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The article presents a case study of a 20-year-old man with parkinsonism who began to experience neurodevelopmental abnormalities after his first year. It reports about the phenotypes of the loss-of-function de novo mutation of the DYNC1H1 gene. It also states the use and positive response of levodopa-carbidopa for treating the disorders.

This paper discusses the cases of siblings that were born healthy, then diagnosed in their neonatal periods with cardiomyopathy and/or severe metabolic acidosis, which ran progressive courses and contributed to death in infancy. Molecular testing of the children confirmed the presence of an m.3303C>T point mutation in the mitochondrial DNA in the MT-TL1 gene, which was also present in their oligosymptomatic mother and their mother's sister, an asymptomatic carrier.

Background and Aims: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition., Approach and Results: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed., Results: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation., Conclusions: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

BACKGROUND Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is an extremely rare autosomal recessive inherited error of metabolism in which gluconeogenesis is impaired, resulting in life-threatening episodes of hypoglycemia and metabolic acidosis. The diagnosis of gluconeogenesis disorders is challenging. In the diagnostic pathway, the molecular test plays a paramount role. CASE REPORT The aim of the paper is to present the case report of a girl with recurrent episodes of severe hypoglycemia, in whom molecular diagnosis enabled the confirmation of PEPCK - C deficiency. The patient experienced 4 episodes of severe hypoglycemia. Most of them were accompanied by hyperlacticaemia, metabolic acidosis, and elevated liver enzymes. All of the metabolic decompensations were triggered by infectious agents. The episodes resolved after continuous infusion of high-dose glucose. Due to the recurrent character of the disease, a genetic condition was suspected. The differential diagnosis included metabolic and endocrinological causes of hypoglycemia. Two variants in the PCK1 gene were detected: c.265G>A p.(Glu89Lys) in exon 3 and c.925G>A p.(Gly309Arg) in exon 6. As c.925G>A p.(Gly309Arg) is a known pathogenic variant, the second variant was first described in June 2023 in the ClinVar database and described as "with unknown clinical significance". CONCLUSIONS According to the clinical symptoms observed in the presented case, the variant c.265G>A p.(Glu89Lys) in PCK1 gene should be considered likely pathogenic. We suggest considering molecular diagnostics in every patient presented with recurrent, severe hypoglycemia with accompanying liver damage as most accurate, feasible, and reliable method.

Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from abnormal mitochondrial function. Currently, there is no causal treatment for MDs. The aim of the study was to assess the effectiveness and safety of the ketogenic diet (KD) in patients with MD and to analyse selected biochemical and clinical parameters evaluating the effectiveness of KD treatment in patients with MDs. A total of 42 paediatric patients were assigned to four groups: group 1-patients with MD in whom KD treatment was started ( n = 11); group 2-patients with MD remaining on an ordinary diet ( n = 10); group 3-patients without MD in whom KD treatment was initiated ( n = 10), group 4-patients without MD on a regular diet ( n = 11). Clinical improvement was observed in 9/11 patients with MD treated with KD. Among patients with MD without KD, the clinical condition deteriorated in 7/10 patients, improved in 2/10 patients, and remained unchanged in one patient. Adverse events of KD occurred with a comparable frequency in groups 1 and 3. There was no significant difference in changes in biomarker concentrations over the course of the study among patients treated and untreated with KD.

