Neuronal Ceroid Lipofuscinoses type 7 (CLN7) is a paediatric lysosomal storage disease caused by mutations of the MFSD8 gene. Affected children have normal early development, but then suffer from progressive cognitive, motor, verbal, and visual decline. Ataxia and myoclonic epilepsy are predominant features of the condition, and there are no effective therapies. Death usually occurs by approximately age 11 years. While adeno-associated virus serotype 9 (AAV9) based gene therapy holds promise for treating monogenetic neurologic disorders, the impact of this intervention is limited by the maximum safe tolerable dose and the host immune response to the capsid and gene product. This study sought to confirm the safety of high dose intrathecal AAV-based gene therapy under a comprehensive immunosuppression regimen. This was a two-year open label, dose escalation, phase 1 first-in-human study of AAV9-based intrathecal gene therapy for CLN7. 4 participants (1 low dose, 3 high dose) were followed at regular intervals with blood work, CSF analysis, EEG, MRI, and measures of neurologic and neuropsychological function. This study provided evidence of safety for high dose intrathecal AAV9 based gene therapy in CLN7 disease under a specific immunosuppression regimen. Additionally, this study provides preliminary evidence of efficacy for this gene therapy. High dose intrathecal AAV based gene therapy can be pursued with adequate immunosuppression and monitoring for immune responses to the gene product. Additional long-term monitoring of the immune system during tapering of immunosuppression is needed to identify potential reactions to the gene product. This study was funded by The Batten's Hope Foundation, Mila's Miracle Foundation, Children's Health Dallas and Philanthropic Gifts to UT Southwestern. In addition, Emily R. Nettesheim received funding from NIH training grant 5T32GM131945-03 and Hamza Dahshi was supported in part by NIH award T32 GM152319.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the ATN1 gene. The juvenile onset type often presents with epilepsy, including progressive myoclonic epilepsy (PME). However, evidence on epilepsy in DRPLA remains limited. This systematic review and meta-analysis aimed to summarize clinical characteristics of DRPLA-related epilepsy. We systematically searched MEDLINE (PubMed), CENTRAL, Embase, Ichushi, and ClinicalTrials.gov for studies on DRPLA-related epilepsy, following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The review protocol was registered with the Open Science Framework. Any study design reporting at least one case of DRPLA-related epilepsy was eligible, including case reports, case series, cohort studies, and clinical trials. Eligible studies underwent screening and full-text assessment, followed by inclusion in descriptive and meta-analytic syntheses. Meta-analyses included only studies reporting ≥5 DRPLA patients. A total of 181 studies encompassing 1191 patients met the eligibility criteria. DRPLA patients with epilepsy had a younger onset age (16.9 [95% confidence interval (CI) = 13.76-20.76] vs. 45.5 years [95% CI = 42.77-48.47]) and more CAG repeats (66.7 [95% CI = 63.63-69.84] vs. 59.2 [95% CI = 55.67-62.92]) than those without epilepsy. DRPLA patients with epilepsy showed a higher likelihood of paternal versus maternal inheritance (odds ratio = 2.47 [95% CI = .97-6.27]). Focal seizures were frequently observed (40.0%-76.5%) alongside myoclonic and generalized tonic-clonic seizures. Electroencephalographic findings included slow bursts (38.0%), photoparoxysmal responses (36.6%), and interictal epileptiform discharges (77.5%). Giant somatosensory-evoked potentials, typically seen in PME, were observed in only two patients and absent in 27. Among antiseizure medications, perampanel and levetiracetam were more frequently reported as effective than sodium channel blockers. This review synthesizes fragmented evidence on DRPLA-related epilepsy and highlights key clinical and electrophysiological patterns. Despite limitations from small-scale studies, these findings support more informed clinical care and underscore the need for larger cohort studies.

The brain is highly susceptible to disturbances in lipid metabolism. Among the rare, genetically-linked epilepsies Progressive Myoclonic Epilepsy Type 8 (PME8), associated with the loss of Ceramide Synthase (CerS) activity, causes epileptic symptoms accompanied by early onset of neurodegenerative traits. The function of CerS is embedded in a complex, conserved metabolic pathway, making it difficult to identify the specific disease-relevant alterations. Here, we show that the expression of an enzymatically inactive cerS allele in Drosophila sensory neurons yielded developmental and early onset dendrite loss. Combining lipidomics and refined genetics with quantitative analysis of neuronal morphology in cerS mutants, we identified which lipids species are dysregulated and how they affect neuronal morphology. In cerS mutants, long and very-long acyl-chain C18-C24-ceramides were missing and necessary for dendrite elaboration. In addition, the substrate of CerS, (dh)S, and its metabolite (dh)S1P, increased. Especially increasing (dh)S1P strongly reduces dendritic complexity in cerS mutant neurons. Finally, we performed in vivo experiments to cell-autonomously rescue the morphological defects of cerS mutant neurons and report that a complete rescue can only be achieved if the toxic CerS substrate is converted to produce specific (C18-C24) ceramides. Thus, despite the complex metabolic alterations, our data provides essential information about the metabolic origin of PME8 and delineates a potential therapeutic avenue.

Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (CLN3) is associated with variants in the gene encoding a lysosomal transmembrane protein. To date, few Japanese patients with CLN3 have been reported. Thus, their neurodevelopmental and clinical features remain unclear. Here, we report the clinical course of a genetically confirmed Japanese patient with CLN3. A 17-year-old Japanese boy was diagnosed with retinitis pigmentosa at age 7. Visual impairment progressed over a 10-year follow-up period. Generalized tonic-clonic seizures also began at age 7. Developmental regression was recognized at age 13, with an accelerated decline in motor and communication skills following a COVID-19 infection at age 17. Tube feeding and gastrostomy were initiated for dysphagia and recurrent respiratory infections. Serial MRI revealed progressive cerebral and cerebellar atrophy. Lymphopenia (351-1467/μL) was present from age 9; peripheral blood smear revealed vacuolated lymphocytes. Exome sequencing identified a heterozygous CLN3 variant, NM_001042432.2:c.295-2A > C. SpliceAI suggested exon 6 skipping and/or an 80-bp deletion, leading to nonsense-mediated mRNA decay. Manual inspection using Integrated Genomic Viewer revealed a second variant (c.178_180delinsACATCCTTAGCCACAAGAG) missed initially. Trio Sanger sequencing confirmed compound heterozygosity: NM_001042432.2:c.[295-2A > C]; [178_180delinsACATCCTTAGCCACAAGAG] p.[?]; [His60Thrfs∗10]. A review of 430 genetically confirmed CLN3 patients (1989-2025) identified no hematologic abnormalities. This Japanese CLN3 patient developed visual impairment 7-8 years before systemic deterioration. Retinal degeneration, together with vacuolated peripheral lymphocytes, may provide early diagnostic clues for CLN3 in Japanese patients.

Next-generation sequencing (NGS) has expedited the diagnostic process and unearthed many rare disorders in leukodystrophy (LD) and genetic leukoencephalopathy (gLE). Despite the progress in genomics, there is a paucity of data on the distribution of genetic white matter disorders (WMDs) and the diagnostic utility of NGS-based assays in a clinical setting. This study was initiated to explore the clinical, radiologic, and genetic spectrum of LD and gLE in the Indian population and also to estimate the diagnostic yield of clinical exome sequencing (CES). This is a retrospective descriptive analysis of patients with a diagnosis of genetic WMDs from a single tertiary referral center who had CES performed as part of the diagnostic evaluation between January 2016 and December 2021. The demographic, clinical, radiologic, and genetic data were collected. The variants were classified using the American College of Medical Genetics and Genomics criteria. Pathogenic and likely pathogenic variants were included in the calculation of the diagnostic yield. In the study period, 138 patients were clinically diagnosed with either LD or gLE, of which 86 patients underwent CES. Pathogenic variants, likely pathogenic variants, and variants of uncertain significance with phenotype match were seen in 40 (41.8%), 13 (29.1%), and 15 (15.2%) patients, respectively. The mean age at onset in these 68 patients was 6.35 years (range 1 month-39 years), and 38 (55.9%) were male. LDs and gLE were diagnosed in 31 and 37 patients, respectively. 56 patients (71.8%) had autosomal recessive inheritance. The common clinical presentations were developmental delay (23.5%), psychomotor regression (20.6%), progressive myoclonic epilepsy syndrome (19.1%), and spastic ataxia (14.7%). Myelin disorders (48.5%) and leuko-axonopathies (41.2%) were the commonest type of disorders. The most frequently identified genes were ARSA, CLN5, ABCD1, CLN6, TPP1, HEXA, and L2HGDH. The diagnostic yield of the study was 61.6% (53/86), which increased to 79.1% when VUS with phenotype match were included. This study demonstrated a high diagnostic yield from proband-only CES in the evaluation of genetic WMDs and should be considered as a first-line investigation for genetic diagnosis. This study provides Class IV evidence that proband-only clinical exome sequencing is a useful "first-line investigation" for patients with genetic white matter disorders.