BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorTANGERAAS, Trine
dc.contributor.authorCONSTANTE, Juliana R.
dc.contributor.authorBACKE, Paul Hoff
dc.contributor.authorOYARZABAL, Alfonso
dc.contributor.authorNEUGEBAUER, Julia
dc.contributor.authorWEINHOLD, Natalie
dc.contributor.authorBOEMER, Francois
dc.contributor.authorDEBRAY, Francois G.
dc.contributor.authorOZTURK-HISM, Burcu
dc.contributor.authorEVREN, Gumus
dc.contributor.authorTUBA, Eminoglu F.
dc.contributor.authorUMMUHAN, Oncul
dc.contributor.authorFOOTITT, Emma
dc.contributor.authorDAVISON, James
dc.contributor.authorMARTINEZ, Caroline
dc.contributor.authorBUENO, Clarissa
dc.contributor.authorMACHADO, Irene
dc.contributor.authorRODRIGUEZ-POMBO, Pilar
dc.contributor.authorAL-SANNAA, Nouriya
dc.contributor.authorSANTOS, Mariela de los
dc.contributor.authorLOPEZ, Jordi Muchart
dc.contributor.authorOZTURKMEN-AKAY, Hatice
dc.contributor.authorKARACA, Meryem
dc.contributor.authorTEKIN, Mustafa
dc.contributor.authorPAJARES, Sonia
dc.contributor.authorORMAZABAL, Aida
dc.contributor.authorSTOWAY, Stephanie D.
dc.contributor.authorARTUCH, Rafael
dc.contributor.authorDIXON, Marjorie
dc.contributor.authorMORKRID, Lars
dc.contributor.authorGARCIA-CAZORLA, Angeles
dc.date.accessioned2023-08-16T18:05:11Z
dc.date.available2023-08-16T18:05:11Z
dc.date.issued2023
dc.description.abstractThere are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators' practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (>= 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes. Tangeraas et al. describe the largest series of BCKDK deficiency patients to date, including responses to dietetic treatment. Early introduction of BCAA ameliorates the BCKDK deficiency phenotype. This treatable neurodevelopmental disease should be considered for inclusion in newborn screening programmes.eng
dc.description.indexMEDLINE
dc.description.indexPubMed
dc.description.indexWoS
dc.description.indexScopus
dc.identifier.citationBRAIN, v.146, n.7, p.3003-3013, 2023
dc.identifier.doi10.1093/brain/awad010
dc.identifier.eissn1460-2156
dc.identifier.issn0006-8950
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/54948
dc.language.isoeng
dc.publisherOXFORD UNIV PRESSeng
dc.relation.ispartofBrain
dc.rightsrestrictedAccesseng
dc.rights.holderCopyright OXFORD UNIV PRESSeng
dc.subjectBCKDKeng
dc.subjectintellectual disabilityeng
dc.subjectautism spectrum disordereng
dc.subjectmicrocephalyeng
dc.subjectnewborn screeningeng
dc.subject.othermutationseng
dc.subject.wosClinical Neurologyeng
dc.subject.wosNeuroscienceseng
dc.titleBCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screeningeng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryÁrabia Saudita
hcfmusp.affiliation.countryNoruega
hcfmusp.affiliation.countryItália
hcfmusp.affiliation.countryEspanha
hcfmusp.affiliation.countryAlemanha
hcfmusp.affiliation.countryBélgica
hcfmusp.affiliation.countryInglaterra
hcfmusp.affiliation.countryisoit
hcfmusp.affiliation.countryisoes
hcfmusp.affiliation.countryisono
hcfmusp.affiliation.countryisode
hcfmusp.affiliation.countryisobe
hcfmusp.affiliation.countryisogb
hcfmusp.affiliation.countryisous
hcfmusp.affiliation.countryisosa
