Early-onset rapidly progressive myoclonic epilepsy associated with G392R likely pathogenic variant in SERPINI1

Kara, Bülent; Sarıkaya, Cansu Eğilmez; Bayrak, Yunus Emre; Güneş, Ayfer Sakarya; Güngör, Mesut; Yeşil, Gözde

doi:10.1016/j.seizure.2020.06.022

Cited by 5 publications

(6 citation statements)

References 4 publications

(12 reference statements)

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“…Clinicians should be aware that patients with neuroserpinosis developed frontal de cits including inattention and disinhibition at the early stage of the disease. Similar to our case, multiple cases have presented with frontal de cits including inattention or hyperactivity at the initial phase 4,[6][7][8][9][10] . Additionally, pediatric patients can be misdiagnosed with attention-de cit hyperactivity disorder (ADHD) 9 because the initial symptoms of neuroserpinosis, such as inattention and hyperactivity, can be di cult to differentiate from those of ADHD.…”

Section: Discussionsupporting

confidence: 76%

“…Similar to our case, multiple cases have presented with frontal de cits including inattention or hyperactivity at the initial phase 4,[6][7][8][9][10] . Additionally, pediatric patients can be misdiagnosed with attention-de cit hyperactivity disorder (ADHD) 9 because the initial symptoms of neuroserpinosis, such as inattention and hyperactivity, can be di cult to differentiate from those of ADHD. These characteristic frontal de cits can be explained by the autopsy ndings of individuals with neuroserpinosis, which revealed that the most of the frontal areas were considerably atrophic and abundant in Collins bodies 4,5 .…”

Section: Discussionsupporting

confidence: 76%

“…Although a few case reports on neuroserpinosis reported that the frontal area is predominantly affected in the early stage of the disease and other brain regions were involved in the late stage of the disease 1,4 , the other case reports suggested that the clinical presentation of neuroserpinosis is indistinguishable from the other causes of progressive myoclonic epilepsies (PMEs, the syndrome that shares epilepsy, cognitive deterioration, and action myoclonus) and that brain magnetic resonance imaging (MRI) in patients with neuroserpinosis shows nonspeci c brain atrophy. Therefore, it has been suggested that only pathological studies or whole genome sequencing can distinguish this disease from other causes of PME [5][6][7][8][9][10] . However, previous reports have not fully described the cognitive dysfunction and brain MRI abnormality of early-stage neuroserpinosis.…”

Section: Introductionmentioning

confidence: 99%

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Frontal deficits and atrophy in a patient with neuroserpinosis detected by single-case voxel-based morphometry: A case report

Handa,

Sugiyama,

Kaname

et al. 2023

Preprint

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Background: Neuroserpinosis is a rare genetic disorder characterized by progressive cognitive decline and myoclonic epilepsy, caused by pathogenic variants of SERPINI1. We reported a case of genetically confirmed neuroserpinosis with de novo H338R mutation in the SERPINI1, in which frontal deficits including inattention and disinhibition, and relevant atrophy in the vmPFC on brain MRI were observed in the early stage of the disease. Case presentation: A 23-year-old Japanese man presented with progressive inattention and disinhibition over 4 years followed by myoclonic epilepsy. The whole-genome sequencing and filtering analysis showed de novoheterozygous H338R mutation in the SERPINI1, confirming the diagnosis of neuroserpinosis. Single-case voxel-based morphometry using brain magnetic resonance imaging obtained at the initial visit revealed focal gray matter volume loss in the ventromedial prefrontal cortices, which is presumed to be associated with inattention and disinhibition. Conclusion: Frontal deficits including inattention and disinhibition can be the presenting symptoms of patients with neuroserpinosis. Single-case voxel-based morphometry may be useful for detecting regional atrophy of the frontal lobe in neuroserpinosis. Detecting these abnormalities in the early stage of disease may be key findings for differentiating neuroserpinosis from other causes of progressive myoclonic epilepsy.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Frontal deficits and atrophy in a patient with neuroserpinosis detected by single-case voxel-based morphometry: A case report

