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Holocarboxylase synthetase deficiency

MedGen UID:
120653
Concept ID:
C0268581
Disease or Syndrome
Synonym: MULTIPLE CARBOXYLASE DEFICIENCY, EARLY ONSET
SNOMED CT: Neonatal multiple carboxylase deficiency (360369003); Early-onset multiple carboxylase deficiency (360369003); Holocarboxylase synthase deficiency (360369003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HLCS (21q22.13)
 
Monarch Initiative: MONDO:0009666
OMIM®: 253270
Orphanet: ORPHA79242

Definition

Holocarboxylase synthetase deficiency, a biotin-responsive multiple carboxylase deficiency (MCD), is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period (summary by Suzuki et al., 2005). Also see biotinidase deficiency (253260), another form of MCD with a later onset. Care must be taken to differentiate the inherited multiple carboxylase deficiencies from acquired biotin deficiencies, such as those that develop after excessive dietary intake of avidin, an egg-white glycoprotein that binds specifically and essentially irreversibly to biotin (Sweetman et al., 1981) or prolonged parenteral alimentation without supplemental biotin (Mock et al., 1981). [from OMIM]

Additional description

From MedlinePlus Genetics
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.

The signs and symptoms of holocarboxylase synthetase deficiency typically appear within the first few months of life, but the age of onset varies. Affected infants often have difficulty feeding, breathing problems, a skin rash, hair loss (alopecia), and a lack of energy (lethargy). Immediate treatment and lifelong management with biotin supplements may prevent many of these complications. If left untreated, the disorder can lead to delayed development, seizures, and coma. These medical problems may be life-threatening in some cases.  https://medlineplus.gov/genetics/condition/holocarboxylase-synthetase-deficiency

Clinical features

From HPO
Inborn organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
3-hydroxyisovaleric aciduria
MedGen UID:
1746334
Concept ID:
C5421619
Finding
Concentration of 3-hydroxyisovaleric acid in the urine above the normal range.
Elevated urinary 3-methylcrotonylglycine level
MedGen UID:
1782488
Concept ID:
C5539708
Finding
An abnormally increased amount of 3-methylcrotonylglycine in the urine.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Hyperventilation
MedGen UID:
9377
Concept ID:
C0020578
Finding
Hyperventilation refers to an increased pulmonary ventilation rate that is faster than necessary for the exchange of gases. Hyperventilation can result from increased frequency of breathing, an increased tidal volume, or both, and leads to an excess intake of oxygen and the blowing off of carbon dioxide.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
Skin rash
MedGen UID:
1830322
Concept ID:
C5779628
Sign or Symptom
A red eruption of the skin.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.
Reduced holocarboxylase synthetase activity in cultured fibroblasts
MedGen UID:
1853217
Concept ID:
C5872949
Finding
Concentration or activity of holocarboxylase synthetase (EC 6.3.4.10) as measured in cultured fibroblasts is below the limits of normal.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • Holocarboxylase synthetase deficiency
    • Holocarboxylase synthetase deficiency
      • Holocarboxylase synthetase deficiency
        • Holocarboxylase synthetase deficiency
          • Holocarboxylase synthetase deficiency
            • Holocarboxylase synthetase deficiency
              • Holocarboxylase synthetase deficiency
Follow this link to review classifications for Holocarboxylase synthetase deficiency in Orphanet.

Professional guidelines

PubMed

Division of Biochemistry and Metabolism, Medical Genetics Branch, Chinese Medical Association, Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health, Division of Genetics and Metabolism, Rare Diseases Committee of Beijing Medical Association
Zhejiang Da Xue Xue Bao Yi Xue Ban 2022 Feb 25;51(1):129-135. doi: 10.3724/zdxbyxb-2022-0164. PMID: 35576117Free PMC Article
Lee HC, Mak CM, Lam CW, Yuen YP, Chan AO, Shek CC, Siu TS, Lai CK, Ching CK, Siu WK, Chen SP, Law CY, Tai HL, Tam S, Chan AY
Chin Med J (Engl) 2011 Apr;124(7):983-9. PMID: 21542954
Thuy LP, Jurecki E, Nemzer L, Nyhan WL
Clin Chim Acta 1999 Jun 15;284(1):59-68. doi: 10.1016/s0009-8981(99)00053-4. PMID: 10437643

