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Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and intermediate chains, have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of neurodevelopmental disorder manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Mitochondrial disorders exhibit clinical and genetic diversity. Nearly 400 distinct genes, located in both the mitochondrial and nuclear genomes, harbor pathogenic variants that can produce a broad spectrum of mitochondrial diseases. This work aims to explore the genetic etiology of a cohort of Egyptian pediatric patients who were clinically suspected of having a mitochondrial disorder. A total of 49 patients from 44 unrelated families were studied. Selection criteria included age below 18 years and meeting Morava criteria (a score ≥ 3). The mitochondrial disease criteria (MDC) have been developed to quantify the clinical picture and evaluate the probability of an underlying mitochondrial disorder Exome sequencing, including mitochondrial genome sequencing, was carried out for each participant. Causative variants likely responsible for the phenotypes were identified in 68% of the study population. The mitochondrial subgroup constituted 41% of the studied population with a median age of 4 years. No primary pathogenic variants in mitochondrial DNA were detected. Pathogenic or likely pathogenic variants in eight mitochondrial genes were identified in 78% of the mitochondrial cohort. Additionally, seven novel variants were identified. Nonmitochondrial diagnoses accounted for 27% of the study population. In 32% of cases, disease-causing variants were not identified. The current study underscores the diverse phenotypic and genetic landscape of mitochondrial disorders among Egyptian patients., (© 2024 Wiley Periodicals LLC.)

Purpose: The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. TAOK1 variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. TAOK2 variants have been reported to be associated with autism and early-onset obesity. However, a distinct TAOK2-NDD has not yet been delineated., Methods: We retrospectively studied the clinical and genetic data of individuals recruited from several centers with TAOK1 and TAOK2 variants that were detected through exome and genome sequencing., Results: We report 50 individuals with TAOK1 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique TAOK1 variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 patients with TAOK2 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%)., Conclusion: We describe the largest cohort of TAOK1-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel TAOK2-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity., Competing Interests: Conflict of Interest Sureni V. Mullegama is an employee of GeneDx, LLC. The other coauthors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. In addition, we not only reported 20 new NDD patients carrying biallelic variants in ADAT3 but also deeply characterized the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. We demonstrated that all the identified variants alter both the abundance and the activity of the complex leading to a significant decrease of I 34 with direct consequence on their steady-state. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.

Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123 I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123 I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to the scarcity of supporting evidence. In this study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity and hyperreflexia, with onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterization of Caenorhabditis elegans RTN2 homologous loss-of-function variants demonstrated morphological and behavioural differences compared with the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite RTN2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with RTN2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

Background: We aimed to determine whether sodium valproate (VPA) should be contraindicated in all mitochondrial diseases, due to known VPA-induced severe hepatotoxicity in some mitochondrial diseases., Methods: We systematically reviewed the published literature for mitochondrial DNA (mtDNA) and common nuclear genotypes of mitochondrial diseases using PubMed, Ovid Embase, Ovid Medline and MitoPhen databases. We extracted patient-level data from peer-reviewed articles, published until July 2022, using the Human Phenotype Ontology to manually code clinical presentations for 156 patients with genetic diagnoses from 90 publications., Results: There were no fatal adverse drug reactions (ADRs) in the mtDNA disease group (35 patients), and only 1 out of 54 patients with a non- POLG mitochondrial disease developed acute liver failure. There were fatal outcomes in 53/102 (52%) POLG VPA-exposed patients who all harboured recessive mutations., Conclusions: Our findings confirm the high risk of severe ADRs in any patient with recessive POLG variants irrespective of the phenotype, and therefore recommend that VPA is contraindicated in this group. However, there was limited evidence of toxicity to support a similar recommendation in other genotypes of mitochondrial diseases., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Microrchidia CW-type zinc finger protein 2 (MORC2) is an ATPase-containing nuclear protein which regulates transcription through chromatin remodelling and epigenetic silencing. MORC2 may have a role in the development of neurones, and dominant variants in this gene have recently been linked with disorders including Charcot-Marie-Tooth type 2Z disease, spinal muscular atrophy and, more recently, a neurodevelopmental syndrome consisting of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN), presenting with hypotonia, microcephaly, brain atrophy, intellectual disability, hearing loss, faltering growth, and craniofacial dysmorphism. Notably, variants in MORC2 have shown clinical features overlapping with those of Cockayne and Leigh syndromes. Here, we report a case of MORC2 -related DIGFAN syndrome in a female infant caused by a novel heterozygous de novo variant. The condition was early onset and severe, further expanding the range of genotypes associated with this disorder. Clinical features included unilateral hearing loss, developmental delay and regression within the first year of life, microcephaly, severe feeding difficulties, and faltering growth, resulting in death at 13 months of age., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2024 Daniel Arbide et al.)

