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Contains fulltext : 283151.pdf (Publisher’s version ) (Open Access) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine-based NBS for LCHADD not only identifies LCHADD, but also the other deficiencies of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex involved in long-chain fatty acid β-oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long-chain enoyl-CoA hydratase (LCEH) and long-chain ketoacyl-CoA thiolase (LCKAT). Deficiency of one or more MTP activities causes generalized MTP deficiency (MTPD), LCHADD, LCEH deficiency (not yet reported), or LCKAT deficiency (LCKATD). To gain insight in the outcomes of MTP-deficient patients diagnosed after the introduction of NBS for LCHADD in the Netherlands, a retrospective evaluation of genetic, biochemical, and clinical characteristics of MTP-deficient patients, identified since 2007, was carried out. Thirteen patients were identified: seven with LCHADD, five with MTPD, and one with LCKATD. All LCHADD patients (one missed by NBS, clinical diagnosis) and one MTPD patient (clinical diagnosis) were alive. Four MTPD patients and one LCKATD patient developed cardiomyopathy and died within 1 month and 13 months of life, respectively. Surviving patients did not develop symptomatic hypoglycemia, but experienced reversible cardiomyopathy and rhabdomyolysis. Five LCHADD patients developed subclinical neuropathy and/or retinopathy. In conclusion, patient outcomes were highly variable, stressing the need for accurate classification of and discrimination between the MTP deficiencies to improve insight in the yield of NBS for LCHADD. NBS allowed the prevention of symptomatic hypoglycemia, but current treatment options failed to treat cardiomyopathy and prevent long-term complications. Moreover, milder patients, who might benefit from NBS, were missed due to normal acylcarnitine profiles.

Contains fulltext : 282651.pdf (Publisher’s version ) (Open Access) Congenital disorders of glycosylation type 1 (CDG-I) comprise a group of 27 genetic defects with heterogeneous multisystem phenotype, mostly presenting with nonspecific neurological symptoms. The biochemical hallmark of CDG-I is a partial absence of complete N-glycans on transferrin. However, recent findings of a diagnostic N-tetrasaccharide for ALG1-CDG and increased high-mannose N-glycans for a few other CDG suggested the potential of glycan structural analysis for CDG-I gene discovery. We analyzed the relative abundance of total plasma N-glycans by high resolution quadrupole time-of-flight mass spectrometry in a large cohort of 111 CDG-I patients with known (n = 75) or unsolved (n = 36) genetic cause. We designed single-molecule molecular inversion probes (smMIPs) for sequencing of CDG-I candidate genes on the basis of specific N-glycan signatures. Glycomics profiling in patients with known defects revealed novel features such as the N-tetrasaccharide in ALG2-CDG patients and a novel fucosylated N-pentasaccharide as specific glycomarker for ALG1-CDG. Moreover, group-specific high-mannose N-glycan signatures were found in ALG3-, ALG9-, ALG11-, ALG12-, RFT1-, SRD5A3-, DOLK-, DPM1-, DPM3-, MPDU1-, ALG13-CDG, and hereditary fructose intolerance. Further differential analysis revealed high-mannose profiles, characteristic for ALG12- and ALG9-CDG. Prediction of candidate genes by glycomics profiling in 36 patients with thus far unsolved CDG-I and subsequent smMIPs sequencing led to a yield of solved cases of 78% (28/36). Combined plasma glycomics profiling and targeted smMIPs sequencing of candidate genes is a powerful approach to identify causative mutations in CDG-I patient cohorts.

Contains fulltext : 292759.pdf (Publisher’s version ) (Closed access) Immunological problems are increasingly acknowledged manifestations in many inherited metabolic diseases (IMDs), ranging from exaggerated inflammation, autoimmunity and abnormal cell counts to recurrent microbial infections. A subgroup of IMDs, the congenital disorders of glycosylation (CDG), includes CDG types that are even classified as primary immunodeficiencies. Here, we reviewed the list of metabolic disorders reported to be associated with various immunological defects and identified 171 IMDs accompanied by immunological manifestations. Most IMDs are accompanied by immune dysfunctions of which immunodeficiency and infections, innate immune defects, and autoimmunity are the most common abnormalities reported in 144/171 (84%), 44/171 (26%) and 33/171 (19%) of IMDs with immune system involvement, respectively, followed by autoinflammation 17/171 (10%). This article belongs to a series aiming at creating and maintaining a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement.