Background: Nijmegen breakage syndrome (NBS) is an autosomal-recessive chromosome instability disorder characterized by, among others, hypersensitivity to X-irradiation and an exceptionally high risk for lymphoid malignancy. The vast majority of NBS patients is homozygous for a common Slavic founder mutation, c.657del5, of the NBN gene, which is involved in the repair of DNA double-strand breaks (DSBs). The founder mutation also predisposes heterozygous carriers to cancer, apparently however, with a higher risk in the Czech Republic/Slovakia (CS) than in Poland., Aim: To examine whether the age of cancer manifestation and cancer death of NBN homozygotes is different between probands from CS and Poland., Methods: The study is restricted to probands born until 1989, before replacement of the communist regime by a democratic system in CS and Poland, and a substantial transition of the health care systems. Moreover, all patients were recruited without knowledge of their genetic status since the NBN gene was not identified until 1998., Results: Here, we show that cancer manifestation of NBN homozygotes is at a significantly earlier age in probands from CS than from Poland. This is explained by the difference in natural and medical radiation exposure, though within the permissible dosage., Conclusion: It is reasonable to assume that this finding also sheds light on the higher cancer risk of NBN heterozygotes in CS than in Poland. This has implications for genetic counseling and individualized medicine also of probands with other DNA repair defects., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Left ventricular noncompaction cardiomyopathy (LVNC) is a rare cardiac disorder characterised by the presence of a two-layer myocardium with prominent ventricular trabeculation, intertrabecular deep depressions and an increased risk of heart failure, atrial and ventricular arrhythmias and systemic thromboembolic events in affected patients. The heterogeneous molecular aetiology solved in 10%-50% of patients more frequently involves sarcomeric, cytoskeletal or ion channel protein dysfunction-mainly related to causative MYH7 , TTN or MYBPC3 variants. The aim of the study was to determine the molecular spectrum of isolated LVNC in a group of children examined in a single paediatric reference centre., Methods: Thirty-one paediatric patients prospectively diagnosed with LVNC by echocardiography and cardiovascular magnetic resonance examination were recruited into the study group. The molecular analysis included next-generation sequencing (gene panel or whole exome) and classic Sanger sequencing. All selected variants with high priority were co-segregated in the available parents., Results: We identified 16 distinct variants in 11 genes in 16 patients (52%), including 10 novel alterations. The most frequent defects in our cohort were found in the genes HCN4 ( n = 4), MYH7 ( n = 2) and PRDM16 ( n = 2). Other likely disease-causing variants were detected in ACTC1, ACTN2, HCCS, LAMA4, MYH6, RBM20, TAFFAZIN and TTN . Patients with established molecular defects more often presented with arrhythmia, thromboembolic events and death, whereas the predominant symptoms in patients with no identified molecular defects were heart failure and the presence of late gadolinium enhancement., Conclusion: This study expands the genetic and clinical spectrum of childhood LVNC. Although the molecular aetiology of LVNC varies widely, the comprehensive testing of a wide panel of cardiomyopathy-related genes helped to identify underlying molecular defects in more than half of the children in the study group. The molecular spectrum in our cohort correlated with the occurrence of arrhythmia, death and a family history of cardiomyopathy. We confirmed that genetic testing is an integral part of the work-up and management LVNC in children.

The recent description of biallelic DNAJC30 variants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome challenged the longstanding assumption for LHON to be exclusively maternally inherited and broadened the genetic spectrum of Leigh syndrome, the most frequent paediatric mitochondrial disease. Herein, we characterize 28 so far unreported individuals from 26 families carrying a homozygous DNAJC30 p.Tyr51Cys founder variant, 24 manifesting with LHON, two manifesting with Leigh syndrome, and two remaining asymptomatic. This collection of unreported variant carriers confirms sex-dependent incomplete penetrance of the homozygous variant given a significant male predominance of disease and the report of asymptomatic homozygous variant carriers. The autosomal recessive LHON patients demonstrate an earlier age of disease onset and a higher rate of idebenone-treated and spontaneous recovery of vision in comparison to reported figures for maternally inherited disease. Moreover, the report of two additional patients with childhood- or adult-onset Leigh syndrome further evidences the association of DNAJC30 with Leigh syndrome, previously only reported in a single childhood-onset case., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics., Methods: We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage., Results: We detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions., Conclusion: Together, these results show that streamlined experimental and computational processes can accelerate the implementation of RNA-seq in routine diagnostics., (© 2022. The Author(s).)

Background: Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous cardiomyopathy in which myocardium consists of two, distinct compacted and noncompacted layers, and prominent ventricular trabeculations and deep intertrabecular recesses are present. LVNC is associated with an increased risk of heart failure, atrial and ventricular arrhythmias and thromboembolic events. Familial forms of primary sinus bradycardia have been attributed to alterations in HCN4 . There are very few reports about the association between HCN4 and LVNC. The aim of our study was to characterize the clinical phenotype of families with LVNC and sinus bradycardia caused by pathogenic variants of the HCN4 gene., Methods: From March 2008 to July 2021, we enrolled six patients from four families with diagnosed isolated LVNC based on the clinical presentation, family history and echocardiographic and cardiovascular magnetic resonance (CMR) evidence of LVNC. Next generation sequencing (NGS) analysis was undertaken for the evaluation of the molecular basis of the disease in each family., Results: A total of six children (median age 11 years) were recruited and followed prospectively for the median of 12 years. All six patients were diagnosed with LVNC by echocardiography, and five participants additionally by CMR. The presence of late gadolinium enhancement (LGE) was found in three children. Sinus bradycardia and dilation of the ascending aorta occurred in five studied patients. In four patients from three families, the molecular studies demonstrated the presence of rare heterozygous HCN4 variants., Conclusion: (1) The HCN4 molecular variants influence the presence of a complex LVNC phenotype, sinus bradycardia and dilation of the ascending aorta. (2) The HCN4 alteration may be associated with the early presentation of clinical symptoms and the severe course of the disease. (3) It is particularly important to assess myocardial fibrosis not only within the ventricles, but also in the atria in patients with LVNC and sinus bradycardia.