This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter- and intrafamilial variability. We identified 16 homozygous disease-causing ALS2 variants; sorted as splice-site, missense, frameshift, nonsense and in-frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype-genotype correlation., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Congenital sideroblastic anemias (CSAs) are a group of inherited bone-marrow disorders manifesting with erythroid hyperplasia and ineffective erythropoiesis., Methods: We describe a detailed clinical and genetic characterization of three siblings with CSA., Results: Two of them had limb-girdle myopathy and global developmental delay. The two elder siblings performed allogenic hematopoietic stem-cell transplantation 5 and 3 years prior with stabilization of the hematological features. Exome sequencing in the non-transplanted sibling revealed a novel homozygous nonsense variant in SLC25A38 gene NM_017875.2:c.559C > T; p.(Arg187*) causing autosomal-recessive sideroblastic anemia type-2, and a second homozygous pathogenic previously reported variant in GMPPB gene NM_013334.3:c.458C > T; p.(Thr153Ile) causing autosomal-recessive muscular dystrophy-dystroglycanopathy type B14. With the established diagnosis, hematopoietic stem cell transplantation is now being scheduled for the youngest sibling, and a trial therapy with acetylcholine esterase inhibitors was started for the two neurologically affected patients with partial clinical improvement., Conclusion: This family emphasizes the importance of whole-exome sequencing for familial cases with complex phenotypes and vague neurological manifestations., (© 2023 John Wiley & Sons Ltd/University College London.)

Objective: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria., Methods: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data., Results: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy., Significance: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Classical homocystinuria (HCU) is caused by cystathionine β-synthase deficiency leading to impaired homocysteine transsulfuration and accumulation of homocysteine and methionine. Patients present with a wide spectrum of manifestations including ocular, skeletal, neuropsychiatric, and vascular manifestations. We report a 48-year-old female with pyridoxine-unresponsive HCU treated with betaine, cyanocobalamin, and folate. Her diet was non-restricted due to intolerance of low-methionine diet. She was admitted to hospital following a fall, with multiple fractures and subsequently developed acute liver failure with encephalopathy. Shock, sepsis, and liver ischaemia/thrombosis were excluded. In the context of glutathione depletion expected in HCU, hepatic dysfunction was presumed to be due to iatrogenic paracetamol toxicity, despite paracetamol intake at conventional therapeutic dose, with role of hypermethioninemia as a contributing factor being uncertain. Betaine was discontinued on hospital admission. N -Acetylcysteine (NAC) infusion was initiated. Plasma total homocysteine (tHcy) was 3.4 μmol/L 9 days following initiation of NAC treatment with a markedly elevated plasma methionine of 1278 μmol/L. tHcy concentration returned to pre-admission baseline after NAC was discontinued. Recovery following this episode was slow with a prolonged cholestatic phase and gradual improvement in jaundice and coagulopathy. We recommend that paracetamol should be administered cautiously in HCU patients due to underlying glutathione depletion and risk of toxicity even at therapeutic doses. NAC is clearly effective in lowering tHcy in classical HCU in the short-term however further research is required to assess clinical efficacy and use as a potential therapy in classical HCU., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Aging is a complex biological process with multifactorial nature underlined by genetic, environmental, and social factors. In the present paper, we review several mechanisms of aging and the pre-clinically and clinically studied anti-aging therapies. Variability characterizes biological processes from the genome to cellular organelles, biochemical processes, and whole organs' function. Aging is associated with alterations in the degrees of variability and complexity of systems. The constrained disorder principle defines living organisms based on their inherent disorder within arbitrary boundaries and defines aging as having a lower variability or moving outside the boundaries of variability. We focus on associations between variability and hallmarks of aging and discuss the roles of disorder and variability of systems in the pathogenesis of aging. The paper presents the concept of implementing the constrained disease principle-based second-generation artificial intelligence systems for improving anti-aging modalities. The platform uses constrained noise to enhance systems' efficiency and slow the aging process. Described is the potential use of second-generation artificial intelligence systems in patients with chronic disease and its implications for the aged population., (Copyright © 2022 Hurvitz, Elkhateeb, Sigawi, Rinsky-Halivni and Ilan.)