Contains fulltext : 231549.pdf (Publisher’s version ) (Closed access) PURPOSE: The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity. METHODS: Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized. RESULTS: Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families. CONCLUSION: We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.

PURPOSE: For patients with inherited metabolic disorders (IMDs), any diagnostic delay should be avoided because early initiation of personalized treatment could prevent irreversible health damage. To improve diagnostic interpretation of genetic data, gene function tests can be valuable assets. For IMDs, variant-transcending functional tests are readily available through (un)targeted metabolomics assays. To support the application of metabolomics for this purpose, we developed a gene-based guide to select functional tests to either confirm or exclude an IMD diagnosis.METHODS: Using information from a diagnostic IMD exome panel, Kyoto Encyclopedia of Genes and Genomes, and Inborn Errors of Metabolism Knowledgebase, we compiled a guide for metabolomics-based gene function tests. From our practical experience with this guide, we retrospectively selected illustrative cases for whom combined metabolomic/genomic testing improved diagnostic success and evaluated the effect hereof on clinical management.RESULTS: The guide contains 2047 metabolism-associated genes for which a validated or putative variant-transcending gene function test is available. We present 16 patients for whom metabolomic testing either confirmed or ruled out the presence of a second pathogenic variant, validated or ruled out pathogenicity of variants of uncertain significance, or identified a diagnosis initially missed by genetic analysis.CONCLUSION: Metabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success.

This chapter describes gene mutations and disorders linked to mitochondrial homeostasis, dynamics, protein import, and quality control. Although clinically highly variable, we here functionally categorized these mutations as impacting on mitochondrial biogenesis, mitochondrial morphology/motility (“mitochondrial dynamics”), and mitochondrial degradation (“mitophagy”). These three processes are described in more detail in the Introduction. In addition, several other mutations that affect mitochondrial function are presented. The gene mutations discussed in this chapter are all nuclear DNA (nDNA) mutations. Most patients with mitochondrial disorders present with a multi-system disorder. The organs requiring the most energy, such as the brain, retina, heart, kidney, and skeletal muscle, are most commonly and severely affected. Onset of disease can be at any age and the symptoms are almost always progressive. A definitive diagnosis solely based on clinical signs and symptoms is very unlikely. Whole exome/genome sequencing (WES/WGS) has greatly improved disease diagnosis and often simplified it, although in some cases has also resulted in new diagnostic challenges. Nonetheless, clinical diagnostic criteria, combined with brain imaging, metabolic, biochemical, and other functional tests are still needed. Since specific treatment options are still limited, the management of the described mitochondrial disorders is largely supportive. For diagnosis and treatment, patients should be referred to a specialized center.

We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs(∗)20), c.1348C>T (p.Arg450(∗)), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.

