Genetic investigation of patients with autosomal recessive ataxia and identification of two novel variants in the SQSTM1 and SYNE1 genes.

Hereditary ataxias are classified by inheritance patterns into autosomal dominant, autosomal recessive, X-linked, and mitochondrial modes of inheritance. A large group of adult hereditary ataxias have autosomal dominant inheritance, and autosomal recessive cerebellar ataxias (ARCAs) are rare, with greater diversity in phenotypic and genotypic features. Therefore, comprehensive genetic testing is useful for identifying the genes responsible for ARCAs. We identified two novel pathogenic variants of the SQSTM1 and SYNE1 genes via whole-exome sequencing in patients with ARCAs.

A novel variant in ASNS gene responsible for syndromic intellectual disability and microcephaly: Case report and literature review.

BACKGROUND: The ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease characterized by cerebral anomalies. These patients have congenital microcephaly, progressive encephalopathy, severe intellectual disability, and intractable seizures. METHOD: Clinical characteristics of the patient were collected. Exome sequencing was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. The structure of the protein was checked using the DynaMut2 web server. RESULTS: The proband is an 11-year-old Iranian-Azeri girl with primary microcephaly and severe intellectual disability in a family with a consanguineous marriage. Symptoms emerged around the 10-20th days of life, when refractory epileptic gaze and unilateral tonic-clonic seizures initiated without any provoking factor such as fever. A brain MRI revealed no abnormalities except for brain atrophy. The karyotype was normal. Using exome sequencing, we identified a novel homozygous variant of thymine to adenine (NM_001673.5:c.538T>A) in the ASNS gene. Both parents had a heterozygous variant in this location. Subsequently, Sanger sequencing confirmed this variant. We also reviewed the clinical manifestations and MRI findings of the previously reported patients. CONCLUSION: In the present study, a novel homozygous variant was recognized in the ASNS gene in an Iranian-Azeri girl manifesting typical ASNSD symptoms, particularly intellectual disability and microcephaly. This study expands the mutation spectrum of ASNSD and reviews previously reported patients.

Successfully treated anti-GAD limbic encephalitis in a 15-year-old diabetic boy with intravenous immunoglobulin: case report.

Introduction and importance: Limbic encephalitides (LE) have symptoms and signs of new-onset seizures accompanied by cognitive impairment and signal changes in the MRI of the limbic system in the brain. Numerous antibodies against the neurons and synapses have been detected so far. Of those, antiglutamic acid decarboxylase antibody (Anti-GAD Ab) impairs the gamma amino butyric acid, one of the primary mediators that naturally prevents abnormal neuronal activity causing seizure. Case presentation: The authors have reported a case of anti-GAD Ab LE in a diabetic male adolescent who responded dramatically to intravenous immunoglobulin and reviewed all similar pediatric cases for 15 years now. Clinical discussion: The symptoms in children suffering from anti-GAD LE in three categories, systemic, psychiatric, and neurological, are heterogeneous. The most common manifestations were seizures followed by altered mental status and behavioral changes, respectively. The two main clinical scenarios described in GAD65-mediated autoimmune epilepsy are (1) an acute/subacute onset of seizures alone or seizures (including new-onset refractory status epilepticus, NORSE) accompanied by some degrees of cognitive and psychiatric manifestations, including amnesia and mesiotemporal inflammatory involvement consistent with LE and (2) epilepsy without clinical or MRI evidence of active central nervous system inflammation. Conclusion: Although rare, the neurologist should consider the potential role of anti-GAD ab-associated encephalitis in the presence of diabetes mellitus.