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BRAT1 Mutation Retrospective Diagnosis: A Case Report
Fabiana Vercellino1, Massimo Valerio1, Maria Pia Dusio2
1Child Neuropsychiatry Unit, SS Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, ITA.
Insights
Biallelic mutations in the BRAT1 gene cause severe neurological disorders like Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL). Novel genetic testing enabled diagnosis of a past case, highlighting its utility for unsolved conditions.
Area of Science:
- Genetics
- Neuroscience
- Pediatrics
Background:
- Biallelic mutations in the BRAT1 gene are linked to Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL), a severe neurodevelopmental disorder.
- BRAT1 mutations have also been associated with milder phenotypes, including epilepsy and congenital ataxia (NEDCAS).
- The proposed mechanism involves impaired mitochondrial homeostasis, affecting neuronal proliferation, migration, and causing atrophy.
Observation:
- A female infant presented with clinical, EEG, and MRI findings consistent with RMFSL.
- The diagnosis was established three years post-mortem.
- Genetic analysis identified a known pathogenic BRAT1 variant in both parents.
Findings:
- This case confirms the association between BRAT1 mutations and the severe RMFSL phenotype.
- The diagnosis was achieved retrospectively through parental genetic testing.
- The study highlights the diagnostic power of advanced genetic technologies in retrospectively analyzing unsolved cases.
Implications:
- This underscores the importance of considering BRAT1 mutations in neonatal encephalopathies with epilepsy.
- Novel genetic technologies offer powerful tools for diagnosing previously unsolved pediatric neurological disorders.
- Retrospective genetic diagnosis can provide closure and inform future research and clinical management.
Abstract:
Biallelic mutations in the BRAT1 gene have been reported in cases with Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL), since 2012. Clinical features include progressive encephalopathy, dysmorphic features, microcephaly, hypertonia, developmental delay, refractory epilepsy, episodic apnea, and bradycardia. More recently, biallelic BRAT1 mutations have been associated with a milder phenotype in patients with migrating focal seizures in the absence of rigidity or with nonprogressive congenital ataxia with or without epilepsy (NEDCAS). It has been proposed that the loss of function caused by BRAT1 mutations may decrease cell proliferation and migration and cause neuronal atrophy through impairment of mitochondrial homeostasis. We here report a female infant with a phenotype, electroencephalogram (EEG), and brain magnetic resonance imaging (MRI) consistent with RMFSL, whose diagnosis was indirectly formulated three years after death upon the identification in both parents of a known pathogenetic variant in the BRAT1 gene. Our report emphasizes the remarkable potential of novel genetic technologies for the diagnosis of past unsolved clinical cases.
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