Background: NANS-CDG is a recently described congenital disorder of glycosylation caused by biallelic genetic variants in NANS, encoding an essential enzyme in de novo sialic acid synthesis. Sialic acid at the end of glycoconjugates plays a key role in biological processes such as brain and skeletal development. Here, we present an observational cohort study to delineate the genetic, biochemical, and clinical phenotype and assess possible correlations.Methods: Medical and laboratory records were reviewed with retrospective extraction and analysis of genetic, biochemical, and clinical data (2016–2020).Results: Nine NANS-CDG patients (nine families, six countries) referred to the Radboudumc CDG Center of Expertise were included. Phenotyping confirmed the hallmark features including intellectual developmental disorder (IDD) (n = 9/9; 100%), facial dysmorphisms (n = 9/9; 100%), neurologic impairment (n = 9/9; 100%), short stature (n = 8/9; 89%), skeletal dysplasia (n = 8/9; 89%), and short limbs (n = 8/9; 89%). Newly identified features include ophthalmological abnormalities (n = 6/9; 67%), an abnormal septum pellucidum (n = 6/9; 67%), (progressive) cerebral atrophy and ventricular dilatation (n = 5/9; 56%), gastrointestinal dysfunction (n = 5/9; 56%), thrombocytopenia (n = 5/9; 56%), and hypo–low-density lipoprotein cholesterol (n = 4/9; 44%). Biochemically, elevated urinary excretion of N-acetylmannosamine (ManNAc) is pathognomonic, the concentrations of which show a significant correlation with clinical severity. Genotypically, eight novel NANS variants were identified. Three severely affected patients harbored identical compound heterozygous pathogenic variants, one of whom was initiated on experimental prenatal and postnatal treatment with oral sialic acid. This patient showed markedly better psychomotor development than the other two genotypically identical males.Conclusions: ManNAc screening should be considered in all patients with IDD, short stature with short limbs, facial dysmorphisms, neurologic impairment, and an abnormal septum pellucidum +/– congenital and neurodegenerative lesions on brain imaging, to establish a precise diagnosis and contribute to prognostication. Personalized management includes accurate genetic counseling and access to proper supports and tailored care for gastrointestinal symptoms, thrombocytopenia, and epilepsy, as well as rehabilitation services for cognitive and physical impairments. Motivated by the short-term positive effects of experimental treatment with oral sialic, we have initiated this intervention with protocolized follow-up of neurologic, systemic, and growth outcomes in four patients. Research is ongoing to unravel pathophysiology and identify novel therapeutic targets.

INTRODUCTION: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an ultra-rare inborn error of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. Individual phenotypes and treatment response can vary markedly. We aimed to identify markers that predict MADD phenotypes.METHODS: We performed a retrospective nationwide cohort study; then developed an MADD -disease severity scoring system (MADD-DS3) based on signs and symptoms with weighed expert opinions; and finally correlated phenotypes and MADD-DS3 scores to FAO flux (oleate and myristate oxidation rates) and acylcarnitine profiles after palmitate loading in fibroblasts.RESULTS: Eighteen patients, diagnosed between 1989 and 2014, were identified. The MADD-DS3 entails enumeration of eight domain scores, which are calculated by averaging the relevant symptom scores. Lifetime MADD-DS3 scores of patients in our cohort ranged from 0-29. FAO flux and [U-13 C]C2-, C5- and [U-13 C]C16-acylcarnitines were identified as key variables that discriminated neonatal from later onset patients (all pCONCLUSION: Functional studies in fibroblasts were found to differentiate between neonatal and later onset MADD-patients and were correlated to MADD-DS3 scores. Our data may improve early prediction of disease severity in order to start (preventive) and follow-up treatment appropriately. This is especially relevant in view of the inclusion of MADD in population newborn screening programs. This article is protected by copyright. All rights reserved.

The advent of next generation sequencing has improved gene discovery in neurodevelopmental disorders. A greater understanding of the genetic basis of these disorders has expanded the spectrum of pathogenic genes, thus enhancing diagnosis and therapeutic management. Genetic overlap between distinct neurodevelopmental disorders has also been revealed, which can make determining a strict genotype-phenotype correlation more difficult. Intellectual disability and cortical malformations are two neurodevelopmental disorders particularly confronted by this difficulty. Indeed, for a given pathogenic gene, intellectual disability can be associated, or not, with cortical malformations. Here, we report for the first time, two individuals with the same de novo mutation in TBR1, leading to a frameshift starting at codon Thr532, and resulting in a premature stop codon 143 amino acids downstream (c.1588_1594dup, p.(Thr532Argfs*144)). These individuals presented with a developmental encephalopathy characterized by frontal pachygyria and severe intellectual disability. Remarkably, 11 TBR1 gene mutations were previously reported in intellectual disability and autism spectrum disorders. Our study supports the observation that TBR1-related disorders range from intellectual disability to frontal pachygyria. We also highlight the need for first-line, good quality neuroimaging for patients with intellectual disability.

