BACKGROUND: Maple syrup urine disease (MSUD) is a rare disease for which newborn screening (NBS) is feasible but not universally applied in China. We shared our experiences with MSUD NBS.
METHODS: Tandem mass spectrometry-based NBS for MSUD was implemented in January 2003, and diagnostic methods included urine organic acid analysis via gas chromatography-mass spectrometry and genetic analysis.
RESULTS: Six MSUD patients were identified from 1.3 million newborns, yielding an incidence of 1:219,472, in Shanghai, China. The areas under the curve (AUCs) of total leucine (Xle), Xle/phenylalanine ratio, and Xle/alanine ratio were all 1.000. Some amino acid and acylcarnitine concentrations were markedly low in MSUD patients. 47 MSUD patients identified here and in other centers were investigated, which included 14 patients identified by NBS and 33 patients diagnosed clinically. Forty-four patients were subclassified into classic (n = 29), intermediate (n = 11) and intermittent (n = 4) subtypes. Due to earlier diagnosis and treatment, screened classic patients showed a higher survival rate (62.5%, 5/8) than clinically diagnosed classic patients (5.2%, 1/19). Overall, 56.8% (25/44) of MSUD patients and 77.8% (21/27) of classic patients carried variants in the BCKDHB gene. Among 61 identified genetic variants, 16 novel variants were identified.
CONCLUSIONS: MSUD NBS in Shanghai, China, enabled earlier detection and increased survivorship in the screened population.

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.
METHODS: 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.
CONCLUSIONS: 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.

Twelve days after birth, the child was admitted to hospital because of \"poor response, lethargy, and poor appetite for 6 days\" and developed into coma immediately. The ventilator is required. The urine had significant maple syrup odor. After different diagnosis, she was diagnosed with classical maple syrup urine disease.

Maple syrup urine disease (MSUD) is a rare autosomal recessive genetic disorder caused by defects in the catabolism of the branched-chain amino acids (BCAAs). Classic form of MSUD (CMSUD) is caused by mutations in BCKDHA, BCKDHB, DBT genes mostly. In this study, we analyzed the clinical and genetic characteristics of two patients with CMSUD. Two homozygous mutations, c.517G > T (p.Asp173Tyr) and c.503G > A (p.Arg168His), both in the exon 5 of BCKDHB were detected respectively. The novel mutation p.Asp173Tyr of patient A, inherited from his parents, is predicted to affect conformation of protein by computer analysis. The reported mutation p.Arg168His observed in patient B seemed to occur in a maternal uniparental disomy inheritance manner. Review of related literature revealed that most missense mutations in exon 5 of BCKDHB in homozygous genotype often result in CMSUD because of its incorrect conformation, and exon 5 of BCKDHB might be a susceptible region. Thus the novel homozygous mutation p.Asp173Tyr and the founder homozygous mutation p.Arg168His may be responsible for the clinical presentation of the two CMSUD patients, facilitating the future genetic counselling and prenatal diagnosis.

Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by mutations either in the BCKDHA, BCKDHB, DBT or DLD genes encoding components of the E1α, E1β, E2 and E3 subunits of branched-chain α-keto acid dehydrogenase complex (BCKDC), respectively. BCKDC is a mitochondrial enzyme which is responsible for the normal breakdown of BCAA. The rate of consanguineous marriage in Iran is 38.6 %, so the prevalence of autosomal recessive disorders is higher in comparison to other countries. Consanguinity increases the chance of the presence of pathogenic mutations in a homoallelic state. This phenomenon has made homozygosity mapping a powerful tool for finding the probable causative gene in heterogeneous disorders like IEM (Inborn Errors of Metabolism). In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above-mentioned genes were selected to identify the probable pathogenic gene in the studied families. The families who showed a homozygous haplotype for the STR markers of the BCKDHB gene were subsequently sequenced. Four novel mutations including c.633 + 1G > A, c.988G > A, c.833_834insCAC, and a homozygous deletion of whole exon 3 c. (274 + 1_275-1) _(343 + 1_344-1), as well as one recently reported (c. 508G > T) mutation have been identified. Interestingly, three families shared a common haplotype structure along with the c. 508G > T mutation. Also, four other families revealed another similar haplotype with c.988G > A mutation. Founder effect can be a suggestive mechanism for the disease. Additionally, structural models of MSUD mutations have been performed to predict the pathogenesis of the newly identified variants.

Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder that affects the degradation of branched chain amino acids (BCAAs). Only a few cases of MSUD have been documented in Mainland China, and prenatal diagnosis has not been performed so far. In this report, 8 patients (4 girls and 4 boys) with MSUD from 8 unrelated Chinese families were diagnosed at the age of 9 days to 1 year and 8 months. The diagnosis was confirmed by serum BCAAs and genetic analyses. Among the 8 patients, only one was detected by newborn screening. The remaining 7 patients were admitted because of neurological disorders and underwent selective screening. Significantly elevated BCAAs were observed in 7 patients. One patient was diagnosed by post-mortem study. 12 mutations were found in the BCKDHA, BCKDHB and DBT genes. 11 of these mutations were novel: c.178G > T, c.491T > C, c.740A > G, c.1214_1219dupCCAACC and IVS6+1delG in BCKDHA; c.482T > G, c.508C > T, c.767A > G, c.768C > G and IVS4,-2A > C in BCKDHB; and c.1A > G in DBT. Only one mutation, c.659C > T in the BCKDHA gene, had been previously reported. 7 patients were treated by dietary intervention and symptomatic therapy. 6 of them showed clinical improvement. The mother of one patient who died from MSUD underwent amniocentesis during her second pregnancy. The BCAAs level in her amniotic fluid was normal. Only one heterozygous mutation, IVS4,-2A > C in the BCKDHB gene, was detected in the cultured amniocytes. The results revealed that the fetus was not affected by MSUD. Normal development and the blood BCAAs profile confirmed the prenatal diagnosis after birth. Thus, we identified eleven novel mutations associated with MSUD in the Chinese population. Prenatal diagnosis of MSUD was successfully performed on one fetus by genetic analysis of the cultured amniocytes.

Intermittent maple syrup urine disease (MSUD) is a potentially life-threatening metabolic disorder caused by a deficiency of branched chain α-ketoacid dehydrogenase (BCKD) complex. In contrast to classic MSUD, children with the intermittent form usually have an atypical clinical manifestation. Here, we describe the presenting symptoms and clinical course of a Chinese boy with intermittent MSUD. Mutation analysis identified two previously unreported mutations in exon 7 of the BCKDHB gene: c.767A > G (p.Y256C) and c.768C > G (p.Y256X); the parents were each heterozygous for one of these mutations. In silico analysis predicted Y256C probably affects protein structure; Y256X leads to a premature stop codon. This case demonstrates intermittent MSUD should be suspected in cases with symptoms of recurrent encephalopathy, especially ataxia or marked drowsiness, which usually present after the neonatal period and in conjunction with infection. symmetrical basal ganglia damage but normal myelination in the posterior limb will assist differential diagnosis; alloisoleucine is a useful diagnostic marker and mutation analysis may be of prognostic value. These novel mutations Y256C and Y256X result in the clinical manifestation of a variant form of MSUD, expanding the mutation spectrum of this disease.