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. AFG3L2-related neurologic disorders comprise four phenotypes. Spinocerebellar ataxia type 28 (SCA28), the most common phenotype, is characterized by young adult onset (26.5 ± 17.2 years); the onset range is from birth to 74 years of a cerebellar syndrome manifesting initially as very slowly progressive gait and limb ataxia resulting in incoordination and balance problems. Less frequently, ptosis/ophthalmoplegia, dysarthria, or upper-limb incoordination may occur as the initial finding. Pyramidal syndrome (increased and brisk reflexes, extensor plantar reflex, and spasticity) is commonly observed in individuals with longer disease duration. Although cognitive impairment, spasticity, and ophthalmologic signs can occur with disease progression, most individuals remain ambulatory and fully independent throughout their lives. Spastic ataxia type 5 (SPAX5), reported in 14 individuals to date, ranges from severe neurodegeneration with microcephaly, poor weight gain, developmental delay, developmental regression around age nine months, and death as early as age 2.5 years. Milder presentations range from onset in infancy to an early-onset complex cerebellar ataxia with myoclonic epilepsy. AFG3L2-related autosomal recessive spinocerebellar ataxia (AFG3L2-SCAR), reported in two individuals to date, is a late-onset ataxia with a clinical phenotype closely resembling that of SCA28. Optic atrophy type 12 (OPA12) manifests as decreased visual acuity (variable but frequently ranging from 0.2/10 to 2/10), photophobia, and impaired color vision. Ophthalmologic findings are optic nerve pallor and highly reduced retinal nerve fiber layer on optical coherence tomography. Although affected individuals do not present with ataxia, some may exhibit sensorineural hearing loss, neurodevelopmental disorders, dystonia, and spasticity. The diagnoses of SCA28 and OPA12 are established in a proband with suggestive findings and a heterozygous pathogenic variant in AFG3L2 identified by molecular genetic testing. The diagnoses of SPAX5 and AFG3L2-SCAR are established in a proband with suggestive findings and biallelic pathogenic variants in AFG3L2 identified by molecular genetic testing. Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields including neurologists (to address pharmacologic treatment of myoclonic epilepsy, spasticity, movement disorders); occupational therapists (to optimize activities of daily living and home safety); physiatrists and physical therapists (to help maintain independence and mobility); nutritionists and feeding therapy programs (to assess the risks of aspiration and need for gastrostomy tube placement for those with dysphagia); speech-language therapists (to address communication for individuals who have expressive language difficulties), ophthalmologists (to consider surgery for ptosis); low vision clinics (for those with optic atrophy); and social workers and psychologists (depending on any cognitive or psychologic manifestations). Surveillance: Routinely scheduled follow-up appointments with treating clinicians are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations. Agents/circumstances to avoid: Alcohol consumption and sedatives such as benzodiazepines that may worsen gait ataxia and coordination. Carbamazepine and phenytoin may exacerbate myoclonus in SPAX5. SCA28 and OPA12 are inherited in an autosomal dominant manner. AFG3L2-SCAR and SPAX5 are inherited in an autosomal recessive manner. Autosomal dominant inheritance: Most individuals diagnosed with SCA28, and some individuals diagnosed with OPA12, have an affected parent. Some individuals diagnosed with an autosomal dominant AFG3L2-related neurologic disorder have the disorder as the result of a de novo pathogenic variant. Each child of an individual with an autosomal dominant AFG3L2-related neurologic disorder has a 50% risk of inheriting the pathogenic variant. If the reproductive partner of an individual with an autosomal dominant AFG3L2-related neurologic disorder also has an AFG3L2 pathogenic variant, offspring are at risk of inheriting biallelic pathogenic variants and having an autosomal recessive AFG3L2-related neurologic disorder. Once the AFG3L2 pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. Autosomal recessive inheritance: The parents of a child with an autosomal recessive AFG3L2-related neurologic disorder are presumed to be heterozygous for an AFG3L2 pathogenic variant. If both parents are known to be heterozygous for an AFG3L2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial AFG3L2 pathogenic variants. Heterozygous family members of an individual with an autosomal recessive AFG3L2-related neurologic disorder are typically asymptomatic and the risk of developing an AFG3L2-related neurologic disorder appears to be low. Once the AFG3L2 pathogenic variants has been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Unverricht-Lundborg disease (ULD) is a rare, progressive myoclonic epilepsy for which no disease-modifying treatments currently exist. Disease biomarkers are critically needed to guide prognosis and monitor therapeutic response. We present a case highlighting progressive deterioration of sleep architecture as a potential marker of disease progression in ULD. Quantitative EEG (qEEG) analysis over serial recordings demonstrated a gradual decline in hallmark features of non-rapid eye movement sleep, including sleep spindles and K-complexes. Over time, these sleep-specific graphoelements became nearly absent, rendering sleep EEG patterns indistinguishable from wakefulness. This loss of sleep architecture occurred in parallel with worsening motor and cognitive function. These findings suggest that sleep EEG abnormalities may reflect underlying cortical dysfunction and could serve as an early, objective indicator of neurodegeneration in ULD. Further prospective studies are warranted to validate qEEG as a noninvasive biomarker for disease monitoring and to explore its potential role in clinical trials.

Lamins play a major role in the mechanical stability of cell nuclei, the organisation of chromatin and the DNA replication, transcription and repair. The expression profiles of A-type and B-type lamins vary depending on developmental stages, cell types and tissues. Lamin B2 is expressed very early in embryogenesis, especially in the central nervous system, where it is essential for neuronal migration and brain development. Pathogenic missense variants in lamin B2 have been linked to conditions such as lipodystrophy, progressive myoclonic epilepsy and primary microcephaly. Here, we report clinical data and molecular findings for two related newborns carrying a homozygous loss-of-function variant in the LMNB2 gene. Both newborns died in the perinatal period and exhibited a similar phenotype at birth, including severe brain development abnormalities, which closely mirror findings observed in several Lmnb2-deficient mouse models. Western blot and immunofluorescence cell labelling performed on the patient's fibroblasts obtained at birth confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. This novel clinical form of laminopathy associated with lamin B2 deficiency expands the molecular causes of brain development abnormalities to LMNB2 gene variants.

Lafora disease (LD) is an ultra-rare and still incurable neurodegenerative condition. Although several therapeutic strategies are being explored, including gene therapy, there are currently no treatments that can alleviate the course of the disease and slow its progression. Recently, gliflozins, a series of SGLT2 transporter inhibitors approved for use in type 2 diabetes mellitus, heart failure and chronic kidney disease, have been proposed as possible repositioning drugs for the treatment of LD. With this in mind, we tested dapagliflozin (50 µM), canagliflozin (2.5 µM) and empagliflozin (200 µM) in our epm2a-/- zebrafish model, investigating their effects on pathological behaviour. In the case of dapagliflozin, we also investigated the possible mechanisms of action. Overall, the gliflozins reduced or rescued neuronal hyperexcitability and locomotor impairment. Dapagliflozin also reduced spontaneous seizure-like events in epm2a-/- larvae. At the biochemical and molecular level, dapagliflozin was found to slightly reduce glycogen content, and suppress inflammation and oxidative stress. It also ameliorates autophagic homeostasis and improves lysosomal markers. In conclusion, our preclinical study showed that dapagliflozin was able to ameliorate part of the pathological phenotype of epm2a-/- zebrafish larvae and could potentially be a suitable drug for repurposing in LD. However, since our model does not present Lafora bodies (LBs), at this early disease stage at least, it would be important to use mouse models in order to ascertain whether it is able to prevent or reduce LB formation.

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.