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Multiple Carboxylase Deficiency

MCD


Presentation

  • Two patients with biotin-responsive multiple carboxylase deficiency, both presenting with predominant lactic acidosis, are reported.[ncbi.nlm.nih.gov]
  • Two patients presented in early childhood with (i) alopecia, skin rashs, and dermatitis, (ii) severe hypotonia, ataxia and motor retardation, (iii) frequent episodes of ketoacidosis with hyperlactacidemia.[ncbi.nlm.nih.gov]
  • In the present experiments there was no change in the uptake of arachidonate, palmitate or oleate following growth of mutant and control fibroblasts in ( ) or (-) biotin conditions.[ncbi.nlm.nih.gov]
  • Other metabolic disorders may present a similar clinical picture. Immunologic dysfunction and/or aberration in lipid or branched chain amino acid metabolism may be the common pathophysiologic link in some or all of these disorders.[ncbi.nlm.nih.gov]
  • The remaining mutations, located outside the biotin binding region, were associated with a more limited biotin responsiveness that may be explained by the degree of residual enzyme activity present.[ncbi.nlm.nih.gov]
Pathologist
  • Assay Assay and technical information Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication[invitae.com]
Painter
  • Diamantopoulos N, Painter MJ, Wolf B, Heard GS, Roe C (1986) Biotinidase deficiency: accumulation of lactate in the brain and response to physiologic doses of biotin. Neurology 36: 1107–1109 PubMed CrossRef Google Scholar 17.[link.springer.com]
Failure to Thrive
  • […] to thrive, seizure, coma, developmental delay, foul smelling urine, lactic acidosis, and high levels of ketones and ammonia in the blood.[en.wikipedia.org]
  • […] to thrive, seizure, coma, developmental delay, foul smelling urine, metabolic acidosis, ketosis and hyperammonemia.[ipfs.io]
  • Partial MethylCrotonyl-CoA Carboxylase Deficiency in an infant with failure to thrive, gastrointestinal dysfunction and hypertonia. Pediatrics 91:664, 1993. Elpeleg, O.N., Havkin, S., Barash, V., et al.[path.upmc.edu]
  • Among chronic symptoms mental retardation including speech retardation were the most common findings followed by seizures, muscular hypotonia, muscle weakness, muscle pain and failure to thrive.[ojrd.biomedcentral.com]
Alopecia
  • Two patients presented in early childhood with (i) alopecia, skin rashs, and dermatitis, (ii) severe hypotonia, ataxia and motor retardation, (iii) frequent episodes of ketoacidosis with hyperlactacidemia.[ncbi.nlm.nih.gov]
  • Recognition of the characteristic dermatologic manifestations, alopecia and periorificial dermatitis, should result in early diagnosis and institution of potentially lifesaving therapy with biotin.[ncbi.nlm.nih.gov]
  • Associated symptoms and signs included erythematous skin rashes, alopecia and developmental delay. The patient responded dramatically to treatment with biotin (10 mg/day) showing normalization of clinical symptoms and most biochemical abnormalities.[ncbi.nlm.nih.gov]
  • Symptoms include seizures, hypotonia, developmental delay, ataxia, alopecia and erythematomous rash.[sas-centre.org]
  • Abstract Late-onset multiple carboxylase deficiency is characterized clinically by skin rash, alopecia, seizures and ataxia and occasionally by candidiasis and developmental delay.[ncbi.nlm.nih.gov]
Eczema
  • Eczema, alopecia, dermatitis, and skin infections are also common findings, and cutaneous presentations in conjunction with neurological symptoms greatly limit the differential diagnosis. Clinical variability is documented.[preventiongenetics.com]
  • Untreated patients with profound biotinidase deficiency can have hypotonia, seizures, alopecia, eczema, and developmental delay.[invitae.com]
Withdrawn
  • The child has been now on 10 mg BD of biotin, B1 has been withdrawn. S.S. is now twelve years old, well built 138 cms inheight with a normal body weight. All of his other anthropometric measurements are well within normal limits.[bhj.org.in]
Foul Smelling Urine
  • smelling urine, lactic acidosis, and high levels of ketones and ammonia in the blood.[en.wikipedia.org]
  • smelling urine, metabolic acidosis, ketosis and hyperammonemia.[ipfs.io]

Workup

Excessive Drooling
  • Fig 1 : Shows the role of holocarboxylase and biotinidase in the catalytic conversion os apocarboxylase to holocarboxylase back At six years of age S.S. was readmitted with total alopecia, excessive drooling, inability to walk, talk or communicate.[bhj.org.in]