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Abstract: The fibroblast growth factor 21 (FGF21) is a new biomarker of mitochondrial diseases (MD). FGF21 concentration may be used to define the severity of mitochondrial disease., Aim of the Study: The study objective was to verify if the FGF21 concentration in paediatric patients with MD was correlated with the disease severity and stage and to assess the correlation between FGF21 levels and the genetic background of MD., Material and Methods: The disease stage in MD subjects was determined on the basis of the International Paediatric Mitochondrial Disease Scale (IPMDS) and the concentrations of FGF21, lactic and pyruvic acids, alanine and creatine kinase in serum were assessed in those patients., Results: The median age of children with MD (n = 32) was 33 months (range: 2-213), in the control group (n = 21) the median age was 42 months (range: 8-202). The concentrations of FGF21, lactic acid and pyruvic acid were higher in MD patients than in the control group. No correlation between the disease severity (IPMDS) and serum FGF21 concentration was found. The FGF21 concentration was higher in patients whose MD resulted from nuclear gene damage (nDNA), median FGF21 = 1022 (84-8873) pg/ml, than in patients with MD resulting from mitochondrial damage (mtDNA), median FGF21 = 736 (188-2906) pg/ml, or with an abnormal variant in the PDHA1 gene, median FGF21 = 58 (25-637) pg/ml., Conclusions: There is no correlation between the stage of MD and FGF21 level. Higher FGF21 values are seen in patients whose MD results from an abnormal nDNA variant rather than mtDNA damage.

Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene were firstly (2015) identified as a cause of fever-triggered recurrent acute liver failure (RALF). Since then, some patients with NBAS deficiency presenting with neurologic features, including a motor delay, intellectual disability, muscular hypotonia and a mild brain atrophy, have been reported. Here, we describe a case of pediatric patient diagnosed with NBAS deficiency due to a homozygous c.2809C > G, p.(Pro937Ala) variant presenting with RALF with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Not reported in the literature findings include severe hyperammonemia during ALF episode, and neurologic features in the form of acquired progressive microcephaly with brain atrophy. The latter raises the hypothesis about a primary neurologic phenotype in NBAS deficiency., (© 2021. The Author(s).)

Ferrodoxin reductase (FDXR) deficiency is a mitochondrial disease described in recent years primarily in association with optic atrophy, acoustic neuropathy, and developmental delays. Here, we identified seven unpublished patients with FDXR deficiency belonging to six independent families. These patients show a broad clinical spectrum ranging from Leigh syndrome with early demise and severe infantile-onset encephalopathy, to milder movement disorders. In total nine individual pathogenic variants, of which seven were novel, were identified in FDXR using whole exome sequencing in suspected mitochondrial disease patients. Over 80% of these variants are missense, a challenging variant class in which to determine pathogenic consequence, especially in the setting of nonspecific phenotypes and in the absence of a reliable biomarker, necessitating functional validation. Here we implement an Arh1-null yeast model to confirm the pathogenicity of variants of uncertain significance in FDXR, bypassing the requirement for patient-derived material., (© 2020 The Authors. Human Mutation Published by Wiley Periodicals LLC.)

Introduction: The most efficient risk stratification algorithms are expected to deliver robust and indefectible identification of high-risk children with hypertrophic cardiomyopathy (HCM). Here we compare algorithms for risk stratification in primary prevention in HCM children and investigate whether novel indices of biatrial performance improve these algorithms., Methods and Results: The endpoints were defined as sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter-defibrillator discharge. We examined the prognostic utility of classic American College of Cardiology/American Heart Association (ACC/AHA) risk factors, the novel HCM Risk-Kids score and the combination of these with indices of biatrial dynamics. The study consisted of 55 HCM children (mean age 12.5 ± 4.6 years, 69.1% males); seven had endpoints (four deaths, three appropriate ICD discharges). A strong trend (DeLong p = 0.08) was observed towards better endpoint identification performance of the HCM Risk-Kids Model compared to the ACC/AHA strategy. Adding the atrial conduit function component significantly improved the prediction capabilities of the AHA/ACC Model (DeLong p = 0.01) and HCM Risk-Kids algorithm (DeLong p = 0.04)., Conclusions: The new HCM Risk-Kids individualised algorithm and score was capable of identifying high-risk children with very good accuracy. The inclusion of one of the atrial dynamic indices improved both risk stratification strategies.

