiency is caused by mutations in the hlcs gene 21q22. Read clustering of mutations in the biotinbinding region of holocarboxylase synthetase in biotinresponsive multiple carboxylase deficiency, human molecular genetics on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Symptoms are due to the toxic buildup of these substances. Little is known with regard to the reaction mechanism and structure of hlcs. Mar 01, 2006 read holocarboxylase synthetase deficiency presenting as ichthyosis, pediatric dermatology on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Information and translations of holocarboxylase synthetase deficiency in the most comprehensive dictionary definitions resource on the web. In humans, the biotin cycle can be disrupted by genetic deficiency of holocarboxylase synthetase hcs deficiency mim 253270 or biotinidase btd deficiency mim 253260, resulting in neonatal or juvenile onset forms, respectively, of the disease multiple carboxylase deficiency mcd 2, 20, 21. This disorder is classified as a multiple carboxylase deficiency, a group of disorders characterized by impaired activity of. Here, we report the obligatory participation of hcs in the biotindependent stimulation of the level of. Holocarboxylase synthetase hcs deficiency was defined as a distinct genetic disorder several years after its initial clinical description, similar. Holocarboxylase synthetase deficiency omim 253270 is a rare.
Scaly skin eruption, developmental delay, generalized muscular hypertonia, and mild ventriculomegaly were noted during the 1st year. Multiple carboxylase deficiency mcd is a term used to describe inborn errors of biotin metabolism characterized by reduced activities of biotindependent enzymes resulting in a wide spectrum of symptoms, including feeding difficulty, breathing difficulties, lethargy, seizures, skin rash, alopecia, and developmental delay. Most patients with hlcs deficiency present with symptoms in the newborn to early infantile period that include metabolic acidosis and organic aciduria, irritability, lethargy, hypotonia, seizures, coma, developmental delay and dermatitis. View enhanced pdf access article on wiley online library html view download pdf for. Clinical presentation and positive outcome of two siblings with holocarboxylase synthetase deficiency caused by a homozygous l216r mutation. We investigated in a patient with holocarboxylase synthetase deficiency, the relation between the biochemical and genetic factors of. If you have problems viewing pdf files, download the. Antenatal imaging and postnatal imaging are useful in making the diagnosis. Holocarboxylase synthetase deficiency is an autosomal recessive disorder of biotin metabolism resulting in multiple. Holocarboxylase synthetase deficiency was diagnosed, and biotin and carnitine were administered.
Multiple carboxylase deficiency kansas department of health. A novel molecular mechanism to explain biotinunresponsive holocarboxylase synthetase deficiency. The signs and symptoms of holocarboxylase synthetase. Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes. Holocarboxylase synthetase hlcs deficiency or multiple carboxylase deficiency is a rare disorder of biotin metabolism. Haplotype analysis suggests that the two predominant. Hcsd or mcd holocarboxylase synthetase deficiency multiple. Holocarboxylase synthetase deficiency integrated genetics.
Rare diseases information specialists for holocarboxylase synthetase deficiency. Clinical manifestations usually present within the first few days of life. Holocarboxylase synthetase deficiency is an inherited metabolic disorder in which the body is. Pdf holocarboxylase synthetase deficiency pre and post newborn. The first chapter of this dissertation focuses on the characterization of a novel class of. Holocarboxylase synthetase hcs catalyzes the covalent attachment of biotin to five biotindependent carboxylases in human cells. Pdf management of a patient with holocarboxylase synthetase. A case of holocarboxylase synthetase hcs deficiency of lateinfantile onset is presented and compared with the common manifestations in previously reported patients. This enzyme is important in covalent binding of biotin to the various biotindependent carboxylases that require the vitamin for activity.
Holocarboxylase synthetase deficiency genetic and rare. He was born prematurely and had bacteremia during the neonatal period. Holocarboxylase synthetase deficiency pre and post newborn. Holocarboxylase synthetase deficiency genetics home. Here, we report the obligatory participation of hcs in the biotindependent. Fibroblasts from the initial patient with the infantile form of biotinresponsive multiple carboxylase deficiency were shown to have abnormal holocarboxylase synthetase activity with a maximum velocity about 3040% of normal, a km for atp of 0. From 19701973, only 3 clinically varied cases of children who excreted betamethylcrotonic acid in their urine were reported. Holocarboxylase synthetase deficiency is an inborn error of biotin metabolism leading to multiple carboxylase deficiency which. Holocarboxylase synthetase is an obligate participant in. Multiple carboxylase deficiency occurs in less than1 in 100,000 births with no increased incidence based on sex or race. The typical presentation described in the medical literature is of neonatal onset within hours to weeks of birth with emesis, hypotonia, lethargy, seizures, metabolic ketolactic acidosis, hyperammonemia, developmental delay, skin rash and alopecia. Researched pathways related to holocarboxylase synthetase deficiency include excretion, response to biotin, gluconeogenesis, transport, biotin transport.
