Diagnosis of an intermediate case of maple syrup urine disease:A case report

BACKGROUND Maple syrup urine disease(MSUD)is an autosomal recessive genetic disorder caused by defects in the catabolism of the branched-chain amino acids(BCAAs).However,the clinical and metabolic screening is limited in identifying all MSUD patients,especially those patients with mild phenotypes or are asymptomatic.This study aims to share the diagnostic experience of an intermediate MSUD case who was missed by metabolic profiling but identified by genetic analysis.CASE SUMMARY This study reports the diagnostic process of a boy with intermediate MSUD.The proband presented with psychomotor retardation and cerebral lesions on magnetic resonance imaging scans at 8 mo of age.Preliminary clinical and metabolic profiling did not support a specific disease.However,whole exome sequencing and subsequent Sanger sequencing at 1 year and 7 mo of age identified bi-allelic pathogenic variants of the BCKDHB gene,confirming the proband as having MSUD with non-classic mild phenotypes.His clinical and laboratory data were retrospectively analyzed.According to his disease course,he was classified into an intermediate form of MSUD.His management was then changed to BCAAs restriction and metabolic monitoring conforming to MSUD.In addition,genetic counseling and prenatal diagnosis were provided to his parents.CONCLUSION Our work provides diagnostic experience of an intermediate MSUD case,suggesting that a genetic analysis is important for ambiguous cases,and alerts clinicians to avoid missing patients with non-classic mild phenotypes of MSUD.

Brain magnetic resonance imaging findings and radiologic review of maple syrup urine disease:Report of three cases

BACKGROUND Maple syrup urine disease(MSUD)is a rare autosomal-recessive disorder that affects branched-chain amino acid(BCAA)metabolism and is named after the distinctive sweet odor of affected infants’urine.This disease is characterized by the accumulation of BCAAs and corresponding branched-chain ketoacids of leucine,isoleucine,and valine in the plasma,urine,and cerebrospinal fluid.However,the mechanisms of MSUD-induced brain damage remain poorly defined.The accumulation of BCAAs in the brain inhibits the activity of pyruvate dehydrogenase andα-ketoglutarate,disrupting the citric acid cycle and consequently impacting the synthesis of amino acids,causing cerebral edema and abnormal myelination.CASE SUMMARY We report three neonates admitted to our hospital with the classic subtype of MSUD.All three patients,with a transient normal period,presented with poor feeding,vomiting,poor weight gain,and increasing lethargy after birth.Laboratory testing revealed metabolic acidosis.The serum tandem mass spectrometry amino acid profile showed elevated plasma levels of BCAAs(leucine,isoleucine,and valine).Brain magnetic resonance imaging(MRI)presented abnormal signals mainly involving the globus pallidus,thalamus,internal capsule,brainstem,and cerebellar white matter,which represent the typical myelinated areas in normal full-term neonates.CONCLUSION In our patients,MRI showed typical features,in concordance with the available literature.Early detection and timely treatment are very helpful for the prognosis of MSUD patients.Therefore,we discuss the neuroimaging features of MSUD to enhance the knowledge of pediatricians about this disease.

Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease

Background Maple syrup urine disease(MSUD)is an autosomal recessive inherited disorder that affects the degradation of branched-chain amino acids and is associated with acute and chronic brain dysfunction.This study presents 11 new patients with MSUD and describes the clinical characteristics and gene mutations reported in Chinese individuals.Methods During 2011–2018,11 pedaitric patients with MSUD from 11 Chinese families were analyzed based on clinical characteristics and mass spectrometry,with confirmation via gene sequencing.Novel mutations affecting protein function were predicted with Mutation-Taster,PolyPhen-2,CADD and SIFT software.3D models of the mutated proteins were generated by using the SWISS-MODEL online server,and the models were visualized in PyMOL.The characteristics and gene mutations in patients with MSUD were analyzed retrospectively.Results Seventeen mutations in the BCKDHA,BCKDHB and DBT genes were found,8 of which are novel:c.55C>/T,c.349C>T,c.565C>T,c.808G>A,c.859C>G,and c.1270dupC in BCKDHA;c.275-2A>G in BCKDHB;and c.1291C>T in DBT.Eight patients died.Two patients had severe mental retardation and were physically handicapped.One patient with the intermediate type had relatively good prognosis,with mild psychomotor retardation and adiposity.Four mothers underwent amniocentesis for prenatal diagnosis during their second pregnancy;two fetuses were wild type,and two were carriers of one heterozygous mutation.Conclusions Eight novel mutations were associated with MSUD in Chinese patients.Prenatal diagnosis was successfully performed by genetic analysis.Mutations in the BCKDHB gene were found in the majority of Chinese patients with MSUD.