Spinocerebellar ataxia-21 (SCA21) is an autosomal dominant neurodegenerative disorder due to pathogenic variants of the TMEM240 gene. Its clinical presentation usually includes slowly progressive cerebellar ataxia, myoclonus-dystonia syndrome, cognitive impairment, and behavioral problems. Here, we reported the first patient with SCA21 presenting with a developmental and epileptic encephalopathy with seizure onset during late childhood, a seizure semeiology including atonic, clonic, myoclonic seizures, and absences with eyelid myoclonia and an EEG pattern characterized by diffuse spike and wave discharges. Epilepsy was associated with a progressive motor deterioration (the International Cooperative Ataxia Rating Scale-ICARS Total Ataxia score switched from 23/100 to 35/100 over a period of 2 years), a worsening of a preexisting tremor, and a disabling drowsiness. Nonverbal measure of intellectual functioning revealed a moderate intellectual disability (Leiter-R: brief IQ 40; fluid reasoning 52). The epileptogenic mechanisms involving TMEM240 might be correlated with disinhibition of excitotoxic networks due to the loss of Purkinje cells in the cerebellum, but also damage in neuronal bioenergetic pathways and synaptic vesicular trafficking within cortico-cerebellar and thalamo-cerebellar circuits. IRF2BPL-related disorder is characterized by mild-to-profound developmental delay (with regression in many individuals), intellectual disability, seizures (generalized tonic-clonic, myoclonic, absence, focal tonic-clonic, complex partial, infantile spasms, and/or atonic seizures), movement disorder (ataxia, dystonia, tremor, and parkinsonism), spasticity, and neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis). Feeding issues, gastrointestinal dysmotility, and ophthalmologic manifestations are also reported. Brain MRI can show focal or diffuse cortical and/or subcortical atrophy, cerebellar atrophy (particularly of the vermis), brain stem atrophy, and corpus callosum abnormalities including thinning/atrophy or thickening. Onset is highly variable and can be in the first year of life through the sixth decade. In some individuals the course of the disorder is progressive or debilitating. The diagnosis of IRF2BPL-related disorder is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in IRF2BPL identified by molecular genetic testing. Treatment of manifestations: Developmental and educational support; standard treatment of epilepsy and movement disorder by an experienced neurologist; standard treatment of spasticity per orthopedist, neurologist, physical medicine and rehabilitation specialist, physical therapist, and occupational therapist; feeding support for poor weight gain; standard treatment for gastric dysmotility; treatment of vision deficits per ophthalmologist with treatment of more complex findings per ophthalmic subspecialist; treatment of pubertal delay per endocrinologist; family and social work support. Surveillance: At each visit, assess developmental progress, educational needs, cognitive function, seizures, movement disorder, spasticity, contractures, behavioral issues, growth, nutritional status, gastrointestinal dysmotility, and family needs; physical medicine and/or occupational and physical therapy assessment for mobility and self-help skills at each visit; dilated eye exam per treating ophthalmologist; assessment of pubertal development at each visit through adolescence. IRF2BPL-related disorder is inherited in an autosomal dominant manner. The majority of individuals diagnosed with IRF2BPL-related disorder have the disorder as the result of a de novo pathogenic variant; approximately 9% of individuals reported to date have an affected parent. Each child of an individual with IRF2BPL-related disorder has a 50% chance of inheriting the IRF2BPL pathogenic variant. Once the IRF2BPL pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), with profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures; familial infantile myoclonic epilepsy (FIME), with early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability; progressive myoclonus epilepsy (PME), with action myoclonus, tonic-clonic seizures, ataxia, and progressive neurologic decline; rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC); developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS); autosomal recessive nonsyndromic hearing loss (DFNB); and autosomal dominant nonsyndromic hearing loss (DFNA). The diagnosis of a TBC1D24-related disorder is established in an individual with suggestive findings biallelic TBC1D24 pathogenic variants when the mode of inheritance is autosomal recessive (i.e., DOORS syndrome, FIME, PME, EPRPDC, DEE, and DFNB), and in an individual with suggestive findings and a heterozygous TBC1D24 pathogenic variant when the mode of inheritance is autosomal dominant (DFNA). Treatment of manifestations: Hearing aids or cochlear implants as needed for hearing loss; early educational intervention and physical, occupational, and speech therapy for developmental delay; symptomatic pharmacologic management for seizures; standard treatment for tremors, dystonic attacks, or other neurologic manifestations; routine management of visual impairment and renal, cardiac, dental, orthopedic, and endocrine issues. Surveillance: Neurologic evaluations with EEGs depending on seizure frequency and/or progression; annual audiologic evaluations to assess for possible progression of hearing loss and/or the efficacy of hearing aids; annual dental evaluations; annual endocrine evaluations. Agents/circumstances to avoid: Excessive ambient noise, which may exacerbate hearing loss in individuals with a heterozygous TBC1D24 pathogenic variant that causes autosomal dominant hearing loss (DFNA). Evaluation of relatives at risk: Molecular genetic testing for the familial TBC1D24 pathogenic variant(s) in older and younger sibs of a proband is appropriate in order to identify as early as possible those who would benefit from early treatment of seizures and/or hearing loss. Most TBC1D24-related disorders are inherited in an autosomal recessive manner (DOORS syndrome, FIME, PME, EPRPDC, and DEE [including EIMFS]). TBC1D24-related nonsyndromic hearing loss can be inherited in an autosomal recessive (DFNB) or autosomal dominant (DFNA) manner. Autosomal recessive inheritance: If both parents are known to be heterozygous for a TBC1D24 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial TBC1D24 pathogenic variants. Heterozygotes (carriers) are typically asymptomatic. Carrier testing for at-risk relatives requires prior identification of the TBC1D24 pathogenic variants in the family. Once the TBC1D24 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

