Objective: To describe the phenotype and genotype of a Mexican patient with epilepsy, mioclono and ataxia with a heterozygote polymorphism in the BRAT1 gene c.453_454insATCTTCTC (p.Leu152Ilefs*70) with a recessive pattern of inheritance

Background: Biallelic mutations in BRAT1 gene, result in variable phenotypes. The disorder typically manifests as a severe phenotype including neonatal microcephaly, hypertonia, and refractory epilepsy with premature death by 2 years. Recent descriptions expand the clinical spectrum. Genotype-phenotype associations are not fully elucidated

Method: We present a case report of a 24 year old mexican man without family history of neurological illness, but neonatal seizures reported by the mother. He reported the onset of  lower limb mioclono and focal to bilateral tonic-clonic seizure at the age of 15. Three years later he noticed imbalance and action tremor in hands. Due to this he had to quit his job and forfeit his master’s degree education. Visual acuity has since declined.

Results: Physical exam with saccadic vertical intrusions and, decreased horizontal and vertical saccade initiation and velocity. Global motor power 5/5 with areflexia in all four limbs. Impaired proprioception and positive Romberg test. Global dysmetria, generalized dysdiadochokinesia, trunk ataxia to Babinski test, ataxic gait, with tandem gait impossibility. Brain MRI showed cortical hyperintensity in the left insular cortex. EEG was abnormal due to mild generalized disfunction, without evidence of epileptic activity. Neuroophthalmology reported keratoconus. The Neuropsychological evaluation demonstrated impared visual and verbal memory and executive dysfunction. NGS was requested for 183 genes associated with epilepsy and 3 variants were found in heterozygosis: BRAT1 c.453_454insATCTTCTC (p.Leu152Ilefs*70) heterozygous pathogenic, ALDH7A1 c.359C>G (p.Ala120Gly) (VUS) and GAL c.223+3G>C (Intronic).

Conclusion: The polymorphisms found in the NGS were considered variants of unknown significance (VUS) but, due to the possibility of treatment in the case of the ALDH7A1 c.359C>G mutation (p.Ala120Gly) (VUS) associated with epilepsy due to pyridoxine deficiency, it was decided to start high dose pyridoxine replacement without conclusive therapeutic effect. Given the neurodegenerative evolution with cognitive, cerebellar, subcortical and cortical involvement we consider the current phenotype may be related to the BRAT1 mutation found expanding.

References: Sara Nuovo, et, al, Clinical variability at the mild end of BRAT1-related spectrum: Evidence from two families with genotype-phenotype discordance. Human Mutaton, 2022; 43:67-73. Nicholas J. Smith, et, al. BRAT1-Associated Neurodegeneration: Intra-Familial Phenotypic Differences in Siblings. Am J of Med Genet, 2016. Siddhart Srivastava, et, al. BRAT1 Mutations Present With a Spectrum of Clinical Severity. Am J of Med Genet, 2016. A. Fernández-Jaén, et, al. Mutations in BRAT1 Cause Autosomal Recessive Progressive Encephalopathy: Report of a Spanish Patient. European Journal of Paediatric Neurology 2016 doi: 10.1016/j.ejpn.2016.02.009.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/brat1-associated-neurodegeneration-and-review-of-literature/