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Biotinidase deficiency

MedGen UID:
66323
Concept ID:
C0220754
Disease or Syndrome
Synonyms: Biotin deficiency; BTD deficiency; Late-onset biotin-responsive multiple carboxylase deficiency
SNOMED CT: Multiple carboxylase deficiency - late onset (8808004); Biotinidase deficiency (8808004); Late-onset multiple carboxylase deficiency (8808004); Deficiency of biotinidase (8808004)
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): BTD (3p25.1)
 
Monarch Initiative: MONDO:0009665
OMIM®: 253260
Orphanet: ORPHA79241

Authors:
Barry Wolf   view full author information

Additional descriptions

From OMIM
Multiple carboxylase deficiency (MCD) is an autosomal recessive metabolic disorder characterized primarily by cutaneous and neurologic abnormalities. Symptoms result from the patient's inability to reutilize biotin, a necessary nutrient. Sweetman (1981) recognized that multiple carboxylase deficiency could be classified into early (see 253270) and late forms. The early form showed higher urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxypropionic acid than the late form and was associated with normal plasma biotin concentrations. Sweetman (1981) proposed a defect in holocarboxylase synthetase and intestinal biotin absorption, respectively. Some patients with biotinidase deficiency present in infancy (Baumgartner et al., 1985; Kalayci et al., 1994), and some individuals with this deficiency are asymptomatic (Wolf et al., 1997).  http://www.omim.org/entry/253260
From MedlinePlus Genetics
Biotinidase deficiency is an inherited disorder in which the body is unable to recycle the vitamin biotin. If this condition is not recognized and treated, its signs and symptoms typically appear within the first few months of life, although it can also become apparent later in childhood.

Profound biotinidase deficiency, the more severe form of the condition, can cause seizures, weak muscle tone (hypotonia), breathing problems, hearing and vision loss, problems with movement and balance (ataxia), skin rashes, hair loss (alopecia), and a fungal infection called candidiasis. Affected children also have delayed development. Lifelong treatment can prevent these complications from occurring or improve them if they have already developed.

Partial biotinidase deficiency is a milder form of this condition. Without treatment, affected children may experience hypotonia, skin rashes, and hair loss, but these problems may appear only during illness, infection, or other times of stress.  https://medlineplus.gov/genetics/condition/biotinidase-deficiency

Clinical features

From HPO
Inborn organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
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.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
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.
Diffuse cerebral atrophy
MedGen UID:
108958
Concept ID:
C0598275
Finding
Diffuse unlocalised atrophy affecting the cerebrum.
Diffuse cerebellar atrophy
MedGen UID:
343184
Concept ID:
C1854699
Finding
Diffuse unlocalised atrophy affecting the cerebellum.
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.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
Conjunctivitis
MedGen UID:
1093
Concept ID:
C0009763
Disease or Syndrome
Inflammation of the conjunctiva.
Seborrheic dermatitis
MedGen UID:
19912
Concept ID:
C0036508
Disease or Syndrome
Seborrheic dermatitis is a form of eczema which is closely related to dandruff. It causes dry or greasy peeling of the scalp, eyebrows, and face, and sometimes trunk.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Recurrent skin infections
MedGen UID:
377848
Concept ID:
C1853193
Disease or Syndrome
Infections of the skin that happen multiple times.
Skin rash
MedGen UID:
1830322
Concept ID:
C5779628
Sign or Symptom
A red eruption of the skin.
Metabolic ketoacidosis
MedGen UID:
381478
Concept ID:
C1854704
Pathologic Function
A metabolic acidosis due to accumulation of ketone bodies generally observed in the setting of poor nutritional intake.
Decreased circulating biotinidase concentration
MedGen UID:
1640230
Concept ID:
C4703644
Finding
Concentration of biotinidase in the blood circulation below the lower limit of normal. Biotidinase is an enzyme that releases biotin from biocytin, the product of biotin-dependent carboxylases degradation.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Visual loss
MedGen UID:
784038
Concept ID:
C3665386
Finding
Loss of visual acuity (implying that vision was better at a certain time point in life). Otherwise the term reduced visual acuity should be used (or a subclass of that).

