HOLOCARBOXYLASE SYNTHETASE DEFICIENCY PDF

This article includes discussion of biotin holocarboxylase synthetase deficiency, biotin-responsive beta-methylcrotonylglycinuria, biotin-responsive multiple carboxylase deficiency, and holocarboxylase synthetase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. The author explains that a child with biotin holocarboxylase synthetase deficiency who is homozygous for the LR mutation, which is usually associated with a poor outcome even with biotin supplementation, can potentially do better clinically if diagnosed early and treated with a daily dose of as much as 1. During the s, inherited isolated deficiencies of the 3 mitochondrial biotin-dependent carboxylases were described Wolf and Feldman The carboxylases include 1 pyruvate carboxylase, which converts pyruvate to oxaloacetate, the initial step of gluconeogenesis; 2 propionyl-coenzyme A carboxylase, which catabolizes several branch-chain amino acids and odd-chain fatty acids; and 3 beta-methylcrotonyl-coenzyme A carboxylase, which is involved in the catabolic pathway of leucine. Each deficiency is due specifically to a structural abnormality in its respective enzyme; the activities of the other carboxylases are normal.

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This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Making a diagnosis for a genetic or rare disease can often be challenging. The following resources provide information relating to diagnosis and testing for this condition.

If you have questions about getting a diagnosis, you should contact a healthcare professional. If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals.

You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments. They may be able to refer you to someone they know through conferences or research efforts.

Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care. You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists. These resources provide more information about this condition or associated symptoms.

The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional. Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. National Institutes of Health. COVID is an emerging, rapidly evolving situation. Menu Search Home Diseases Holocarboxylase synthetase deficiency.

You can help advance rare disease research! Title Other Names:. Early-onset multiple carboxylase deficiency; Neonatal multiple carboxylase deficiency. This disease is grouped under:. Multiple carboxylase deficiency. Summary Summary. The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. A life-threatening early-onset form of multiple carboxylase deficiency, an inborn error of biotin metabolism, that, if untreated, is characterized by vomiting, tachypnea, irritability, lethargy, exfoliative dermatitis, and seizures that can worsen to coma.

The exact prevalence of HCSD is unknown, but the condition is one of the rarest inborn errors of metabolism. Clinical description. Clinical onset is usually within hours, days or weeks of birth. Individuals with the disorder usually exhibit poor appetite, vomiting, lethargy, irritability, hypotonia and exfoliative dermatitis. Metabolically, they have ketolactic acidosis, organic acidemia -uria and hyperammonemia. Without treatment, affected infants may progress to intractable seizures, cerebral edema and coma.

These children often develop growth and developmental delays. Holocarboxylase synthetase deficiency is caused by mutations in the HLCS gene 21q This enzyme is important in covalent binding of biotin to the various biotin-dependent carboxylases that require the vitamin for activity.

Failure to attach the biotin results in multiple carboxylase deficiency and accumulation of various, specific abnormal organic acids. Diagnostic methods. Some affected individuals are identified through newborn screening by demonstration of abnormal organic acids, consistent with multiple carboxyalse deficiency. Diagnosis is based on clinical signs and typical organic acid abnormalities. Confirmational testing can be performed by demonstrating deficient HCS activity in leukocytes or fibroblast extracts or by mutation analysis.

Differential diagnosis. Conditions to be considered in the differential diagnosis based on organic acids include biotinidase deficiency see this term and isolated carboxyalse deficiencies; based on hyperammonemia, include urea cycle defects see this term ; and based on neurological compromise and seizures in the neonatal period, include sepsis and other inborn errors of metabolism.

Antenatal diagnosis. Prenatal diagnosis can be performed by organic acid analysis by stable isotope dilution techniques in amniotic fluid, enzymatic determination of HCS activity in amniocytes , or mutation analysis on DNA from chorionic villus biopsy or amniocentesis. Genetic counseling. HCS deficiency is inherited as an autosomal recessive trait. Genetic counseling is available to families who have children with the disorder.

Siblings of affected children are unlikely to have the disorder or they would have developed symptoms, but they may be carriers. The primary treatment for HCS deficiency is free biotin supplementation which can improve the clinical status of symptomatic individuals with the enzyme deficiency and prevent some or all symptoms from developing in asymptomatic individuals with the disorder.

Treatment should be started as soon as possible after diagnosis and must be continued lifelong. Affected individuals should be monitored for later-onset complications and for compliance with therapy.

Timely and ongoing treatment makes it possible to reduce symptoms considerably, although some patients develop complications despite appropriate treatment often requiring higher doses of biotin. In the absence of early diagnosis and treatment, mortality is high. Morbidity in surviving affected individuals depends on the time of diagnosis and on the degree of damage related to metabolic crises.

Visit the Orphanet disease page for more resources. Symptoms Symptoms. Showing of 28 View All. Delayed growth. Growth deficiency. Growth failure. Growth retardation. Poor growth. Retarded growth. Low or weak muscle tone. Eczema around the mouth. High blood ammonia levels. Breathing difficulties. Difficulty breathing. Increased respiratory rate or depth of breathing. Hair loss. Low platelet count. Decreased muscle tone. Low muscle tone. Rapid breathing. Throwing up. Do you have more information about symptoms of this disease?

We want to hear from you. Do you have updated information on this disease? Diagnosis Diagnosis. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Newborn Screening An ACTion ACT sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result.

Algorithms are developed by experts in collaboration with the American College of Medical Genetics. Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.

National Newborn Screening and Global Resource Center NNSGRC provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials. Find a Specialist Find a Specialist. Healthcare Resources To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Learn More Learn More.

This website is maintained by the National Library of Medicine. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

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Holocarboxylase synthetase deficiency

Alternative titles; symbols. Holocarboxylase synthetase deficiency, a biotin-responsive multiple carboxylase deficiency MCD , is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period summary by Suzuki et al. Also see biotinidase deficiency , another form of MCD with a later onset. Care must be taken to differentiate the inherited multiple carboxylase deficiencies from acquired biotin deficiencies, such as those that develop after excessive dietary intake of avidin, an egg-white glycoprotein that binds specifically and essentially irreversibly to biotin Sweetman et al. Thoene et al. The severe manifestations included lactic acidosis, alopecia, keratoconjunctivitis, perioral erosions, and seizures; all symptoms were completely reversed by biotin treatment.

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Biotin holocarboxylase synthetase deficiency

Holocarboxylase synthetase deficiency MCD is a condition in which the body is unable to break down proteins and carbohydrates. People with this condition have trouble using biotin, a vitamin that helps turn certain carbohydrates and proteins into energy for the body. Holocarboxylase synthetase deficiency is considered an organic acid condition because it can lead to a harmful buildup of organic acids and toxins in the body. Early detection and treatment often can prevent the severe outcomes of MCD. It is important to remember that an out-of-range screening result does not necessarily mean that your child has the condition.

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