A review of the clinical spectrum of BRAT1 disorders and case of developmental and epileptic encephalopathy surviving into adulthood

Fowkes, R.; Elwan, Menatalla; Akay, Ela; Mitchell, Clint; Thomas, Rhys H.; Lewis‐Smith, David

doi:10.1016/j.ebr.2022.100549

Cited by 6 publications

(8 citation statements)

References 31 publications

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“…Five SNVs have been previously reported in published patients. 19 11 variants are unpublished: 3 nonsense SNVs–p. (Glu105*), p.(Tyr733*), and p.(Glu522*); 5 frameshifts SNVs–p.…”

Section: Resultsmentioning

confidence: 99%

“…While BRAT1 encephalopathy is considered ultra-rare, with less than 30 patients reported, 19 it is most likely underdiagnosed. For instance, previous reports of severe, even lethal, cases of hyperekplexia may have included infants with BRAT1 encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, this study does not represent the whole spectrum of BRAT1 -associated disorders, which also includes the late-onset milder phenotype. 19 Neuropathologic examination was performed only in 3 infants of different ages, which limits the generalization of results. In addition, postnatal exposure to environmental factors, including chronic hypoxia, may have contributed to neuronal apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…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. 11-19 Yet, most neonates were diagnosed only later in life or after death, and the reported electroclinical data were often limited to a late stage. 5,13-15,20 We aimed to define the neonatal electroclinical phenotype of BRAT1 encephalopathy to improve early recognition and allow early diagnosis in the neonatal intensive care unit (ICU), orienting workup and management and providing families with appropriate counseling.…”

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confidence: 99%

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Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

et al. 2023

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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.

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“…Five SNVs have been previously reported in published patients. 19 11 variants are unpublished: 3 nonsense SNVs–p. (Glu105*), p.(Tyr733*), and p.(Glu522*); 5 frameshifts SNVs–p.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

et al. 2023

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“…2,3 As BRAT1 variants are not as well reported in adults, the prevalence of BRAT1-associated adult epilepsy is not as well known. [2][3][4][5] To the authors' knowledge, there have been no reports of adult-onset BRAT1-associated leukodystrophy. Herein, we describe a case of the BRAT1 variant with associated progressive leukodystrophy associated with cognitive and motor decline exacerbated by exposure to lymphomadirected chemotherapy and trimethoprim-sulfamethoxazole (TMP/SMX).…”

Section: Discussionmentioning

confidence: 99%

BRAT1-Associated Leukodystrophy Exacerbated by Classic Hodgkin Lymphoma–Directed Therapy

Hooshmand,

Chohan,

Raghunathan

et al. 2023

The Neurologist

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Introduction: BRCA1-associated ataxia-telangiectasia–mutated activator-1 (BRAT1) is responsible for cell cycle surveillance and mitochondrial function. The implications of adult-onset BRAT1-variant and the resulting phenotypic neurocognitive and imaging features have not been previously described. Case Report: A 66-year-old man with a recent diagnosis of classic Hodgkin lymphoma was referred to neuro-oncology for cognitive and motor decline, and progressive cerebral white matter changes noted on magnetic resonance imaging (MRI). A neurological examination revealed global weakness, broad-based gait, and bilateral extensor plantar responses. Brain MRI demonstrated periventricular, deep, and subcortical white matter T2/FLAIR hyperintensities without contrast enhancement. Cerebral spinal fluid studies were unremarkable. A GeneDX genetic leukodystrophy panel conduction revealed a pathogenic variant (c.294dupA; p.L99TfsX92) resulting in a truncated protein of BRAT1, along with a variant of uncertain significance (c.746A>G;p.E249G). A presumptive diagnosis of late-onset leukoencephalopathy secondary to the BRAT1 variant was made. In an attempt to combat his mitochondrial dysfunction, he was initiated on a mitochondrial cocktail, including B-100 complex and coenzyme Q10. He began lymphoma-directed combination chemotherapy and developed precipitous functional decline after 2 cycles of therapy. Compared with prechemotherapy imaging, repeat positron emission tomography/computed tomography metabolic imaging showed a response after 3 cycles of chemotherapy; however, repeat brain MRI showed worsening diffuse white matter hyperintensities and cerebral atrophy. Conclusion: Given the variability in phenotypes and clinical onset, leukodystrophies can be a diagnostic challenge. This case demonstrated progressive BRAT1-associated leukodystrophy exacerbated by chemotherapy-induced toxic leukoencephalopathy. Mitochondrial energy deficiency in the context of multiple metabolic insults was likely underlying the progressive neurological decline observed in this case of genetic leukodystrophy.

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Hochdurchsatzsequenzierung in der Neonatologie: Chancen und Risiken

Rudnik-Schöneborn,

Ralser,

Konzett

2024

Monatsschr Kinderheilkd

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ZusammenfassungGenetische Erkrankungen, die bereits pränatal oder in der frühen Neonatalperiode klinisch auffällig werden, stellen an betreuende Ärzte besondere Anforderungen. Die Klärung von genetischen Verdachtsdiagnosen steht in der Mehrzahl der Fälle unter großem Zeitdruck und schwerer emotionaler Belastung der betroffenen Eltern. Die korrekte Diagnose kann eine kurative Therapie zur Folge und dann einen wesentlichen Einfluss auf die Prognose für das Kind haben. Auch ohne Therapieoptionen ist die rasche genetische Diagnose beim kranken Neugeborenen von großer Bedeutung für den Rückzug aus einer möglicherweise belastenden klinischen Diagnostik und das Einleiten einer palliativen Pflege.Nach größeren Studien aus den letzten 10 Jahren zur genetischen Diagnostik in der pädiatrischen und neonatologischen Intensivmedizin kann durch Hochdurchsatzsequenzierung eine genetische Diagnose wahrscheinlich bei bis zu 30–50 % der Patienten gestellt werden. Zu bedenken ist, dass nicht immer ein klarer Bezug zwischen Erbgutveränderung und klinischem Bild besteht, wodurch gerade bei unspezifisch kranken Neugeborenen das Risiko einer diagnostischen Fehlinterpretation gegeben ist. Eine enge interdisziplinäre Zusammenarbeit zwischen Ärzten für Kinderheilkunde und Humangenetik ist unabdingbar für eine komplexe genetische Diagnostik. Ethisch schwierige Fragen können sich aus genetischen Zusatzbefunden ergeben; diese sind nicht nur für die (spätere) Gesundheit des Kindes, sondern auch die der ganzen Familie relevant. Anhand von 4 Fallbeispielen illustriert der vorliegende Beitrag die Chancen, aber auch die Risiken, die sich aus den aktuellen Möglichkeiten der genetischen Analysen ergeben.

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A review of the clinical spectrum of BRAT1 disorders and case of developmental and epileptic encephalopathy surviving into adulthood

Cited by 6 publications

References 31 publications

Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

BRAT1-Associated Leukodystrophy Exacerbated by Classic Hodgkin Lymphoma–Directed Therapy

Hochdurchsatzsequenzierung in der Neonatologie: Chancen und Risiken

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