Background: Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by kidney and extra-renal complications due to the accumulation of cystine crystals in various tissues and organs. Herein, we describe the early neuromuscular complications in a cohort of pediatric nephropathic cystinosis patients., Methods: We prospectively evaluated the clinical, biochemical, and neurophysiological data of 15 cystinosis patients. Neurophysiological evaluation was performed to confirm or exclude presence of neuropathy and/or myopathy., Results: Patients' age ranged between 20 and 216 months at time of examination. Nine patients were males. Three patients had early abnormal neurophysiological features consistent with neuromuscular involvement (clinically asymptomatic proximal myopathy with a patchy distribution in one patient and isolated asymptomatic sensory nerve conduction changes in two patients). A fourth patient had mixed abnormal motor and sensory axonal neuropathic changes associated with overt clinical features (predominantly motor symptoms). Patients with abnormal neuromuscular features were significantly older in age than the unaffected group (P = 0.005) and had a diagnosis of cystinosis with subsequent cysteamine therapy at a significantly older age than the unaffected group (P = 0.027 and 0.001, respectively)., Conclusions: We expanded the recognized phenotypes of cystinosis neuromuscular complications with early proximal skeletal myopathy and symptomatic motor and sensory axonal neuropathy. Early asymptomatic neuromuscular complications could develop in pediatric patients and would require neurophysiological studies for early detection prior to development of overt clinical manifestations. Prompt diagnosis and timely initiation of cysteamine therapy with recommended dose can delay the development of neuromuscular complications. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

We report the case of a 29-year-old adult presenting with severe IgA vasculitis, with cutaneous, urologic, and renal manifestations. The late appearance of severe gastrointestinal bleeding dominated the clinical picture, necessitating the administration of tens of units of packed cells and the augmentation of the immunosuppressive protocol. It was not until therapy with intravenous immunoglobulin (IVIG) was introduced that the massive bleeding was controlled. We herein discuss the patient's presentation, the gastrointestinal manifestations of IgA vasculitis, the recommended treatments, and the existent evidence about IVIG therapy., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Ibrahim Nassereddin et al.)