hcfmusp.author.externalTANGERAAS, Trine:Oslo Univ Hosp, Paediat & Adolescent Med, N-0424 Oslo, Norway; European Reference Network Hereditary Metab Dis M, Udine, Italy
hcfmusp.author.externalCONSTANTE, Juliana R.:European Reference Network Hereditary Metab Dis M, Udine, Italy; Sant Joan Deu Hosp, Dept Neurol, Neurometab Unit, IPR, Barcelona 08950, Spain; Sant Joan Deu Hosp, Dept Neurol, Synapt Metab Lab, IPR, Barcelona 08950, Spain; Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
hcfmusp.author.externalBACKE, Paul Hoff:European Reference Network Hereditary Metab Dis M, Udine, Italy; Natl Hosp Norway, Oslo Univ Hosp, Dept Med Biochem, OUS HF Rikshosp, POB 4950, N-0424 Oslo, Norway; Natl Hosp Norway, Oslo Univ Hosp, Dept Microbiol Clin Diagnost & Intervent, N-0424 Oslo, Norway
hcfmusp.author.externalOYARZABAL, Alfonso:European Reference Network Hereditary Metab Dis M, Udine, Italy; Sant Joan Deu Hosp, Dept Neurol, Neurometab Unit, IPR, Barcelona 08950, Spain; Sant Joan Deu Hosp, Dept Neurol, Synapt Metab Lab, IPR, Barcelona 08950, Spain; Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
hcfmusp.author.externalNEUGEBAUER, Julia:European Reference Network Hereditary Metab Dis M, Udine, Italy; Charite Univ Med Berlin, Dept Pediat Gastroenterol Nephrol & Metab Med, D-13353 Berlin, Germany; Charite Uni Med Berlin, Ctr Chronically Sick Children, D-13353 Berlin, Germany
hcfmusp.author.externalWEINHOLD, Natalie:European Reference Network Hereditary Metab Dis M, Udine, Italy; Charite Univ Med Berlin, Dept Pediat Gastroenterol Nephrol & Metab Med, D-13353 Berlin, Germany; Charite Uni Med Berlin, Ctr Chronically Sick Children, D-13353 Berlin, Germany
hcfmusp.author.externalBOEMER, Francois:European Reference Network Hereditary Metab Dis M, Udine, Italy; Univ Liege, Biochem Genet Lab, Human Genet, CHU Liege, B-4000 Liege, Belgium
hcfmusp.author.externalDEBRAY, Francois G.:European Reference Network Hereditary Metab Dis M, Udine, Italy; Univ Liege, Dept Human Genet, CHU Liege, B-4000 Liege, Belgium
hcfmusp.author.externalOZTURK-HISM, Burcu:Marmara Univ, Dept Pediat Metab Dis, Sch Med, TR-34854 Istanbul, Turkiye
hcfmusp.author.externalEVREN, Gumus:Univ Harran, Dept Med Genet, TR-63000 Sanliurfa, Turkiye
hcfmusp.author.externalTUBA, Eminoglu F.:Ankara Univ, Dept Pediat Metab, Sch Med, TR-06100 Ankara, Turkiye
hcfmusp.author.externalUMMUHAN, Oncul:Ankara Univ, Dept Pediat Metab, Sch Med, TR-06100 Ankara, Turkiye
hcfmusp.author.externalFOOTITT, Emma:European Reference Network Hereditary Metab Dis M, Udine, Italy; Great Ormond St Hosp Sick Children, Dept Metab Med, London WC1N 3JH, England; NIHR Great Ormond St Hosp Biomed Res Ctr NIHR GOS, London WC1N 3JH, England
hcfmusp.author.externalDAVISON, James:European Reference Network Hereditary Metab Dis M, Udine, Italy; Great Ormond St Hosp Sick Children, Dept Metab Med, London WC1N 3JH, England; NIHR Great Ormond St Hosp Biomed Res Ctr NIHR GOS, London WC1N 3JH, England
hcfmusp.author.externalMARTINEZ, Caroline:Mt Sinai Hosp, Dept Pediat & Psychiat, New York, NY USA
hcfmusp.author.externalMACHADO, Irene:Hosp Univ Clin San Cecilio, Neuropediat Dept, Granada 18016, Spain
