Search

The pivotal role of the cell entry receptor ACE2 for SARS‐CoV‐2 infection is well‐established. When ACE2 is shed from cell surface into plasma as soluble ACE2 (sACE2), it can effectively neutralize SARS‐CoV‐2. This longitudinal prospective cohort study analyzed sACE2 activity in 1192 participants, aged 4 months to 81 years, 3 and 12 months after SARS‐CoV‐2 household exposure. Following SARS‐CoV‐2 exposure, participants exhibited significantly elevated sACE2 activity, irrespective of confirmed infection, with the highest levels observed in exposed children. Longitudinal analysis revealed a decline in sACE2 levels over time, reaching levels comparable to age‐ and sex‐matched pre‐pandemic controls. An increase in sACE2 activity was also confirmed in vitro in Calu‐3 (human lung) cells within hours of SARS‐CoV‐2 exposure, providing a direct link between SARS‐CoV‐2 exposure and elevated sACE2. This study, therefore, challenges the dichotomy of categorizing SARS‐CoV‐2 exposed participants as infected or not infected solely on currently established diagnostic assays. It demonstrates lasting host responses independent of B‐ and T‐cell memory and may help to keep SARS‐CoV‐2 infections in balance and contribute to successful virus clearance in children and adults lacking humoral and cellular immune responses following SARS‐CoV‐2 exposure. Trial Registration: German Registry for Clinical Studies; Identifier: D 00021521. [ABSTRACT FROM AUTHOR]

Leucine aminoacyl tRNA‐synthetase 1 (LARS1)‐deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever‐associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1‐deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro‐active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination. [ABSTRACT FROM AUTHOR]

Objective: Structured transition of adolescents and young adults with a chronic endocrine disease from paediatric to adult care is important. Until now, no data on time and resources required for the necessary components of the transition process and the associated costs are available. Design, Patients and Measurements: In a prospective cohort study of 147 patients with chronic endocrinopathies, for the key elements of a structured transition pathway including (i) assessment of patients' disease‐related knowledge and needs, (ii) required education and counselling sessions, (iii) compiling an epicrisis and a transfer appointment of the patient together with the current paediatric and the future adult endocrinologist resource consumption and costs were determined. Results: One hundred and forty‐three of 147 enroled patients (97.3%) completed the transition pathway and were transferred to adult care. The mean time from the decision to start the transition process to the final transfer consultation was 399 ± 159 days. Transfer consultations were performed in 143 patients, including 128 patients jointly with the future adult endocrinologist. Most consultations were performed by a multidisciplinary team consisting of a paediatric and adult endocrinologist, psychologist, nurse, and a social worker acting also as a case manager with a median of three team members and lasted 87.6 ± 23.7 min. The mean cumulative costs per patient of all key elements were 519 ± 206 Euros. In addition, costs for case management through the transition process were 104.8 ± 28.0 Euros. Conclusions: Using chronic endocrine diseases as an example, it shows how to calculate the time and cost of a structured transition pathway from paediatric to adult care, which can serve as a starting point for sustainable funding for other chronic rare diseases. [ABSTRACT FROM AUTHOR]

The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine β‐synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple‐tier algorithm. The long‐term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [N = 13], MMA [N = 6], cblC deficiency [N = 5], MTHFR deficiency [N = 2] and CBS deficiency [N = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl‐nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple‐tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl‐responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl‐nonresponsive MMA. Synopsis: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine‐β‐synthase deficiency, and to some extent in cobalamin‐responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin‐nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long‐term complications. [ABSTRACT FROM AUTHOR]

Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa‐refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty‐six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5–30, 1st–3rd quartiles: 12.25–17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation‐related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia‐related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow‐up evaluations. The potential of slow‐release levodopa formulations and low‐dose dopamine agonists as part of first‐line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia‐related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex is associated with the occurrence of cardiac rhabdomyomas that may result in life‐threatening arrhythmia unresponsive to standard antiarrhythmic therapy. We report the case of an infant with multiple cardiac rhabdomyomas who developed severe refractory supraventricular tachycardia (SVT) that was successfully treated with everolimus. Pharmacological mTOR inhibition rapidly improved arrhythmia within few weeks after treatment initiation and correlated with a reduction in tumor size. Intermediate attempts to discontinue everolimus resulted in rhabdomyoma size rebound and recurrence of arrhythmic episodes, which resolved on resumption of therapy. While everolimus treatment led to successful control of arrhythmia in the first years of life, episodes of SVT reoccurred at the age of 6 years. Electrophysiologic testing confirmed an accessory pathway that was successfully ablated, resulting in freedom of arrhythmic events. In summary we present an in‐depth evaluation of the long‐term use of everolimus in a child with TSC‐associated SVT, including the correlation between drug use and arrhythmia outcome. This case report provides important information on the safety and efficacy of an mTOR inhibitor for the treatment of a potentially life‐threatening cardiac disease manifestation in TSC for which the optimal treatment strategy is still not well established. [ABSTRACT FROM AUTHOR]

