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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
Sources: HPO, OMIM
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.\n\nThe 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
Organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in 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
Complete absence of wakefulness and content of conscience, which manifests itself as a lack of response to any kind of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterestedness, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised 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 condition of being 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.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
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:
8732
Concept ID:
C0015230
Finding
A widespread, acute rash.
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:
113136
Concept ID:
C0220994
Disease or Syndrome
An increased concentration of ammonia in the blood.
Organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.
Skin rash
MedGen UID:
8732
Concept ID:
C0015230
Finding
A widespread, acute rash.

Term Hierarchy

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

Recent clinical studies

Etiology

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
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
Hui J, Law E, Chung C, Fung S, Yuen P, Tang N
World J Pediatr 2012 Aug;8(3):278-80. Epub 2011 Aug 27 doi: 10.1007/s12519-011-0301-9. PMID: 21874615
Malvagia S, Morrone A, Pasquini E, Funghini S, la Marca G, Zammarchi E, Donati MA
Prenat Diagn 2005 Dec;25(12):1117-9. doi: 10.1002/pd.1291. PMID: 16231399
Tang NL, Hui J, Yong CK, Wong LT, Applegarth DA, Vallance HD, Law LK, Fung SL, Mak TW, Sung YM, Cheung KL, Fok TF
Clin Biochem 2003 Mar;36(2):145-9. doi: 10.1016/s0009-9120(02)00432-0. PMID: 12633764

Diagnosis

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
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
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
Watabe D, Watanabe A, Akasaka T, Sakamoto O, Amano H
Acta Derm Venereol 2018 Aug 29;98(8):805-806. doi: 10.2340/00015555-2954. PMID: 29701239
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

Therapy

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
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
Nyhan WL, Willis M, Barshop BA, Gangoiti J
J Inherit Metab Dis 2009 Dec;32 Suppl 1:S79-82. Epub 2009 Apr 11 doi: 10.1007/s10545-009-1062-7. PMID: 19357990
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
Mol Genet Metab 2008 Dec;95(4):201-5. Epub 2008 Oct 29 doi: 10.1016/j.ymgme.2008.09.006. PMID: 18974016Free PMC Article

Prognosis

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
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
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
Mayende L, Swift RD, Bailey LM, Soares da Costa TP, Wallace JC, Booker GW, Polyak SW
J Mol Med (Berl) 2012 Jan;90(1):81-8. Epub 2011 Sep 6 doi: 10.1007/s00109-011-0811-x. PMID: 21894551
Wilson CJ, Myer M, Darlow BA, Stanley T, Thomson G, Baumgartner ER, Kirby DM, Thorburn DR
J Pediatr 2005 Jul;147(1):115-8. doi: 10.1016/j.jpeds.2005.03.006. PMID: 16027709

Clinical prediction guides

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
Nyhan WL, Willis M, Barshop BA, Gangoiti J
J Inherit Metab Dis 2009 Dec;32 Suppl 1:S79-82. Epub 2009 Apr 11 doi: 10.1007/s10545-009-1062-7. PMID: 19357990
Yokoi K, Ito T, Maeda Y, Nakajima Y, Kurono Y, Sugiyama N, Togari H
Brain Dev 2009 Nov;31(10):775-8. Epub 2009 Feb 6 doi: 10.1016/j.braindev.2008.12.016. PMID: 19201116
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

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

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