Background: Deoxyguanosine kinase (DGUOK) deficiency is one of the causes of the hepatocerebral form of mitochondrial depletion syndrome (MDS). It is characterized by an early onset of liver failure with concomitant neurological deterioration. In the current literature, there are only few reports regarding long-term observation of children with DGUOK deficiency. Liver transplantation (LTx) is controversial due to extrahepatic involvement and unpredictable outcome., Methods: Five patients (2 boys) from 4 different families with hepatocerebral MDS associated with DGUOK mutations diagnosed with liver failure were treated in our hospital between 2010-2019., Results: In all children clinical symptoms developed within the first days of live and hypoglycemia (hypoketotic), conjugated hyperbilirubinemia (cholestasis), severe lactic acidosis, and coagulopathy were observed. Two neonates had low birth-weight for gestational age and failed to thrive. Mild neurological involvement as hypotonia was observed in all children. Three children died at the age of 2, 6 months and 6,5 months of age, respectively, due to end-stage liver failure. In one case, LTx was not considered, in two patients (sisters) parents did not agree to this procedure. LTx was subsequently performed in two patients at the age of 6 and 7 months, respectively, one from deceased, and one from living related donor, in both before the final confirmation of DGUOK mutations. One boy died 2 months after LTx due to post-LTx procedure-related complications; one is still alive with 3years of follow-up, with good liver function and mild neurological disturbances. The diagnosis of DGUOK deficiency was confirmed by biallelic DGUOK mutations detection. Equally, patients were compound heterozygotes (three cases) and homozygotes (two cases). Three known molecular variants, including regulatory substitutions (c.1A>G, c.3G>A) and in-frame insertion (c.813_814insTTT) were identified., Conclusions: Prognosis in patients with DGUOK deficiency is generally poor. Based on a review of the literature and our experience liver transplantation in selected patients with DGUOK mutation does not appear to be contraindicated, especially in those without or with minimal neurologic abnormalities., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Diseases related to DNA polymerase gamma dysfunction comprise of heterogeneous clinical presentations with variable severity and age of onset. Molecular screening for the common POLG variants: p.Ala467Thr, p.Trp748Ser, p.Gly848Ser, and p.Tre251Ile has been conducted in a large population cohort (n = 3123) and in a clinically heterogeneous group of 1289 patients. Recessive pathogenic variants, including six novel ones were revealed in 22/26 patients. Infantile Alpers-Huttenlocher syndrome and adulthood ataxia spectrum were the most common found in our group. Distinct molecular profile identified in the Polish patients with significant predominance of p.Trp748Ser variant (50% of mutant alleles) reflected strikingly low population frequency of the three remaining variants and slightly higher p.Trp748Ser allele frequency in the general Polish population as compared to the non-Finish European population., (Copyright © 2018 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Objectives: Although hearing loss is a well-known symptom of mitochondria-related disorders, it is not clear how often it is a congenital and cochlear impairment. The Newborn Hearing Screening Program (NHSP) enables to distinguish congenital cochlear deafness from an acquired hearing deficit. The initial aim of the study was to research the frequency of the congenital cochlear hearing loss among patients with various gene defects resulting in mitochondrial disorders. The research process brought on an additional gain: basing on our preliminary study group of 80 patients, in 12 patients altogether we identified two defected genes responsible for mitochondrial disorders, whose carriers did not pass the NHSP. Finally, these patients were diagnosed with the congenital cochlear deafness., Material and Methods: The results of the NHSP in the patients with mitochondrial disorders diagnosed in our tertiary reference center were analyzed. Only the cases with confirmed mutations were qualified for the study group. The NHSP database included 80 patients with mutations in 31 different genes: 25 nuclear-encoded and 6 mtDNA-encoded. We searched the literature for the presence of a congenital hearing impairment (CHI) in mitochondrial disorders caused by changes in 278 already known genes., Results: For 68 patients from the study group the NHSP test indicated a proper cochlear function and thus suggested normal hearing. For 12 mitochondrial patients, the NHSP test indicated the requirement for the further audiological diagnosis, and finally CHI was confirmed in 8 of them. This latter subset included patients with pathogenic variants in RRM2B and SERAC1, known as "deafness-causing genes". Contrary to our initial expectations, the patients carrying mutations in other "deafness-causing genes": MPV17, POLG, COX10, as well as other mitochondria-related genes, all reported in literature, did not indicate any CHI following the NHSP test., Conclusion: Our study indicates that the cochlear CHI is a phenotypic feature of the RRM2B and SERAC1 related defects. The diagnosis of the CHI following the NHSP allows to early distinguish those defects from other mitochondria-related disorders in which the NHSP test result is correct. Wider studies are needed to assess the significance of this observation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Mitochondrial methionyl-tRNA formyltransferase (MTFMT) is required for the initiation of translation and elongation of mitochondrial protein synthesis . Pathogenic variants in MTFMT have been associated with Leigh syndrome (LS) and mitochondrial multiple respiratory chain deficiencies. We sought to elucidate the spectrum of clinical, neuroradiological and molecular genetic findings of patients with bi-allelic pathogenic variants in MTFMT ., Methods: Retrospective cohort study combining new cases and previously published cases., Results: Thirty-eight patients with pathogenic variants in MTFMT were identified, including eight new cases. The median age of presentation was 14 months (range: birth to 17 years, interquartile range [IQR] 4.5 years), with developmental delay and motor symptoms being the most frequent initial manifestation. Twenty-nine percent of the patients survived into adulthood. MRI headings in MTFMT pathogenic variants included symmetrical basal ganglia changes (62%), periventricular and subcortical white matter abnormalities (55%), and brainstem lesions (48%). Isolated complex I and combined respiratory chain deficiencies were identified in 31% and 59% of the cases, respectively. Reduction of the mitochondrial complex I and complex IV subunits was identified in the fibroblasts (13/13). Sixteen pathogenic variants were identified, of which c.626C>T was the most common. Seventy-four percent of the patients were alive at their last clinical review (median 6.8 years, range: 14 months to 31 years, IQR 14.5 years)., Interpretation: Patients that harbour pathogenic variants in MTFMT have a milder clinical phenotype and disease progression compared to LS caused by other nuclear defects. Fibroblasts may preclude the need for muscle biopsy, to prove causality of any novel variant., Competing Interests: None declared.

ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD + to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Most of the 19 mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) involved in mitochondrial protein synthesis are already linked to specific entities, one of the exceptions being PARS2 mutations for which pathogenic significance is not finally validated. The aim of the study was to characterize the PARS2- related phenotype.Three siblings with biallelic PARS2 mutations presented from birth with infantile spasms, secondary microcephaly, and similar facial dysmorphy. Mental development was deeply impaired with speech absence and no eye contact. A dilated cardiomyopathy and multiorgan failure developed in childhood at the terminal stage, together with mitochondrial dysfunction triggered by valproate administration.Brain MRI showed progressive volume loss of the frontal lobes, both cortical and subcortical, with widening of the cortical sulci and frontal horns of the lateral ventricles. Hypoplasia of the corpus callosum and progressive demyelination were additional findings. Similar brain features were seen in three already reported PARS2 patients and seemed specific for this defect when compared with other mt-aaRSs defects (DARS2, EARS2, IARS2, and RARS2).Striking resemblance of the phenotype and Alpers-like brain MRI changes with predominance of frontal cerebral volume loss (FCVL-AS) in six patients from three families of different ethnicity with PARS2 mutations, justifies to distinguish the condition as a new disease entity.

Respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases. Clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies. To date, disease-causing variants in genes coding for 27 complex I subunits, including 7 mitochondrial DNA genes, and in 11 genes encoding complex I assembly factors have been reported. Here, we describe rare biallelic variants in NDUFB8 encoding a complex I accessory subunit revealed by whole-exome sequencing in two individuals from two families. Both presented with a progressive course of disease with encephalo(cardio)myopathic features including muscular hypotonia, cardiac hypertrophy, respiratory failure, failure to thrive, and developmental delay. Blood lactate was elevated. Neuroimaging disclosed progressive changes in the basal ganglia and either brain stem or internal capsule. Biochemical analyses showed an isolated decrease in complex I enzymatic activity in muscle and fibroblasts. Complementation studies by expression of wild-type NDUFB8 in cells from affected individuals restored mitochondrial function, confirming NDUFB8 variants as the cause of complex I deficiency. Hereby we establish NDUFB8 as a relevant gene in childhood-onset mitochondrial disease., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Leigh syndrome (LS), subacute necrotizing encephalomyelopathy is caused by various genetic defects, including m.9185T>C MTATP6 variant. Mechanism of LS development remains unknown. We report on the acid-base status of three patients with m.9185T>C related LS. At the onset, it showed respiratory alkalosis, reflecting excessive respiration effort (hyperventilation with low pCO 2 ). In patient 1, the deterioration occurred in temporal relation to passive oxygen therapy. To the contrary, on the recovery, she demonstrated a relatively low respiratory drive, suggesting that a "hypoventilation" might be beneficial for m.9185T>C carriers. As long as circumstances of the development of LS have not been fully explained, we recommend to counteract hyperventilation and carefully dose oxygen in patients with m.9185T>C related LS.

