This case report describes a patient (male, 10 years old) with Autism Spectrum Disorder (ASD) and multiple comorbidities, including epilepsy, gastrointestinal and sleep disturbances, and obesity. Whole-exome sequencing (WES) identified two variants of uncertain significance (VUS) in the GRID2 gene. Mutations in this gene are associated with spinocerebellar ataxia type 18 (SCA18). However, this finding did not correlate with the clinical presentation of the patient. This study evaluates the effects of Radio Electric Asymmetric Conveyer (REAC) stimulation on the cognitive-behavioral dysfunctions of a child with severe ASD and multiple comorbidities. Two stimulation protocols-Neuro Postural Optimization (NPO) and Neuro Psychophysical Optimization (NPPO)-and REAC were performed sequentially. After five weeks of treatment, a 34.9% reduction in total scores on the Autism Treatment Evaluation Checklist (ATEC) and an 8.2% on the Autism Behavior Checklist (ABC) were observed. Assessment of the severity of ASD symptoms using the Childhood Autism Rating Scale (CARS) tool showed less pronounced improvement. The REAC intervention yielded a reduction in Social Relating impairment and an improvement in Sensory/Cognitive Awareness. Further research in this area should employ extended REAC protocols to replicate and amplify clinical responses among individuals with ASD.

Spinocerebellar ataxias (SCAs) are heterogeneous disorders with multiple genetic etiology. Mutations in the GRID2 gene are associated with spinocerebellar ataxia type 18 (SCA-18). We report the first Indian case of SCA-18. The proband is a 7-year-old boy with motor delay, cerebellar signs, and cerebellar atrophy. Whole exome and direct sequencing identified compound heterozygous mutations of the coding and noncoding regions of the GRID2 gene. A literature review of the published cases with pathogenic GRID2 variants was performed. Beside our patients, 32 cases were identified. The majority of reported cases were males, of consanguineous kindreds, with autosomal recessive inheritance. However, a proportion of cases (39%) had autosomal dominant/semidominant inheritance with heterozygous variants. In addition to childhood-onset cerebellar ataxia, other reported features were: early-onset dementia, complicated spastic paraparesis, retinal dystrophy, hearing loss, lower motor neuron signs, and severe global developmental delay in some homozygous cases. Cerebellar atrophy was the commonest neuroimaging finding, with few cases demonstrating brain stem, supratentorial, and white matter abnormalities. Although SCA-18 should be suspected in patients with early-onset cerebellar ataxia, eye movement abnormalities, and motor delay, clinicians should be aware of late-onset, variable presentations with pyramidal signs, dementia, and hearing loss. In suspected cases, if mutations were not detected by whole-exome sequencing, direct sequencing of noncoding regions and chromosomal microarray should be considered.

Autosomal recessive cerebellar ataxias (ARCA) are characterized by the abnormal structure of the cerebellum and spinal cord. Spinocerebellar ataxia type 18 (MIM 616204), one of the ARCA, is caused by the loss-of-function mutations of the GRID2 gene due to deletions. Missense mutations in the GRID2 cause ataxia with the gain-of-function mechanism. We report a homozygous GRID2  duplication in childhood-onset ataxia in two siblings. The clinical exome sequencing was performed on one of the siblings. No disease-causing mutations were reported as a result of the clinical exome test. Chromosomal microarray analysis was performed on the entire family using Affymetrix Optima® chips. Chromosomal microarray analysis showed a ~ 121-kb homozygous duplication of GRID2 (arr[GRCh37]4q22.2(94426536_94613158) × 4), including exon 14, in both siblings. Previously, GRID2 has been associated with an autosomal recessive (loss-of-function) and autosomal semi-dominant (gain-of-function) forms of ataxia. To the best of our knowledge, this is the first study to identify a homozygous duplication of GRID2 causing loss of function of the GluRD2 protein. These findings provide us with the conclusion that copy number variation analyses should be in the diagnostic process of autosomal recessive ataxia types.

Autosomal recessive spinocerebellar ataxia type 18 (SCAR18) is caused by pathogenic variants in the Glutamate Receptor, Ionotropic, Delta-2 (GRID2) gene. We describe the long-term follow-up from 1 to 31 years of an Italian patient with congenital SCAR18 who is compound heterozygous for a maternally-inherited nonsense variant and a de novo microdeletion. To date, this is the longest follow-up in congenital SCAR18.

Autosomal-recessive spinocerebellar ataxia type 18 (SCAR18) is a rare neurologic disorder. It is caused by bi-allelic aberrations in the GRID2 gene, encoding an ionotropic glutamate receptor. In total, 20 affected individuals with mainly homozygous/compound heterozygous intragenic deletions/duplications, two different missense variants and one nonsense variant in GRID2 have been reported, so far. SCAR18 is characterized by delayed psychomotor development, intellectual disability, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and cerebellar atrophy in brain imaging. By trio exome sequencing, we now identified a novel homozygous nonsense variant (c.568C > T; p.Gln190*) in GRID2 in a four year old female from a consanguineous family who presented with a particularly severe manifestation of SCAR18. The girl was born after an uneventful pregnancy and showed early-onset, profoundly delayed psychomotor development with no achieved psychomotor milestones at age 4 years. Additionally, she presented with severe muscular hypotonia, progressive truncal and appendicular ataxia, binocular vertical nystagmus, central hearing loss and incomplete loss of sight. She was dystrophic, interacted only very little and had behavioral anomalies such as eating hair and bruxism. Brain imaging showed cerebellar hypoplasia, extended cerebrospinal fluid spaces and beginning reduction of cerebral volume. Our findings further delineate the mutational and clinical spectrum of GRID2-associated spinocerebellar ataxia type 18 and indicate that homozygous nonsense variants are possibly associated with the severe end of the SCAR18 phenotypic spectrum.