Functional decompensation after administration of compound diphenoxylate in a maple syrup urine disease patient:case report and literature review / 中华全科医师杂志

A 14-year girl was admitted with akinesia and difficulty walking due to gait instability after two oral doses of compound diphenoxylate (lomotil). When she was 18-month old, drowsiness and inability to walk were observed after taking lomotil, the symptoms were relieved by taking B vitamins for treatment. The laboratory tests showed the increased blood branched chain amino acid levels; gene detection indicated that the child had compound heterozygous variations of c.745G>A(p.G249S) and c.485-1G>C in the BCKDHA gene. The girl was finally diagnosed as maple syrup urine disease. The domestic and foreign literature was searched, and 11 child cases of maple syrup urine disease with onset of unsteadiness and ataxia were reported, none of whom was associated with oral administration of compound diphenoxylate.

Necrosis en espejo de ganglios basales en la enfermedad de la orina con olor a jarabe de arce. Presentación de un caso / Mirror necrosis of basal ganglia in maple syrup urine disease. A case report

RESUMEN La enfermedad de la orina con olor a jarabe de arce es una enfermedad genética autosómica recesiva, cerebral degenerativa. Es causada por un déficit en la actividad de la deshidrogenasa de los cetoácidos de cadena ramificada, que provoca inadecuado almacenamiento de los tres aminoácidos esenciales de dicha cadena. Esto genera una neurotoxicidad severa que puede llevar a la muerte. Se manifiesta clínicamente por deterioro neurológico, retraso psicomotor, problemas de alimentación, orina con olor característico. Sus consecuencias cerebrales pueden ser definidas mediante tomografía axial computarizada. Este artículo tiene como objetivo presentar un caso de enfermedad de la orina con olor a jarabe de arce con hipodensidad bilateral de los ganglios basales por necrosis en espejo, detectado mediante estudio tomográfico. Se trata de una paciente femenina, de 9 años de edad con cuadro anterior de cetoacidosis no diabética. Posterior a la realización de apendicectomía, comenzó con cuadro comatoso que requirió estudio tomográfico mediante el cual se constató edema cerebral. Evolucionó tórpidamente, por lo que requirió nuevo estudio tomográfico que demostró empeoramiento de las condiciones neurológicas al reflejarse en la imagen hipodensidad bilateral a nivel de los núcleos basales por necrosis. La enfermedad de la orina con olor a jarabe de arce es una afección rara, con diversas formas clínicas. Requiere de estudios de laboratorio que la confirmen e imágenes como tomografía computarizada que, como en este caso, ayuden a evidenciar el daño neurológico. Fue muy característica la hipodensidad de ganglios basales asociada a edema cerebral.

ABSTRACT Maple syrup urine disease is an autosomal recessive genetic degenerative brain disease. It is caused by a deficit in branched-chain ketoacid dehydrogenase activity, which causes inadequate storage of the three essential amino acids of said chain. This generates severe neurotoxicity that can lead to death. It is clinically manifested by neurological deterioration, psychomotor retardation, feeding problems, urine with a characteristic odor. Its cerebral consequences can be defined by computerized axial tomography. This article aims to present a case of maple syrup urine disease with bilateral hypodensity of the basal ganglia due to mirror necrosis, detected by tomographic study. This is a 9-years-old female patient with a history of non-diabetic ketoacidosis. After the appendectomy, she began with a coma that required a tomographic study, which revealed cerebral edema. She evolved torpidly, requiring a new tomographic study that showed worsening of the neurological conditions as bilateral hypodensity at the level of the basal nuclei due to necrosis was reflected in the image. Maple syrup urine disease is a rare condition with various clinical forms. It requires laboratory studies to confirm it and images such as computed tomography that, as in this case, help to show the neurological damage. The hypodensity of the basal ganglia associated with cerebral edema was very characteristic.

