Hydrocephalus in cblC type methylmalonic acidemia.

Methylmalonic acidemia (MMA) is a typical type of organic acidemia caused by defects in methylmalonyl-CoA mutase or adenosyl-cobalamin synthesis. Hydrocephalus (HC), results from an imbalance between production and absorption of cerebrospinal fluid (CSF), causeing enlarged cerebral ventricles and increased intracranial pressure, is a condition that requires urgent clinical decision-making. MMA without treatment could result in brain damage. However, HC in MMA was rarely reported. In this study, 147 MMA were identified from 9117 high risk children by gas chromatography mass spectrometry (GC/MS) for organic acidurias screening in urine samples and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for amino acids detection in blood samples. Totally 10 cases with MMA and HC were determined by brain MRI/CT, as well as gene mutation testing either by high throughput sequencing or Sanger sequencing. Besides, homocysteine was also analyzed for the 10 MMA with HC. Out of them, 9 cases carry out compound heterozygous mutations or homozygous mutation in MMACHC gene, and 1 case has MUTmutation. The mutation c.609G > A in MMACHC was the most common in the cbl type patients. Although MMA has a high incidence in Shandong province of China, especially cblC type. All of the 10 patients were not correctly diagnosed before developing HC. As a result, when a child develops progressive and refractory HC, the screening for inherited metabolic diseases should be immediately conducted.

Clinical characteristics and mutation analysis of five Chinese patients with maple syrup urine disease.

Maple syrup urine disease (MSUD) is an autosomal recessive disorder affecting branched-chain amino acids (BCAAs) metabolism and caused by a defect in the thiamine-dependent enzyme branched chain α-ketoacid dehydrogenase (BCKD) with subsequent accumulation of BCAAs and corresponding branched-chain keto acids (BCKAs) metabolites. Presently, at least 4 genes of BCKDHA, BCKDHB, DLD and DBT have been reported to cause MSUD. Furthermore, more than 265 mutations have been identified as the cause across different populations worldwide. Some studies have reported the data of gene mutations in Chinese people with MSUD. In this study, we present clinical characteristics and mutational analyses in five Chinese Han child with MSUD, which had been screened out by tandem mass spectrometry detection of amino acids in blood samples. High-throughput sequencing, Sanger sequence and real-time qualitative PCR were performed to detect and verify the genetic mutations. Six different novel genetic variants were validated in BCKDHB gene and BCKDHA gene, including c.523 T > C, c.659delA, c.550delT, c.863G > A and two gross deletions. Interestingly, 3 cases had identical mutation of BCKDHB gene (c.659delA). We predicted the pathogenicity and analyzed the clinical characteristics. The identification of these mutations in this study further expands the mutation spectrum of MSUD and contributes to prenatal molecular diagnosis of MSUD.

Analysis of clinical and genetic characteristics in 10 Chinese individuals with Cornelia de Lange syndrome and literature review.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder with variable multisystem involvement and genetic heterogeneity. We aimed to analyze the clinical and genetic characteristics of Chinese individuals with CdLS. METHODS: We collected data regarding the neonatal period, maternal status, clinical manifestation, including facial dimorphisms and development, and follow-up treatment for individuals diagnosed with CdLS. In individuals with suspected CdLS, high-throughput sequencing, Sanger sequencing, and real-time qualitative PCR were used to verify the diagnosis. RESULTS: Variants, including six that were novel, were concentrated in the NIPBL (70%), HDAC8 (20%), and SMC3 (10%) genes. We found two nonsense, three splicing, and two deletion variants in NIPBL; a missense variant and an absence variant in HDAC8; and a missense variant in SMC3. Eleven cardinal features of CdLS were present in more than 80% of Chinese individuals. Compared with non-Chinese individuals of diverse ancestry, there were significant differences in the clinical characteristics of eight of these features. CONCLUSION: Six novel pathological variants were identified; thus, the study expanded the gene variant spectrum. Furthermore, most cardinal features of CdLS found in Chinese individuals were also found in individuals from other countries. However, there were significant differences in eight clinical features.