Background: Ornithine transcarbamylase deficiency (OTCD) due to an X‐linked OTC mutation, is responsible for moderate to severe hyperammonemia (HA) with substantial morbidity and mortality. About 80% of females with OTCD remain apparently "asymptomatic" with limited studies of their clinical characteristics and long‐term health vulnerabilities. Multimodal neuroimaging studies and executive function testing have shown that asymptomatic females exhibit limitations when stressed to perform at higher cognitive load and had reduced activation of the prefrontal cortex. This retrospective study aims to improve understanding of factors that might predict development of defined complications and serious illness in apparent asymptomatic females. A proband and her daughter are presented to highlight the utility of multimodal neuroimaging studies and to underscore that asymptomatic females with OTCD are not always asymptomatic. Methods: We review data from 302 heterozygote females with OTCD enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history database. We apply multiple neuroimaging modalities in the workup of a proband and her daughter. Results: Among the females in the database, 143 were noted as symptomatic at baseline (Sym). We focused on females who were asymptomatic (Asx, n = 111) and those who were asymptomatic initially upon enrollment in study but who later became symptomatic sometime during follow‐up (Asx/Sym, n = 22). The majority of Asx (86%) and Asx/Sym (75%) subjects did not restrict protein at baseline, and ~38% of Asx and 33% of Asx/Sym subjects suffered from mild to severe neuropsychiatric conditions such as mood disorder and sleep problems. The risk of mild to severe HA sometime later in life for the Asx and Asx/Sym subjects as a combined group was ~4% (5/133), with ammonia ranging from 77 to 470 μM and at least half (2/4) of subjects requiring hospital admission and nitrogen scavenger therapy. For this combined group, the median age of first HA crisis was 50 years, whereas the median age of first symptom which included neuropsychiatric and/or behavioral symptoms was 17 years. The multimodal neuroimaging studies in female heterozygotes with OTCD also underscore that asymptomatic female heterozygotes with OTCD (e.g., proband) are not always asymptomatic. Conclusions: Analysis of Asx and Asx/Sym females with OTCD in this study suggests that future evidence‐based management guidelines and/or a clinical risk score calculator for this cohort could be useful management tools to reduce morbidity and improve long‐term quality of life. [ABSTRACT FROM AUTHOR]

The Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) are the worldwide largest databases for individuals with urea cycle disorders (UCDs) comprising longitudinal data from more than 1100 individuals with an overall long‐term follow‐up of approximately 25 years. However, heterogeneity of the clinical phenotype as well as different diagnostic and therapeutic strategies hamper our understanding on the predictors of phenotypic diversity and the impact of disease‐immanent and interventional variables (e.g., diagnostic and therapeutic interventions) on the long‐term outcome. A new strategy using combined and comparative data analyses helped overcome this challenge. This review presents the mechanisms and relevant principles that are necessary for the identification of meaningful clinical associations by combining data from different data sources, and serves as a blueprint for future analyses of rare disease registries. [ABSTRACT FROM AUTHOR]

There is a clinical need for early detection of chronic kidney disease (CKD) in patients with organic acidurias. We measured kidney markers in a longitudinal study over 5 years in 40 patients with methylmalonic aciduria (Mut0), propionic aciduria (PA), cobalamin A (CblA), and cobalamin C (CblC) deficiencies. Neutrophil gelatinase‐associated lipocalin (NGAL), calprotectin (CLP), kidney injury molecule‐1 (KIM‐1), dickkopf‐3 (DKK‐3), albumin and beta‐2‐microglobulin (B2MG) in urine, as well as cystatin C (CysC) in serum were quantified. In Mut0 patients, mean concentrations of B2MG, KIM‐1, and DKK‐3 were elevated compared with healthy controls, all markers indicative of proximal tubule damage. In PA patients, mean B2MG, albumin, and CLP were elevated, indicating signs of proximal tubule and glomerulus damage and inflammation. In CblC patients, mean B2MG, NGAL, and CLP were increased, and considered as markers for proximal and distal tubule damage and inflammation. B2MG, was elevated in all three diseases, and correlated with DKK‐3 in Mut0/CblA and with eGFR(CysC) and KIM‐1 in PA patients, respectively. None of the markers were elevated in CblA patients. Significant deterioration of kidney function, as determined by steady increase in CysC concentrations was noted in seven patients within the observation period. None of the investigated biomarker profiles showed a clear increase or added value for early detection. In conclusion, we identified disease‐specific biomarker profiles for inflammation, tubular, and proximal damage in the urine of Mut0, PA, and CblC patients. Whether these biomarkers can be used for early detection of CKD requires further investigation, as significant kidney function deterioration was observed in only a few patients. [ABSTRACT FROM AUTHOR]

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl‐CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3‐hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre‐symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long‐term outcomes is still unclear. This third revision of evidence‐based recommendations aims to re‐evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75–101; Kolker et al., J Inherit Metab Dis 2011;34(3):677–694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5–22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non‐interventional variables and treatment quality on clinical outcomes. Click here to access the podcast for this paper. [ABSTRACT FROM AUTHOR]

Data on cross‐neutralization of the SARS‐CoV‐2 omicron variant more than 1 year after SARS‐CoV‐2 infection are urgently needed, especially in children, to predict the likelihood of reinfection and to guide vaccination strategies. In a prospective observational cohort study, we evaluated live‐virus neutralization of the SARS‐CoV‐2 omicron (BA.1) variant in children compared with adults 14 months after mild or asymptomatic wild‐type SARS‐CoV‐2 infection. We also evaluated immunity to reinfection conferred by previous infection plus COVID‐19 mRNA vaccination. We studied 36 adults and 34 children 14 months after acute SARS‐CoV‐2 infection. While 94% of unvaccinated adults (16/17) and children (32/34) neutralized the delta (B.1.617.2) variant, only 1/17 (5.9%) unvaccinated adults, 0/16 (0%) adolescents and 5/18 (27.8%) children <12 years of age had neutralizing activity against omicron (BA.1). In convalescent adults, one or two doses of mRNA vaccine increased delta and omicron neutralization 32‐fold, similar to a third mRNA vaccination in uninfected adults. Neutralization of omicron was 8‐fold lower than that of delta in both groups. In conclusion, our data indicate that humoral immunity induced by previous SARS‐CoV‐2 wild‐type infection more than 1 year ago is insufficient to neutralize the current immune escape omicron variant. [ABSTRACT FROM AUTHOR]

