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Screening & Prevention >> Newborn Screening >> Organic Acidemias >> Holocarboxylase/multiple carboxylase deficiency

Holocarboxylase/multiple carboxylase deficiency

Disorder Category

an organic acid disorder

Screening

Finding

elevated C5:1 (methylcrotonyl or tiglyl carnitine) or elevated C5-OH (3-hydoxyisovaleryl carnitine)

Tested By

tandem mass spectrometry (MS/MS); sensitivity: NA; specificity: NA

Names

Holocarboxylase/multiple carboxylase deficiency

MCD

Holocarboxylase synthetase deficiency (HCSD)

Holocarboxylase deficiency

ICD-9

269.2, Unspecified vitamin deficiency

Overview

Caused by a a defect in holocarboxylase synthetase which is responsible for binding biotin to three biotin-dependent enzymes, propionyl CoA carboxylase, beta-methylcrotonyl CoA carboxylase, and pyruvate carboxylase. The loss of function of these enzymes disrupts the citric acid cycle, gluconeogenesis, and leucine catabolism. This leads to inadequate energy production, accumulation of precursors, and loss of metabolites critical for other pathways, such as the urea cycle. A late-onset form of multiple carboxylase deficiency may be due to defective biotin absorption or transport.

Prevalence

about 1/87,000 live births [Holocarboxylase/multiple carboxylase deficiency, Genetics Home Reference]

Inheritance

autosomal recessive

Prenatal Testing

DNA testing by amniocentesis or CVS.

Clinical Characteristics

With treatment, most children will have normal growth and development, though some have only partly or not responded to therapy. Without treatment, repeated episodes of metabolic acidosis lead to severe impairment or death. Infants may begin to show symptoms within a few hours or days of life while other infants may not have symptoms till two years of age. Children may be healthy between metabolic crisis episodes.

Initial signs/symptoms may include:
  • poor feeding,
  • vomiting,
  • skin rashes,
  • lethargy,
  • lab findings:
    • hyperammonemia,
    • keturia,
    • thrombocytopenia,
    • hypoglycemia, and
    • elevated organic acid levels in the blood and urine.


If not treated promptly, patients may experience:
  • difficulty breathing,
  • alopecia,
  • motor skill delays,
  • hearing loss,
  • speech loss,
  • spasticity,
  • problems with coordination,
  • seizures,
  • brain damage, and
  • death.

Follow-up on positive screening test

Quantitative plasma acylcarnitine profile, serum biotinidase assay, urine organic acids.

Primary care management

Upon notification of the + screen

  • Contact the family and evaluate the infant for poor feeding, vomiting, or lethargy;
  • Provide emergency treatment/referral for signs/symptoms of hypoglycemia, metabolic acidosis, ketonuria, or seizures;
  • To confirm the diagnosis, work with the following service(s): Utah Newborn Screening Program, (801-584-8256); See also Services below;
  • For evaluation and ongoing collaborative management, consult the following service(s): Metabolic Clinic, (801-585-2457); See also Services below;

If the diagnosis is confirmed

  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Holocarboxylase/multiple carboxylase deficiency info for parents, STAR-G for additional information);
  • Meals high in biotin, including liver, egg yolks, milk, fish, cereals, yeast, broccoli, lean beef, white and sweet potatoes, may be indicated for affected children;
  • Biotin supplements may be indicated for some children;
  • For those identified after irreversible consequences, assist in management, particularly with hearing aids or cochlear implants, and developmental and educational interventions.

Specialty Care Management

Initial consultation and ongoing collaboration, particularly for dietary management. Genetic counseling for the family.

Resources

Links

For Professionals

ACT Sheet for Holocarboxylase/multiple carboxylase deficiency from ACMG
Developed by the American College of Medical Genetics (ACMG), includes recommended responses to positive newborn screening test results, diagnostic evaluation, clinical expectations, and sources of additional information. See the ACMG ACT Sheets and Confirmatory Algorithms (link elsewhere on this page) for more info and sheets on other conditions.

ACMG ACT Sheets and Confirmatory Algorithms
The American College of Medical Genetics (ACMG) has developed ACTion (ACT) Sheets and algorithms for responding to positive newborn screening test results. This page contains a table with links to all of the ACT Sheets and related algorithms.

Holocarboxylase/multiple carboxylase deficiency, OMIM
From the Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University, providing technical information for providers on genetic disorders, links to MEDLINE, and links to other scientific information and sites.

Holocarboxylase/multiple carboxylase deficiency Fact Sheet, Iowa Dept. of Health
This fact sheet, developed by the Iowa Department of Health, provides information for parents and professionals.

For Parents

Holocarboxylase/multiple carboxylase deficiency info for parents, STAR-G
From the Screening, Technology and Research in Genetics (STAR-G) site, providing information for parents about holocarboxylase/multiple carboxylase deficiency and links to other sites including parent support groups.

Holocarboxylase/multiple carboxylase deficiency, Genetics Home Reference
Excellent, detailed review aimed at patients and families from the National Library of Medicine's Genetics Home Reference site.

Organic Acidemia Association (OAA)
A non-profit organization that provides information for parents and providers; newsletters; event information; connections with other parents; a listserv; a discussion board; information about nutrition and recipes; translation of their web pages into five other languages; hosting of the Propionic Acidemia Research Network and other research funds; and links to other sites.

Services

Newborn Screening Programs

Utah Newborn Screening Program, more info...
44 Mario Capecchi Drive
Salt Lake City, UT84114
Phone: 801-584-8256
Fax: 801-536-0966
http://health.utah.gov/newbornscreening

Pediatric Genetics

Metabolic Clinic, more info...
100 Mario Capecchi Drive
Salt Lake City, UT84113
Phone: 801-585-2457
Fax: 585-7252
http://www.ped.med.utah.edu/divisions/divisions.htm

See all Pediatric Genetics services providers (3) in our database.

For other services related to this condition, browse our Services categories or search our database.

Helpful Articles

PubMed search on holocarboxylase/multiple carboxylase deficiency and neonatal screening in the last 5 years.

Authors

Reviewing Author: Nicola Longo MD, PhD, 3/2007
Compiled and edited by: Alfred Romeo RN, PhD, 3/2007
Content Last Updated: 3/2008
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