Introduction: Levetiracetam (LEV) is a second-generation antiseizure medicine (ASM) with broad-spectrum efficacy and tolerability. Few studies have compared the efficacy of valproate (VPA) and LEV as monotherapy in the pediatric population. Herein, we compare the efficacy, tolerability and safety of LEV monotherapy with those of VPA monotherapy in ASM-naïve pediatric patients with idiopathic generalized epilepsy with tonic-clonic (GTC) seizures., Methods: We retrospectively analyzed the clinical and electroencephalographic (EEG) data of these ASM-naïve pediatric patients who were treated with either oral VPA or oral LEV as monotherapy for over 2 years at our center., Results: This study included 60 patients with a seizure onset age between 2 months and 12 years. The patients on VPA (29 patients) and LEV monotherapy (31 patients) showed similar favorable 6-month treatment outcomes (complete seizure control in 79.31% vs 80.64%, p = 0.468052). Age at epilepsy onset, epilepsy syndrome, EEG features and ASM dose were not significant predictors of the 6-month treatment outcomes in either group. Lower seizure frequency at presentation was a predictor of favorable 6-month treatment outcomes in the LEV group but not in the VPA group. VPA and LEV treatment showed similar favorable 6-month treatment outcomes in the febrile seizures plus and patients with unidentified epilepsy syndrome subgroups. None of the patients discontinued VPA or LEV due to treatment-associated adverse effects., Discussion: Our study showed that compared to VPA monotherapy, LEV monotherapy in ASM-naïve infants and children with idiopathic generalized epilepsy with GTC seizures has a similarly favorable efficacy and tolerability, independent of age, EEG features and epilepsy syndrome., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Although the radiotherapy utilization rate (RUR) is determined for most adult cancers, it is seldom reported in childhood tumors, particularly in low- and middle-income countries (LMIC) where the majority of pediatric cancer patients reside. This study aims to investigate the real-life RUR for pediatric tumors in a large LMIC center., Materials and Methods: The electronic files of patients treated at a single institution during 2010-2017 were reviewed and the RUR was defined as the percentage of patients who received at least one radiotherapy (RT) course from the total number of patients., Results: A total of 4390 out of 13,305 pediatric cancer patients received at least one RT course with a RUR of 33%. The curative, salvage, and palliative RURs were 27.8%, 2%, and 5.7%, respectively. There was a considerable variation in the RUR between various tumors, ranging from 0% in choroid plexus papilloma and other rare tumors to 100% in intracranial germinoma. Moreover, the RUR varied among different stages within each tumor type. Overall, 753 patients received 920 palliative RT courses (range 1-9) at a median dose of 30 Gy. The most commonly irradiated metastatic sites were the bone (34%) and the brain (9.8%)., Conclusion: This is the first analysis to provide valuable insights into the RUR for childhood tumors. Together with population-based pediatric cancer registries, this will help decipher pediatric RT needs and deficits. Additionally, the underutilization of palliative RT calls for multidisciplinary palliative care provision for pediatric cancer patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Multiple acyl-CoA dehydrogenase (MADD) deficiency represents a rare fatty acid oxidation disorder where sporadic reports of pancreatitis already exist. Here, we report three cases of MADD with pancreatic involvement raising questions whether this represents an incidental finding or it is related to the pathophysiology of MADD., Methods: We have retrospectively studied the clinical, biochemical and radiologic data of patients with MADD diagnosed in our department over the last 20 years to identify patients with pancreatic involvement., Results: Three out of 17 patients had pancreatic involvement. All three patients were diagnosed with MADD in the neonatal period (two-third symptomatic-riboflavin nonresponsive, one-third asymptomatic via newborn screening-riboflavin responsive). Age at presentation of pancreatitis ranged from 20 months to 11 years. Presentations included a single episode of acute pancreatitis in the first patient, chronic necrotizing pancreatitis in the second patient, while the third patient was diagnosed with chronic pancreatitis (CP) incidentally through ultrasonography. All patients had inflammation features on either abdominal computed tomography or ultrasound. Pancreatic enzymes were elevated in two patients. Management of pancreatitis was done conservatively while the patient with necrotic CP required subtotal pancreatectomy., Discussion: Our data suggest that pancreatitis might be more common in patients with MADD than previously reported, requiring a high index of suspicion in patients with acute metabolic decompensation or nonspecific abdominal symptoms. We hypothesize that the underlying mechanism of pancreatitis in MADD is similar to that in mitochondrial disorders, both resulting from disordered energy metabolism and oxidative phosphorylation., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Walker-Warburg syndrome (WWS) is a severe form of congenital muscular dystrophy secondary to α-dystroglycanopathy with muscle, brain, and eye abnormalities often leading to death in the first weeks of life. It is transmitted in an autosomal recessive pattern, and has been linked to at least 15 different genes; including protein O-mannosyltransferase 1 (POMT1), protein O-mannosyltransferase 2 (POMT2), protein O-mannose beta-1,2-N acetylglucosaminyltransferase (POMGNT1), fukutin (FKTN), isoprenoid synthase domain-containing protein (ISPD), and other genes. We report on a consanguineous family with four consecutive siblings affected by this condition with lethal outcome in three (still birth), and termination of the fourth pregnancy based on antenatal MRI identification of brain and kidney anomalies that heralded proper and deep clinical phenotyping. The diagnosis of WWS was suggested based on the unique collective phenotype comprising brain anomalies in the form of lissencephaly, subcortical/subependymal heterotopia, and cerebellar hypoplasia shared by all four siblings; microphthalmia in one sibling; and large cystic kidneys in the fetus and another sibling. Other unshared neurological abnormalities included hydrocephalus and Dandy-Walker malformation. Whole exome sequencing of the fetus revealed a highly conserved missense mutation in POMT2 that is known to cause WWS with brain and eye anomalies.In conclusion, the heterogeneous clinical presentation in the four affected conceptions with POMT2 mutation expands the current clinical spectrum of POMT2-associated WWS to include large cystic kidneys; and confirms intra-familial variability in terms of brain, kidney, and eye anomalies., (© 2017 Wiley Periodicals, Inc.)

Background: The pediatric diffuse intrinsic pontine glioma (DIPG) outcome remains dismal despite multiple therapeutic attempts., Purpose: To compare the results of treatment of pediatric diffuse intrinsic pontine glioma (DIPG) using hypofractionated versus conventional radiotherapy., Patients and Methods: Seventy-one newly diagnosed DIPG children were randomized into hypofractionated (HF) (39Gy/13 fractions in 2.6weeks) and conventional (CF) arm (54Gy/30 fractions in 6weeks)., Results: The median and one-year overall survival (OS) was 7.8months and 36.4±8.2% for the hypofractionated arm, and 9.5 and 26.2±7.4% for the conventional arm respectively. The 18-month OS difference was 2.2%. The OS hazard ratio (HR) was 1.14 (95% CI: 0.70-1.89) (p=0.59). The hypofractionated arm had a median and one-year progression-free survival (PFS) of 6.6months and 22.5±7.1%, compared to 7.3 and 17.9±7.1% for the conventional arm. The PFS HR was 1.10 (95% CI: 0.67-1.90) (p=0.71). The 18-month PFS difference was 1.1%. These differences exceed the non-inferiority margin. The immediate and delayed side effects were not different in the 2 arms., Conclusions: Hypofractionated radiotherapy offers lesser burden on the patients, their families and the treating departments, with nearly comparable results to conventional fractionation, though not fulfilling the non-inferiority assumption., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)