Newborn screening (NBS) for inherited metabolic diseases (IMDs) substantially shortens a patient's journey. It enables the early start of metabolic treatment which might prevent potentially lethal neonatal disease manifestations, while promoting favorable development and long‐term clinical outcomes. This study aims to assess growth in screened individuals with IMDs under different dietary regimes. Anthropometric data (3585 prospective measures) of 350 screened individuals with IMDs born between 1999 and 2018 and participating in a German prospective multicenter observational study were evaluated. Overall, birth measures were within the reference ranges, suggesting unaffected prenatal growth, except for phenylketonuria (weight) and glutaric aciduria Type 1 (head circumference). After birth, longitudinal analysis of anthropometric measures revealed a loss of height standard deviation score (SDS; −0.5 SDS; p < 0.0001), head circumference SDS (−0.2 SDS; p = 0.0028), but not for weight SDS (0.1 SDS; p = 0.5097) until the age of 18 years, while BMI SDS increased (0.4 SDS; p < 0.0001). The significant interaction with age and diet groups was pronounced for the linear growth in individuals receiving diets being low in protein, long‐chain triglycerides, and galactose (p < 0.001). Identification by NBS and subsequent early (dietary) treatment cannot completely protect against alterations in growths. Disease‐specific (e.g., metabolic impairments, neurotoxins) and dietary‐specific (e.g., diets reduced in protein) factors may have an amplified impact on longitudinal growth. Therefore, alongside other important follow‐ups, the continuous observation of the anthropometric development of screened individuals with IMDs needs special attention to early identify and support individuals at risk. [ABSTRACT FROM AUTHOR]

Non‐syndromic retinitis pigmentosa (NSRP) is a clinically and genetically heterogeneous group of disorders characterized by progressive degeneration of the rod and cone photoreceptors, often leading to blindness. The evolving association of syndromic genes to cause NSRP and the increasing role of intronic variants in explaining missing heritability in genetic disorders present challenges in establishing conclusive clinical and genetic diagnoses. This study sought to identify and validate the causative genetic variant(s) in a 13‐year‐old male initially diagnosed with NSRP. Genome sequencing identified a pathogenic missense variant in MVK [NM_000431.3:c.803T>C (p.Ile268Thr)], in trans with a novel intronic variant predicted to create a new donor splice site (c.768+71C>A). Proband cDNA analysis confirmed the inclusion of the first 68 base pairs of intron 8 that resulted in a frameshift in MVK (r.768_769ins[768+1_768+68]) and significantly reduced the expression of reference transcript (17.6%). Patient re‐phenotyping revealed ataxia, cerebellar atrophy, elevated urinary mevalonate and LTE4, in keeping with mild mevalonic aciduria and associated syndromic retinitis pigmentosa. Leakage of reference transcript likely explains the milder phenotype observed in our patient. This is the first association of a deep intronic splice variant to cause MVK‐related disorder. This report highlights the importance of variant validation and patient re‐phenotyping in establishing accurate diagnosis in the era of genome sequencing. [ABSTRACT FROM AUTHOR]

Objective: Ornithine transcarbamylase deficiency (OTC‐D) is an X‐linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity‐adjusted classification system based on in vitro residual enzymatic OTC activity. Methods: Applying a cell‐based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC‐D (mOTC‐D) as reported in the UCDC and E‐IMD registries. Results: Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC‐D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Interpretation: Residual enzymatic OTC activity reliably predicts the disease severity in mOTC‐D and could thus serve as a tool for severity‐adjusted evaluation of therapeutic strategies and counselling patients and parents. [ABSTRACT FROM AUTHOR]

Objective: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed. Methods: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants. Results: Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age ≥ 3 months (66% specificity, 100% sensitivity, area under the curve [AUC] = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤ 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration ≥ 116.5μmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio ≥ 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model. Interpretation: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022;92:292–303 [ABSTRACT FROM AUTHOR]

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (MKD/HIDS) are disorders of cholesterol biosynthesis caused by variants in the MVK gene and characterized by increased urinary excretion of mevalonic acid. So far, 30 MVA patients have been reported, suffering from recurrent febrile crises and neurologic impairment. Here, we present an in‐depth analysis of the phenotypic spectrum of MVA and provide an in‐silico pathogenicity model analysis of MVK missense variants. The phenotypic spectrum of 11 MVA patients (age range 0‐51 years) registered in the Unified European Registry for Inherited Metabolic Disorders database was systematically analyzed using terms of the Human Phenotype Ontology. Biochemical, radiological as well as genetic characteristics were investigated. Six of eleven patients have reached adulthood and four have reached adolescence. One of the adolescent patients died at the age of 16 years and one patient died shortly after birth. Symptoms started within the first year of life, including episodic fever, developmental delay, ataxia, and ocular involvement. We also describe a case with absence of symptoms despite massive excretion of mevalonic acid. Pathogenic variants causing MVA cluster within highly conserved regions, which are involved in mevalonate and ATP binding. The phenotype of adult and adolescent MVA patients is more heterogeneous than previously assumed. Outcome varies from an asymptomatic course to early death. MVK variants cluster in functionally important and highly conserved protein domains and show high concordance regarding their expected pathogenicity. [ABSTRACT FROM AUTHOR]

SYNCRIP encodes for the Synaptotagmin‐binding cytoplasmic RNA‐interacting protein, involved in RNA‐binding and regulation of multiple cellular pathways. It has been proposed as a candidate gene for neurodevelopmental disorders (NDDs) with autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. We ascertained genetic, clinical, and neuroradiological data of three additional individuals with novel de novo SYNCRIP variants. All individuals had ID. Autistic features were observed in two. One individual showed myoclonic‐atonic epilepsy. Neuroradiological features comprised periventricular nodular heterotopia and widening of subarachnoid spaces. Two frameshift variants in the more severely affected individuals, likely result in haploinsufficiency. The third missense variant lies in the conserved RNA recognition motif (RRM) 2 domain likely affecting RNA‐binding. Our findings support the importance of RRM domains for SYNCRIP functionality and suggest genotype‐phenotype correlations. Our study provides further evidence for a SYNCRIP‐associated NDD characterized by ID and ASD sporadically accompanied by malformations of cortical development and myoclonic‐atonic epilepsy. [ABSTRACT FROM AUTHOR]

