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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.

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. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Nour Elkhateeb [sup.1] , Rasha Selim [sup.2] , Neveen A. Soliman [sup.2] , Fatma M. Atia [sup.2] , Ihab Ibrahim Abouelwoun [sup.3] , Mohamed. A. Elmonem [sup.4] , Rasha [...]

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 123I‐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 123I‐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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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.)

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.)