Search results for " Inborn Error"
showing 10 items of 39 documents
Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study.
2015
Summary Background Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. Methods In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous…
A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
2020
We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1lp.S78G mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cybp.D254N), affecting the CIII subunit cytochrome b (MT-CYB), in the background with short survival. We utilize maternal inheritance of mtDNA to confirm this as the causative variant and show that it further decreases the low CIII activity in Bcs1lp.S78G tissues to below survival threshold by 35 days of age. Molecular dynamics simulations predict D254N to restrict the flexibility of MT-CYB ef loop, potentially affecting RISP dyna…
Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C
2016
Objective Congenital sodium diarrhoea (CSD) refers to a form of secretory diarrhoea with intrauterine onset and high faecal losses of sodium without congenital malformations. The molecular basis for CSD remains unknown. We clinically characterised a cohort of infants with CSD and set out to identify disease-causing mutations by genome-wide genetic testing. Design We performed whole-exome sequencing and chromosomal microarray analyses in 4 unrelated patients, followed by confirmatory Sanger sequencing of the likely disease-causing mutations in patients and in their family members, followed by functional studies. Results We identified novel de novo missense mutations in GUCY2C, the gene encod…
Chronic Diarrhea in a 5-Year-Old Girl: Pitfall in Routine Laboratory Testing with Potentially Severe Consequences
2009
A 5-year-old girl was referred because of recurrent watery diarrhea, abdominal pain, and flatulence. She was the second of 3 children. Her 10-year-old sister was normally developed and healthy. Her younger brother has meningomyelocele and hydrocephalus. At 1 year of age, the patient was admitted to the hospital for recurrent bronchitis, otitis media, food refusal, mild diarrhea, and abdominal distension since weaning. A sweat chloride analysis excluded cystic fibrosis. At that time, the patient’s laboratory results showed increased C-reactive protein (139 mg/L; reference interval, <5 mg/L) and moderate leukocytosis (14.6 × 109/L; reference interval, 4.5–13.5 × 109/L). Values for all other v…
Human cationic amino acid transporter gene hCAT-2 is assigned to 8p22 but is not the causative gene in lysinuric protein intolerance
1997
Lysinuric protein intolerance (LPI) is a recessively inherited amino acid disorder characterized by defective efflux of cationic amino acids at the basolateral membrane of the intestinal and renal tubular epithelium. Recently, cDNAs encoding the related proteins hCAT-2A and hCAT-2B have been cloned. These two carrier proteins are most likely the product of the same gene, hCAT-2. Using the hCAT-2B cDNA, we assigned the hCAT-2 gene to chromosome 8p22. Furthermore, by linkage analysis in Finnish LPI families, we ruled out that hCAT-2B is involved in LPI disease.
Molybdenum Trioxide Nanoparticles with Intrinsic Sulfite Oxidase Activity
2014
Sulfite oxidase is a mitochondria-located molybdenum-containing enzyme catalyzing the oxidation of sulfite to sulfate in the amino acid and lipid metabolism. Therefore, it plays a major role in detoxification processes, where defects in the enzyme cause a severe infant disease leading to early death with no efficient or cost-effective therapy in sight. Here we report that molybdenum trioxide (MoO3) nanoparticles display an intrinsic biomimetic sulfite oxidase activity under physiological conditions, and, functionalized with a customized bifunctional ligand containing dopamine as anchor group and triphenylphosphonium ion as targeting agent, they selectively target the mitochondria while bein…
Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency
2016
S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blo…
Quantitative Acylcarnitine Profiling in Peripheral Blood Mononuclear Cells Using In Vitro Loading With Palmitic and 2-Oxoadipic Acids: Biochemical Co…
2005
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…
Liver pathology in transient neonatal hyperammonemia.
1983
Ultrastructural investigations have been performed on two cases of transient neonatal hyperammonaemia (TNH). This newly recognized metabolic disorder is chiefly characterized by severe hyperammonaemia in the postnatal period, a comatous state, absence of abnormal organic aciduria, normal activity of urea cycle enzymes and, usually, complete recovery. The aetiology is presently unknown. Electron microscopy uncovered rather congruent alterations of hepatocyte structure, with a wide spectrum of mitochondrial lesions, an increase of autophagous bodies with organelle remnants, and changes in the excretory apparatus. Thus, in contrast to some of the hereditary disorders of the urea cycle, no spec…
Newborn screening and disease variants predict neurological outcome in isovaleric aciduria.
2021
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…