Holocarboxylase synthetase deficiency

Baby Detect > Metabology > Holocarboxylase synthetase deficiency

HLCS gene

OMIM#253270 https://omim.org/entry/253270

1. The disease:

Holocarboxylase synthetase (HLCS) deficiency is a rare inborn disorder of biotin metabolism, which results in defects in several biotin-dependent carboxylases and presents with metabolic ketoacidosis and skin lesions.

2. The Symptoms:

Clinical onset is usually within hours, days or weeks of birth, although it may occur during infancy or early childhood. Individuals with the disorder usually exhibit poor appetite, vomiting, lethargy, irritability, hypotonia and exfoliative dermatitis (can also appear as skin rash and alopecia). Metabolically, they have ketolactic acidosis, organic aciduria and hyperammonemia. Without treatment, affected infants may progress to intractable seizures, cerebral edema and coma. These children often develop growth and developmental delays. The lack of early signs or symptoms does not exclude the diagnosis.

3. Actions to take in case of early diagnosis:

  • Infants with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the HLCS gene) should IMMEDIATELY start biotin treatment (20 mg capsule diluted in water or breast milk/day). Early treatment with initiation of biotin therapy is essential in preventing complications.
  • Biochemical correlation is essential for confirming diagnosis with plasma acylcarnitines (increased C3 and C5-OH levels) and urinary organic acids (elevated lactic, 3-OH isovaleric, 3-OH propionic, 3-MCC, methylcitric, and tiglylglycine consistent with loss of function of the above carboxylases). Biochemical NBS with tandem mass spectrometry can also help. Ammonia levels if the patient is in a metabolic crisis.
  • HLCSD is a lifelong disease that requires regular evaluation by a metabolic physician to avoid metabolic crisis.
  • All individuals with HLCSD should be treated with high doses of biotin (literature shows doses of 30mg twice a day in children and 200mg daily in adults).
  • No serious side effects of biotin treatment have been recognized.
  • No dietary restrictions are necessary. It is not recommended to dose the biotin level.
  • The prognosis is excellent, especially for those who were treated before symptoms occurred. Compliance with biotin is an issue for many patients. In the absence of early diagnosis and treatment, mortality is high.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

4. For more information

Orphanet: https://www.orpha.net/consor4.01/www/cgi-bin/Disease_Search.php?lng=EN&data_id=11268&Disease_Disease_Search_diseaseGroup=Holocarboxylase-synthetase-deficiency&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Holocarboxylase-synthetase-deficiency&title=Holocarboxylase%20synthetase%20deficiency&search=Disease_Search_Simple

Biblio:

  • Donti TR, Blackburn PR, Atwal PS. Holocarboxylase synthetase deficiency pre and post newborn screening. Mol Genet Metab Rep. 2016;7:40-44. PMID: 27114915.
  • Wu HR, Chen KJ, Hsiao HP, Chao MC. Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review. J Pediatr Endocrinol Metab. 2020;33(11):1481-1486. PMID: 32841162.