We have identified six different point mutations in the hcs gene in nine patients with mcd. Carbamoyl phosphate synthetase i deficiency is an inherited disorder that causes ammonia to accumulate in the blood hyperammonemia. Jan 11, 2016 holocarboxylase synthetase deficiency results in impaired activation of enzymes implicated in glucose, fatty acid and amino acid metabolism. Carbamoyl phosphate synthetase i deficiency genetics. Holocarboxylase synthetase hcs deficiency is a rare autosomal recessive disorder of biotin metabolism. Hlcs is the enzyme that covalently links biotin to the biotin dependent carboxylases propionylcoacarboxylase, pyruvate carboxylase, and betamethylcrotonylcoa carboxylase. A lifethreatening earlyonset form of multiple carboxylase deficiency, an inborn error of biotin. Pdf holocarboxylase synthetase deficiency is an autosomal recessive disorder of biotin metabolism resulting in. Holocarboxylase synthetase deficiency is an inherited metabolic disorder in which the body is unable to use the vitamin. Holocarboxylase synthetase hcs is an essential enzyme for the biotinylation of several mammalian carboxylases. Because of the acute and fulminant initial presentation of holocarboxylase synthetase.
Biotin holocarboxylase synthetase deficiency request pdf. Holocarboxylase synthetase deficiency selfdecode genome. Slavin tp, zaidi sj, neal c, nishikawa b, seaver lh. Management of a patient 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. Holocarboxylase synthetase deficiency, a biotinresponsive multiple carboxylase deficiency mcdis characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Michalski aj, berry gt, segal s 1989 holocarboxylase synthetase deficiency.
Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. Holocarboxylase synthetase deficiency genetic and rare diseases. Apr 16, 2002 holocarboxylase synthetase hcs catalyzes the covalent attachment of biotin to five biotindependent carboxylases in human cells. The patient was the sibling of the deceased child in whose cultured skin fibroblasts the precise enzymatic disorder was first. Multiple carboxylase deficiency mcd is a lifethreatening disease characterized by the lack of carboxylase activities because of deficiency of hcs activity.
It involves abnormalities in the enzyme holocarboxylase synthetase, which uses the vitamin biotin for the normal processing of proteins, fats, and carbohydrates. Researchers believe that these disruptions in important cellular functions lead to breathing problems, skin rashes, and the other characteristic signs and symptoms of holocarboxylase synthetase deficiency. Mutations in the hlcs gene cause multiple carboxylase deficiency. Tammachote r, janklat s, tongkobpetch s, suphapeetiporn k and shotelersuk v. The study of holocarboxylase synthetase deficiency has been mentioned in research publications which can be found using our bioinformatics tool below. Multiple carboxylase deficiency, or holocarboxylase synthetase deficiency, is an organic acid disorder caused by a reduction or lack of the enzyme. These enzymes use covalently attached biotin as a vector to transfer a carboxyl group between donor and acceptor molecules during carboxylation reactions. Jul 01, 2011 holocarboxylase synthetase deficiency is caused by mutations in the hlcs gene 21q22. Holocarboxylase synthetase deficiency presenting as. People with hcsd have problems changing protein and carbohydrates from food into energy for the body.
What does holocarboxylase synthetase deficiency mean. The vitamin biotin is an essential nutrient for the metabolism and survival of all organisms owing to its function as a cofactor of enzymes collectively known as biotindependent carboxylases. Multiple carboxylase deficiency neonatal mcd what is it. The clinical and biochemical features of an infant affected by holocarboxylase synthetase deficiency are presented. Definition of holocarboxylase synthetase deficiency in the dictionary. Multiple carboxylase deficiency mcd is an autosomal recessive metabolic disorder caused by defective activity of biotinidase or holocarboxylase synthetase hlcs. A deficiency in hcs results in biotinresponsive multiple carboxylase deficiency mcd. Holocarboxylase synthetase an overview sciencedirect. This is a pdf file of an unedited manuscript that has. We investigated in a patient with holocarboxylase synthetase deficiency, the relation between the biochemical and genetic factors of the mutant protein with the pharmacokinetic factors of successful biotin treatment.
Holocarboxylase synthetase deficiency is an autosomal recessive disorder of biotin metabolism resulting in multiple carboxylase deficiency. Holocarboxylase synthetase deficiency is an inherited metabolic disorder in which the body is unable to use the vitamin biotin effectively. We present a new case of holocarboxylase synthetase hcs deficiency, a rare autosomal recessive metabolic disorder. Holocarboxylase synthetase hlcs is a monomeric protein biotin ligase encoded by a single gene localized on chromosome 21 21q22. Hcsd stands for holocarboxylase synthetase deficiency. Because of the acute and fulminant initial presentation of holocarboxylase synthetase hcs deficiency, treatment is almost always initiated in.
We investigated in a patient with holocarboxylase synthetase deficiency, the relation between the biochemical and genetic factors of the mutant protein with the. The first reported hlcs gene mutation causing holocarboxylase. Our patient had her first episode at 20 months followed by recurrent episodes of metabolic acidosis with ketolactic acidosis responding dramatically to a short trial of biotin and thiamin. Clustering of mutations in the biotinbinding region of. Impaired biotinidase activity disrupts holocarboxylase. First prenatal molecular diagnosis in a family with. Holocarboxylase synthetase hcs catalyses the biotinylation of the four biotindependent carboxylases found in humans. Holocarboxylase synthetase deficiency is a rare autosomal recessive disorder of biotin metabolism. Novel roles of holocarboxylase synthetase in gene regulation. Holocarboxylase synthetase hcs deficiency was defined as a distinct genetic disorder several years after its initial clinical description, similar to the discovery of propionic acidemia. If you have problems viewing pdf files, download the latest version of adobe.
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