Mitochondrial DNA depletion consisting of the systemic reduction of mtDNA copy number in cells may have a heterogenous genetic basis, resulting from a pathogenic change in the nuclear genes involved in mtDNA synthesis. The mode of inheritance is autosomal recessive. Severe hepatocerebral disease represents one of many different clinical forms of so-called mitochondrial depletion syndrome (MDS). We present the liver histopathology of 13 children who eventually died in the course of hepatocerebral MDS confirmed molecularly, harbouring mutations of DGUOK , MPV17 , and POLG genes. Material comprising eight autopsy and five liver biopsy specimens showed a moderately reproducible pattern of parenchymal damage, which we consider potentially helpful in the differential diagnosis and planning of the diagnostic investigation in families of children who died due to early-onset acute liver failure and encephalopathy.

Choroid plexus tumors (CPT) constitute 2%-5% of all pediatric brain tumors and include high grade choroid plexus carcinoma (CPC). About 40% of CPC patients harbor germline TP53 mutations, associated with diminished survival rates. However, the number of TP53 carriers might be underestimated due to suboptimal ability of Sanger sequencing to identify mosaicism. We describe an 18-month-old boy with ultra-rare, bilateral disseminated CPC and negative family history of cancer. Next generation sequencing (NGS) revealed constitutional mosaicism of de novo TP53 mutation, which was barely detectable by Sanger sequencing. This is the first description of a de novo TP53 mutation mosaicism in a patient with CPC. Up to now four cases of de novo TP53 mutations in CPC patients have been described but none of them were mosaic. Since TP53 mutation mosaicism may have an impact on management of patients and predisposition to other cancers, a reliable method of identification is important. Our results highlight the utility of high-throughput technologies in detection of potentially important genetic markers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The urea cycle disorder carbamoyl phosphate synthetase I deficiency is an important differential diagnosis in the encephalopathic neonate. This intoxication type inborn error of metabolism often leads to neonatal death or severe and irreversible damage of the central nervous system, even despite appropriate treatment. Timely diagnosis is crucial, but can be difficult on routine metabolite level. Here, we report ten neonates from eight families (finally) diagnosed with CPS1 deficiency at three tertiary metabolic centres. In seven of them the laboratory findings were dominated by significantly elevated urinary 3-methylglutaconic acid levels which complicated the diagnostic process. Our findings are both important for the differential diagnosis of patients with urea cycle disorders and also broaden the differential diagnosis of hyperammonemia associated with 3-methylglutaconic aciduria, which was earlier only reported in TMEM70 and SERAC1 defect., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The defects in DNA repair genes are potentially linked to development and response to therapy in medulloblastoma. Therefore the purpose of this study was to establish the spectrum and frequency of germline variants in selected DNA repair genes and their impact on response to chemotherapy in medulloblastoma patients., Methods: The following genes were investigated in 102 paediatric patients: MSH2 and RAD50 using targeted gene panel sequencing and NBN variants (p.I171V and p.K219fs*19) by Sanger sequencing. In three patients with presence of rare life-threatening adverse events (AE) and no detected variants in the analyzed genes, whole exome sequencing was performed. Based on combination of molecular and immunohistochemical evaluations tumors were divided into molecular subgroups. Presence of variants was tested for potential association with the occurrence of rare life-threatening AE and other clinical features., Results: We have identified altogether six new potentially pathogenic variants in MSH2 (p.A733T and p.V606I), RAD50 (p.R1093*), FANCM (p.L694*), ERCC2 (p.R695C) and EXO1 (p.V738L), in addition to two known NBN variants. Five out of twelve patients with defects in either of MSH2, RAD50 and NBN genes suffered from rare life-threatening AE, more frequently than in control group (p = 0.0005). When all detected variants were taken into account, the majority of patients (8 out of 15) suffered from life-threatening toxicity during chemotherapy., Conclusion: Our results, based on the largest systematic study performed in a clinical setting, provide preliminary evidence for a link between defects in DNA repair genes and treatment related toxicity in children with medulloblastoma. The data suggest that patients with DNA repair gene variants could need special vigilance during and after courses of chemotherapy.