Clinical utility of low branched-chain amino acid modular diets in patients with isovaleric aciduria and maple syrup urine disease

@#Introduction: Modular diets (MDs) with low amount of offending amino acids have been developed using locally available food ingredients as alternatives to commercial formulas for the treatment of branched-chain organic acidurias (BCOAs). Herein, we conducted a clinical investigation of MDs in patients with BCOAs. Methods: Modular diet A (MDA), with low leucine was produced for maple syrup urine disease (MSUD), and modular diet B (MDB) products, MDB-1, -2, -3, and -4, with low leucine, valine, methionine and threonine were made for isovaleric aciduria (IVA)/methylmalonic aciduria (MMA)/propionic aciduria (PA). Children aged 4-18 years, with MSUD, IVA, PA or MMA were invited to participate in the study. The research subjects switched from metabolic formula protocol to modular diet protocol. They were followed-up at 0, 1, 2, 4, and 6 months. Clinical efficacies of MDs were determined by completion of study, compliance to MDs, clinical outcomes and complications, and parental satisfaction. Results: Six children (2 MSUD and 4 IVA) participated and completed the study. Compliance to MDA was 100% in MSUD subjects with G-tube feeding, while compliance to MDB varied among self-fed individuals with IVA. One subject with MSUD was clinically stable throughout the study, while the other experienced metabolic instability. All IVA individuals showed clinical and laboratory stability during the study. One MSUD and three IVA families preferred the metabolic formula, whereas the other IVA family reported no preference and the other MSUD subject preferred MDs. Conclusion: We provided a proof of concept in developing modular diets for BCOAs, and showed favourable outcomes when using MDs in IVA and varying clinical benefits in MSUD.

Heterozygous living donor liver transplantation for pediatric maple syrup urine disease with new compound mutation of BCKDHB gene: a case report and literature review / 器官移植

Objective To evaluate the clinical efficacy of heterozygous living donor liver transplantation for pediatric maple syrup urine disease. Methods A 3-year-old boy was admitted to the hospital on July 5, 2017 due to maple syrup urine disease for half a year. The child presented with paroxysmal dysarthria and motor dysfunction of the lower limbs under fasting status for half a year, accompanied with obvious maple syrup urine odor and slow language development. No other growth abnormality or mental defects were observed. Serum branched chain amino acid (BCAA) assay detected that the level of leucine was 684 μmol/L and 559 μmol/L for the valine. The child was diagnosed with maple syrup urine disease type b based on gene detection combined with BCAA assay. Living donor liver transplantation from his biological father was performed. Postoperatively, routine immunosuppression, anti-virus, anti-infection therapies, maintenance of fluid, electrolyte, and acid-base balance and other necessary nutritional support were given. The dose of tacrolimus was adjusted according to biochemical parameters and cytochrome P450(CYP)3A5 genotype of the recipient. Glucocorticoid administration was terminated at approximately 6 months after operation. Results The liver function of the recipient was recovered to normal range at postoperative 1 month, and basically stabilized at 3 years after surgery. The amino acid level was decreased to normal level immediately after operation, and BCAA was continually declined after normal diet for postoperative 1 month. As of the submission date, the recipient grew well in a stable condition and achieved high quality of life. Conclusions Heterozygous living donor liver transplantation is a safe and effective treatment of maple syrup urine disease, which reduces the possibility of sudden acute metabolic events, significantly improves the quality of life of the recipient and provides a novel idea for surgical treatment of maple syrup urine disease.

Quantitative Determination of Branched-Chain Amino Acids in Dried Blood Spot Samples by LC-MSMS and its Application in Diagnosis and Follow-Up of Chilean Patients with Maple Syrup Urine Disease

Abstract Elevation of branched-chain amino acids (BCAAs) in biological fluids indicates a deficiency in the branched-chain ketoacid dehydrogenase complex, which causes maple syrup urine disease (MSUD). Detection of increased levels of alloisoleucine confirms the diagnosis, while routine monitoring of leucine concentration is crucial for preventing metabolic decompensation and neurological dysfunction. In the metabolic center at Universidad de Chile, we have confirmed and monitored more than fifty MSUD patients in the last 20 years. Most diagnoses were made by clinical and sibling diagnosis, as MSUD is not included in the Chilean national newborn screening program. Shortening diagnosis time has a fundamental impact on the outcome of patients, therefore we focused on implementing detection of BCAAs in dried blood spot by liquid chromatography mass spectrometry (LC-MSMS) for disease confirmation as well as for biochemical monitoring. Retrospective analysis of samples from 9 diagnosed MSUD patients were performed; BCAAs values were determined via MSMS and LC-MSMS conducted in parallel. Leucine and alloisoleucine levels were positively correlated with patient's diagnosis age. Alloisoleucine was significatively elevated as early as 24 hr after birth. A predictable variation in BCAAs levels after nutritional intervention among diagnosed MSUD patients was found.

