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Holocarboxylase/Multiple Carboxylase Deficiency

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Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Holocarboxylase deficiency
Holocarboxylase synthetase deficiency (HCSD)
MCD
Neonatal multiple carboxylase deficiency

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 deficiency in holocarboxylase synthetase resulting from variants in the HLCS gene. This enzyme is necessary to attach biotin to 4 biotin-dependent carboxylase enzymes (propionyl CoA carboxylase, beta-methylcrotonyl CoA carboxylase, acetyl-CoA carboxylase, and pyruvate carboxylase). Without holocarboxylase activity, these biotin-dependent enzymes cause impaired gluconeogenesis and 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 varying phenotypes. Multiple carboxylase deficiency is a descriptive term that includes many disorders, such as holocarboxylase synthetase deficiency as well as disorders of defective biotin absorption or transport and biotinidase deficiency.

Clinical Characteristics

With treatment, most children will have normal growth and development, though some have only partially or have not responded to therapy.
Without treatment, repeated episodes of metabolic acidosis lead to severe impairment or death. Infants may show symptoms within a few hours or days of life, while other infants may not have symptoms until 2 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
  • Hypotonia
  • Irritability
  • Lab findings:
    • Metabolic acidosis
    • Hyperammonemia
    • Ketonuria
    • Thrombocytopenia
    • Hypoglycemia
    • Elevated organic acid levels in the blood and urine
If not treated promptly, patients may experience:
  • Global developmental delay
  • Alopecia
  • Eczematous skin rash
  • Hearing loss
  • Hyperventilation/apnea
  • Spasticity
  • 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 NW providers [1]).
  • Additional testing may include quantitative plasma acylcarnitine profile, serum biotinidase assay, and urine organic acids. Definitive confirmation requires enzyme assay in white blood cells, fibroblasts, or DNA testing. Enzyme assay may 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

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, along with resources for consultation and patient education/support; from the American College of Genetics and Genomics

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 Nationwide (NW)

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.

Helpful Articles

PubMed search for holocarboxylase/multiple carboxylase deficiency and neonatal screening, last 5 years.

Donti TR, Blackburn PR, Atwal PS.
Holocarboxylase synthetase deficiency pre and post newborn screening.
Mol Genet Metab Rep. 2016;7:40-4. PubMed abstract / Full Text

León-Del-Río A.
Biotin in metabolism, gene expression, and human disease.
J Inherit Metab Dis. 2019;42(4):647-654. PubMed abstract

Van Hove JL, Josefsberg S, Freehauf C, Thomas JA, Thuy le P, Barshop BA, Woontner M, Mock DM, Chiang PW, Spector E, Meneses-Morales I, Cervantes-Roldán R, León-Del-Río A.
Management of a patient with holocarboxylase synthetase deficiency.
Mol Genet Metab. 2008;95(4):201-5. PubMed abstract / Full Text

Authors & Reviewers

Initial publication: January 2007; last update/revision: November 2022
Current Authors and Reviewers:
Authors: Hannah Holik, MD
Kimberly Stowers, MD
Senior Author: Brian J. Shayota, MD, MPH
Reviewer: Nancy C. Rose, MD
Authoring history
2012: revision: Kimberly Hart, MS, LCGCR
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Donti TR, Blackburn PR, Atwal PS.
Holocarboxylase synthetase deficiency pre and post newborn screening.
Mol Genet Metab Rep. 2016;7:40-4. PubMed abstract / Full Text

León-Del-Río A.
Biotin in metabolism, gene expression, and human disease.
J Inherit Metab Dis. 2019;42(4):647-654. PubMed abstract

MedLinePlus.
Holocarboxylase synthetase deficiency.
National Library of Medicine; (2020) https://medlineplus.gov/genetics/condition/holocarboxylase-synthetase-.... Accessed on Oct. 5, 2022.

Van Hove JL, Josefsberg S, Freehauf C, Thomas JA, Thuy le P, Barshop BA, Woontner M, Mock DM, Chiang PW, Spector E, Meneses-Morales I, Cervantes-Roldán R, León-Del-Río A.
Management of a patient with holocarboxylase synthetase deficiency.
Mol Genet Metab. 2008;95(4):201-5. PubMed abstract / Full Text