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  3. Holocarboxylase synthetase deficiency
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Holocarboxylase synthetase deficiency


Title




Other Names:
Early-onset multiple carboxylase deficiency; Neonatal multiple carboxylase deficiency
Categories:
Congenital and Genetic Diseases; Newborn Screening; Skin Diseases
This disease is grouped under:
Multiple carboxylase deficiency

Summary Summary


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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 79242

Definition
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.

Epidemiology
The exact prevalence of HCSD is unknown, but the condition is one of the rarest inborn errors of metabolism. Annual incidence is estimated to be less than 1/200,000 live births.

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.

Etiology
Holocarboxylase synthetase deficiency is caused by mutations in the HLCS gene (21q22.1) resulting in reduced HCS activity. 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.

Management and treatment
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.

Prognosis
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.
Last updated: 7/1/2011

Symptoms Symptoms


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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. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 28 |
Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Anorexia 0002039
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth
[ more ]
0001510
Irritability
Irritable
0000737
Keratoconjunctivitis 0001096
Muscular hypotonia
Low or weak muscle tone
0001252
Nausea and vomiting 0002017
Perioral eczema
Eczema around the mouth
0011127
Seizure 0001250
Weight loss 0001824
30%-79% of people have these symptoms
Hyperammonemia
High blood ammonia levels
0001987
Organic aciduria 0001992
Respiratory distress
Breathing difficulties
Difficulty breathing
[ more ]
0002098
Tachypnea
Increased respiratory rate or depth of breathing
0002789
5%-29% of people have these symptoms
Alopecia
Hair loss
0001596
Ataxia 0001251
Coma 0001259
Desquamation of skin soon after birth 0007549
Lethargy 0001254
Thrombocytopenia
Low platelet count
0001873
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance 0000007
Feeding difficulties in infancy 0008872
Generalized hypotonia
Decreased muscle tone
Low muscle tone
[ more ]
0001290
Global developmental delay 0001263
Hypertonia 0001276
Hyperventilation
Rapid breathing
0002883
Metabolic acidosis 0001942
Skin rash 0000988
Vomiting
Throwing up
0002013
Showing of 28 |
Do you have more information about symptoms of this disease? We want to hear from you.
Last updated: 2/1/2021
Do you have updated information on this disease? We want to hear from you.

Diagnosis Diagnosis


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Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. 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.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. 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. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
  • 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


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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.

If you can’t find a specialist in your local area, try contacting national or international specialists. 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.

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. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

Learn More Learn More


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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.

Where to Start

  • Genetics Home Reference (GHR) contains information on Holocarboxylase synthetase deficiency. This website is maintained by the National Library of Medicine.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
  • The Screening, Technology And Research in Genetics (STAR-G) Project has a fact sheet on this condition, which was written specifically for families that have received a diagnosis as a result of newborn screening. This fact sheet provides general information about the condition and answers questions that are of particular concern to parents.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.

News & Events News & Events


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News

  • Rare Disease Day at NIH 2021
    March 1, 2021

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Have a question? Contact a GARD Information Specialist.
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