A Gain-of-Function Mutation on BCKDK Gene and Its Possible Pathogenic Role in Branched-Chain Amino Acid Metabolism.

BCKDK is an important key regulator of branched-chain ketoacid dehydrogenase complex activity by phosphorylating and so inactivating branched-chain ketoacid dehydrogenases, the rate-limiting enzyme of the branched-chain amino acid metabolism. We identified, by whole exome-sequencing analysis, the p.His162Gln variant of the BCKDK gene in a neonate, picked up by newborn screening, with a biochemical phenotype of a mild form of maple syrup urine disease (MSUD). The same biochemical and genetic picture was present in the father. Computational analysis of the mutation was performed to better understand its role. Extensive atomistic molecular dynamics simulations showed that the described mutation leads to a conformational change of the BCKDK protein, which reduces the effect of inhibitory binding bound to the protein itself, resulting in its increased activity with subsequent inactivation of BCKDC and increased plasmatic branched-chain amino acid levels. Our study describes the first evidence of the involvement of the BCKDK gene in a mild form of MSUD. Although further data are needed to elucidate the clinical relevance of the phenotype caused by this variant, awareness of this regulatory activation of BCKDK is very important, especially in newborn screening data interpretation.

Enfermedad de la orina con olor a jarabe de arce, caso único en Cuba / Maple syrup urine disease, a unique case in Cuba

La leucinosis, también conocida como enfermedad de la orina olor a jarabe de arce, es un error innato del metabolismo de los aminoácidos de cadena ramificada (valina, isoleucina y leucina), cuya acumulación produce una encefalopatía neonatal grave, que de no ser diagnosticada y tratada de forma precoz y oportuna, lleva invariablemente a una aparición de secuelas neurológicas permanentes y un posterior desenlace letal. El diagnóstico se hace por la clínica, de la que existen 5 formas; y por la presencia de aminoácidos de cadena ramificada (leucina, isoleucina y valina y sus correspondientes cetoácidos) elevados en orina y sangre. Se trata del primer y único caso reportado en Cuba, con diagnóstico y seguimiento por equipo multidisciplinario (a nivel provincial y nacional) en el Hospital Provincial Pediátrico Docente Eliseo Noel Caamaño, de Matanzas. Se realizó una revisión de la literatura sobre la enfermedad, resaltando su fisiopatología, formas clínicas, diagnóstico, así como el tratamiento a seguir, demostrando cómo el país dispone de todos los recursos necesarios para el costoso tratamiento de la enfermedad, logrando una vez más evadir el bloqueo impuesto por los Estados Unidos(AU)

Leucinosis, also known as maple syrup urine disease, is an innate mistake of the branched chain amino acids (valine, isoleucine and leucine), which concentration produces a serious neonatal encephalopathy that, if it is not precociously and timely diagnosed and treated, unavoidably leads to the emergence of permanent neurologic sequels and the subsequent lethal outcome. The diagnosis is reached clinically, in five different ways, and based on the presence of higher levels of branched chain amino acids (leucine, isoleucine and valine and their correspondent ceto acids) in urine and blood. We dealt with the first and unique case reported in Cuba, diagnosed and followed up by a multidisciplinary team (at the national and provincial level) in the Teaching Pediatric Provincial Hospital Eliseo Noel Caamaño, of Matanzas. We carried out a review of the literature on the disease, highlighting its physiopathology, clinical forms, diagnosis, and also the treatment to apply, showing that the country has the necessary recourses for the disease expensive treatment, evading again the blockade imposed by the United States of America(AU)

Enfermedad de la orina con olor a jarabe de arce. Caso único en Cuba / Maple syrup urine disease. A unique case in Cuba

La leucinosis, también conocida como enfermedad de la orina olor a jarabe de arce, es un error innato del metabolismo de los aminoácidos de cadena ramificada (valina, isoleucina y leucina), cuya acumulación produce una encefalopatía neonatal grave, que de no ser diagnosticada y tratada de forma precoz y oportuna, lleva invariablemente a una aparición de secuelas neurológicas permanentes y un posterior desenlace letal. El diagnóstico se hace por la clínica, de la que existen 5 formas; y por la presencia de aminoácidos de cadena ramificada (leucina, isoleucina y valina y sus correspondientes cetoácidos) elevados en orina y sangre. Se trata del primer y único caso reportado en Cuba, con diagnóstico y seguimiento por equipo multidisciplinario (a nivel provincial y nacional) en el Hospital Provincial Pediátrico Docente Eliseo Noel Caamaño, de Matanzas. Se realizó una revisión de la literatura sobre la enfermedad, resaltando su fisiopatología, formas clínicas, diagnóstico, así como el tratamiento a seguir, demostrando cómo el país dispone de todos los recursos necesarios para el costoso tratamiento de la enfermedad, logrando una vez más evadir el bloqueo impuesto por los Estados Unidos.

Leucinosis, also known as maple syrup urine disease, is an innate mistake of the branched chain amino acids (valine, isoleucine and leucine), which concentration produces a serious neonatal encephalopathy that, if it is not precociously and timely diagnosed and treated, unavoidably leads to the emergence of permanent neurologic sequels and the subsequent lethal outcome. The diagnosis is reached clinically, in five different ways, and based on the presence of higher levels of branched chain amino acids (leucine, isoleucine and valine and their correspondent ceto acids) in urine and blood. We dealt with the first and unique case reported in Cuba, diagnosed and followed up by a multidisciplinary team (at the national and provincial level) in the Teaching Pediatric Provincial Hospital Eliseo Noel Caamaño, of Matanzas. We carried out a review of the literature on the disease, highlighting its physiopathology, clinical forms, diagnosis, and also the treatment to apply, showing that the country has the necessary recourses for the disease expensive treatment, evading again the blockade imposed by the United States of America.

Enfermedad de orina a jarabe de arce / Maple syrup urine disease

Las enfermedades metabólicas pueden presentarse con síntomas, signos y laboratorios inespecíficos, que si no se consideran entre los diagnósticos diferenciales pueden retrasar el diagnóstico de estos pacientes, lo que lleva a un alto grado de secuelas neurológicas o muerte en etapas tempranas. La enfermedad de Orina a Jarabe de Arce es una enfermedad metabólica de baja incidencia caracterizada por la acumulación de niveles tóxicos de valina, isoleucina y principalmente leucina. Se presenta un paciente sin antecedentes que a los 11 días de vida comienza con mala actitud alimentaria, letargia y fontanela tensa. Descartadas las causas infectológicas se realizó un screening para enfermedades metabólicas. Se diagnosticó Leucinosis (Enfermedad de orina con olor a Jarabe de Arce) y se inició el tratamiento con restricción de leucina, valina e isoleucina en la dieta. A los pocos días del tratamiento el paciente mostró evidencias de mejoría clínica y en los parámetros de laboratorio.

Clinical signs, symptoms and lab tests of neonatal metabolic diseases may be unspecific and a high grade of suspicion is necessary to include them among the differential diagnosis avoiding a significant delay in recognizing this condition and consequent risk of neurologic handicap or early dead. Maple syrup urine disease is a congenital metabolic disorder with a low rate of prevalence and characterized by a toxic accumulation of the amino acids valine, isoleucine and mainly leucine. In this report we describe the history of a patient apparently healthy that on the 11th day after birth initiates symptoms like poor feeding, lethargy and tense fontanel. Excluded sepsis a work up for metabolic disease was performed, being diagnosed a leucinosis (Maple syrup urine disease). A dietary treatment with leucine, valine and isoleucine restriction was immediately initiated and a few days after the patient showed significant clinical and lab improvement. A short description and discussion of this disease is presented.