Diálisis peritoneal en un neonato con enfermedad de la orina con olor a jarabe de arce. A propósito de un caso / Peritoneal dialysis in a neonate with maple syrup urine disease. A case report

La enfermedad de jarabe de arce es una entidad autosómica recesiva producida por un error congénito en el metabolismo de tres aminoácidos esenciales de cadena ramificada: valina, leucina e isoleucina. La forma neonatal de esta enfermedad se manifiesta por un cuadro de compromiso neurológico grave y progresivo, asociado a un olor peculiar de la orina, consecuencia de la eliminación del exceso de estos aminoácidos. Este olor a azúcar quemada remeda a la melaza obtenida de los arces, lo que da nombre a esta enfermedad. El mejor método para eliminar estos tóxicos es la hemodiafiltración, pero, en los centros en los que esta práctica no es posible, la diálisis peritoneal constituye una alternativa.Se presenta a un recién nacido con leucinosis, con compromiso grave del sistema nervioso central, en quien la diálisis peritoneal fue de utilidad para superar la descompensación metabólica.

Maple syrup disease is an autosomal recessive entity caused by a congenital error in the metabolism of three essential branched-chain amino acids: valine, leucine and isoleucine. The neonatal form of this disease is expressed by a severe and progressive neurological compromise, associated with a peculiar smell of urine, a consequence of the elimination of the excess of these amino acids. This smell of burnt sugar mimics the molasses obtained from maples, which gives its name to this disease. The best method to eliminate these toxins is hemodiafiltration, but in centers where this practice is not possible, peritoneal dialysis is an alternative.We present a newborn with leukinosis with severe central nervous system involvement in whom peritoneal dialysis was useful to overcome metabolic decompensation.

Enfermedad de orina con olor a jarabe de arce: reporte de dos casos / Maple urine disease: two case reports

Introducción: La enfermedad de orina con olor a jarabe de arce (EOJA) es un trastorno del metabolismo de los aminoácidos de cadena ramificada (ACR). Tiene una incidencia de 1 en 85.000­185.000 recién nacidos (RN) vivos, siendo mayor en poblaciones con alta tasa de consanguineidad. Se debe al déficit del complejo enzimático BCKDC (Branched-chain alpha-keto acid dehydrogenase complex). Objetivo: Sensibilizar respecto al diagnóstico precoz, describiendo la presentación y evolución clínica de 2 casos presentados en menos de un año. Presentación del caso: Caso 1: Recién nacido de término (RNT), sin antecedentes mórbidos personales ni familiares, consulta al 11er día de vida (DDV) por cuadro de irritabilidad, rechazo alimentario, mirada fija e hipertonía. Hospitalizado por 55 días con progresiva mejoría neurológica. Al alta solo leve retraso del desarrollo psicomotor (RDSM). Caso 2: RNT, sin antecedentes mórbidos personales ni familiares, consultó al 12° DDV por cuadro de hipoactividad y rechazo alimentario. Hospitalizado por 70 días con evolución clínica y neurológica dificultosa. Al alta con trastorno deglutorio que requirió gastrostomía. En ambos casos se planteó sospecha de EOJA por aminoacidemia y aminoaciduria característica, confirmándose por medición cuantitativa de aminoácidos. Discusión: Existen cinco fenotipos diferentes, clasificados principalmente por presentación clínica y edad de debut, siendo el más frecuente la forma clásica (ambos casos). Resulta muy importante el diagnóstico precoz y manejo por su relación con el pronóstico neurológico, sin embargo, en Chile no se cuenta actualmente con un screening neonatal universal. El tratamiento se basa en un manejo nutricional estricto y la corrección de desequilibrios metabólicos e hidroelectrolíticos, ambos frecuentes en esta condición.

Introduction: The maple syrup urine disease (MSUD) is a metabolic disorder of branchedchain amino acids. It has an incidence of 1/85000 ­ 185000 live newborns being higher in in populations with a high rate of consanguinity. It is due to deficit BKDC enzyme complex (Branched-chain alpha-keto acid dehydrogenase complex). Objective: To raise awareness to early diagnosis, describing the presentation and clinical course of 2 cases presented in less than one year. Case report: Case 1: Full-term newborn with no personal or family history of morbidity presented the 11th day of life with irritability, food rejection, fixed stare and hypertonia. He was hospitalized for 55 days with progressive neurological improvement. At discharge only slightly delayed psychomotor development. Case 2: Full-term newborn with no personal or family history of morbidity presented the 12th day of life with hipoactivity and food rejection. He was hospitalized for 70 days with difficult clinical and neurological outcome. The patient was discharged with swallowing disorder that required gastrostomy. In both cases MSUP suspicion arises by aminoacidemia and aminoaciduria and confirmed by quantitative measurement of amino acids. Discussion: There are 5 different phenotypes classified chiefly by clinical presentation and age, being most frequent the classical form. It is very important to do an early diagnosis and management for its impact on neurological outcome; however, Chile does not currently has an universal neonatal screening. The treatment is based on a strict nutritional management and correction of metabolic and electrolyte imbalances, both common in this condition.