Introduction: Migraine is a common neurological disorder characterized by a particular phenotype, complex pathophysiology and a heterogeneous genetic background. Among several heritable forms, familial hemiplegic migraine is the best described one. In the majority of cases it is caused by mutations in one of three different genes., Case Report: Clinical symptoms of a 47 year old proband (and independently described in his 20 year old son) as well as differential diagnosis are discussed in the presented report. The most characteristic were recurrent attacks of blurred vision, paresthesias and hemiparesis often accompanied by speech disturbances and followed by severe headache with vomiting. Advanced morphological and genetic procedures were required to exclude MELAS, CADASIL and Call-Fleming syndrome. Finally, the definite diagnosis was possible after the application of the whole exome sequencing technique. It confirmed, for the first time in the Polish population, a heterozygous T666M mutation (c.1997C>T; p.Thr666Met) in the CACNA1A gene in the proband, the proband's son and in several other family members., Conclusion: The presented report provides clinical and genetic insight into familial hemiplegic migraine 1 resulting from a mutation in the CACNA1A gene., (Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Biotin-thiamine-responsive basal ganglia disease is a severe form of a rare neurogenetic disorder caused by pathogenic molecular variants in the thiamine transporter gene. Nowadays, a potentially effective treatment is known, therefore the early diagnosis is mandatory. The aim of the paper was to assess the contribution of neuropathological and magnetic resonance imaging (MRI) studies to a proper diagnosis. We present the brain study of two Polish patients with SLC19A3 mutations, including (1) an infant with an intriguing "walnut" appearance of the brain autopsied many years before the discovery of the SLC19A3 defect, and (2) a one-year-old patient with clinical features of Leigh syndrome. In patient 2, biotin/thiamine responsiveness was not tested at the time of diagnosis and causal treatment started with one-year delay. The central nervous system lesions found in the patients displayed almost clearly a specific pattern for SLC19A3 defect, as previously proposed in diagnostic criteria. Our study presents a detailed description of neuropathological and MRI findings of both patients. We confirm that the autopsy and/or MRI of the brain is sufficient to qualify a patient with an unknown neuropathological disorder directly for SLC19A3 mutations testing and a prompt trial of specific treatment. .

To safeguard the cell from the accumulation of potentially harmful metabolic intermediates, specific repair mechanisms have evolved. APOA1BP, now renamed NAXE, encodes an epimerase essential in the cellular metabolite repair for NADHX and NADPHX. The enzyme catalyzes the epimerization of NAD(P)HX, thereby avoiding the accumulation of toxic metabolites. The clinical importance of the NAD(P)HX repair system has been unknown. Exome sequencing revealed pathogenic biallelic mutations in NAXE in children from four families with (sub-) acute-onset ataxia, cerebellar edema, spinal myelopathy, and skin lesions. Lactate was elevated in cerebrospinal fluid of all affected individuals. Disease onset was during the second year of life and clinical signs as well as episodes of deterioration were triggered by febrile infections. Disease course was rapidly progressive, leading to coma, global brain atrophy, and finally to death in all affected individuals. NAXE levels were undetectable in fibroblasts from affected individuals of two families. In these fibroblasts we measured highly elevated concentrations of the toxic metabolite cyclic-NADHX, confirming a deficiency of the mitochondrial NAD(P)HX repair system. Finally, NAD or nicotinic acid (vitamin B3) supplementation might have therapeutic implications for this fatal disorder., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Whole-exome sequencing (WES) has led to an exponential increase in identification of causative variants in mitochondrial disorders (MD)., Methods: We performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family., Results: Likely causative mutations were identified in 67 (59.3 %) patients; these included variants in mtDNA (6 patients) and nDNA: X-linked (9 patients), autosomal dominant (5 patients), and autosomal recessive (47 patients, 11 homozygotes). Novel variants accounted for 50.5 % (50/99) of all detected changes. In 47 patients, changes in 31 MD-related genes (ACAD9, ADCK3, AIFM1, CLPB, COX10, DLD, EARS2, FBXL4, MTATP6, MTFMT, MTND1, MTND3, MTND5, NAXE, NDUFS6, NDUFS7, NDUFV1, OPA1, PARS2, PC, PDHA1, POLG, RARS2, RRM2B, SCO2, SERAC1, SLC19A3, SLC25A12, TAZ, TMEM126B, VARS2) were identified. The ACAD9, CLPB, FBXL4, PDHA1 genes recurred more than twice suggesting higher general/ethnic prevalence. In 19 cases, variants in 18 non-MD related genes (ADAR, CACNA1A, CDKL5, CLN3, CPS1, DMD, DYSF, GBE1, GFAP, HSD17B4, MECP2, MYBPC3, PEX5, PGAP2, PIGN, PRF1, SBDS, SCN2A) were found. The percentage of positive WES results rose gradually with increasing probability of MD according to the Mitochondrial Disease Criteria (MDC) scale (from 36 to 90 % for low and high probability, respectively). The percentage of detected MD-related genes compared with non MD-related genes also grew with the increasing MD likelihood (from 20 to 97 %). Molecular diagnosis was established in 30/47 (63.8 %) neonates and in 17/28 (60.7 %) patients with basal ganglia involvement. Mutations in CLPB, SERAC1, TAZ genes were identified in neonates with 3-methylglutaconic aciduria (3-MGA) as a discriminative feature. New MD-related candidate gene (NDUFB8) is under verification., Conclusions: We suggest WES rather than targeted NGS as the method of choice in diagnostics of MD in children, including neonates with 3-MGA aciduria, who died without determination of disease cause and with limited availability of laboratory data. There is a strong correlation between the degree of MD diagnosis by WES and MD likelihood expressed by the MDC scale.

