A 32-year-old woman had experienced recurrent seizures since infancy, with progressive ataxia, dystonia, and electrolyte disturbances, suggesting a possible genetic tubulopathy with neurological manifestations. The complexity of her presentation highlights the importance of a multidisciplinary approach and the role of genetic investigations in uncovering rare conditions that bridge neurology and nephrology.

Mutations in the KCNJ10 gene cause SeSAME syndrome, an autosomal recessive disorder characterised by seizures, sensorineural deafness, ataxia, intellectual impairment and electrolyte imbalances. KCNJ10 encodes an inwardly rectifying potassium channel Kir4.1, which is essential for preserving potassium ion homeostasis. We assessed three Iranian families with SeSAME syndrome-like symptoms through whole-exome sequencing (WES). Segregation analysis and Sanger sequencing were also used to confirm identified mutations. Additionally, bioinformatic tools were utilised to predict the pathogenicity of the variants. We identified two novel KCNJ10 mutations, c.967 T>C (p.Y323H) and c.352G>A (p.A118T) in three families. While there was no evidence of renal involvement, the probands from these families displayed early-onset seizures, ataxia, developmental delays and hearing abnormalities. Based on the Kir4.1 protein's structural modelling, the stability of the channel is influenced by both mutations. Precisely, p.A118T alters the transmembrane domain that is critical to channel operation, whereas p.Y323H modifies the cytoplasmic C-terminal domain, which may compromise intracellular localisation and regulation. Our findings can expand the spectrum of mutations in the KCNJ10 gene and provide insight into the genotype-phenotype correlation in the SeSAME syndrome.

EAST syndrome - Epilepsy, Ataxia, Sensorineural hearing loss, and renal Tubulopathy - is an autosomal recessive disorder affecting the potassium channel in the brain, inner ear, and basolateral membrane of the distal nephron of the kidney. The mutation in the KCNJ10 gene is responsible for defective potassium transport in those locations, resulting in seizures, hearing loss, and hypokalemia. Imaging findings of this disease are typical, such as cerebellar hypoplasia and signal changes in bilateral dentate nuclei, midbrain, pons, and medulla, with variable restricted diffusion due to intramyelinic edema. Variable degrees of atrophy can be seen in the brainstem, spinal cord, corpus callosum, and cortex. No definitive treatment has been described yet in literature, and management is focussed mainly on symptomatic treatment like antiepileptics for seizures and potassium supplementations for hypokalemia. Although limited case reports are described in the literature, most reports described this as a non-progressive disorder. Herein, we describe a case of EAST syndrome in a three-year-old male child with a history of seizures, global developmental delay, bilateral sensorineural hearing loss, salt-wasting renal tubulopathy, and imaging of the brain showed diffuse cerebral atrophy with signal changes in the brainstem and bilateral dentate nuclei, showed clinical improvement on symptomatic management.

Although the group of paroxysmal kinesigenic dyskinesia (PKD) genes is expanding, the molecular cause remains elusive in more than 50% of cases. The aim is to identify the missing genetic causes of PKD. Phenotypic characterization, whole exome sequencing and association test were performed among 53 PKD cases. We identified four causative variants in KCNJ10, already associated with EAST syndrome (epilepsy, cerebellar ataxia, sensorineural hearing impairment and renal tubulopathy). Homozygous p.(Ile209Thr) variant was found in two brothers from a single autosomal recessive PKD family, whereas heterozygous p.(Cys294Tyr) and p.(Thr178Ile) variants were found in six patients from two autosomal dominant PKD families. Heterozygous p.(Arg180His) variant was identified in one additional sporadic PKD case. Compared to the Genome Aggregation Database v2.1.1, our PKD cohort was significantly enriched in both rare heterozygous (odds ratio, 21.6; P = 9.7 × 10-8) and rare homozygous (odds ratio, 2047; P = 1.65 × 10-6) missense variants in KCNJ10. We demonstrated that both rare monoallelic and biallelic missense variants in KCNJ10 are associated with PKD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

KCNJ10 and CAPN1 variants cause "spinocerebellar" ataxia in dogs, but their association with generalized myokymia and neuromyotonia remains unclear. To investigate the association between KCNJ10 and CAPN1 and myokymia or neuromyotonia, with or without concurrent spinocerebellar ataxia. Thirty-three client-owned dogs with spinocerebellar ataxia, myokymia neuromytonia, or a combination of these signs. Genetic analysis of a cohort of dogs clinically diagnosed with spinocerebellar ataxia, myokymia or neuromyotonia. KCNJ10 c.627C>G and CAPN1 c.344G>A variants and the coding sequence of KCNA1, KCNA2, KCNA6, KCNJ10 and HINT1 were sequenced using DNA extracted from blood samples. Twenty-four Jack Russell terriers, 1 Jack Russell terrier cross, 1 Dachshund and 1 mixed breed with spinocerebellar ataxia were biallelic (homozygous) for the KCNJ10 c.627C>G variant. Twenty-one of those dogs had myokymia, neuromyotonia, or both. One Parson Russell terrier with spinocerebellar ataxia alone was biallelic for the CAPN1 c.344G>A variant. Neither variant was found in 1 Jack Russell terrier with ataxia alone, nor in 3 Jack Russell terriers and 1 Yorkshire terrier with myokymia and neuromyotonia alone. No other causal variants were found in the coding sequence of the investigated candidate genes in these latter 5 dogs. The KCNJ10 c.627C>G variant, or rarely the CAPN1 c.344G>A variant, was confirmed to be the causal variant of spinocerebellar ataxia. We also report the presence of the KCNJ10 c.627C>G variant in the Dachshund breed. In dogs with myokymia and neuromyotonia alone the reported gene variants were not found. Other genetic or immune-mediated causes should be investigated to explain the clinical signs of these cases.