Holocarboxylase/multiple carboxylase deficiency

Other Names


Holocarboxylase synthetase deficiency (HCSD)

Holocarboxylase deficiency

Diagnosis Coding

269.2, Unspecified vitamin deficiency

Disorder Category

An organic acidemia



Elevated C5:1 (methylcrotonyl or tiglyl carnitine), C5-OH (3-hydoxyisovaleryl carnitine) or C3 (propionyl carnitine)

Tested By

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


Caused by a a defect in holocarboxylase synthetase which is responsible for attaching biotin to four biotin-dependent enzymes, propionyl CoA carboxylase, beta-methylcrotonyl CoA, carboxylase, acetyl-CoA carboxylase, and pyruvate carboxylase. The loss of function of these enzymes impairs gluconeogenesis, results in the accumulation of multiple organic acids, in the pathways of propionic acid and leucine catabolism. This leads to inadequate energy production and the accumulation of toxic compounds leading to metabolic acidosis and other problems. Other forms of multiple carboxylase deficiency may be due to defective biotin absorption or transport or to biotinidase deficiency that in the past was known as late-onset multiple carboxylase deficiency.


Approximately 1 in 87,000 live births [Holocarboxylase/multiple carboxylase deficiency (Genetics Home Reference)]


Autosomal recessive

Prenatal Testing

DNA testing possible by amniocentesis or chorionic villus sampling (CVS) if both disease causing mutations of an affected family member have been identified.

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:
    • metabolic acidosis
    • hyperammonemia
    • keturia
    • thrombocytopenia
    • hypoglycemia
    • 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
  • death

Treatment consists of biotin at high doses (20-300 mg per day), fasting avoidance and prompt treatment of infections, fever, gastroenteritis with fluids containing glucose.

Follow-up Testing after Positive Screen

Quantitative plasma acylcarnitine profile, serum biotinidase assay, urine organic acids. Definitive confirmation requires enzyme assay in white blood cells or fibroblasts or DNA testing. Enzyme assay might miss mild forms due to the presence of biotin in culture media.

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

Specialty Care Collaboration

Initial consultation with the following service(s): Pediatric Medical Genetics , (801-213-3599); See also Services below; and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Genetic counseling for the family.


Information & Support

For Professionals

ACT Sheet for Elevated C5-OH Acylcarnitine (ACMG) (PDF Document 400 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Newborn Screening ACT Sheets & Confirmatory Algorithms (ACMG)
ACTion (ACT) Sheets and algorithms for responding to positive newborn screening test results, membership required; American College of Medical Genetics.

Resources for Holocarboxylase/multiple carboxylase deficiency (NLM)
Comprehensive compilation of links to information, articles, research, case studies, genetics, and more; from the National Library of Medicine and the Genetic Alliance.

Holocarboxylase/Multiple Carboxylase Deficiency (OMIM)
Extensive review of literature that provides technical information on genetic disorders; Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

Holocarboxylase/multiple carboxylase deficiency Fact Sheet (Iowa Dept. of Health) (PDF Document 21 KB)
This fact sheet, developed by the Iowa Department of Health, provides information for parents and professionals.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. Includes health supervision guidelines and other useful resources; a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

For Parents and Patients

Holocarboxylase/Multiple Carboxylase Deficiency - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

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 nonprofit organization that provides information, newsletters, calendars of events, connections with other parents, a listserv, a discussion board, and nutrition and recipe ideas.


Genetics-related clinical services throughout the world can be found through Genetics Clinic Directory (GeneTests).

Newborn Screening Programs

See all Newborn Screening Programs services providers (3) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (5) in our database.

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


Reviewing Authors: Kimberly Hart, MS, LCGC - 7/2012
Nicola Longo, MD, PhD - 3/2011
Compiled and edited by: Alfred Romeo, RN, PhD - 3/2007
Content Last Updated: 7/2012