Back to Search Start Over

BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening

Authors :
Trine Tangeraas
Juliana R Constante
Paul Hoff Backe
Alfonso Oyarzábal
Julia Neugebauer
Natalie Weinhold
Francois Boemer
François G Debray
Burcu Ozturk-Hism
Gumus Evren
Eminoglu F Tuba
Oncul Ummuhan
Emma Footitt
James Davison
Caroline Martinez
Clarissa Bueno
Irene Machado
Pilar Rodríguez-Pombo
Nouriya Al-Sannaa
Mariela De Los Santos
Jordi Muchart López
Hatice Ozturkmen-Akay
Meryem Karaca
Mustafa Tekin
Sonia Pajares
Aida Ormazabal
Stephanie D Stoway
Rafael Artuch
Marjorie Dixon
Lars Mørkrid
Angeles García-Cazorla
Source :
Brain.
Publication Year :
2023
Publisher :
Oxford University Press (OUP), 2023.

Abstract

There 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.

Subjects

Subjects :
Neurology (clinical)

Details

ISSN :
14602156 and 00068950
Database :
OpenAIRE
Journal :
Brain
Accession number :
edsair.doi...........9ea24ee9aad654a9ff2783e846f89ea0
Full Text :
https://doi.org/10.1093/brain/awad010