Boricua Founder Variant in FRRS1L Causes Epileptic Encephalopathy With Hyperkinetic Movements

Objective: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. Background: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. Methods: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. Results: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). Conclusions: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.

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Inherited Metabolic Disorders Presenting with Ataxia

International Journal of Molecular Sciences ◽

10.3390/ijms21155519 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5519 ◽

Cited By ~ 1

Author(s):

Grace Silver ◽

Saadet Mercimek-Andrews

Keyword(s):

Metabolic Disorders ◽

Early Death ◽

Clinical Feature ◽

Global Developmental Delay ◽

Facial Features ◽

Neurodevelopmental Outcomes ◽

Inherited Metabolic Disorder ◽

Developmental Regression ◽

Inherited Metabolic Disorders ◽

History Of

Ataxia is a common clinical feature in inherited metabolic disorders. There are more than 150 inherited metabolic disorders in patients presenting with ataxia in addition to global developmental delay, encephalopathy episodes, a history of developmental regression, coarse facial features, seizures, and other types of movement disorders. Seizures and a history of developmental regression especially are important clinical denominators to consider an underlying inherited metabolic disorder in a patient with ataxia. Some of the inherited metabolic disorders have disease specific treatments to improve outcomes or prevent early death. Early diagnosis and treatment affect positive neurodevelopmental outcomes, so it is important to think of inherited metabolic disorders in the differential diagnosis of ataxia.

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GABA Transaminase Deficiency With Survival Into Adulthood

Journal of Child Neurology ◽

10.1177/0883073818823359 ◽

2019 ◽

Vol 34 (4) ◽

pp. 216-220 ◽

Cited By ~ 2

Author(s):

Anaita U. Hegde ◽

Purva K. Karnavat ◽

R. Vyas ◽

Melissa L. DiBacco ◽

P. Ellen Grant ◽

...

Keyword(s):

Early Childhood ◽

Movement Disorder ◽

Early Onset ◽

Intractable Epilepsy ◽

Epileptic Encephalopathy ◽

Rare Disorder ◽

Aminobutyric Acid ◽

Gaba Transaminase ◽

Gaba Metabolism ◽

Developmental Impairment

γ-Aminobutyric acid (GABA)-transaminase deficiency is an ultra-rare disorder of GABA metabolism that was described for decades as an early-onset epileptic encephalopathy plus movement disorder and hypersomnolence with mortality in early childhood. We report 2 affected siblings in adolescence and adulthood, both with profound developmental impairment, intractable epilepsy, movement disorder, and behavioral fluctuations. This considerably expands the phenotype and longevity of this inherited neurotransmitter disease.

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Biological Bases of Symptomatic Generalized Epilepsies in Children

10.1093/med/9780199937837.003.0040 ◽

2017 ◽

Author(s):

Dragos A. Nita ◽

Miguel A. Cortez ◽

Jose Luis Perez Velazquez ◽

O. Carter Snead

Keyword(s):

Mental Retardation ◽

Intractable Epilepsy ◽

Epileptic Encephalopathy ◽

Global Developmental Delay ◽

Epilepsy Syndrome ◽

Mortality And Morbidity ◽

Age Related ◽

Ohtahara Syndrome ◽

Brain Involvement ◽

Myoclonic Encephalopathy

Symptomatic generalized epilepsies represent a group of challenging epilepsy syndromes, most often seen in children, which share the hallmark of a triad encompassing multiple seizure types, electroencephalographical (EEG) evidence of diffuse brain involvement, and dysfunction in the intellectual domain (global developmental delay or mental retardation). SGEs include the early myoclonic encephalopathy, early infantile epileptic encephalopathy (Ohtahara syndrome), West syndrome, epilepsy with myoclonic-astatic seizures, epilepsy with myoclonic absence, Lennox-Gastaut syndrome, and the progressive myoclonic epilepsies. SGEs may arise from various genetic, developmental, or acquired brain pathologies and also can be associated with other cerebral or systemic defects and thus being part of a broader epilepsy syndrome phenotype. SGEs are associated with significant mortality and morbidity and most patients with SGE grow up to have intractable epilepsy, mental retardation, and depend on parents and institutions for the activities of the daily living. The mechanisms of SGE are numerous and heterogeneous and the EEG findings usually reflect the age-related changes as the brain matures.

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Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes

10.1101/2021.04.27.441575 ◽

2021 ◽

Author(s):

Srinivasarao Repudi ◽

Irina Kustanovich ◽

Sara Abu-Swai ◽

Shani Stern ◽

Rami I. Aqeilan

Keyword(s):

Gene Therapy ◽

Autosomal Recessive ◽

Viral Vector ◽

Intractable Epilepsy ◽

Epileptic Encephalopathy ◽

Global Developmental Delay ◽

The Central Nervous System ◽

Biallelic Mutations ◽

Brain Hyperexcitability ◽

Wwox Gene

AbstractWW domain-containing oxidoreductase (WWOX) is an emerging neural gene regulating homeostasis of the central nervous system. Germline biallelic mutations in WWOX cause WWOX-related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia, and autosomal recessive 12 (SCAR12), two devastating neurodevelopmental disorders with highly heterogenous clinical outcomes, the most common being severe epileptic encephalopathy and profound global developmental delay. We recently demonstrated that neuronal ablation of murine Wwox recapitulates phenotypes of Wwox-null mice leading to intractable epilepsy, hypomyelination and postnatal lethality. Here, we designed and produced an adeno-associated viral vector harboring murine Wwox or human WWOX cDNA and driven by the human neuronal Synapsin I promoter (AAV-SynI-WWOX). Testing the efficacy of AAV-SynI-WWOX delivery in Wwox null mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, and myelination deficits as well as the premature lethality of Wwox-null mice. These findings provide a proof-of-concept for WWOX gene therapy as a promising approach to curing children with WOREE and SCAR12.