Term Hierarchy

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

Professional guidelines

PubMed

Castilla-Rodríguez I, Vallejo-Torres L, Couce ML, Valcárcel-Nazco C, Mar J, Serrano-Aguilar P
Adv Exp Med Biol 2017;1031:267-281. doi: 10.1007/978-3-319-67144-4_16. PMID: 29214578
Küry S, Ramaekers V, Bézieau S, Wolf B
Eur J Hum Genet 2016 Jul;24(7) Epub 2015 Nov 18 doi: 10.1038/ejhg.2015.246. PMID: 26577040Free PMC Article
Lavin LR, Higby N, Abramo T
Pediatr Emerg Care 2015 Sep;31(9):661-7; quiz 667-9. doi: 10.1097/PEC.0000000000000549. PMID: 26335232

Curated

Küry S, Ramaekers V, Bézieau S, Wolf B
Eur J Hum Genet 2012 May;20(5) Epub 2012 Feb 29 doi: 10.1038/ejhg.2012.28. PMID: 22378278Free PMC Article

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

American College of Medical Genetics and Genomics, Algorithm, Biotinidase Deficiency, 2022

American College of Medical Genetics ACT Sheet, Newborn Screening ACT Sheet, [Absent/ Reduced Biotinidase Activity], Biotinidase Deficiency

American College of Medical Genetics Algorithm, Biotinidase Deficiency, 2022

American College of Medical Genetics ACT SHEET, Biotinidase Deficiency

American College of Medical Genetics Algorithm, Biotinidase Deficiency, 2006

Recent clinical studies

Etiology

Biswas A, McNamara C, Gowda VK, Gala F, Sudhakar S, Sidpra J, Vari MS, Striano P, Blaser S, Severino M, Batzios S, Mankad K
AJNR Am J Neuroradiol 2023 Mar;44(3):328-333. Epub 2023 Feb 9 doi: 10.3174/ajnr.A7781. PMID: 36759144Free PMC Article
Henderson MPA, McIntosh N, Chambers A, Desormeaux E, Kowalski M, Milburn J, Chakraborty P
Clin Biochem 2023 May;115:129-136. Epub 2022 Apr 7 doi: 10.1016/j.clinbiochem.2022.03.010. PMID: 35398329
Akgun A, Sen A, Onal H
J Pediatr Endocrinol Metab 2021 Nov 25;34(11):1425-1433. Epub 2021 Aug 26 doi: 10.1515/jpem-2021-0242. PMID: 34448386
Piraccini BM, Berardesca E, Fabbrocini G, Micali G, Tosti A
G Ital Dermatol Venereol 2019 Oct;154(5):557-566. doi: 10.23736/S0392-0488.19.06434-4. PMID: 31638351
León-Del-Río A
J Inherit Metab Dis 2019 Jul;42(4):647-654. Epub 2019 Mar 19 doi: 10.1002/jimd.12073. PMID: 30746739

Diagnosis

Piraccini BM, Berardesca E, Fabbrocini G, Micali G, Tosti A
G Ital Dermatol Venereol 2019 Oct;154(5):557-566. doi: 10.23736/S0392-0488.19.06434-4. PMID: 31638351
Wolf B
Gene 2016 Sep 10;589(2):142-50. Epub 2015 Oct 9 doi: 10.1016/j.gene.2015.10.010. PMID: 26456103
Winchester S, Singh PK, Mikati MA
Handb Clin Neurol 2013;112:1213-7. doi: 10.1016/B978-0-444-52910-7.00043-X. PMID: 23622331
Said HM
Subcell Biochem 2012;56:1-19. doi: 10.1007/978-94-007-2199-9_1. PMID: 22116691
Wolf B, Heard GS
Adv Pediatr 1991;38:1-21. PMID: 1927696

Therapy

Biswas A, McNamara C, Gowda VK, Gala F, Sudhakar S, Sidpra J, Vari MS, Striano P, Blaser S, Severino M, Batzios S, Mankad K
AJNR Am J Neuroradiol 2023 Mar;44(3):328-333. Epub 2023 Feb 9 doi: 10.3174/ajnr.A7781. PMID: 36759144Free PMC Article
Piraccini BM, Berardesca E, Fabbrocini G, Micali G, Tosti A
G Ital Dermatol Venereol 2019 Oct;154(5):557-566. doi: 10.23736/S0392-0488.19.06434-4. PMID: 31638351
Wolf B
Gene 2016 Sep 10;589(2):142-50. Epub 2015 Oct 9 doi: 10.1016/j.gene.2015.10.010. PMID: 26456103
Zempleni J, Kuroishi T
Adv Nutr 2012 Mar 1;3(2):213-4. doi: 10.3945/an.111.001305. PMID: 22516729Free PMC Article
Wolf B, Heard GS
Adv Pediatr 1991;38:1-21. PMID: 1927696