Handa,

Sugiyama,

Kaname

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Similar to our case, multiple cases have presented with frontal deficits including inattention or hyperactivity at the initial phase [ 5 , 7 – 11 ]. Additionally, pediatric patients can be misdiagnosed with attention-deficit hyperactivity disorder (ADHD) [ 10 ] because the initial symptoms of FENIB, such as inattention and hyperactivity, can be difficult to differentiate from those of ADHD. These characteristic frontal deficits can be explained by the autopsy findings of individuals with FENIB, which revealed that the most of the frontal areas were considerably atrophic and abundant in Collins bodies [ 5 , 6 ].…”

Section: Discussionmentioning

confidence: 99%

Frontal deficits and atrophy in a patient with familial encephalopathy with neuroserpin inclusion bodies detected by single-case voxel-based morphometry: a case report

Handa,

Sugiyama,

Kaname

et al. 2024

BMC Neurol

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Background Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare genetic disorder characterized by progressive cognitive decline and myoclonic epilepsy, caused by pathogenic variants of SERPINI1. We reported a case of genetically confirmed FENIB with de novo H338R mutation in the SERPINI1, in which frontal deficits including inattention and disinhibition, and relevant atrophy in the vmPFC on brain MRI were observed in the early stage of the disease. Case presentation A 23-year-old Japanese man presented with progressive inattention and disinhibition over 4 years followed by myoclonic epilepsy. The whole-genome sequencing and filtering analysis showed de novo heterozygous H338R mutation in the SERPINI1, confirming the diagnosis of FENIB. Single-case voxel-based morphometry using brain magnetic resonance imaging obtained at the initial visit revealed focal gray matter volume loss in the ventromedial prefrontal cortices, which is presumed to be associated with inattention and disinhibition. Conclusion Frontal deficits including inattention and disinhibition can be the presenting symptoms of patients with FENIB. Single-case voxel-based morphometry may be useful for detecting regional atrophy of the frontal lobe in FENIB. Detecting these abnormalities in the early stage of disease may be key findings for differentiating FENIB from other causes of progressive myoclonic epilepsy.

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“…8,9 The variant, SERPINI1 c.1175 G>A (p.Gly392Glu) causes one of the most severe form of FENIB, characterized by absence seizures, myoclonic and tonic-clonic seizures, and progressive dementia begin in late childhood to early adolescence. 9,10 There are no disease-modifying therapies. 11,12…”

Section: Introductionmentioning

confidence: 99%

Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing

Konishi,

Moulayes,

Butola

et al. 2024

Preprint

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Altered protein conformation can cause incurable neurodegenerative disorders. Mutations inSERPINI1, the gene encoding neuroserpin, alter protein conformation resulting in cytotoxic aggregation in neuronal endoplasmic reticulum. Aggregates cause oxidative stress impairing function, leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy. Patients present with seizures and cognitive impairments that progress to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring the patient's pathogenicSERPINI1variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). FENIB cells form neuroserpin inclusions which increase in size and number. Here, we utilized a personalized adenine base editor (ABE)-mediated approach to efficiently correct the pathogenic variant and to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted neuronal impairments. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery. Preventing mutant protein with altered conformation production improved toxic protein clearance. Our findings provide a targeted strategy and may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimer's and Huntington's diseases.

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Early-onset rapidly progressive myoclonic epilepsy associated with G392R likely pathogenic variant in SERPINI1

Cited by 5 publications

References 4 publications

Frontal deficits and atrophy in a patient with neuroserpinosis detected by single-case voxel-based morphometry: A case report

Frontal deficits and atrophy in a patient with neuroserpinosis detected by single-case voxel-based morphometry: A case report

Frontal deficits and atrophy in a patient with familial encephalopathy with neuroserpin inclusion bodies detected by single-case voxel-based morphometry: a case report

Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing

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