Branched-chain keto acid dehydrogenase kinase deficiency (BCKDK deficiency) is a disease resulting from mutations of the BCKDK gene. Patients with BCKDK deficiency have low levels of branched chain amino acids (BCAA) in their organism due to accelerated breakdown of these essential amino acids. This results in delayed brain development, which may present as

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...

and

autism spectrum disorder The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

. Patients may suffer from

epileptic seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

History

The disease was first described in 2012 in three unrelated families. Later on, García-Cazorla, Oyarzabal et al. confirmed that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention. In their 2013 study, they found out BCAA (

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- ...

, isoleucine, and

valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...

) supplementation every 5 hours plus an high protein diet showed significant improvement for BCKDK deficit disease patients.

Signs and symptoms

BCKDK deficit disease symptoms may include autism,

and

developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech ...

. R.Constante, Juliana et al. reported a list of symptoms in a study of 20 cases. Those symptoms included: neurodevelopmental delay , gross motor function impairment,

, language impairment,

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

and

clumsiness Clumsy or clumsiness may refer to: Behaviour * Accident-proneness *Developmental coordination disorder, a motor skills disorder which brings about chronic clumsiness Music * ''Clumsy'' (Our Lady Peace album), a 1997 album by Our Lady Peace ** "C ...

, and also

microcephaly Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...

, non present at birth.

Prevalence

According to Garcia-Cazorla (2020), there are currently 21 documented cases worldwide R.Constante, Juliana et al. reported a list of symptoms in a study of 20 cases. It was communicated in the 14th European Paediatric Neurology Society Congress . Those symptoms included: neurodevelopmental delay , gross motor function impairment,

, language impairment,

and

, and also

, non present at birth.

Cause

Treatment

Continuous replenishment of BCAA levels has been reported to alleviate the symptoms in patients, combined with an high protein diet. Ongoing studies, not yet published, may indicate a greater improvement if the supplementation is administrated every 3 hours. When treatment was applied, (supplementation of 100–260 mg/kg/day and high protein diet), all patients improved in motor functions, and half the patients reached normocephaly. None of the patients that started treatment before 2 years old developed autism, and the patient who started treatment earlier (8 months) experimented almost normal development at 3 years old. 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, BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening, Brain, 2023;, awad010, https://doi.org/10.1093/brain/awad010

References

External links

Branched-chain keto acid dehydrogenase kinase deficiency
- a record in

OMIM Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in OMIM ...

{{Amino acid metabolic pathology Genetic diseases and disorders Amino acid metabolism disorders Rare diseases