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-OH Acylcarnitine, Organic Acidemias, 2022

American College of Medical Genetics and Genomics, Algorithm, Organic Acidemias: Elevated C5-OH, 2022

Recent clinical studies

Etiology

Ling S, Qiu W, Zhang H, Liang L, Lu D, Chen T, Zhan X, Wang Y, Gu X, Han L
Orphanet J Rare Dis 2023 Mar 8;18(1):48. doi: 10.1186/s13023-023-02656-y. PMID: 36890565Free PMC Article
Bandaralage SP, Farnaghi S, Dulhunty JM, Kothari A
Pediatr Radiol 2016 Mar;46(3):357-64. Epub 2016 Jan 11 doi: 10.1007/s00247-015-3492-8. PMID: 26754537
Yang X, Aoki Y, Li X, Sakamoto O, Hiratsuka M, Kure S, Taheri S, Christensen E, Inui K, Kubota M, Ohira M, Ohki M, Kudoh J, Kawasaki K, Shibuya K, Shintani A, Asakawa S, Minoshima S, Shimizu N, Narisawa K, Matsubara Y, Suzuki Y
Hum Genet 2001 Nov;109(5):526-34. Epub 2001 Oct 5 doi: 10.1007/s004390100603. PMID: 11735028
Thuy LP, Jurecki E, Nemzer L, Nyhan WL
Clin Chim Acta 1999 Jun 15;284(1):59-68. doi: 10.1016/s0009-8981(99)00053-4. PMID: 10437643
Michalski AJ, Berry GT, Segal S
J Inherit Metab Dis 1989;12(3):312-6. doi: 10.1007/BF01799223. PMID: 2515372

Diagnosis

Ling S, Qiu W, Zhang H, Liang L, Lu D, Chen T, Zhan X, Wang Y, Gu X, Han L
Orphanet J Rare Dis 2023 Mar 8;18(1):48. doi: 10.1186/s13023-023-02656-y. PMID: 36890565Free PMC Article
Division of Biochemistry and Metabolism, Medical Genetics Branch, Chinese Medical Association, Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health, Division of Genetics and Metabolism, Rare Diseases Committee of Beijing Medical Association
Zhejiang Da Xue Xue Bao Yi Xue Ban 2022 Feb 25;51(1):129-135. doi: 10.3724/zdxbyxb-2022-0164. PMID: 35576117Free PMC Article
Wu HR, Chen KJ, Hsiao HP, Chao MC
J Pediatr Endocrinol Metab 2020 Nov 26;33(11):1481-1486. doi: 10.1515/jpem-2020-0106. PMID: 32841162
Bandaralage SP, Farnaghi S, Dulhunty JM, Kothari A
Pediatr Radiol 2016 Mar;46(3):357-64. Epub 2016 Jan 11 doi: 10.1007/s00247-015-3492-8. PMID: 26754537
Tammachote R, Janklat S, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V
Clin Genet 2010 Jul;78(1):88-93. Epub 2009 Dec 2 doi: 10.1111/j.1399-0004.2009.01357.x. PMID: 20095979

