Studinski, April

AbstractPhosphoglucomutase 1 (PGM1) catalyzes the interconversion of glucose‐6‐phosphate to glucose‐1‐phosphate and is a key enzyme of glycolysis, glycogenesis, and glycogenolysis. PGM1 deficiency (OMIM: 614921) was initially defined as a glycogen storage disorder (type XIV), and later re‐classified as a PGM1‐congenital disorder of glycosylation (PGM1‐CDG). Serum transferrin (Tf) glycan isoform analysis by liquid chromatography‐mass spectrometry (LC‐MS) is used as a primary diagnostic screen tool, and reveals a very unique CDG profile described as a mixture of CDG‐type I and CDG‐type II patterns. Oral d‐galactose supplementation shows significant clinical and metabolic improvements, which are indicated by the Tf glycan isoform normalization over time in patients with PGM1‐CDG. Thus, there is a need for biomarkers to guide d‐galactose dosage in patients in order to maintain effective and safe drug levels. Here, we present a simplified algorithm called PGM1‐CDG Treatment Monitoring Index (PGM1‐TMI) for assessing the response of PGM1‐CDG patients to d‐galactose supplementation. For our single‐center cohort of 16 PGM1‐CDG patients, the Tf glycan profile analysis provided the biochemical diagnosis in all of them. In addition, the PGM1‐TMI was reduced in PGM1‐CDG patients under d‐galactose supplementation as compared with their corresponding values before treatment, indicating that glycosylation proceeds towards normalization. PGM1‐TMI allows tracking Tf glycan isoform normalization over time when the patients are on d‐galactose supplementation.

AbstractIntroductionNonaccidental trauma (NAT) is considered when pediatric patients present with intracranial injuries and a negative history of an accidental injury or concomitant medical diagnosis. The evaluation of NAT should include the consideration of possible medical causes including coagulation, hematologic, metabolic and other genetic disorders, as well as witnessed and unwitnessed accidental injuries.Case PresentationWe present a 7‐month‐old male with spells and incidental findings of bilateral subdural hematomas, retinal hemorrhages, and secondary macrocephaly, leading to investigation for NAT. Biochemical analysis showed excretion of a large amount of D‐2‐hydroxyglutaric in urine consistent with a biochemical diagnosis of D‐2‐hydroxyglutaric aciduria, a rare neurometabolic disorder characterized by developmental delay, epilepsy, hypotonia, and psychomotor retardation. None of these symptoms were present in our patient at the time of diagnosis. Molecular genetic testing revealed a pathogenic splice site variant (c.685‐2A>G) and a variant of uncertain significance (c.1256G>T) with evidence of pathogenicity in the D2HGDH gene, consistent with a molecular diagnosis of D‐2‐hydroxyglutaric aciduria type I (OMIM #600721).ConclusionSince several metabolic disorders, including D‐2‐hydroxyglutaric aciduria type I, can present solely with symptoms suggestive of NAT (subdural and retinal hemorrhages), an early metabolic evaluation by urine organic acid analysis should be included in clinical protocols evaluating NAT. A methodical and nonjudgmental approach coordinated between pediatricians and metabolic specialists is also necessary to ensure that rare genetic conditions are not overlooked to prevent devastating social, legal, and financial consequences of suspected child abuse.

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.