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent‐offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different—mostly constrained—genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio‐approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases. [ABSTRACT FROM AUTHOR]

The natural history of most rare diseases is incompletely understood and usually relies on studies with low level of evidence. Consistent with the goals for future research of rare disease research set by the International Rare Diseases Research Consortium in 2017, the purpose of this paper is to review the recently developed method of quantitative retrospective natural history modeling (QUARNAM) and to illustrate its usefulness through didactically selected analyses examples in an overall population of 849 patients worldwide with seven (ultra‐) rare neurogenetic disorders. A quantitative understanding of the natural history of the disease is fundamental for the development of specific interventions and counseling afflicted families. QUARNAM has a similar relationship to a published case study as a meta‐analysis has to an individual published study. QUARNAM relies on sophisticated statistical analyses of published case reports focusing on four research questions: How long does it take to make the diagnosis? How long do patients live? Which factors predict disease severity (eg, genotypes, signs/symptoms, biomarkers)? Where can patients be recruited for studies? Useful statistical techniques include Kaplan‐Meier estimates, cluster analysis, regression techniques, binary decisions trees, word clouds, and geographic mapping. In comparison to other natural history study methods (prospective studies or retrospective studies such as chart reviews), QUARNAM can provide fast information on hard clinical endpoints (ie, survival, diagnostic delay) with a lower effort. The choice of method for a particular drug development program may be driven by the research question and may encompass combinatory approaches. [ABSTRACT FROM AUTHOR]

Background: Laboratory investigations of cerebrospinal fluid (CSF) are essential when suspecting an inborn error of metabolism (IEM) involving neurological features. Available tests are currently performed on different analytical platforms, requiring a large sample volume and long turnaround time, which often delays timely diagnosis. Therefore, it would be preferable to have an "one‐instrument" targeted multi‐metabolite approach. Method: A liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) platform, based on two different methods for analysing 38 metabolites using positive and negative electrospray ionisation modes, was established. To allow for platform extension, both methods were designed to use the same CSF sample preparation procedure and to be run on the same separation column (ACE C18‐PFP). Results: Assessment of the LC‐MS/MS platform methods was first made by analytical validation, followed by the establishment of literature‐based CSF cut‐off values and reference ranges, and by the measurement of available samples obtained from patients with confirmed diagnoses of aromatic l‐amino acid decarboxylase deficiency, guanidinoacetate methyltransferase deficiency, ornithine aminotransferase deficiency, cerebral folate deficiency and methylenetetrahydrofolate reductase deficiency. Conclusion: An extendable targeted LC‐MS/MS platform was developed for the analysis of multiple metabolites in CSF, thereby distinguishing samples from patients with IEM from non‐IEM samples. Reference concentrations for several biomarkers in CSF are provided for the first time. By measurement on a single analytical platform, less sample volume is required (200 μL), diagnostic results are obtained faster, and preanalytical issues are reduced. Synopsis: LC‐MS/MS platform for CSF analysis consisting of two differentially designed methods. [ABSTRACT FROM AUTHOR]

Aromatic l‐amino‐acid decarboxylase (AADC) deficiency is an inherited disorder of biogenic amine metabolism with a broad neurological phenotype. The clinical symptoms overlap with other diseases resulting in an often delayed diagnosis. Innovative disease‐changing treatment options, particularly gene therapy, have emphasised the need for an early diagnosis. We describe the first method for 3‐O‐methyldopa (3‐OMD) analysis in dried blood spots (DBS) suitable for high throughput newborn screening (NBS). We established a novel tandem mass spectrometry method to quantify 3‐OMD in DBS and successfully tested it in 38 888 unaffected newborns, 14 heterozygous DDC variant carriers, seven known AADC deficient patients, and 1079 healthy control subjects. 3‐OMD concentrations in 38 888 healthy newborns revealed a mean of 1.16 μmol/L (SD = 0.31, range 0.31‐4.6 μmol/L). 1079 non‐AADC control subjects (0‐18 years) showed a mean 3‐OMD concentration of 0.78 μmol/L (SD = 1.75, range 0.24‐2.36 μmol/L) with a negative correlation with age. Inter‐ and intra‐assay variability was low, and 3‐OMD was stable over 32 days under different storage conditions. We identified seven confirmed AADC deficient patients (mean 3‐OMD 9.88 μmol/L [SD = 13.42, range 1.82‐36.93 μmol/L]). The highest concentration of 3‐OMD was found in a NBS filter card of a confirmed AADC deficient patient with a mean 3‐OMD of 35.95 μmol/L. 14 DDC variant carriers showed normal 3‐OMD concentrations. We demonstrate a novel high‐throughput method to measure 3‐OMD in DBS, which allows integration in existing NBS programs enabling early diagnosis of AADC deficiency. [ABSTRACT FROM AUTHOR]

Argininosuccinic aciduria (ASA) is an inherited urea cycle disorder and has a highly variable phenotypic spectrum ranging from individuals with lethal hyperammonemic encephalopathy, liver dysfunction, and cognitive deterioration, to individuals with a mild disease course. As it is difficult to predict the phenotypic severity, we aimed at identifying a reliable disease prediction model. We applied a biallelic expression system to assess the functional impact of pathogenic argininosuccinate lyase (ASL) variants and to determine the enzymatic activity of ASL in 58 individuals with ASA. This cohort represented 42 ASL gene variants and 42 combinations in total. Enzymatic ASL activity was compared with biochemical and clinical endpoints from the UCDC and E‐IMD databases. Enzymatic ASL activity correlated with peak plasma ammonium concentration at initial presentation and with the number of hyperammonemic events (HAEs) per year of observation. Individuals with ≤9% of enzymatic activity had more severe initial decompensations and a higher annual frequency of HAEs than individuals above this threshold. Enzymatic ASL activity also correlated with the cognitive outcome and the severity of the liver disease, enabling a reliable severity prediction for individuals with ASA. Thus, enzymatic activity measured by this novel expression system can serve as an important marker of phenotypic severity. [ABSTRACT FROM AUTHOR]

