Holocarboxylase/Multiple Carboxylase Deficiency

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Holocarboxylase deficiency
Holocarboxylase synthetase deficiency (HCSD)
MCD

ICD-10 Coding

D81.818, Other biotin-dependent carboxylase deficiency

Disorder Category

Organic acidemia

Screening

Abnormal Finding

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

Description

Holocarboxylase/multiple carboxylase deficiency is caused by a defect in holocarboxylase synthetase, which is responsible for attaching biotin to 4 biotin-dependent enzymes (propionyl CoA carboxylase, beta-methylcrotonyl CoA, carboxylase, acetyl-CoA carboxylase, and pyruvate carboxylase). The loss of function in these enzymes impairs gluconeogenesis, resulting 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 biotinidase deficiency (known as late-onset multiple carboxylase deficiency in the past).

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 Presentation (Classic Type)
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, and gastroenteritis with fluids containing glucose.

Incidence

Approximately 1:87,000 live births [MedLinePlus: 2020]

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive 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.

Confirming the Diagnosis

  • To confirm the diagnosis, work with Newborn Screening Services (see ID providers [22]).
  • Additional testing may. Include quantitative plasma acylcarnitine profile, serum biotinidase assay, urine organic acids. Definitive confirmation requires enzyme assay in white blood cells, fibroblasts, or DNA testing. Enzyme assay might miss mild forms due to the presence of biotin in culture media.

If the Diagnosis is Confirmed

Resources

Information & Support

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

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

For Parents and Patients

Support

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 (Medlineplus)
Holocarboxylase synthetase deficiency is an inherited disorder in which the body is unable to use the vitamin biotin effectively. This disorder is classified as a multiple carboxylase deficiency, which is a group of disorders characterized by impaired activity of certain enzymes that depend on biotin.

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

Tools

ACT Sheet for Elevated C5-OH Acylcarnitine (ACMG) (PDF Document 336 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithms for Elevated C5-OH (ACMG) (PDF Document 224 KB)
Basic steps involved in determining the final diagnosis of an infant with a positive newborn screen for this condition; American College of Medical Genetics.

Services for Patients & Families in Idaho (ID)

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

Page Bibliography

MedLinePlus.
Holocarboxylase synthetase deficiency.
National Library of Medicine; (2020) https://medlineplus.gov/genetics/condition/holocarboxylase-synthetase-.... Accessed on Feb 14, 2022.