Brain MRI and clinical characteristics of maple syrup urine disease / 实用放射学杂志

Objective To investigate the characteristics of brain MRI in the patients with maple syrup urine disease(MSUD). Methods Nine patients with MSUD were diagnosed by gas chromatography mass spectrometry,tandem mass spectrometry and gene test.The MRI,clinical featuresand laboratory tests were analyzed.Results The 9 patients onset age were 3 days to 6 years old.The symptoms were varied such as poor response,lethargy,seizures and learning difficulties.Remarkable elevations of blood levels of leucine and valine were found in all patients.All patients had MRI examination,2 of them also took the examination of proton magnetic resonance spectroscopy (1 H-MRS).Involving cerebellar hemisphere,cerebellar peduncle,cerebral peduncle,brain stem,globus pallidus in 5 cases respectively,thalamus and posterior limb of internal capsule in 4 cases,centrum semiovale in 3 cases.2 cases also showed abnormal signal in corpus callosum,occipital,deep temporal lobe,and frontal lobe,parietal lobe.All lesions showed mild low signal intensity in T1 ,mild high signal intensity in T2 and obvious high signal intensity in DWI,except one case.1 H-MRS did not show a methyl resonance peak at 0.9 ppm in the two patients.Conclusion The MSUD lacked of specific clinical features.The MRI characteristics are the myelinated white matter such as the cerebellar hemispheres,posterior limb of the internal capsule,the brainstem,cerebellar peduncle,cerebral peduncle showing high signal in DWI.

Maple syrup urine disease in Brazil: a panorama of the last two decades / Doença da urina de xarope de bordo no Brasil: um panorama das últimas duas décadas

OBJECTIVE: To characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. METHODS: In this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. RESULTS: Eighty-three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57-7). Median age at onset of symptoms was 10 days (IQR 5-30), whereas median age at diagnosis was 60 days (IQR 29-240, p = 0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n = 12) and without (n = 71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. CONCLUSION: In Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country. .

OBJETIVO: Caracterizar uma amostra de pacientes brasileiros com a doença da urina de xarope de bordo (DXB) diagnosticados entre 1992 e 2011. MÉTODOS: Os pacientes foram identificados por meio de um laboratório de referência nacional para o diagnóstico de DXB e por meio do contato com outros serviços de genética médica no Brasil. Os dados foram coletados por meio de uma revisão de prontuários. RESULTADOS: Foram incluídos no estudo 83 pacientes de 75 famílias (idade média: três anos; intervalo interquartil (IQR): 0,57-7). A idade média no surgimento dos sintomas era de 10 dias (IQR: 5-30), ao passo que a idade média no diagnóstico era de 60 dias (IQR: 29-240; p = 0,001). Somente três (3,6%) pacientes foram diagnosticados antes do surgimento de manifestações clínicas. Uma comparação entre pacientes com (n = 12) e sem (n = 71) um diagnóstico precoce mostra que o diagnóstico precoce está associado à presença de histórico familiar positivo e à redução na prevalência de manifestações clínicas no momento do diagnóstico, porém sem melhor resultado. Em geral, 98,8% dos pacientes têm algum atraso no desenvolvimento psicomotor ou neurológico. CONCLUSÃO: No Brasil, os pacientes com DXB normalmente recebem um diagnóstico tardio e exibem um envolvimento neurológico e baixa sobrevivência, mesmo com um diagnóstico precoce. Sugerimos que políticas públicas específicas para o diagnóstico e tratamento da DXB sejam desenvolvidas e implementadas no país. .