Treatment

  • All disease treatments should be under the direction of a qualified healthcare provider. Last Updated: 10/3/2017[preventiongenetics.com]
  • After two weeks of biotin treatment the excretion of abnormal organic acid metabolites was reduced and his carboxylase activities increased to the normal range.[ncbi.nlm.nih.gov]
  • The initially low carboxylase activities in thrombocytes were increased but not normalized after 3 months of treatment.[ncbi.nlm.nih.gov]
  • Clinical Characteristics With treatment, most children will have normal growth and development, though some have only partly or not responded to therapy. Without treatment, repeated episodes of metabolic acidosis lead to severe impairment or death.[medicalhomeportal.org]
  • The patient responded dramatically to treatment with biotin (10 mg/day) showing normalization of clinical symptoms and most biochemical abnormalities.[ncbi.nlm.nih.gov]

Prognosis

  • The disorder has a good prognosis if biotin therapy is introduced early. If not, it can result in irreversible damage to the central nervous system and early death from metabolic acidosis.[ncbi.nlm.nih.gov]
  • Patients who display incomplete responsiveness to this therapy have a poor long-term prognosis. Here we investigated cell lines from two such HLCS-deficient patients homozygous for the c.647T G p.L216R allele.[ncbi.nlm.nih.gov]
  • Both types of multiple carboxylase deficiency respond dramatically to treatment with oral bioin and prognosis is good if the condition is diagnosed and treated early.[sas-centre.org]
  • These medical problems may be life-threatening in some cases Prognosis - Multiple carboxylase deficiency- biotin responsive Not supplied. Treatment - Multiple carboxylase deficiency- biotin responsive Not supplied.[checkorphan.org]
  • […] enteropathica (p. 328) Mucocutaneous candidiasis Essential fatty acid deficiency Lab Screen urine for organic aciduria Serum biotinidase/holocarboxylase synthetase assay Screen blood metabolic acidosis, hyperammonemia Management Biotin 10 mg per day for life Prognosis[cram.com]

Etiology

  • The clinical heterogeneity, taken together with the distinct responses of cultured skin fibroblasts to biotin deprivation in vitro, probably reflect fundamentally different etiologies for the two categories of biotin-responsive multiple carboxylase deficiency[ncbi.nlm.nih.gov]
  • Accurate etiologic classification cannot be based on clinical presentation alone, and biochemical studies should be performed on all patients. Accordingly, we propose a classification of multiple carboxylase deficiency based on biochemical criteria.[ncbi.nlm.nih.gov]
  • Etiology Biotinidase deficiency is caused by mutations in the BTD gene (3p25) and holocarboxylase synthetase deficiency by mutations in the HLCS gene (21q22.1). Genetic counseling Both disorders are inherited as autosomal recessive traits.[rarediseases.info.nih.gov]
  • B. 1982 41 Evidence for a defect of holocarboxylase synthetase activity in cultured lymphoblasts from a patient with biotin-responsive multiple carboxylase deficiency. ( 7102675 ) Saunders M.E....Gravel R.A. 1982 42 Biochemical evidence for diverse etiologies[malacards.org]
  • Etiology Holocarboxylase synthetase deficiency is caused by mutations in the HLCS gene (21q22.1) resulting in reduced HCS activity.[orpha.net]

Epidemiology

  • Epidemiology The prevalence of MCD is unknown, but the condition is rare. There is no specific geographic or ethnic predominance.[rarediseases.info.nih.gov]
  • Summary Epidemiology The exact prevalence of HCSD is unknown, but the condition is one of the rarest inborn errors of metabolism. Annual incidence is estimated to be less than 1/200,000 live births.[orpha.net]
  • Summary Epidemiology Prevalence is unknown but less than 30 affected families have been reported in the literature so far.[orpha.net]
  • Epidemiology Incidence is less than 1 in 60,000 babies - no more than 12 cases per year. [ 3 ] The carrier frequency in the general population is 1 in 120. [ 4 ] Presentation [ 1, 2 ] Usually presents aged 1 week to 2 years (earlier-onset carboxylase[patient.info]
Sex distribution
Age distribution

Pathophysiology

  • Immunologic dysfunction and/or aberration in lipid or branched chain amino acid metabolism may be the common pathophysiologic link in some or all of these disorders.[ncbi.nlm.nih.gov]
  • Despite its rarity, early recognition is imperative because expeditious treatment may prevent or minimize clinical insult. [8] Pathophysiology Biotin is one of the water-soluble B-complex vitamins. [9] This imidazole derivative [9] is present in various[emedicine.medscape.com]

Prevention

  • Prevention - Multiple carboxylase deficiency- biotin responsive Not supplied.[checkorphan.org]
  • Children lacking biotinidase activity are unable to recycle biotin, and are thus entirely dependent upon exogenous biotin to prevent deficiency.[ncbi.nlm.nih.gov]
  • Prevention Immediate diagnosis and treatment of multiple carboxylase deficiency is often critical to normal growth and development.[preventiongenetics.com]
  • Mutations in the HLCS gene reduce the enzyme's ability to attach biotin to these enzymes, preventing them from processing nutrients properly and disrupting many cellular functions.[ghr.nlm.nih.gov]

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