Spectrum of mutations underlying Propionic acidemia and further insight into a genotype-phenotype correlation for the common mutation in Saudi Arabia.

Propionic acidemia (PA) is an autosomal recessive metabolic disorder. PA is characterized by deficiency of the mitochondrial enzyme propionyl CoA carboxylase (PCC) that results in the accumulation of propionic acid. Alpha and beta subunits of the PCC enzyme are encoded by the PCCA and PCCB genes, respectively. Pathogenic variants in PCCA or PCCB disrupt the function of the PCC enzyme preventing the proper breakdown of certain amino acids and metabolites. To determine the frequency of pathogenic variants in PA in our population, 84 Saudi Arabian patients affected with PA were sequenced for both the PCCA and PCCB genes. We found that variants in PCCA accounted for 81% of our cohort (68 patients), while variants in PCCB only accounted for 19% (16 patients). In total, sixteen different sequence variants were detected in the study, where 7 were found in PCCA and 9 in PCCB. The pathogenic variant (c.425G > A; p.Gly142Asp) in PCCA is the most common cause of PA in our cohort and was found in 59 families (70.2%), followed by the frameshift variant (c.990dupT; p.E331Xfs*1) in PCCB that was found in 7 families (8.3%). The p.Gly142Asp missense variant is likely to be a founder pathogenic variant in patients of Saudi Arabian tribal origin and is associated with a severe phenotype. All variants were inherited in a homozygous state except for one family who was compound heterozygous. A total of 11 novel pathogenic variants were detected in this study thereby increasing the known spectrum of pathogenic variants in the PCCA and PCCB genes.

Expanded Newborn Screening Program in Saudi Arabia: Incidence of screened disorders.

AIM: To address the implementation of the National Newborn Screening Program (NBS) in Saudi Arabia and stratify the incidence of the screened disorders. METHODS: A retrospective study conducted between 1 August 2005 and 31 December 2012, total of 775 000 newborns were screened from 139 hospitals distributed among all regions of Saudi Arabia. The NBS Program screens for 16 disorders from a selective list of inborn errors of metabolism (IEM) and endocrine disorders. Heel prick dry blood spot samples were obtained from all newborns for biochemical and immunoassay testing. Recall screening testing was performed for Initial positive results and confirmed by specific biochemical assays. RESULTS: A total of 743 cases were identified giving an overall incidence of 1:1043. Frequently detected disorders nationwide were congenital hypothyroidism and congenital adrenal hyperplasia with an incidence of 1:7175 and 1:7908 correspondingly. The highest incidence among the IEM was propionic acidaemia with an incidence rate of 1:14 000. CONCLUSION: The article highlights the experience of the NBS Program in Saudi Arabia and providing data on specific regional incidences of all the screened disorders included in the programme; and showed that the incidence of these disorders is one of the highest reported so far world-wide.

Chiral liquid chromatography tandem mass spectrometry in the determination of the configuration of glyceric acid in urine of patients with D-glyceric and L-glyceric acidurias.

Glyceric acid is a highly polar chiral carboxylic acid that is usually not detected during routine organic acid analysis. Increased excretion is observed in two phenotypically distinct and rare inherited metabolic diseases, D-glyceric aciduria, and L-glyceric aciduria (also known as primary hyperoxaluria type 2). The determination of the exact configuration of the excreted glyceric acid is necessary for the accurate diagnosis of D-glyceric aciduria and for the differentiation between type 1 and type 2 primary hyperoxaluria. The separation of the two stereoisomers was achieved using a narrow-bore ristocetin A glycopeptide antibiotic silica gel bonded column. Triethylamine acetate at pH 4.1 with 10% methanol was used as mobile phase. The column was directly interfaced to a triple quadrupole tandem mass spectrometer and the electrospray ion source was operated in the negative ion mode. Three parent-to-daughter transitions were employed to specifically detect eluting glyceric enantiomers from essentially untreated urine samples. The two forms of glyceric acid were satisfactorily separated at 3.6 and 4.5 min. Application of the method led to the confirmation of three cases of D-glyceric aciduria from three different families. Two other cases are suspected to be L-glyceric aciduria but further confirmation is needed. The method allowed the detection of the glyceric acid stereoisomers in control urine where it was found without exception that L-glyceric was the predominate metabolite.