Evaluación del seguimiento de 29 niños chilenos con la enfermedad de la orina olor a jarabe de arce clásica / Follow up evaluation of 29 chilean children with classical maple syrup urine disease

Introduction: Maple Syrup Urine Disease (MSUD) is caused by a defect of the ketoacid dehydrogenase enzyme complex of the branched amino acids Valine, Isoleucine and Leucine (VIL). The treatment consists of a leucine-restricted diet. Objective: To evaluate the long-term follow-up in children with MSUD. Methodology: 29 records were reviewed of patients with MSUD, of which 24 were clinically identified (> 5th day of life), 4 cases by MSUD family history and one by neonatal screening (< 5th day of life). Leucine (Leu) levels were measured at diagnosis (Biotronic 2000) and during follow-up (mass spectrometry). The number of decompensation events, Total Intellectual Quotient (TIQ, Bayley and Wechsler scale) and nutritional status were also measured. STATA statistical software version 9.2 was applied (p≤0.05). Results: Mean age at diagnosis was 14 days old. In all cases the diagnosis was confirmed by elevated levels of Leu and alloisoleucin. When comparing the TIQ of 19 cases over 3 years old with their age at diagnosis, it was observed that those cases screened by the 5th day of life had a TIQ 84.6 ± 13, while those diagnosed later had a TIQ 73 ± 17 (p≤0.05). In assessing the number of hospitalizations that occurred during follow-up, we determined that the 5 cases screened early never had a metabolic crisis and had a higher TIQ than those who had had one or more decompensation (92 and 74, respectively, p≤0.05). An inverse correlation was observed between the Leu+Isoleucine value and TIQ. Conclusion: The diagnosis before the 5th day of life and a good metabolic control during follow-up, enables children with MSUD to have normal cognitive development.

La enfermedad de la orina olor a jarabe de arce (EOJA) se produce por un defecto del complejo enzimático deshidrogenasa de los cetoácidos de los aminoácidos ramificados: Valina, Isoleucina, Leucina (VIL). El tratamiento es una dieta restringida en leucina (Leu). Objetivo: evaluar el seguimiento a largo plazo en niños con EOJA. Metodología: Se revisaron 29 fichas de pacientes EOJA, 24 fueron pesquisados por clínica (> 5to día de vida) y 4 casos por antecedentes familiares con EOJA y 1 por pesquisa neonatal (< 5to día de vida). Se midió nivel de Leu al diagnóstico (Biotronic 2000) y durante el seguimiento (Espectrometría de masa), número de descompensaciones, Coeficiente Intelectual Total (CIT) (Escalas de Bayley y Wechsler) y estado nutricional. Se aplicó programa estadístico STATA versión 9.2 (p≤0.05). Resultados: La edad de diagnóstico fue a los 14 días de edad. En todos se confirmó el diagnóstico por los niveles elevados de Leu y presencia de alloisoleucina. Al comparar el CIT de los 19 casos mayores de 3 años con la edad de diagnóstico, se observó que aquellos casos pesquisados antes del 5to día tenían un CIT de 84,6±13, a diferencia de los diagnosticados posteriormente que tenían un CIT=73±17 (p≤0.05). Al evaluar el número de descompensaciones ocurridas durante el seguimiento, se determinó que los 5 casos nunca habían tenido una crisis metabólica, tuvieron un CI mayor que aquellos que habían tenido una o más descompensaciones (92 y 74 respectivamente) (p≤0.05). Cuando se correlacionó el valor de Leu+Iso de seguimiento con el CIT, se observó una correlación inversamente proporcional. Conclusión: el diagnóstico antes de los 5to día de vida y un buen control metabólico durante el seguimiento, permite que los niños con EOJA tengan un desarrollo cognitivo normal.

Identification of Two Novel BCKDHB Mutations in Korean Siblings with Maple Syrup Urine Disease Showing Mild Clinical Presentation

Maple syrup urine disease (MSUD) is a disorder that involves the metabolism of branched chain amino acids, arising from a defect in branched-chain alpha-keto acid dehydrogenase complex. Mutations have been identified in the BCKDHA, BCKDHB, or DBT genes, which encode different subunits of the BCKDH complex. Although encephalopathy and progressive neurodegeneration are its major manifestations, the severity of the disease may range from the severe classic type to milder intermediate variants. We report two Korean siblings with the milder intermediate MSUD who were diagnosed with MSUD by a combination of newborn screening tests using tandem mass spectrometry and family genetic screening for MSUD. At diagnosis, the patients' plasma levels were elevated for leucine, isoleucine, valine, and alloisoleucine, and branched-chain alpha-keto acids and branched-chain alpha-hydroxy acids were detected in their urine. BCKDHA, BCKDHB, and DBT analysis was performed, and two novel mutations were identified in BCKDHB. Our patients were thought to have the milder intermediate variant of MSUD, rather than the classic form. Although MSUD is a typical metabolic disease with poor prognosis, better outcomes can be expected if early diagnosis and prompt management are provided, particularly for milder forms of the disease.