Prognosis

Yılmaz B, Ceylan AC, Gündüz M, Ünal Uzun Ö, Küçükcongar Yavaş A, Bilginer Gürbüz B, Öncül Ü, Güleç Ceylan G, Kasapkara ÇS
Eur J Pediatr 2024 Mar;183(3):1341-1351. Epub 2023 Dec 23 doi: 10.1007/s00431-023-05376-4. PMID: 38141137
El Moussaoui S, Bennaoui F, El Idrissi Slitine N, Houcar O, Maoulainine FMR
J Neonatal Perinatal Med 2020;13(1):139-141. doi: 10.3233/NPM-180130. PMID: 31594257
Castilla-Rodríguez I, Vallejo-Torres L, Couce ML, Valcárcel-Nazco C, Mar J, Serrano-Aguilar P
Adv Exp Med Biol 2017;1031:267-281. doi: 10.1007/978-3-319-67144-4_16. PMID: 29214578
Winchester S, Singh PK, Mikati MA
Handb Clin Neurol 2013;112:1213-7. doi: 10.1016/B978-0-444-52910-7.00043-X. PMID: 23622331
Nance WE
Ment Retard Dev Disabil Res Rev 2003;9(2):109-19. doi: 10.1002/mrdd.10067. PMID: 12784229

Clinical prediction guides

Henderson MPA, McIntosh N, Chambers A, Desormeaux E, Kowalski M, Milburn J, Chakraborty P
Clin Biochem 2023 May;115:129-136. Epub 2022 Apr 7 doi: 10.1016/j.clinbiochem.2022.03.010. PMID: 35398329
Onder AB, Guven S, Demir S, Mentese A, Guvendag Guven ES
J Obstet Gynaecol 2019 Nov;39(8):1160-1163. Epub 2019 Jul 23 doi: 10.1080/01443615.2019.1604640. PMID: 31335232
Castilla-Rodríguez I, Vallejo-Torres L, Couce ML, Valcárcel-Nazco C, Mar J, Serrano-Aguilar P
Adv Exp Med Biol 2017;1031:267-281. doi: 10.1007/978-3-319-67144-4_16. PMID: 29214578
Borsatto T, Sperb-Ludwig F, Pinto LL, Luca GR, Carvalho FL, Souza CF, Medeiros PF, Lourenço CM, Lo Filho R, Neto EC, Bernardi P, Leistner-Segal S, Schwartz IV
BMC Med Genet 2014 Sep 1;15:96. doi: 10.1186/s12881-014-0096-3. PMID: 25174816Free PMC Article
Prendiville JS, Manfredi LN
Semin Dermatol 1992 Mar;11(1):88-97. PMID: 1550720

Recent systematic reviews

Thomason MJ, Lord J, Bain MD, Chalmers RA, Littlejohns P, Addison GM, Wilcox AH, Seymour CA
J Public Health Med 1998 Sep;20(3):331-43. doi: 10.1093/oxfordjournals.pubmed.a024777. PMID: 9793900

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.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. 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
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Biotinidase Deficiency, 2022
    • ACMG ACT, 2022
      American College of Medical Genetics ACT Sheet, Newborn Screening ACT Sheet, [Absent/ Reduced Biotinidase Activity], Biotinidase Deficiency
    • ACMG Algorithm, 2022
      American College of Medical Genetics Algorithm, Biotinidase Deficiency, 2022
    • ACMG ACT Sheet, 2010
      American College of Medical Genetics ACT SHEET, Biotinidase Deficiency
    • ACMG Algorithm, 2006
      American College of Medical Genetics Algorithm, Biotinidase Deficiency, 2006
    • EuroGentest, 2012
      Clinical utility gene card for: biotinidase deficiency.

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