hcfmusp.author.externalRODRIGUEZ-POMBO, Pilar:Univ Autonoma Madrid, Inst Mol Biol IUBM, Ctr Diagnost Enfermedades Mol,CIBERER,IDIPAZ, Ctr Biol Mol Severo Ochoa,CBM CSIC,Dept Biol Mol, Madrid 28049, Spain
hcfmusp.author.externalAL-SANNAA, Nouriya:Johns Hopkins Aramco Healthcare, Pediat Serv Div, Dhahran 34465, Saudi Arabia
hcfmusp.author.externalSANTOS, Mariela de los:European Reference Network Hereditary Metab Dis M, Udine, Italy; Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain; Sant Joan Deu Hosp, Dept Gastroenterol & Nutr, Neurometab Unit, Barcelona 08950, Spain
hcfmusp.author.externalLOPEZ, Jordi Muchart:Hosp San Juan Dios, Inst Recerca Sant Joan Deu, Pediat Radiol Dept Esplugues Llobregat, Barcelona 08950, Spain
hcfmusp.author.externalOZTURKMEN-AKAY, Hatice:Baskent Univ, Dept Radiol, Sch Med, TR-06790 Ankara, Turkiye
hcfmusp.author.externalKARACA, Meryem:Univ Harran, Dept Pediat Metab Dis, TR-63000 Sanliurfa, Turkiye
hcfmusp.author.externalTEKIN, Mustafa:Univ Miami, Dr John T Macdonald Fdn, Miller Sch Med, Dept Human Genet, Miami, FL 33136 USA; Univ Miami, John P Hussman Inst Human Genom, Miller Sch Med, Miami, FL 33136 USA
hcfmusp.author.externalPAJARES, Sonia:Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain; Hosp Clin Barcelona, Dept Biochem & Mol Genet, Sect Inborn Errors Metab IBC, Barcelona 08036, Spain
hcfmusp.author.externalORMAZABAL, Aida:European Reference Network Hereditary Metab Dis M, Udine, Italy; Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain; Sant Joan Deu Hosp, Dept Clin Biochem, Barcelona 08950, Spain
hcfmusp.author.externalSTOWAY, Stephanie D.:Oslo Univ Hosp, Div Paediat & Adolescent Med, Norwegian Natl Unit Newborn Screening, N-0424 Oslo, Norway; Mayo Clin, Dept Lab Med & Pathol, Biochem Genet Lab, Rochester, NY 55905 USA
hcfmusp.author.externalARTUCH, Rafael:European Reference Network Hereditary Metab Dis M, Udine, Italy; Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain; Sant Joan Deu Hosp, Dept Clin Biochem, Barcelona 08950, Spain
hcfmusp.author.externalDIXON, Marjorie:European Reference Network Hereditary Metab Dis M, Udine, Italy; Great Ormond St Hosp Children NHS Fdn Trust, Dietet, London WC1N 3JH, England
hcfmusp.author.externalMORKRID, Lars:European Reference Network Hereditary Metab Dis M, Udine, Italy; Natl Hosp Norway, Oslo Univ Hosp, Dept Med Biochem, OUS HF Rikshosp, POB 4950, N-0424 Oslo, Norway; Univ Oslo, Inst Clin Med, N-0424 Oslo, Norway
hcfmusp.author.externalGARCIA-CAZORLA, Angeles:European Reference Network Hereditary Metab Dis M, Udine, Italy; Sant Joan Deu Hosp, Dept Neurol, Neurometab Unit, IPR, Barcelona 08950, Spain; Sant Joan Deu Hosp, Dept Neurol, Synapt Metab Lab, IPR, Barcelona 08950, Spain; Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
hcfmusp.citation.scopus3
hcfmusp.contributor.author-fmusphcCLARISSA BUENO
hcfmusp.description.beginpage3003
hcfmusp.description.endpage3013
hcfmusp.description.issue7
hcfmusp.description.volume146
hcfmusp.origemWOS
hcfmusp.origem.pubmed36729635
hcfmusp.origem.scopus2-s2.0-85164240203
hcfmusp.origem.wosWOS:000951560400001
hcfmusp.publisher.cityOXFORDeng
hcfmusp.publisher.countryENGLANDeng
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