Analysis of gene mutations among South Indian patients with maple syrup urine disease: Identification of four novel mutations.

Maple syrup urine disease (MSUD) is predominantly caused by mutations in the BCKDHA, BCKDHB and DBT genes, which encode for the E1α, E1β and E2 subunits of the branched-chain α-keto acid dehydrogenase complex, respectively. Because disease causing mutations play a major role in the development of the disease, prenatal diagnosis at gestational level may have significance in making decisions by parents. Thus, this study was aimed to screen South Indian MSUD patients for mutations and assess the genotype-phenotype correlation. Thirteen patients diagnosed with MSUD by conventional biochemical screening such as urine analysis by DNPH test, thin layer chromatography for amino acids and blood amino acid quantification by HPLC were selected for mutation analysis. The entire coding regions of the BCKDHA, BCKDHB and DBT genes were analyzed for mutations by PCR-based direct DNA sequencing. BCKDHA and BCKDHB mutations were seen in 43% of the total ten patients, while disease-causing DBT gene mutation was observed only in 14%. Three patients displayed no mutations. Novel mutations were c.130C>T in BCKDHA gene, c. 599C>T and c.121_122delAC in BCKDHB gene and c.190G>A in DBT gene. Notably, patients harbouring these mutations were non-responsive to thiamine supplementation and other treatment regimens and might have a worse prognosis as compared to the patients not having such mutations. Thus, identification of these mutations may have a crucial role in the treatment as well as understanding the molecular mechanisms in MSUD.

Diagnostic and therapeutic advancement of maple syrup urine disease / 临床儿科杂志

Maple syrup urine disease (MSUD) is an autosomally recessively inherited disorder of branched-chain amino acid (BCAA) metabolism caused by the defective activity of branched-chainα-ketoacid dehydrogenase complex (BCKD). The disease is characterized by severe ketoacidosis, mental retardation, and neurological impairments. So far, application of tandem mass spectrom-etry and HPLC has allowed newborn screening and early detection, but some patients with variant forms of the disorder will escape detection. Liver transplantation is an effective treatment. However, the rareness of liver donation limits the liver transplantation. In this review, the screening, diagnosis and therapy of MSUD will be discussed.

A report of 18-month follow-up study on a case of classic maple syrup urine disease / 临床儿科杂志

Objectives To explore the long-term prognosis, treatment (especially dietary treatment) of classic maple syrup urine disease. Methods The complications and dietary treatment were observed by follow-up study of a classic MSUD patient. Results The patient have obvious damage in nervous system. However, reasonable dietary leucine tolerance therapy after the neonatal period can effectively reduce the metabolic crisis and complications. A mutation in BCKDHB gene was detected in the patient by genetic testing. Conclusion It is suggested that dietary restriction and monitoring of branched-chain amino acids are helpful to reduce the development of acute metabolic crisis and complications and improve the quality of life.

Progress in maple syrup urine disease / 国际儿科学杂志

Maple syrup urine disease (MSUD) is a rare inherited disorder of branched-chain amino acid metabolism presenting with life threatening encephalopathy and maple syrup odor in urine in affected individuals.Blood levels of branched-chain amino acids(BCAA) significantly increase.It is classified into 5 forms according to the clinical course,and classified 4 molecular phenotypes based on the affected locus of the branched chain αr-ketoacid dehydrogenase complex.Treatment of MSUD is divided into acute decompensation stage treatment and life-long dietary restriction treatment.

