Molecular and biochemical study of glutaric aciduria type 1 in 49 Russian families: nine novel mutations in the GCDH gene

Metabolic Brain Disease - Glutaric aciduria type 1 (GA1, deficiency of glutaryl CoA dehydrogenase, glutaric acidemia type 1) (ICD-10 code: E72.3; MIM 231670) is an autosomal recessive disease...     

Alkaptonuria in Russia: mutational spectrum and novel variants

Alkaptonuria is a rare genetic disease caused by mutations in HGD gene. Here we report the results of genetic and biochemical analysis of 49 Russian patients with alkaptonuria. One of the common variants c.481G > A; p.(Gly161Arg) comprising 72.4% of identified alleles was found in 45 of 49 patients in our cohort, which is probably the highest frequency of this variant worldwide. 9 novel variants were found: 6 missense, 2 splicing and 1 loss of start-codon. For missense variants we performed bioinformatic analysis, protein 3D-modeling and molecular dynamics simulations, which strongly suggest their pathogenic effect. For the rare synonymous variant c.753C > T; p.(Gly251Gly), which was found in 3 cases and predicted to activate cryptic splice site, we performed the detailed functional analysis on patient's cDNA and minigene assay and confirmed its pathogenicity.     

Blood lysosphingolipids accumulation in patients with parkinson's disease with glucocerebrosidase 1 mutations

Introduction: Glucocerebrosidase 1 mutations, the most common genetic contributor to Parkinson's disease (PD), have been associated with decreased glucocerebrosidase enzymatic activity in PD patients with glucocerebrosidase 1 mutations (glucocerebrosidase 1–PD). However, it is unknown whether this decrease in enzymatic activity leads to lysosphingolipid accumulations. Methods: The levels of hexosylsphingosines, globotriaosylsphingosine, sphingomyelin, and sphingomyelin‐509 were measured in dried blood spots from glucocerebrosidase 1–PD patients (n = 23), sporadic PD patients (n = 105), Gaucher disease patients (n = 32), and controls (n = 88) by liquid chromatography‐tandem mass spectrometry. Results: Glucocerebrosidase 1–PD patients had increased hexosylsphingosine levels when compared with sporadic PD patients (P < .001) and controls (P < .0001). Hexosylsphingosine levels were increased in glucocerebrosidase 1 mutation carriers of glucocerebrosidase 1 (L444P; N370S; n = 11, P = .001) and glucocerebrosidase 1 polymorphic variants (E326K, T369M) associated with PD (n = 12, P = .04) when compared with controls. Conclusions: Lysosphingolipid accumulations in PD patients who bear glucocerebrosidase 1 mutations suggest that substrate reduction therapy might be viewed as a possible strategy for glucocerebrosidase 1–PD treatment. © 2018 International Parkinson and Movement Disorder Society