The results clearly highlight the importance of self-compassion for individuals' well-being. Future research should further investigate the relationship between self-compassion and the different forms of well-being, and focus on the examination of possible additional moderators.
Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n ϭ 218) or presymptomatically by neonatal screening (n ϭ 23), high-risk screening (n ϭ 24), or macrocephaly (n ϭ 14). Most symptomatic patients (n ϭ 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with L-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening.
Isolated methylmalonic acidurias comprise a heterogeneous group of inborn errors of metabolism caused by defects of methylmalonyl-CoA mutase (MCM) (mut0, mut-) or deficient synthesis of its cofactor 5'-deoxyadenosylcobalamin (AdoCbl) (cblA, cblB). The aim of this study was to compare the long-term outcome in patients from these four enzymatic subgroups. Eighty-three patients with isolated methylmalonic acidurias (age 7-33 y) born between 1971 and 1997 were enzymatically characterized and prospectively followed to evaluate the long-term outcome (median follow-up period, 18 y). Patients with mut0 (n = 42), mut- (n = 10), cblA (n = 20), and cblB (n = 11) defects were included into the study. Thirty patients (37%) died, and 26 patients survived with a severe or moderate neurologic handicap (31%), whereas 27 patients (32%) remained neurologically uncompromised. Chronic renal failure (CRF) was found most frequently in mut0 (61%) and cblB patients (66%), and was predicted by the urinary excretion of methylmalonic acid (MMA) before CRF. Overall, patients with mut0 and cblB defects had an earlier onset of symptoms, a higher frequency of complications and deaths, and a more pronounced urinary excretion of MMA than those with mut- and cblA defects. In addition, long-term outcome was dependent on the age cohort and cobalamin responsiveness.
In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3-36 months). The frequency of striatal injury is significantly less in patients diagnosed as asymptomatic newborns by newborn screening. Most previous studies have focused on the onset and mechanism of striatal injury, whereas little is known about neuroradiological abnormalities in pre-symptomatically diagnosed patients and about dynamic changes of extrastriatal abnormalities. Thus, the major aim of the present retrospective study was to improve our understanding of striatal and extrastriatal abnormalities in affected individuals including those diagnosed by newborn screening. To this end, we systematically analysed magnetic resonance imagings (MRIs) in 38 patients with glutaric aciduria type I diagnosed before or after the manifestation of neurological symptoms. To identify brain regions that are susceptible to cerebral injury during acute encephalopathic crises, we compared the frequency of magnetic resonance abnormalities in patients with and without such crises. Major specific changes after encephalopathic crises were found in the putamen (P < 0.001), nucleus caudatus (P < 0.001), globus pallidus (P = 0.012) and ventricles (P = 0.001). Analysis of empirical cumulative distribution frequencies, however, demonstrated that isolated pallidal abnormalities did not significantly differ over time in both groups (P = 0.544) suggesting that isolated pallidal abnormalities are not induced by acute crises--in contrast to striatal abnormalities. The manifestation of motor disability was associated with signal abnormalities in putamen, caudate, pallidum and ventricles. In addition, we found a large number of extrastriatal abnormalities in patients with and without preceding encephalophatic crises. These abnormalities include widening of anterior temporal and sylvian CSF spaces, pseudocysts, signal changes of substantia nigra, nucleus dentatus, thalamus, tractus tegmentalis centralis and supratentorial white matter as well as signs of delayed maturation (myelination and gyral pattern). In contrast to the striatum, extrastriatal abnormalities were variable and could regress or even normalize with time. This includes widening of sylvian fissures, delayed maturation, pallidal signal changes and pseudocysts. Based on these results, we hypothesize that neuroradiological abnormalities and neurological symptoms in glutaric aciduria type I can be explained by overlaying episodes of cerebral alterations including maturational delay of the brain in utero, acute striatal injury during a vulnerable period in infancy and chronic progressive changes that may continue lifelong. This may have widespread consequences for the pathophysiological understanding of this disease, long-term outcomes and therapeutic considerations.
NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979.
Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A](2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.
Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare neurometabolic disorder that is considered treatable if patients are identified before the onset of acute encephalopathic crises. To allow early identification of affected individuals, tandem mass spectrometrybased newborn screening for GCDH deficiency has been started in Germany in 1999. We prospectively followed neonatally screened pa-
daycare closures were enforced as measures to confine the novel coronavirus disease 2019 (COVID-19) pandemic, based on the assumption that young children may play a key role in severe acute respiratory coronavirus 2 (SARS-CoV-2) spread. Given the grave consequences of contact restrictions for children, a better understanding of their contribution to the COVID-19 pandemic is of great importance. OBJECTIVE To describe the rate of SARS-CoV-2 infections and the seroprevalence of SARS-CoV-2 antibodies in children aged 1 to 10 years, compared with a corresponding parent of each child, in a population-based sample. DESIGN, SETTING, AND PARTICIPANTS This large-scale, multicenter, cross-sectional investigation (the COVID-19 BaWü study) enrolled children aged 1 to 10 years and a corresponding parent between April 22 and May 15, 2020, in southwest Germany. EXPOSURES Potential exposure to SARS-CoV-2. MAIN OUTCOMES AND MEASURES The main outcomes were infection and seroprevalence of SARS-CoV-2. Participants were tested for SARS-CoV-2 RNA from nasopharyngeal swabs by reverse transcription-polymerase chain reaction and SARS-CoV-2 specific IgG antibodies in serum by enzyme-linked immunosorbent assays and immunofluorescence tests. Discordant results were clarified by electrochemiluminescence immunoassays, a second enzyme-linked immunosorbent assay, or an in-house Luminex-based assay. RESULTS This study included 4964 participants: 2482 children (median age, 6 [range, 1-10] years; 1265 boys [51.0%]) and 2482 parents (median age, 40 [range, 23-66] years; 615 men [24.8%]). Two participants (0.04%) tested positive for SARS-CoV-2 RNA. The estimated SARS-CoV-2 seroprevalence was low in parents (1.8% [95% CI, 1.2-2.4%]) and 3-fold lower in children (0.6% [95% CI, 0.3-1.0%]). Among 56 families with at least 1 child or parent with seropositivity, the combination of a parent with seropositivity and a corresponding child with seronegativity was 4.3 (95% CI, 1.19-15.52) times higher than the combination of a parent who was seronegative and a corresponding child with seropositivity. We observed virus-neutralizing activity for 66 of 70 IgG-positive serum samples (94.3%). CONCLUSIONS AND RELEVANCE In this cross-sectional study, the spread of SARS-CoV-2 infection during a period of lockdown in southwest Germany was particularly low in children aged 1 to 10 years. Accordingly, it is unlikely that children have boosted the pandemic. This SARS-CoV-2 prevalence study, which appears to be the largest focusing on children, is instructive for how ad hoc mass testing provides the basis for rational political decision-making in a pandemic.
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