Rose-Mary Boustany

Background: Children presenting with progressive gait abnormality may suffer from a genetic disorder. NDUFS1-related mitochondrial complex I deficiency is a rare disorder with highly variable phenotypes. Predominant axonal neuropathy without prominent systemic metabolic dysfunction is unusual. Expanding reports of such presentations is important for accurate diagnosis. Case presentation: A young adolescent boy with non-consanguineous parents presented with an atypical and severe axonal sensorimotor polyneuropathy. His metabolic workup was negative. Molecular genetic analysis uncovered a rare form of mitochondrial complex I deficiency due to compound heterozygous variants of the NDUFS1 gene. Conclusions: This case highlights a rare and atypical presentation associated with two NDUFS1 variants, one previously annotated as variant of uncertain significance in ClinVar. The other is novel. This expands the phenotypic and genetic spectrum linked to NDUFS1 -related disorders.

Neuronal ceroid lipofuscinosis type 6 (CLN6) is a fatal, autosomal recessive neurodegenerative disorder characterized by cognitive/motor impairment, vision loss, as well as neuronal loss and gliosis in the brain, and premature death. Onset typically occurs in childhood. No approved pharmacological treatments exist that halt or reverse disease progression. A novel flupirtine benzyl carbamate was orally administered to male and female Cln6^nclf mice from 4 to 28 weeks of age to evaluate its neuroprotective and antispastic effects. Drug treatment produced significant, sex-dependent phenotypic improvements. Treated mice of both sexes exhibited reduced hindlimb spasticity, but only treated males demonstrated diminution in locomotor hyperactivity and recovery of visuospatial performance. In the brains of male and female Cln6^nclf mice, flupirtine benzyl carbamate significantly decreased astrocytosis, microgliosis and mitochondrial ATP synthase subunit C (SCMAS) accumulation, increased neuronal marker expression and reduced the number of TUNEL-positive cells. The treatment failed to rescue photoreceptor loss or clear retinal SCMAS storage. These outcomes result in distinct sex-specific differences in neuronal vulnerability and drug responsiveness. Overall, these findings demonstrate that flupirtine benzyl carbamate diminishes key motor, visual and pathological deficits in CLN6 disease, highlighting its promise as a potential disease-modifying therapy for CLN6 in humans despite sex-specific differences.

The TRIP12 gene, encoding an E3 ligase involved in the ubiquitin-proteasome pathway, is implicated in Clark-Baraitser syndrome which causes neurodevelopmen

BACKGROUND Human herpesvirus 6 (HHV-6) is a common pathogen known to cause roseola infantum in children and encephalitis in immunocompromised individuals. In immunocompetent children, HHV-6 encephalitis is rare and typically self-limiting. Although neurological symptoms such as seizures and altered consciousness have been reported, neuropsychiatric manifestations - particularly catatonia - are extremely uncommon. CASE REPORT A 4-year-old immunocompetent boy presented with sudden behavioral changes 1 week after a viral infection. Cerebrospinal fluid testing showed HHV-6 positivity. His symptoms included anxiety, irritability, compulsive handwashing, unprovoked laughter, reduced responsiveness, insomnia, and stereotypies, consistent with hyperkinetic catatonia. Autoimmune workup findings were negative, and the patient did not meet criteria for seronegative autoimmune encephalitis, resulting in attribution of his symptoms to HHV-6 encephalitis. Magnetic resonance imaging and electroencephalography findings were unremarkable. The patient received ganciclovir and lorazepam, resulting in substantial improvement. At a follow-up visit 1.5 months after discharge, he had returned to baseline except for mild insomnia. Lorazepam was tapered off 2 months after he achieved full recovery. CONCLUSIONS This is the first report of HHV-6 central nervous system infection causing neuropsychiatric manifestations in an immunocompetent child within the pediatric age group. This case highlights HHV-6 encephalitis as a potential cause of acute neuropsychiatric symptoms in immunocompetent children. Neuropsychiatric manifestations, including catatonia, may occur even in the absence of classical signs of encephalitis. Awareness of this rare presentation may facilitate timely diagnosis and treatment.

Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurogenetic disorders caused by mutations in 14 different genes. CLN6 disease manifests as variant late-infantile NCL (vLINCL) or as an adult variant. In childhood, symptoms include speech delay, vision loss, cognitive and motor decline, seizures, and early death. An in-depth characterization of a naturally occurring Cln6 mutant mouse (Cln6^nclf) is presented, with implications for translational research. The expanded phenotype provides data showing early death, vision loss, and motor deficits in male and female Cln6^nclf mice. Diminished visual acuity in Cln6^nclf mice was noted at 28 weeks of age, but the pathological loss of retinal layers began as early as 2 weeks or postnatal day 14 (P14). Apoptosis was confirmed by TUNEL staining in the Cln6^nclf mouse brain at P8 and in the retina at P12. A peak in glial fibrillary acidic protein (GFAP) expression was established as a normal developmental phenomenon in the wild-type and Cln6^nclf mouse brain cerebellum and the CA2–CA3 regions of the hippocampus at P8. In Cln6^nclf mice, GFAP levels were elevated at P12 in the cerebellum and hippocampus. In the retina, a developmental peak in gliosis was absent, with increased astrogliosis noted at P6 and P8 in female and male Cln6^nclf mice, respectively. This highlights the lack of a sex-dependent response in wild-type mice. These novel data position the Cln6^nclf mouse model as a useful tool for screening potential therapeutics for human CLN6 disease.

Advances in genetics led to the identification of hundreds of epilepsy-related genes, some of which are treatable with etiology-specific interventions. However, the diagnostic yield of next-generation sequencing (NGS) in unexplained epilepsy is highly variable (10–50%). We sought to determine the diagnostic yield and clinical utility of NGS in children with unexplained epilepsy that is accompanied by neurodevelopmental delays and/or is medically intractable. A 5-year retrospective review was conducted at the American University of Beirut Medical Center to identify children who underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Data on patient demographics, neurodevelopment, seizures, and treatments were collected. Forty-nine children underwent NGS with an overall diagnostic rate of 68.9% (27/38 for WES, and 4/7 for WGS). Most children (42) had neurodevelopmental delays with (18) or without (24) refractory epilepsy, and only three had refractory epilepsy without delays. The diagnostic yield was 77.8% in consanguineous families (18), and 61.5% in non-consanguineous families (26); consanguinity information was not available for one family. Genetic test results led to anti-seizure medication optimization or dietary therapies in six children, with subsequent improvements in seizure control and neurodevelopmental trajectories. Not only is the diagnostic rate of NGS high in children with unexplained epilepsy and neurodevelopmental delays, but also genetic testing in this population may often lead to potentially life-altering interventions.

The landscape of autism spectrum disorder (ASD) in Lebanon is unique because of high rates of consanguinity, shared ancestry, and increased remote consanguinity. ASD prevalence in Lebanon is 1 in 68 with a male-to-female ratio of 2:1. This study aims to investigate the impact of an inherited deletion in UBLCP1 (Ubiquitin-Like Domain-Containing CTD Phosphatase 1) on the ubiquitin-proteasome system (UPS) and proteolysis. Whole exome sequencing in a Lebanese family with ASD without pathogenic copy number variations (CNVs) uncovered a deletion in UBLCP1. Functional evaluation of the identified variant is described in fibroblasts from the affected. The deletion in UBLCP1 exon 10 (g.158,710,261CAAAG > C) generates a premature stop codon interrupting the phosphatase domain and is predicted as pathogenic. It is absent from databases of normal variation worldwide and in Lebanon. Wild-type UBLCP1 is widely expressed in mouse brains. The mutation results in decreased UBLCP1 protein expression in patient-derived fibroblasts from the autistic patient compared to controls. The truncated UBLCP1 protein results in increased proteasome activity decreased ubiquitinated protein levels, and downregulation in expression of other proteasome subunits in samples from the affected compared to controls. Inhibition of the proteasome by using MG132 in proband cells reverses alterations in gene expression due to the restoration of protein levels of the common transcription factor, NRF1. Finally, treatment with gentamicin, which promotes premature termination codon read-through, restores UBLCP1 expression and function. Discovery of an ASD-linked mutation in UBLCP1 leading to overactivation of cell proteolysis is reported. This, in turn, leads to dysregulation of proteasome subunit transcript levels as a compensatory response.