The Mediterranean diet (MedDiet) is one of the most widely described and evaluated dietary patterns in scientific literature. It is characterized by high intakes of vegetables, legumes, fruits, nuts, grains, fish, seafood, extra virgin olive oil, and a moderate intake of red wine. A large body of observational and experimental evidence suggests that higher adherence to the MedDiet is associated with lower risk of mortality, cardiovascular disease, metabolic disease, and cancer. Current mechanisms underlying the beneficial effects of the MedDiet include reduction of blood lipids, inflammatory and oxidative stress markers, improvement of insulin sensitivity, enhancement of endothelial function, and antithrombotic function. Most likely, these effects are attributable to bioactive ingredients such as polyphenols, monounsaturated and polyunsaturated fatty acids, or fibre. This review will focus on both established and less established mechanisms of action of biochemical compounds contained in a MedDiet. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc. [ABSTRACT FROM AUTHOR]

Alpha‐mannosidosis (OMIM 248500) is a rare lysosomal storage disorder caused by a deficiency of the enzyme alpha‐mannosidase. Recently, enzyme replacement therapy was approved in the European Union for the treatment of alpha‐mannosidosis, but evaluation regarding long‐term efficacy and safety is hard to assess due to missing quantitative natural history data, in particular survival. We performed a quantitative analysis of published cases (N = 111) with alpha‐mannosidosis. Main outcome measures were age of disease onset, diagnostic delay and survival (overall and by subgroup exploration). Residual alpha‐mannosidase activity and age of onset were explored as potential predictors of survival. STROBE criteria were respected. Median age of onset was 12 months. Median diagnostic delay was 6 years. At the age of 41 years 72.3% of patients were alive (N = 111). Residual alpha‐mannosidase activity (N = 34) predicted survival: Patients with a residual alpha‐mannosidase activity below or equal to 4.5% of normal in fibroblasts had a median survival of 3.5 years, whereas patients with alpha‐mannosidase activity above this threshold all survived during the observation period reported. Patients with age of onset above 7 years survived significantly longer than patients with age of onset below or equal to 7 years. Patient distribution was panethnic with hotspots in the United States and Germany. We defined age of onset, diagnostic delay, and survival characteristics in a global cohort of 111 patients with alpha‐mannosidosis by retrospective quantitative natural history modeling. These data expand the quantitative understanding of the clinical phenotype. [ABSTRACT FROM AUTHOR]

Objective: Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild‐to‐moderate or asymptomatic disease course. Since the phenotypic severity has not been predictable early during the disease course so far, we aimed to design a reliable disease prediction model. Methods: We used a newly established mammalian biallelic expression system to determine residual enzymatic activity of argininosuccinate synthetase 1 (ASS1; OMIM #215700) in 71 individuals with CTLN1, representing 48 ASS1 gene variants and 50 different, mostly compound heterozygous combinations in total. Residual enzymatic ASS1 activity was correlated to standardized biochemical and clinical endpoints available from the UCDC and E‐IMD databases. Results: Residual enzymatic ASS1 activity correlates with peak plasma ammonium and L‐citrulline concentrations at initial presentation. Individuals with 8% of residual enzymatic ASS1 activity or less had more frequent and more severe hyperammonemic events and lower cognitive function than those above 8%, highlighting that residual enzymatic ASS1 activity allows reliable severity prediction. Noteworthy, empiric clinical practice of affected individuals is in line with the predicted disease severity supporting the notion of a risk stratification‐based guidance of therapeutic decision‐making based on residual enzymatic ASS1 activity in the future. Interpretation: Residual enzymatic ASS1 activity reliably predicts the phenotypic severity in CTLN1. We propose a new severity‐adjusted classification system for individuals with CTLN1 based on the activity results of the newly established biallelic expression system. [ABSTRACT FROM AUTHOR]

Objective: Individuals with urea cycle disorders (UCDs) often present with intellectual and developmental disabilities. The major aim of this study was to evaluate the impact of diagnostic and therapeutic interventions on cognitive outcomes in UCDs.Methods: This prospective, observational, multicenter study includes data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow-up of 702 patient-years.Results: The mean cognitive standard deviation score (cSDS) was lower in symptomatic than in asymptomatic (p < 0.001, t test) individuals with UCDs. Intellectual disability (intellectual quotient < 70, cSDS < -2.0) was associated with the respective subtype of UCD and early disease onset, whereas height of the initial peak plasma ammonium concentration was inversely associated with neurocognitive outcomes in mitochondrial (proximal) rather than cytosolic (distal) UCDs. In ornithine transcarbamylase and argininosuccinate synthetase 1 deficiencies, we did not find evidence that monoscavenger therapy with sodium or glycerol phenylbutyrate was superior to sodium benzoate in providing cognitive protection. Early liver transplantation appears to be beneficial for UCDs. It is noteworthy that individuals with argininosuccinate synthetase 1 and argininosuccinate lyase deficiencies identified by newborn screening had better neurocognitive outcomes than those diagnosed after the manifestation of first symptoms.Interpretation: Cognitive function is related to interventional and non-interventional variables. Early detection by newborn screening and early liver transplantation appear to offer greater cognitive protection, but none of the currently used nitrogen scavengers was superior with regard to long-term neurocognitive outcome. Further confirmation could determine these variables as important clinical indicators of neuroprotection for individuals with UCDs. ANN NEUROL 2019. [ABSTRACT FROM AUTHOR]

ALG3‐CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER‐mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic data of four new ALG3‐CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man5GlcNAc2‐PP‐dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right‐descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3‐CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open‐reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP‐ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect. [ABSTRACT FROM AUTHOR]