Contains fulltext : 170581.pdf (Publisher’s version ) (Closed access) We developed the first user-friendly, semi-quantitative, and quick-to-perform Radboud Centre for Mitochondrial Medicine Pediatric MRI score (RCMM-PMRIS), focusing on the six most commonly described neuroimaging abnormalities in the literature. The RCMM-PMRIS was validated through individual review of 30 sets of brain MRI studies in 24 patients with genetically confirmed mitochondrial disorders by six raters. The application of RCMM-PMRIS can help to define the extent of the brain involvement and therefore to assess the radiological mitochondrial disease severity, to monitor disease progression and consequently to act as an outcome measure for treatment effects in patients with mitochondrial disease.

Contains fulltext : 167896.pdf (Publisher’s version ) (Open Access) OBJECTIVE: There is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study. METHODS: A clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6-16 years) from five different expert centres from four different continents were evaluated in this study. RESULTS: The feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three factors, which explained 57.9 % of the variance. Good construct validity was found using hypothesis testing. The overall interrater reliability was good [median intraclass correlation coefficient for agreement between raters (ICCagreement) 0.85; range 0.23-0.99). CONCLUSION: In conclusion, we suggest using the IPMDS for assessing natural history in children with mitochondrial diseases. These data should be used to further explore construct validity of the IPMDS and to set age limits. In parallel, responsiveness and the minimal clinically important difference should be studied to facilitate sample size calculations in future clinical trials.

Contains fulltext : 152981.pdf (Publisher’s version ) (Closed access) Despite major advances in understanding the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive, and no effective treatment is available. We therefore assumed that the burden of disease combined with the lack of adequate treatment leaves open a big market for complementary and alternative medicine use. The objective of this study was to evaluate the use and perceived effectiveness of complementary and alternative medicine in children and adults with genetically proven mitochondrial disease. The reported use was surprisingly high, with 88 % of children and 91 % of adults having used some kind of complementary and alternative medicine in the last 2 years. Also, the mean cost of these treatments was impressive, being 489/year for children and 359/year for adult patients. Over-the-counter remedies (e.g., food supplements, homeopathy) and self-help techniques (e.g., Reiki, yoga) were the most frequently used complementary and alternative therapies in our cohort: 54 % of children and 60 % of adults reported the various complementary and alternative medicine therapies to be effective. Given the fact that currently no effective treatment exists, further research toward the different therapies is needed, as our study clearly demonstrates that such therapies are highly sought after by affected patients.

Aim: Nuclear receptor-binding SET domain-containing protein 1 (NSD1) gene mutations and deletions (NSD1 -/- ) are the major cause of Sotos syndrome. The aim was to investigate which auxology parameters relate to NSD1 +/- in patients clinically suspected of Sotos syndrome. Methods: In 32 patients clinically suspected of Sotos syndrome, we compared auxology parameters between NSD1 +/- patients and patients without NSD1 gene alterations (NSD1 +/+ ). The statistical performance of these parameters to predict NSD1 +/- was assessed. Results: Arm span-for-height standard deviation score (SDS) and hand length SDS were significantly higher in NSD1 +/- patients. Conclusion: Arm span for height and hand length are discriminating parameters between NSD1 +/- and NSD1 +/+ .

According to the endocrine model of hereditary dizygotic twinning, high FSH is responsible for multiple ovulation and pregnancy. Our study explored the underlying neuroendocrine causes. In a prospective clinical study, we compared the third day of menses parameters of episodic secretion of LH and FSH, the pituitary response to LHRH, plasma estradiol, and dimeric inhibin A and B in 16 regularly menstruating and 9 postmenopausal mothers of dizygotic twins with a family history of twinning and 14 premenopausal and 9 postmenopausal controls. Seven of 16 premenopausal mothers of twins had abnormally high FSH levels of more than 10 IU/L compared with 1/14 in controls (P = 0.024). In the premenopausal mothers of twins, mean FSH concentrations (P = 0.025) and FSH pulse frequency (P = 0.003) were significantly elevated, whereas FSH pulse amplitude and FSH response to LHRH were unaltered. For LH, neither the secretory parameters nor the response to LHRH was different. There were no differences between estradiol and inhibin A and B levels. Postmenopausal mothers of twin and controls did not differ with respect to the secretory pattern of LH and FSH. We conclude that under equal ovarian feedback conditions, premenopausal mothers of a dizygotic twin have hyper stimulation by endogenous FSH caused by neuroendocrine, hypothalamic, or pituitary mechanisms. This is the result of altered responsiveness to ovarian feedback and/or pituitary or suprapituitary, non-LHRH-like mechanisms that stimulate pulsatile FSH.

