Clinical features and MUT gene mutation spectrum in Chinese patients with isolated methylmalonic acidemia:identification of ten novel allelic variants

Background: This study aims to study MUT gene mutation spectrum in Chinese patients with isolated methylmalonic academia (MMA) and their clinical features for the potential genotype-phenotype correlation. Methods: Forty-three patients were diagnosed with isolated MMA by elevated blood propionylcarnitine, propionylcarnitine to acetylcarnitine ratio, and urine methylmalonate without hyperhomocysteinemia. The MUT gene was amplifi ed by polymerase chain reaction and directly sequenced. Those patients with at least one variant allele were included. The novel missense mutations were assessed by bioinformatic analysis and screened against alleles sequenced from 50 control participants. Results: Among the 43 patients, 38 had typical clinical presentations, and the majority (30/38) experienced early-onset MMA. Eight patients died and seven were lost to follow-up. Twenty patients had poor outcomes and eight showed normal development. The 43 identified MUT gene mutations had at least one variant allele, whereas 35 had two mutant alleles. Of the 33 mutations reported before, eight recurrent mutations were identified in 32 patients, and c.729_730insTT (p.D244Lfs*39) was the most common (12/78) in the mutant alleles. Of the 10 novel mutations, six were missense mutations and four were premature termination codon mutations. The six novel missense mutations seemed to be pathogenic. Conclusions: A total of 10 novelMUT mutations were detected in the Chinese population. c.729_730insTT (p.D244Lfs*39) was the most frequent mutation. A genotype-phenotype correlation could not be found, but the genotypic characterization indicated the need of genetic counseling for MMA patients and early prenatal diagnoses for high-risk families.

Fractional anisotropy for assessment of white matter tracts injury in methylmalonic acidemia

Background Methylmalonic acidemia （MMA） is a multifactorial autosomal recessive inborn error of organic acid metabolism, often presenting with neurological symptoms. As neurological disorders are often related to white matter injury, diffusion tensor imaging （DTI） is an excellent tool for assessment of white matter injury and possibly for diagnosing this disorder. Methods We retrospectively analyzed DTI images of 12 patients with MMA （7 males, 5 females, age range： 7-12 months, mean age： 9.25±1.70 months） with negative MRI findings. And another 12 age-matched and gender-matched infants were enrolled as control subjects. Fractional anisotropy （FA） of different white matter tracts of the brain was measured in both groups. Results For patients with negative MRI findings, compared with healthy infants, a statistically significant reduction in DTI FA value of the frontal white matter, temporal white matter, and occipital white matter was observed （P〈0.01）. Conclusions In addition to conventional TlW and T2W MR Image, Brain DTI presents a useful, sensitive and complementary tool for the assessment of brain damage in patients with MMA.