Galactosialidosis (GS; OMIM #256540) is a rare multisystemic inborn glycoprotein storage disease caused by biallelic mutations in the cathepsin A gene resulting in combined deficiency of the lysosomal enzymes β‐galactosidase and α‐neuraminidase. The precise understanding of the natural course of the disease is limited. Development of enzyme replacement therapy is at the preclinical stage. The purpose of this research project was to quantitatively characterize the natural history of the condition. Quantitative analysis of all published cases in the literature with sufficient data (N = 142 patients) was carried out. Main outcome variables were survival, diagnostic delay, description of symptoms, biomarker‐phenotype associations, and radiological findings. STROBE criteria were respected. Median survival age of the cohort was 48 years. Median age of onset was 4.25 years with interquartile range (IQR) 1 to 16 years. Median age at diagnosis was 19 (IQR: 8.92‐29) years, with median diagnostic delay of 8 (IQR: 4‐12) years. Patients with residual β‐galactosidase activity of more than 8.6% (leukocytes) survived significantly longer than patients with lower enzyme activities. [ABSTRACT FROM AUTHOR]

Background: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. Aims: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. Methods: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. Results: The proportion of females with ornithine transcarbamylase deficiency (fOTC‐D), particularly those being asymptomatic (asfOTC‐D), was higher in the NA than in the EU sample. Exclusion of asfOTC‐D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC‐D), diagnosis was made after the onset of symptoms (59.9%) or by high‐risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. Conclusions: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long‐term outcome studies. [ABSTRACT FROM AUTHOR]

In recent years, disease‐modifying and life‐prolonging therapies for spinal muscular atrophy (SMA) have been developed. However, patients are currently diagnosed with significant delay and therapies are often administered in advanced stages of motor neuron degeneration, showing limited effects. Methods to identify children in presymptomatic stages are currently evaluated in newborn screening programs. Yet, not all children develop symptoms shortly after birth raising the question whom to treat and when to initiate therapy. Finally, monitoring disease progression becomes essential to individualize management. Here, we review the literature on screening approaches, strategies to predict disease severity, and biomarkers to monitor therapy. [ABSTRACT FROM AUTHOR]

Objective: Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programs has improved the short-term outcome. It remains unclear, however, whether NBS changes the long-term outcome and which variables are predictive.Methods: This prospective, observational, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 women with GA1 identified by positive NBS results of their unaffected children.Results: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany during 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study.Interpretation: 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. [ABSTRACT FROM AUTHOR]

The aim of this systematic review and meta‐analysis was to summarize the evidence on the relationship between intake of 12 major food groups, including whole grains, refined grains, vegetables, fruit, nuts, legumes, eggs, dairy, fish, red meat, processed meat and sugar‐sweetened beverages with risk of colorectal cancer (CRC). We conducted a systematic search in PubMed and Embase for prospective studies investigating the association between these 12 food groups and risk of CRC until April 2017. Summary risk ratios (RRs) and 95% confidence intervals (95% CI) were estimated using a random effects model for high vs. low intake categories, as well as for linear and nonlinear relationships. An inverse association was observed for whole grains (RR30g/d: 0.95, 95% CI 0.93, 0.97; n = 9 studies), vegetables (RR100g/d: 0.97, 95% CI 0.96, 0.98; n = 15), fruit (RR100g/d: 0.97, 95% CI 0.95, 0.99; n = 16) and dairy (RR200g/d: 0.93, 95% CI 0.91, 0.94; n = 15), while a positive association for red meat (RR100g/d: 1.12, 95% CI 1.06, 1.19; n = 21) and processed meat (RR50g/d: 1.17, 95% CI 1.10, 1.23; n = 16), was seen in the linear dose‐response meta‐analysis. Some evidence for nonlinear relationships was observed between vegetables, fruit and dairy and risk of colorectal cancer. Findings of this meta‐analysis showed that a diet characterized by high intake of whole grains, vegetables, fruit and dairy products and low amounts of red meat and processed meat was associated with lower risk of CRC. [ABSTRACT FROM AUTHOR]

Background: Urea cycle disorders (UCDs) still have a poor prognosis despite several therapeutic advancements. As liver transplantation can provide a cure, liver cell therapy (LCT) might be a new therapeutic option in these patients. Methods: Twelve patients with severe UCDs were included in this prospective clinical trial. Patients received up to six infusions of cryopreserved human heterologous liver cells via a surgically placed catheter in the portal vein. Portal vein pressure, portal vein flow, and vital signs were monitored continuously. Calcineurin inhibitors and steroids were used for immunosuppression. In four patients, ureagenesis was determined with stable isotopes. Number and severity of hyperammonemic events and side effects of immunosuppression were analyzed during an observation period of up to 2 years. Results: No study-related mortality was observed. The application catheter dislocated in two children. No significant side effects of catheter application or cell infusion were noted in the other ten patients. The overall incidence of infections did not differ significantly from a historical control group, and no specific side effects of immunosuppression were found. Seven patients were treated per protocol and could be analyzed for efficacy. Severe metabolic crises could be prevented in all of these patients, moderate crises in four of seven. Ureagenesis increased after cell infusion in all patients investigated. Conclusions: We found a favorable safety profile with respect to catheter placement, intraportal liver cell infusion, and immunosuppression. More than half of the children treated per protocol experienced metabolic stabilization and could be safely bridged to liver transplantation. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASD) have a prevalence of up to 2.7% and show significant rates of comorbidities. Pharmacological treatment can be difficult. New treatment options are needed, several are currently under investigation. Publication bias presents a major problem in current clinical research. This study was designed to quantify publication bias in rigorously designed ASD research. The database at was searched for all completed randomized controlled clinical trials investigating interventions in ASD and their results made public. If results could neither be retrieved through search of the database, nor of scientific databases nor by enquiries of the responsible parties or sponsors listed, a trial was defined as not published. The search delivered N = 30 (60%) trials were published, N = 20 (40%) remained unpublished, N = 2,421 (59%) patients were enrolled in the published trials, N = 1,664 (41%) patients in the unpublished trials, time to publication was 21.4 months [standard deviation (SD) = 18.48; range = −5 to 80 months]. Results of N = 22 trials were available through . Characteristics of published compared to unpublished trials did not show apparent differences. The majority of trials investigated drugs. The results emphasize the serious issue of publication bias. The large proportion of unpublished results precludes valuable information and has the potential to distort evidence for treatment approaches in ASD. [ABSTRACT FROM AUTHOR]

