Clinical variability at the mild end of
            <i>BRAT1</i>
            ‐related spectrum: Evidence from two families with genotype–phenotype discordance

Nuovo, Sara; Baglioni, Valentina; Mori, Roberta De; Tardivo, Silvia; Caputi, Caterina; Ginevrino, Monia; Micalizzi, Alessia; Masuelli, Laura; Federici, Giulia; Casella, Antonella; Lorefice, Elisa; Anello, Danila; Tolve, Manuela; Farini, Donatella; Bertini, E.; Zanni, Ginevra; Travaglini, Lorena; Vasco, Gessica; Sette, Claudio; Carducci, Carla; Valente, Enza Maria; Leuzzi, Vincenzo

doi:10.1002/humu.24293

Cited by 12 publications

(6 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 Children with a later onset and milder phenotype have also been reported. [6][7][8][9][10] This study focuses on the neonatal presentation of BRAT1 encephalopathy. Few single-case reports, small series, and a comprehensive review of the literature have been published so far, describing intractable seizures, hypertonia, microcephaly, severe developmental delay, and early death.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

et al. 2023

View full text Add to dashboard Cite

Background and Objective:BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.Methods:Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with bi-allelic pathogenic variants inBRAT1for whom detailed clinical, neurophysiological, and neuroimaging information was available from the onset of symptoms. Neuropathological changes were also analyzed.Results:We included nineteen neonates. Most neonates were born at term (16/19) from non-consanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal ICU, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except one progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but one infant, was the most prominent manifestation, and did not show any EEG correlate in 16/19 (84%). vEEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only seven infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25 to 126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years post mortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.Discussion:BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurological disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counselling.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Death usually occurs within the first years of life, although a few cases with a milder phenotype have been described [10]. In recent years, mutations in BRAT1 were discovered in patients with migrating focal seizures in the absence of rigidity or with nonprogressive cerebellar signs even in the absence of a neurodevelopmental disorder [12,13]. A wide range of homozygous or compound heterozygous BRAT1 mutations has been reported in affected children.…”

Section: Discussionmentioning

confidence: 99%

BRAT1 Mutation Retrospective Diagnosis: A Case Report

Vercellino¹,

Valério²,

Dusio³

et al. 2023

Cureus

View full text Add to dashboard Cite

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.

show abstract

“…The developmental impairment was borderline in 2 patients belonging to group A (patients 8 and 24 in Table 1). Patient 8 in Table 1 was a female carrying a pathogenic variant of BRAT1 gene who had also a less severe epilepsy phenotype compared to other cases previously reported in the literature harboring the same variant (11). Patient 24 in Table 1 presented with a previously reported SCN8A variant associated with a benign childhood focal epilepsy, paroxysmal dyskinesia, and borderline cognitive functioning with minor coordination issues (12).…”

Section: Developmental Historymentioning

confidence: 97%

Presenting Patterns of Genetically Determined Developmental Encephalopathies With Epilepsy and Movement Disorders: A Single Tertiary Center Retrospective Cohort Study

Mastrangelo

Galosi²,

Cesario³

et al. 2022

Front. Neurol.

Self Cite

View full text Add to dashboard Cite

BackgroundThis paper aimed to evaluate the frequency of observation of genetically determined developmental encephalopathies with epilepsy and movement disorders in a specialistic center, the distribution of etiologies and presenting clinical hallmarks, and the mean times for the achievement of molecular genetic diagnosis.Patients and MethodsRetrospective data about clinical phenotypes, etiology, and diagnostic pathways were collected in all the genetically confirmed patients with developmental encephalopathies with epilepsy and movement disorders referred to our institution between 2010 and 2020. The cohort was divided into two groups according to the predominant movement disorder type: 1) Group A: patients with hyperkinetic movement disorders; 2) Group B: patients with hypokinetic movement disorders. Both groups were analyzed in terms of developmental, epileptic, and movement disorder phenotypes.ResultsThe cohort included 69 patients (Group A = 53; Group B = 16). The etiological spectrum was heterogeneous with a predominance of Rett and Angelman syndrome in Group A and neurodegenerative disorders in Group B. A moderate/severe intellectual disability was assessed in 58/69 patients (mean age at the first signs of developmental impairment = 1,87 ± 1,72 years). Group A included patients with an earlier onset of epileptic seizures (2,63 ± 3,15 vs. 4,45 ± 5,55 years of group B) and a predominant generalized motor semiology of seizures at the onset. Focal seizures were the main initial epileptic manifestations in Group B. Seizures were noticed earlier than movement disorders in Group A while the opposite occurred in Group B. A higher increase in molecular genetic diagnosis was obtained in the last five years. Mean diagnostic delay was longer in Group B than in Group A (12,26 ± 13,32 vs. 5.66 ± 6.41 years). Chorea as an initial movement disorder was associated with a significantly longer diagnostic delay and a higher age at etiological diagnosis.ConclusionsThis study suggested: (a) a higher frequency of genetic defects involving neurotransmission, neuronal excitability, or neural development in patients with hyperkinetic movement disorders; (b) a higher frequency of neurodegenerative courses and a longer diagnostic delay in patients with hypokinetic movement disorders.

show abstract

Clinical variability at the mild end of BRAT1 ‐related spectrum: Evidence from two families with genotype–phenotype discordance

Cited by 12 publications

References 21 publications

Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

BRAT1 Mutation Retrospective Diagnosis: A Case Report

Presenting Patterns of Genetically Determined Developmental Encephalopathies With Epilepsy and Movement Disorders: A Single Tertiary Center Retrospective Cohort Study

Contact Info

Product

Resources

About