Therapy

Ling S, Qiu W, Zhang H, Liang L, Lu D, Chen T, Zhan X, Wang Y, Gu X, Han L
Orphanet J Rare Dis 2023 Mar 8;18(1):48. doi: 10.1186/s13023-023-02656-y. PMID: 36890565Free PMC Article
Liu H, Wei R, Yang Y, Zhang Z, Yang Y, Tang J, Chen J, Zhang J, Gu Y, Yao Z
J Dermatol 2023 Mar;50(3):401-406. Epub 2022 Nov 7 doi: 10.1111/1346-8138.16625. PMID: 36342067
Wu HR, Chen KJ, Hsiao HP, Chao MC
J Pediatr Endocrinol Metab 2020 Nov 26;33(11):1481-1486. doi: 10.1515/jpem-2020-0106. PMID: 32841162
Tammachote R, Janklat S, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V
Clin Genet 2010 Jul;78(1):88-93. Epub 2009 Dec 2 doi: 10.1111/j.1399-0004.2009.01357.x. PMID: 20095979
Michalski AJ, Berry GT, Segal S
J Inherit Metab Dis 1989;12(3):312-6. doi: 10.1007/BF01799223. PMID: 2515372

Prognosis

Ling S, Qiu W, Zhang H, Liang L, Lu D, Chen T, Zhan X, Wang Y, Gu X, Han L
Orphanet J Rare Dis 2023 Mar 8;18(1):48. doi: 10.1186/s13023-023-02656-y. PMID: 36890565Free PMC Article
Wu HR, Chen KJ, Hsiao HP, Chao MC
J Pediatr Endocrinol Metab 2020 Nov 26;33(11):1481-1486. doi: 10.1515/jpem-2020-0106. PMID: 32841162
Xiong Z, Zhang G, Luo X, Zhang N, Zheng J
Medicine (Baltimore) 2020 May;99(18):e19964. doi: 10.1097/MD.0000000000019964. PMID: 32358368Free PMC Article
Morrone A, Malvagia S, Donati MA, Funghini S, Ciani F, Pela I, Boneh A, Peters H, Pasquini E, Zammarchi E
Am J Med Genet 2002 Jul 22;111(1):10-8. doi: 10.1002/ajmg.10532. PMID: 12124727
Michalski AJ, Berry GT, Segal S
J Inherit Metab Dis 1989;12(3):312-6. doi: 10.1007/BF01799223. PMID: 2515372

Clinical prediction guides

Sadri M, Wang H, Kuroishi T, Li Y, Zempleni J
PLoS One 2022;17(4):e0265539. Epub 2022 Apr 6 doi: 10.1371/journal.pone.0265539. PMID: 35385533Free PMC Article
Zheng Z, Yuan G, Zheng M, Lin Y, Zheng F, Jiang M, Zhu L, Fu Q
BMC Med Genet 2020 Jul 29;21(1):155. doi: 10.1186/s12881-020-01080-4. PMID: 32727382Free PMC Article
Morrone A, Malvagia S, Donati MA, Funghini S, Ciani F, Pela I, Boneh A, Peters H, Pasquini E, Zammarchi E
Am J Med Genet 2002 Jul 22;111(1):10-8. doi: 10.1002/ajmg.10532. PMID: 12124727
Yang X, Aoki Y, Li X, Sakamoto O, Hiratsuka M, Kure S, Taheri S, Christensen E, Inui K, Kubota M, Ohira M, Ohki M, Kudoh J, Kawasaki K, Shibuya K, Shintani A, Asakawa S, Minoshima S, Shimizu N, Narisawa K, Matsubara Y, Suzuki Y
Hum Genet 2001 Nov;109(5):526-34. Epub 2001 Oct 5 doi: 10.1007/s004390100603. PMID: 11735028
Sakamoto O, Suzuki Y, Li X, Aoki Y, Hiratsuka M, Suormala T, Baumgartner ER, Gibson KM, Narisawa K
Pediatr Res 1999 Dec;46(6):671-6. doi: 10.1203/00006450-199912000-00004. PMID: 10590022

Recent systematic reviews

Bandaralage SP, Farnaghi S, Dulhunty JM, Kothari A
Pediatr Radiol 2016 Mar;46(3):357-64. Epub 2016 Jan 11 doi: 10.1007/s00247-015-3492-8. PMID: 26754537

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-OH Acylcarnitine, Organic Acidemias, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Organic Acidemias: Elevated C5-OH, 2022

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