Introduction: Molybdenum cofactor deficiency (MoCD) is an ultra-orphan, life-threatening disease. Substrate substitution therapy has successfully been performed in single cases of MoCD type A and clinical trials are underway for drug registration. We present an innovative approach for classification of genotype severity to test the hypothesis that milder sequence variants in MoCD result in a less severe disease phenotype quantitated by patient survival. Methods: All available worldwide published cases with clinical and genetic data were included ( n = 40). We stratified the already published disease causing sequence variants as mild or severe with the use of in silico prediction programs, where possible and assessed the possible impact of the variants on the expression of the gene or function of the expressed protein. In a compound heterozygous situation the mildest sequence variant determined the genotype. Subsequently, clinical manifestations and outcomes of both groups were compared. Results: Patients with a severe genotype showed a median survival of 15 months and had a lower probability of survival compared to patients with mild genotypes who were all alive at last reported follow-up ( p = 0.0203, Log-rank test). Discussion: The severity of the genotype assessed by in silico prediction and further classification explained survival in molybdenum cofactor deficiency and may therefore be considered a confounder for the outcome of therapeutic clinical trials requiring adjustment in the clinical trial design or analysis. These results should further be investigated by future in vitro or in vivo functional studies. Caution should be taken with this approach for the classification of variants in molecular genetic diagnostics or genetic counseling. [ABSTRACT FROM AUTHOR]

Lysosomal storage diseases (LSD) are inborn errors of metabolism resulting in multisystem disease. Central nervous system involvement, often with progressive neurodegeneration, accounts for a large portion of the morbidity and mortality seen in many LSD. Available treatments fail to prevent or correct neurologic symptoms and decline. Emerging evidence points to an important role for mitochondrial dysfunction in the pathogenesis and progression of LSD-associated neurodegeneration. Mitochondrial dysfunction in LSD is characterized by alterations in mitochondrial mass, morphology and function. Disturbed mitochondrial metabolism in the CNS may lead to excessive production of mitochondrial reactive oxygen species and dysregulated calcium homeostasis. These metabolic disturbances ultimately result in mitochondria-induced apoptosis and neuronal degeneration. Here, we review the current evidence for mitochondrial dysfunction in neuronal models of seven LSD, including GM1-gangliosidosis, mucopolysaccharidosis IIIC, multiple sulfatase deficiency, Krabbe disease, Gaucher disease, Niemann Pick disease type C and the neural ceroid lipofuscinoses and outline current experimental therapies aimed at restoring mitochondrial function and neuroprotection in LSD. [ABSTRACT FROM AUTHOR]

Bone disease in patients with phenylketonuria (PKU) is incompletely characterized. We therefore analyzed, in a cross-sectional study radius macroscopic bone architecture and forearm muscle size by peripheral quantitative computed tomography (pQCT) and muscle strength by hand dynamometry in a large cohort ( n = 56) of adolescent and adult patients with PKU aged 26.0 ± 8.9 (range, 11.8-41.5) years. Data were compared with a reference population ( n = 700) from the DONALD study using identical methodology. We observed a significant reduction of cortical thickness (z-score −1.01 ± 0.79), Strength-Strain Index (SSI) (z-score −0.81 ± 1.03), and total bone mineral density (BMD) of the distal radius (z-score −1.05 ± 1.00). Mean muscle cross-sectional area (z-score −0.98 ± 1.19) and muscle grip force (z-score −0.64 ± 1.26) were also significantly reduced, indicating an impaired muscular system as part of the clinical phenotype of PKU. SSI positively correlated ( r = 0.53, P < 0.001) with the corresponding muscle cross-sectional area in the reference population; however, the regression line slope in PKU patients was less steep ( P < 0.001), indicating that bone strength is not adequately adapted to muscle force. In conclusion, the radial bone in PKU patients is characterized by reduced bone strength in relation to muscular force, decreased cortical thickness, and impaired total BMD at the metaphyseal site. These alterations indicate a mixed bone defect in PKU, both of which are due to primary alterations of bone metabolism and to secondary alterations in response to neuromuscular abnormalities. [ABSTRACT FROM AUTHOR]

Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals. [ABSTRACT FROM AUTHOR]

Background: Hydroxyprolinemia is an inborn error of amino acid degradation that is considered a non-disease. Known for more than 50 years, its genetic cause and prevalence have remained unclear. In MS/MS newborn screening, the mass spectrum of hydroxyproline cannot be differentiated from isoleucine and leucine causing false positive newborn screening test results for maple syrup urine disease (MSUD). Methods: We studied two siblings with hydroxyprolinemia via exome sequencing and confirmed the candidate gene in five further individuals with hydroxyprolinemia, who were all characterized biochemically and clinically. The prevalence was calculated based on the number of individuals with hydroxyprolinemia detected via MS/MS newborn screening at our centre from 2003 to 2014. Results: In six cases, we identified homozygous or compound heterozygous mutations in PRODH2 as the underlying genetic cause of hydroxyprolinemia. One individual was heterozygous for a deletion in PRODH2 and had an intermittent biochemical phenotype with partial normalization of hydroxyproline concentrations. In one further individual with persistent hydroxyprolinemia no mutation in PRODH2 was found, raising the possibility of another defect of hydroxyproline degradation yet to be identified as the underlying cause of hydroxyprolinemia. Plasma hydroxyproline concentrations were clearly elevated in all individuals with biallelic mutations in PRODH2. All studied individuals remained asymptomatic, giving further evidence that hydroxyprolinemia is a benign condition. The estimated prevalence of hydroxyprolinemia in Germany is about one in 47,300 newborns. Conclusion: Our results establish mutations in PRODH2 as a cause of human hydroxyprolinemia via impaired dehydrogenation of hydroxyproline to delta1-pyroline-3-hydroxy-5-carboxylic acid, and we suggest PRODH2 be renamed HYPDH. Hydroxyprolinemia is an autosomal-recessively inherited benign condition. It is a frequent cause of false positive screening results for MSUD, the prevalence being about 2.5 times higher than that of MSUD. [ABSTRACT FROM AUTHOR]