Doença da urina de xarope de bordo: semiologia e terapêutica / Maple syrup urine disease: semiology and therapy

A leucinose é uma doença metabólica hereditária com caráter autossômico recessivo, que afeta principalmente recém-nascidos, mas também lactentes e infantes. Caracteriza-se por crises metabólicas que, na forma mais comum e perigosa da doença, a leucinose clássica, acomete recém-nascidos após quatro a sete dias de vida, ocasionando alteração do tônus, letargia, soluços, recusa alimentar ou sucção débil, seguidos por perda de peso, cetoacidose, cheiro característico de açúcar queimado na urina e sinais neurológicos de intoxicação, podendo evoluir para o coma e a morte. O prognóstico é extremamente desfavorável se não for instituído o tratamento precocemente, com piora progressiva até o óbito em cerca de três meses. O tratamento se baseia na eliminação dos metabólitos tóxicos que se acumulam em detrimento do déficit enzimático na atividade do complexo desidrogenase dos a-cetoácidos de cadeia ramificada e que compreendem os aminoácidos de cadeia ramificada leucina, valina, isoleucina e seus respectivos alfa-cetoácidos, ácido a-cetoisocaproico, ácido a-cetoisovalérico e ácido a-ceto-b-metilvalérico. Além disso, a prescrição de uma dieta hipercalória e hipoproteica, restrita em aminoácidos de cadeia ramificada, com possível suplementação de minerais e vitaminas é essencial no bom êxito do tratamento, que deve ser iniciado tão logo se suspeite da doença e mantido por toda a vida do paciente.

Analysis of diagnosis and treatment in twelve patients with maple syrup urine disease / 中华内分泌代谢杂志

Twelve patients with maple syrup urine disease were treated with restricted natural protein intake,special nutrition powder,and vitmin B1.The manifestations of these patients were greatly improved after treatment.The blood levels ofleucine and valine were significantly decreased after treatment(P＜0.01).Although the level of branched-chain α-ketoacids in urine was reduced,but not significantly.

Gene mutations and prenatal diagnosis in families with maple syrup urine disease / 中华围产医学杂志

Objective Maple syrup urine disease (MSUD) is a rare metabolic disorder caused by deficiency of the activity of branched-chain 2-keto acid dehydrogenase complex.The complex contains E1α,E1β and E2 subunits which are encoded by BCKDHA,BCKDHB or DBT genes respectively.Mutation in any gene will cause MSUD.The aim of this study was to analyze the gene mutations of four cases with MSUD and carry out prenatal diagnosis for these four families for MSUD.Methods From 2005 to 2010,four neonates (two males and two females) were diagnosed as MSUD at 2,5,10and 26 days of life.The coding regions of BCKDHA gene and BCKDHB gene in the above four cases were amplified by polymerase chain reaction and analyzed by direct DNA sequencing.During the second pregnancy of the same mother,the amniotic fluid was drawn out at 16-20 weeks for gene mutation analysis after the amniocytes were cultured.Results Mutation analysis revealed six mutations in four patients,including four novel mutations (c.308T＞C,c.562G＞T,c.1279C＞G and c.1280-1291de112) and two previously reported mutations.Five mutations (c.308T＞C,c.562G ＞T,c.868G＞A,c.1279C＞G and c.1280-1291de112) were detected on BCKDHA gene in three patients.While one mutation (c.853C＞T) was found on BCKDHB gene in one patient.Only one mutation was found in the amniocytes of each patient's mother at their second pregnancies suggesting a MSUD heterozygous fetus.Conclusions Analysis of BCKDHA and BCKDHB allowed preliminary understand of gene mutations in the four MSUD families,and made prenatal diagnosis possible,which helped in consultation in the second pregnancy.

Tratamento metabólico da doença da urina do xarope de bordo / Metabolic treatment of the maple syrup urine disease

Objetivo: relatar caso de doença da urina do xarope de bordo (leucinose) e demonstrar como obterem-se bons resultados com o tratamento metabólico da doença. Descrição do caso: recém-nascida, desenvolveu no quinto dia de vida dificuldade de sucção, prostração e alternação de hipotonia e hipertonia axial. Foi admitida com 12 dias de vida em unidade de tratamento intensivo com crises de hipertonia, opistótono, movimentos de pedalar e apneia. Foi submetida à CPAP nasal e instituído tratamento de suporte, com triagem infecciosa negativa. A cromatografia sanguínea de aminoácidos revelou aumento pronunciado de leucina (5.986,4 nmol/mL), isoleucina (488,1 nmol/mL) e valina (755,9 mmol/mL), sendo diagnosticada leucinose e iniciado o seu tratamento metabólico. Evoluiu com melhora neurológica, ganho de peso e redução dos níveis de leucina. Recebeu alta em boas condições. Comentários: houve queda mais lenta nos níveis de leucina do que o relatado na literatura, o que pode ser explicado pelo tempo necessário para conseguir-se a dieta especial (MSUD 1) e pelo fato da mistura de aminoácidos usada na nutrição parenteral conter leucina. Poder-se-ia alcançar controle bioquímico mais rápido se houvesse disponibilidade diária da análise sérica quantitativa de aminoácidos e mais agilidade na liberação dos resultados.

