Neonatal maple syrup urine disease in China: two novel mutations in the BCKDHB gene and literature review

Objectives To report two novel mutations in the BCKDHB gene with Maple syrup urine disease (MSUD) and compare their data with 52 cases of MSUD reported in the available Chinese literature. Methods Clinical data of a case of a newborn with MSUD was retrospectively studied. Literatures on MSUD in the local medical journals from January 1990 till December 2019 in China were reviewed. Results Two novel BCKDHB mutations c.90_91insCTGGCGCGGGG (p.Phe35TrpfsTer41) and c.80_90del (p.Ala32PhefsTer48) were identified. We found a total of 52 cases of MSUD reports so far. A total of 49 cases had the symptom of poor feeding (94.2%), 50 cases showed poor responses to stimulation (96.2%), 21 cases had odor of maple syrup (40.3%), 29 cases had seizures (55.7%), and 13 cases had respiratory failure (25.0%). The average of the blood ammonia was 127.2 ± 75.0 μmol/L. A total of 18 cases reported the gene testing, among of them 9 cases of BCKDHA mutations, 6 cases of BCKDHB mutations, and 2 cases of DBT mutations. A total of 13 cases (25%) were treated with mechanical ventilation, 50 cases (96.2%) with protein-restricted diet and l-carnitine, 29 cases with thiamine, and only 2 cases were treated with blood purification. Finally, 19 patients (36.5%) were died, 21 cases (40.4%) were improved after treatments. Conclusions The clinical phenotype of neonatal MSUD in China belongs to the classical type currently. Suspected patients should have blood or urine branched-chain amino acid levels tested and brain MRI as early as possible to enable early diagnosis, thus improvement in prognosis.

Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease

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. 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. All the coding regions and exon/intron boundaries of BCKDHA, BCDKHB, DBT, DLD genes were analyzed by targeted NGS in the 8 MSUD pedigrees. Targeted NGS revealed 2 pedigrees with MSUD Ia, 5 pedigrees with Ib, 1 pedigree with MSUD II. Totally, 13 variants were detected, including 2 variants (p.Ala216Val and p.Gly281Arg) in BCKDHA gene，10 variants (p.Gly95Ala, p.Ser171Pro, p.Phe175Leu, p.Arg183Trp, p.Lys222Thr, p.Arg285Ter，p.Arg111Ter，p.S184Pfs*46, p.Arg170Cys, p.I160Ffs*25) in BCKDHB gene, 1 variants (p.Arg431Ter) in DBT gene. In addition, 4 previously unidentified variants (p.Gly281Arg in BCKDHA gene, p.Ser171Pro, p.Gly95Ala and p.Lys222Thr in BCKDHB gene) were found. NGS plus Sanger sequencing detection is effective and accurate for making gene diagnosis. Computational structural modeling indicated that these novel variations might affect structural stability.

Hereditary characteristics of the S339L mutation in a patient with maple syrup urine disease in Vietnam

Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by malfunction of the branched-chain α-ketoacid dehydrogenase complex (BCKDH). This enzyme complex participates in the catalyzing metabolisms of the branched-chain α-ketoacids, the second step of the degradation of branched-chain amino acids. Impaired activities of the BCKAD complex lead to an increase of the levels of branched- chain amino acid such as leucine, valine, and isoleucine in the blood. In children with maple syrup urine disease, catalysis of the metabolisms of some amino acids failed to be implemented, leading to an accumulation of the amino acids which has been shown as one of the causes of neurological complications, intellectual disabilities, and nervous paralysis or even death. Pathogenic mutations normally occur in BCKDHA, BCKDHB, DBT and DLD genes which encode the E1α, E1β, and E2 subunits of the BCKDH complex. In the present study, a homozygous mutation in the BCKDHB gene (c. 1016C>T) in a pediatric patient with MSUD diagnosed at The National Hospital of Pediatrics was identified using whole exome and Sanger sequencing methods. As a result, the inheritance of the homozygous mutation related to MSUD in BCKDHB gene within the pedigree of the patient’s family was determined. The results indicated that the mutation in the BCKDHB gene was inherited from both of the patient’s parents. In addition, this finding provides an important scientific basis to researches on MSUD in the Vietnamese population.

A clinical case of SYNGAP1-associated encephalopathy in a girl with epilepsy, intellectual disability, and autism

This paper describes a female patient aged 3 years 6 months with SYNGAP1-associated encephalopathy manifesting with symptomatic epilepsy, intellectual disability, and autism. There were difficulties in differential diagnosis, since in addition to SYNGAP1 mutation (c2214_2217deltgag), heterozygous BCKDHB gene mutation (chr6: 80910740G>a, rs3834233) and microduplication of a segment of chromosome 22 were found de novo. The features of the course and treatment of epilepsy in SYNGAP1 are discussed. A combination of valproic acid and oxcarbazepine was the most effective treatment for epilepsy.