Over the last 10 years, a total of 90 urine samples from patients with metabolic disorders and controls were circulated to different laboratories in Europe and overseas, starting with 67 laboratories in 2005 and reaching 101 in 2014. The participants were asked to analyse the samples in their usual way and to prepare a report as if to a non-specialist pediatrician. The performance for the detection of fumarase deficiency, glutaric aciduria type I, isovaleric aciduria, methylmalonic aciduria, mevalonic aciduria, phenylketonuria and propionic aciduria was excellent (98-100 %). Over the last few years, detection has clearly improved for tyrosinaemia type I (39 % in 2008 to over 80 % in 2011/2014), maple syrup urine disease (85 % in 2005 to 98 % in 2012), hawkinsinuria (62 % in 2010 to 88 % in 2014), aminoacylase I deficiency (43 % in 2009 to 73 % in 2012) and 3-methylcrotonyl-CoA carboxylase deficiency (60 % in 2005 to 93 % by 2011). Normal urines were mostly considered as normal (83-100 %), but laboratories often made additional diagnostic suggestions. When the findings were unambiguous, the reports were mostly clear. However, when they were less obvious, the content and quality of reports varied greatly. Repetition of organic acid measurements on a fresh sample was rarely suggested, while more complex or invasive diagnostic strategies, including further metabolic screening or biopsy were recommended. Surprisingly very few participants suggested referral from the general paediatrician to a specialist metabolic centre to confirm a diagnosis and, if applicable, to initiate treatment despite evidence suggesting that this improves the outcome for patients with inherited metabolic disorders. The reliability of qualitative organic acid analysis has improved over the last few years. However, several aspects of reporting to non-specialists may need discussion and clinicians need to be aware of the uncertainty inherent in all forms of laboratory diagnostic analysis. [ABSTRACT FROM AUTHOR]

Background: For urea cycle disorders (UCD), proportions and mortality of early onset (EO) patients, as well as outcome at one year of life show large variability. We aimed to integrate available evidence to create benchmarks for new diagnostic and therapeutic strategies. Methods: Medline search for reports published between 1978 and Dec 22, 2014 was completed by hand search. Random effects meta-analysis was done for four UCDs, deficiency of carbamylphosphate synthetase 1 (CPS1D), male/female ornithine transcarbamylase (OTCDm/f), argininosuccinate synthetase (ASSD) and lyase (ASLD). Effects of publication year and geographic area were analysed by meta-regression. Results: Twenty-four publications report onset time (n = 1542 patients), survival of EO (n = 665 patients) and outcome at one year of life (n = 172 patients). Proportions for EO manifestation (95 % confidence interval) were: CPS1D = 0.75 (0.61;0.88); OTCDm = 0.52 (0.39;0.65); OTCDf = 0.07 (0.03;0.11); ASSD = 0.65 (0.57;0.73); ASLD = 0.60 (0.44;0.77); for surviving EO patients: CPS1D = 0.64 (0.50;0.79); OTCDm = 0.40 (0.16;0.64); OTCDf = 0.57 (0.29;0.85); ASSD = 0.67 (0.48;0.86); ASLD = 0.81 (0.68;0.94); and for normal outcome at one year for survivors: CPS1D = 0.20 (0.07;0.38); OTCDm = 0.15 (0.00;0.39); OTCDf no data; ASSD = 0.36 (0.13;0.60); ASLD = 0.36 (0.17;0.58). Between study variation was large. Year of publication had no effect. Studies from Europe showed lower survival rates than those from Japan or USA. Conclusions: UCDs, except for OTCDf, have high risks of EO disease manifestation and, except for ASLD, of neonatal death. No improvement of survival was observed over more than three decades. Geographic variation remains to be explained. This comprehensive description of the natural history of EO UCDs should be considered by scientists, clinicians, health policy makers and guideline developers. [ABSTRACT FROM AUTHOR]

Background: Adenosine kinase deficiency is a recently described defect affecting methionine metabolism with a severe clinical phenotype comprising mainly neurological and hepatic impairment and dysmorphism. Methods: Clinical data of 11 additional patients from eight families with adenosine kinase deficiency were gathered through a retrospective questionnaire. Two liver biopsies of one patient were systematically evaluated. Results: The main clinical symptoms are mild to severe liver dysfunction with neonatal onset, muscular hypotonia, global developmental retardation and dysmorphism (especially frontal bossing). Hepatic involvement is not a constant finding. Most patients have epilepsy and recurrent hypoglycemia due to hyperinsulinism. Major biochemical findings are intermittent hypermethioninemia, increased S-adenosylmethionine and S-adenosylhomocysteine in plasma and increased adenosine in urine. S-adenosylmethionine and S-adenosylhomocysteine are the most reliable biochemical markers. The major histological finding was pronounced microvesicular hepatic steatosis. Therapeutic trials with a methionine restricted diet indicate a potential beneficial effect on biochemical and clinical parameters in four patients and hyperinsulinism was responsive to diazoxide in two patients. Conclusion: Adenosine kinase deficiency is a severe inborn error at the cross-road of methionine and adenosine metabolism that mainly causes dysmorphism, brain and liver symptoms, but also recurrent hypoglycemia. The clinical phenotype varies from an exclusively neurological to a multi-organ manifestation. Methionine-restricted diet should be considered as a therapeutic option. [ABSTRACT FROM AUTHOR]