Objective: Case report of the maple syrup urine disease (leucinosis) and show how to get good results with the disease metabolic treatment. Case description: newborn developed in the 5th day of life difficulty poor sucking, prostration and alternating axial hypotonia and hypertonia, was admitted with 12 days of life in the intensive treatment unit, with attacks of hypertonia, opisthotonus, paddling movements and apnea. She underwent nasal CPAP and supportive care instituted, with negative infectious screening. The blood amino acid chromatography showed a pronounced increase of leucine(5.986,4 nmol/mL), isoleucine (488,1 nmol/mL) and valine (755,9 mmol/mL), with leucinosis diagnosis and started the metabolic treatment. Evolved with neurological improvement, weight gain and decreased the levels of leucine. She was discharged in good condition. Comments: there was a slower fall in levels of leucine than that reported in the literature, which can be explained by the time needed to get the specialdiet (MSUD 1) and because the mixture of amino acids used in the parenteral nutrition contain leucine. The biochemical control could be achieved faster if there was daily availability of the quantitative analysis of serum amino acids and more speed in the release of results.

Elevada mortalidad y discapacidad en niños mexicanos con enfermedad de orina con olor a jarabe de arce (EOJA) / Increased mortality and disability in a cohort of Mexican children with maple syrup urine disease

Introducción: La enfermedad de jarabe de arce es una enfermedad genética que produce crisis de cetoacidosis y deterioro neurológico progresivo que llevan a un coma fatal. El inicio del tratamiento temprano es determinante en el pronóstico. Objetivo: Describir las características de una cohorte de pacientes mexicanos con enfermedad de orina con olor a jarabe de arce (EOJA). Material y métodos: Se hizo un análisis retrospectivo de casos de EOJA de 1991 a 2006. Resultados: Encontramos 36 pacientes (16 niñas y 20 niños). Tres fueron inicialmente detectados mediante tamiz neonatal, uno de ellos realizado en México y los otros dos en el extranjero. Estos últimos recibieron tratamiento oportuno y exhiben desarrollo psicomotor normal. El caso detectado en México no recibió tratamiento adecuado y falleció. Los otros 33 pacientes se diagnosticaron entre los 2 y los 73 meses de edad mediante tamiz metabólico (postsintomático) ante la sospecha clínica. Todos los pacientes sintomáticos presentaron resultado positivo a la prueba de dinitrofenilhidrazina y aminoácidos ramificados elevados. La hipotonía, rechazo al alimento, y las crisis convulsivas fueron los síntomas más frecuentes. En esta cohorte, la mortalidad fue del 50 % (18/36) y el 81.2 % de los sobrevivientes (13/18) muestran actualmente retraso psicomotor. Discusión: Es necesario establecer en México un modelo de atención integral para la EOJA que incluya la detección presintomática preventiva, el tratamiento temprano, el seguimiento y asesoramiento genético.

INTRODUCTION: Maple syrup urine disease (MSUD) is a genetic disorder that produces ketoacidosis crises and neurological complications often leading to death. The age of diagnosis and treatment determine a child's adequate and healthy outcome. OBJECTIVE: Describe the characteristics of a pediatric Mexican cohort with MSUD. MATERIAL AND METHODS: Retrospective analysis of MSUD cases seen at our Metabolic Unit between 1991- 2006. RESULTS: We studied 36 patients; three were initially detected through neonatal screening, one of them done in Mexico and two in the United States. The latter were given timely treatment and developed normally, both intellectually and physically. The patient detected in Mexico was not given adequate treatment and died at 3 months of age. The remaining 33 patients were diagnosed between 2-24 months using standard biochemical tests performed after symptoms became noticeable. All symptomatic patients had high levels of branched-chain amino acids. Hypotonia, refusal to eat and seizures were the most frequent symptoms. The cohort's mortality was 50% (18/36), while 81.2% (13/18) of survivors displayed cognitive impairment. DISCUSSION: Mexico needs a comprehensive treatment protocol for the care of MSUD patients including newborn screening, early treatment, follow-up and genetic counseling.