Item does not contain fulltext Adenylosuccinate lyase (ADSL) deficiency is a rare inborn error of metabolism resulting in accumulation of metabolites including succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado) in the brain and other tissues. Patients with ADSL have progressive psychomotor retardation, neonatal seizures, global developmental delay, hypotonia, and autistic features, although variable clinical manifestations may make the initial diagnosis challenging. Two cases of the severe form of the disease are reported here: an 18-month-old boy with global developmental delay, intractable neonatal seizures, progressive cerebral atrophy, and marked hypomyelination, and a 3-month-old girl presenting with microcephaly, neonatal seizures, and marked psychomotor retardation. In both patients in vivo proton magnetic resonance spectroscopy (MRS) showed the presence of S-Ado signal at 8.3 ppm, consistent with a prior report. Interestingly, SAICAr signal was also detectable at 7.5 ppm in affected white matter, which has not been reported in vivo before. A novel splice-site mutation, c.IVS12 + 1/G > C, in the ADSL gene was identified in the second patient. Our findings confirm the utility of in vivo proton MRS in suggesting a specific diagnosis of ADSL deficiency, and also demonstrate an additional in vivo resonance (7.5 ppm) of SAICAr in the cases of severe disease. J. Magn. Reson. Imaging 2013;37:974-980. (c) 2012 Wiley Periodicals, Inc.

Nuclear receptor-binding SET domain-containing protein 1 (NSD1) gene mutations and deletions (NSD1+/-) are the major cause of Sotos syndrome. The aim was to investigate which auxology parameters relate to NSD1+/- in patients clinically suspected of Sotos syndrome.In 32 patients clinically suspected of Sotos syndrome, we compared auxology parameters between NSD1+/- patients and patients without NSD1 gene alterations (NSD1+/+). The statistical performance of these parameters to predict NSD1+/- was assessed.Arm span-for-height standard deviation score (SDS) and hand length SDS were significantly higher in NSD1+/- patients.Arm span for height and hand length are discriminating parameters between NSD1+/- and NSD1+/+.

Contains fulltext : 58369.pdf (Publisher’s version ) (Open Access) BACKGROUND: Deletions and mutations in the NSD1 gene are the major cause of Sotos syndrome. We wanted to evaluate the genotype-phenotype correlation in patients suspected of having Sotos syndrome and determine the best discriminating parameters for the presence of a NSD1 gene alteration. METHODS: Mutation and fluorescence in situ hybridization analysis was performed on blood samples of 59 patients who were clinically scored into 3 groups. Clinical data were compared between patients with and without NSD1 alterations. With logistic regression analysis the best combination of predictive variables was obtained. RESULTS: In the groups of typical, dubious and atypical Sotos syndrome, 81, 36 and 0% of the patients, respectively, showed NSD1 gene alterations. Four deletions were detected. In 23 patients (2 families) 19 mutations were detected (1 splicing defect, 3 non-sense, 7 frameshift and 8 missense mutations). The best predictive parameters for a NSD1 gene alteration were frontal bossing, down-slanted palpebral fissures, pointed chin and overgrowth. Higher incidences of feeding problems and cardiac anomalies were found. The parameters, delayed development and advanced bone age, did not differ between the 2 subgroups. CONCLUSIONS: In our patients suspected of having Sotos syndrome, facial features and overgrowth were highly predictive of a NSD1 gene aberration, whereas developmental delay and advanced bone age were not.