Holocarboxylase/Multiple Carboxylase Deficiency

Other Names


Holocarboxylase synthetase deficiency (HCSD)

Holocarboxylase deficiency

Diagnosis Coding

D81.818, other biotin-dependent carboxylase 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 1:87,000 live births (Holocarboxylase synthetase deficiency (MedlinePlus))


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 Genetics (see ID providers [3]); 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.

Resources for Holocarboxylase/Multiple Carboxylase Deficiency (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

Holocarboxylase/Multiple Carboxylase Deficiency (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Holocarboxylase/Multiple Carboxylase Deficiency Fact Sheet (Iowa Dept. of Health)
Provides information for parents and professionals.

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 synthetase deficiency (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Organic Acidemia Association (OAA)
A nonprofit organization that provides information, support, events, connections with other parents, a discussion board, and nutrition and recipe ideas.


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.

Services for Patients & Families in Idaho (ID)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: March 2007; last update/revision: July 2012
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.
Reviewer: Kimberly Hart, MS, LCGC