The current study investigates the intricate connection between neurology and islands shedding light on the historical, epidemiological, and genetic aspects. Based on an elaborate literature review, we identified neurological conditions having a significant clustering in an island(s), confined to a particular island(s), named after an island, and described first in an island. The genetic factors played a crucial role, uncovering disorders like Cayman ataxia, Machado Joseph disease, SGCE-mediated dystonia-myoclonus syndrome, X-linked dystonia parkinsonism, hereditary transthyretinrelated amyloidosis, Charcot Marie Tooth 4F, and progressive myoclonic epilepsy syndromes, that exhibited remarkable clustering in diverse islands. Local customs also left enduring imprints. Practices such as cannibalism in Papua New Guinea led to Kuru, while cycad seed consumption in Guam triggered Lytico-Bodig disease. Toxin-mediated neurologic disorders exhibited intricate island connections, exemplified by Minamata disease in Kyushu islands and atypical parkinsonism in French Caribbean islands. Additionally, the Cuban epidemic of amblyopia and neuropathy was associated with severe nutritional deficiencies. This study pioneers a comprehensive review narrating the genetic, environmental, and cultural factors highlighting the spectrum of neurological disorders in island settings. It enriches the medical literature with a unique understanding of the diverse influences shaping neurological health in island environments.

KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Variants of the NUS1 gene have been associated with an extensive spectrum of phenotypes, including epilepsy, intellectual disability, cerebellar ataxia, Parkinson's disease, dystonia, and congenital disorder of glycosylation. It is rarely reported in progressive myoclonus epilepsy (PME). Herein, we report the case of PME caused by a novel de novo NUS1 missense variant (c.302T>A, p.Met101Lys). In addition, we reviewed the current literature of NUS1-associated PME. At present, five patients with NUS1 variants and PME have been reported in the literature. Due to limited cases reported, the relationship between NUS1 variants and PME is not well-established. Our case provides further evidence of the role of NUS1 variants in PME. These findings expand the clinical phenotypes of NUS1 variants, which should be included in the PME genetic screening panel.

Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic-clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype-phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures. Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive autosomal dominant disorder characterized by myoclonic epilepsy, ataxia, choreoathetosis/dystonia, cognitive impairment/dementia, and psychiatric disturbances. Rarely, corneal endothelial degeneration, head tremor, or optic atrophy may be present. The presentation varies with the age of onset. The disorder was first described in 1946, and the name was given in1958.