An early diagnosis and some diet changes can decrease the risk of severe symptoms in children with BCKDK metabolic deficiency

The research, under the leadership of Dr. Àngels García-Cazorla at the Institut de Recerca Sant Joan de Déu, has demonstrated that early identification of this disease is possible through the standard neonatal screening test, also known as the heel prick test.

The SJD Barcelona Children's Hospital was one of the first centres in the world to identify patients with a rare disease that would be described in 2012 by Gaia Novarino's team: BCKDK deficiency. Now, a study published in the journal Brain, one of the best publications in its field of knowledge, and coordinated by Dr Àngels García-Cazorla, resercher at Institut de Recerca Sant Joan de Déu and chief pediatric neurologist of the Metabolic Diseases Unit at the SJD Barcelona Children's Hospital, shows that early treatment of this disease can significantly improve its symptoms.

BCKDK deficiency is a genetic mutation that causes a severe deficit of what are called branched-chain amino acids, or BCAA. These amino acids cannot be made by the human body naturally and must be taken in through the diet. This deficiency causes a wide range of symptoms, such as autism, epilepsy, intellectual disability, or motor delay. Stagnation in the growth of the skull circumference, which can result in microcephaly, has also been observed in some patients.

Data from the study that has been published compile information from 21 patients with this disease, the number of which is unknown worldwide. One of its main conclusions is that early treatment through diet changes significantly improves the symptoms of these patients.

'When supplementation of branched-chain amino acids is offered along with a high-protein diet in patients diagnosed after the age of four, we have observed an improvement in all symptoms, but the results are modest. Nevertheless, in one of our patients, who started treatment a few months after birth, her situation has been practically normalized," explains Dr Àngels García-Cazorla, coordinator of the Paediatric Neurometabolic Disorders: Neural Communication Mechanisms and Personalised Therapies at IRSJD. "The change is very significant when detecting the disease early and being able to intervene in the diet of these affected children, as opposed to severe symptoms that affect them for life," adds Dr Juliana Ribeiro, a neuropediatrician in the Metabolic Diseases Unit at the SJD Barcelona Children's Hospital who also participated in this study.

The heel prick test

It is currently common practice for all newborns to undergo the heel prick test. This is a blood test used to diagnose congenital metabolic diseases in order to initiate early treatment to reduce morbidity and possible complications that may arise. This test, which is easy to perform, is performed between 48 and 72 hours into the newborns life and involves a puncture in the heel area to collect a blood sample.

Furthermore, the study, published in the journal Brain, has demonstrated that this test is valid for detecting BCKDK deficiency, having retrospectively analyzed samples from all known patients and verified that metabolic analysis is possible.

"This screening would not pose an additional difficulty to the one currently being carried out because a test is already being done to identify amino acidopathies that looks at whether these same branched-chain amino acids are present in high doses, so their levels are already being checked. And it would only be necessary to develop protocols that help establish when they are low enough to suspect this disease," adds the neurologist at Hospital Sant Joan de Déu, Dr García-Cazorla.

Despite the low number of known cases of this disease, the nonspecificity of the symptoms raises the suspicion that there may be a high rate of underdiagnosis, especially in milder cases where more detailed tests are not performed.

"Implementing neonatal screening would help us determine if we are finding many more cases that suffer from this deficiency of amino acids and that are currently diagnosed with other conditions, and, above all, it would allow them to benefit from this early dietary treatment and thus prevent the intellectual disability and other symptoms they suffer so that they can lead the most normal life possible," concludes Dr García-Cazorla.

Reference paper

Tangeraas T, Constante JR, Backe PH, Oyarzábal A, Neugebauer J, Weinhold N, Boemer F, Debray FG, Ozturk-Hism B, Evren G, Tuba EF, Ummuhan O, Footitt E, Davison J, Martinez C, Bueno C, Machado I, Rodríguez-Pombo P, Al-Sannaa N, De Los Santos M, Muchart López J, Ozturkmen-Akay H, Karaca M, Tekin M, Pajares S, Ormazabal A, Stoway SD, Artuch R, Dixon M, Mørkrid L, García-Cazorla A. BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening. Brain. 2023 Feb 2:awad010. doi: 10.1093/brain/awad010. Epub ahead of print. PMID: 36729635.