Background: Glycosylphosphatidylinositol (GPI)-anchor deficiencies are a new subclass of congenital disorders of glycosylation. About 26 genes are involved in the GPI-anchor biosynthesis and remodeling pathway, of which mutations in thirteen have been reported to date as causative of a diverse spectrum of intellectual disabilities. Since the clinical phenotype of these disorders varies and the number of described individuals is limited, we present new patients with inherited GPI-anchor deficiency (IGD) caused by mutations in the PGAP2 and PIGN genes., Patients and Methods: The first girl presented with profound psychomotor retardation, low birth parameters, and chest deformities already existing in neonatal period. The disease course was slowly progressive with severe hypotonia, chronic fever, and respiration insufficiency at the age of 6. The second girl showed profound psychomotor retardation, marked hypotonia, and high birth weight (97 centile). Dysmorphy was mild or absent in both girls. Whole exome sequencing revealed novel variants in the genes PGAP2 (c.2T>G and c.221G>A) and PIGN (c.790G>A and c.932T>G). Impaired GPI binding were was subsequently uncovered, although the hyperactivity of alkaline phosphatase (a GPI-anchored protein) occurred only in first case., Conclusions: Based on our results we can conclude that: 1. GPI-anchor biosynthesis disorders may represent a relatively frequent and overlooked metabolic defect; 2. The utility of GPI binding assessment as a screening test for this group of rare diseases requires further studies., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objectives: Mucopolysaccharidoses (MPSs) are a group of rare, inherited metabolic disorders which result from the lack of one of the lysosomal enzymes responsible for the degradation of glycosaminoglycans. Early recognition of MPS is important as it enables prompt implementation of enzyme replacement therapy (ERT). Dipeptidyl peptidase-IV (DPP-IV) is a ubiquitous ectopeptidase which activity has been associated with the cell surface protein CD26. Our aims were to investigate plasma DPP-IV activity in untreated patients with MPS type II in comparison to control individuals and to evaluate changes of DPP-IV during ERT in MPS I or II patients., Design and Methods: One MPS I and five MPS II patients were treated with ERT for up to 19 months. DPP-IV activity was measured in plasma with a colorimetric method using Gly-Pro-p-nitroanilide as a substrate. The reference intervals were observed in 17 healthy donors and in 9 MPS II individuals before ERT implementation., Results: DPP-IV activity ranged from 557 to 1959 nmol/ml/h (median and interquartile range: 1453 [955– 1554], n = 17) in plasma of control samples. In 9 untreated MPS II individuals, DPP-IV activity was higher and ranged from 2565 to 5968 nmol/ml/h (median and interquartile range: 4458 [4031–5161]). In 6 MPS patients receiving ERT, DPP-IV activity ranged from 2984 to 8628 nmol/ml/h. No declining tendency was observed during the treatment., Conclusions: DPP-IV activity is a good, newa nd valuable biomarker distinguishing between MPS and healthy individuals. However, it is not a useful marker of treatment efficacy and is unsuitable for monitoring.

SCO2 mutations cause recessively inherited cytochrome c oxidase deficiency. Recently Tran-Viet et al. proposed that heterozygosity for pathogenic SCO2 variants, including the common E140K variant, causes high-grade myopia. To investigate the association of SCO2 mutations with myopia, ophthalmic examinations were performed on 35 E140K carriers, one homozygous infant, and on a mouse model of Sco2 deficiency. Additionally, a screen for other putative effects of SCO2 heterozygosity was carried out by comparing the prevalence of the common E140K variant in a population of patients with undiagnosed diseases compatible with SCO2-related pathogenesis to that in a general population sample. High-grade myopia was not identified in any of the studied individuals. Of the carriers, 17 were emmetropic, and 18 possessed refractive errors. Additionally, no significant axial elongation indicative of high-grade myopia was found in mice carrying E129K (corresponding to E140K in humans) knock-in mutations. The prevalence of E140K carriers in the symptomatic cohort was evaluated as 1:103 (CI: 0.44-2.09) and did not differ significantly from the population prevalence (1:147, CI: 0.45-1.04).Our study demonstrates that heterozygosity for pathogenic SCO2 variants is not associated with high-grade myopia in either human patients or in mice.