Newborn screening and disease variants predict neurological outcome in isovaleric aciduria.

Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long-term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi-center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long-term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent si…

PRRT2 mutations are the major cause of benign familial infantile seizures.

Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large fami…

Health Outcomes of Infants with Vitamin B12 Deficiency Identified by Newborn Screening and Early Treated

Objective To evaluate the clinical outcomes at age 1.5 ± 0.5 years of infants with vitamin B12 deficiency identified by newborn screening (NBS). Study design Prospective multicenter observational study on health outcomes of 31 infants with vitamin B12 deficiency identified by NBS. Neurodevelopment was assessed by the Denver Developmental Screening Test. Results In 285 862 newborns screened between 2016 and 2019, the estimated birth prevalence of vitamin B12 deficiency was 26 in 100 000 newborns, with high seasonal variations (lowest in summer: 8 in 100 000). Infants participating in the outcome study (N = 31) were supplemented with vitamin B12 for a median (range) of 5.9 (1.1-16.2) months. …

Issues with European guidelines for phenylketonuria

Maternal vitamin deficiency mimicking multiple acyl-CoA dehydrogenase deficiency on newborn screening

Abstract Background In infancy multiple acyl-CoA dehydrogenase deficiency (MADD) is commonly a severe inherited metabolic disease caused by genetic defects in electron transfer flavoprotein (ETF) or ETF ubiquinone oxidoreductase. Both enzymes require flavin adenine dinucleotide (FAD) as a cofactor. Riboflavin (vitamin B2) is a precursor in the synthesis of FAD. MADD can be detected by newborn screening (NBS) based on elevation of multiple acylcarnitines. Methods We present the results of two children whose NBS results and subsequent confirmatory testing resulted in a suspected diagnosis of MADD. In parallel in both children vitamin B12 deficiency was detected. Results Biochemical profiles n…

Quantitative Acylcarnitine Profiling in Peripheral Blood Mononuclear Cells Using In Vitro Loading With Palmitic and 2-Oxoadipic Acids: Biochemical Confirmation of Fatty Acid Oxidation and Organic Acid Disorders

Organic acid (OAD) and fatty acid oxidation disorders (FAOD) are inborn errors of metabolism often presenting with life-threatening metabolic decompensation followed by (irreversible) organ failure, and even death during catabolic state. Most of these diseases are considered as treatable, and metabolic decompensations can be avoided by early diagnosis and start of therapy. Confirmation of suspected diagnosis currently relies on enzymatic and mutation analyses and in vitro loading of palmitic acid in human skin fibroblast cultures. Furthermore, in some cases potentially life-threatening in vivo loading or fasting tests are still performed. In this study, we established a standardized in vitr…

Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle a…