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Acute Strokelike Presentation and Long-term Evolution of Diffusion Restriction Pattern in Ethylmalonic Encephalopathy

Journal of Child Neurology ◽

10.1177/08830738211006507 ◽

2021 ◽

pp. 088307382110065

Author(s):

Jaehyung Lim ◽

Brian J. Shayota ◽

Erica Lay ◽

Sarah H. Elsea ◽

Mir Reza Bekheirnia ◽

...

Keyword(s):

Autosomal Recessive ◽

Mitochondrial Disorder ◽

Brain Magnetic Resonance Imaging ◽

Restriction Pattern ◽

Spastic Diplegia ◽

Ethylmalonic Encephalopathy ◽

Developmental Regression ◽

Downstream Effects ◽

Cystic Changes

Ethylmalonic encephalopathy is a rare autosomal recessive mitochondrial disorder caused by pathogenic biallelic variants in the ETHE1 gene. The phenotype of this disease has been attributed to deficiency in the mitochondrial sulfur dioxygenase leading to many downstream effects. Ethylmalonic encephalopathy classically presents with developmental regression, petechiae, acrocyanosis, and chronic diarrhea. The neurologic phenotype includes hypotonia, spastic diplegia, ataxia, and developmental delay. As more patients with this condition are described, the neurologic phenotype continues to expand. Although strokelike episodes or metabolic strokes have been studied in other mitochondrial disorders, they have not been thoroughly reported in this disorder. Herein, we describe 3 patients with ethylmalonic encephalopathy who presented clinically with strokelike episodes and strokelike abnormalities on brain magnetic resonance imaging in the setting of acute illness, and the long-term sequelae with evolution into cystic changes in one of these subjects.

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Sleep Exacerbations and Facial Twitching: Diagnostic Clues for ADCY5-Related Dyskinesias

Neuropediatrics ◽

10.1055/s-0040-1721685 ◽

2020 ◽

Author(s):

Margherita Nosadini ◽

Gianluca D'Onofrio ◽

Maria Federica Pelizza ◽

Concetta Luisi ◽

Davide Padrin ◽

...

Keyword(s):

Movement Disorder ◽

Developmental Delay ◽

De Novo ◽

Brain Magnetic Resonance Imaging ◽

Neurological Impairment ◽

De Novo Mutation ◽

Oligoclonal Bands ◽

Emotional Stimuli ◽

Childhood Onset ◽

Ataxic Gait

Abstract Background Mutations in the adenylate cyclase 5 (ADCY5) gene are associated with childhood-onset paroxysmal dyskinesia. Methods We report a new video-documented case of pediatric ADCY5-related dyskinesia with de novo ADCY5 mutation. Results A boy born to nonconsanguineous parents after an uneventful pregnancy had developmental delay and hypotonia. At the age of 7 months, he presented with paroxysmal jerky–choreic–dystonic involuntary movements in wakefulness involving limbs, trunk, and face, exacerbated by emotional stimuli. These episodes gradually worsened in duration and frequency: at the age of 2.5 years, they occurred up to six times per day, and appeared also during sleep in prolonged bouts; the boy also had basal choreoathetoid–dystonic movements, hyperactivity, paraparetic–ataxic gait, generalized hypotonia with brisk tendon reflexes, drooling, and language delay with intellectual disability. Brain magnetic resonance imaging, electroencephalogram, electromyogram, eye review, metabolic investigations, oligoclonal bands, and autoantibodies were normal. Extensive genetic testing had not let to a diagnosis, until a heterozygous de novo mutation c.1252C > T (p.Arg418Trp) was identified in the ADCY5 gene. Clonazepam had partial effectiveness. The boy walked at the age of 3.5 years. At the age of 5 years, the paroxysmal movement disorder has slightly improved. Conclusion ADCY5 mutations should be considered among the differential diagnoses of early-onset paroxysmal choreic–athetosic–myoclonic–dystonic movement disorder involving limbs, trunk, and face, in patients with global neurological impairment with hypotonia and developmental delay. Facial dyskinesias and exacerbation by drowsiness/sleep and emotional stimuli are important clues that may allow a timely recognition of the disorder and avoidance of unnecessary diagnostic investigations.

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Frontal Hypoperfusion and the Effectiveness of Perampanel in Long-Lived Patient with Lafora Disease

Case Reports in Neurology ◽

10.1159/000514243 ◽

2021 ◽

pp. 211-217

Author(s):

Koji Obara ◽

Erika Abe ◽

Itaru Toyoshima

Keyword(s):

Single Photon ◽

Early Stage ◽

Photon Emission ◽

Cerebellar Atrophy ◽

Brain Magnetic Resonance Imaging ◽

Emission Computed Tomography ◽

Homozygous Mutation ◽

Lafora Disease ◽

Mental Deterioration ◽

Exon 1

We report a long-lived patient with Lafora disease (LD). A 34-year-old woman experienced onset of seizures at the age of 11 years. She was bedridden in her early twenties due to frequent generalized tonic-clonic seizures, myoclonus, and progressive mental deterioration. Her seizures occurred all the time despite administration of multiple anticonvulsants at high doses. At the age of 31, she started perampanel, which resulted in reduction of anticonvulsants after her visible myoclonus and convulsions disappeared. Brain magnetic resonance imaging showed marked cerebral and cerebellar atrophy, and single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine (IMP-SPECT) revealed significant hypoperfusion of the frontal lobe and cerebellum. We identified a W219R homozygous mutation in exon 1 of the NHLRC1 gene. Because perampanel may not only control seizures but also prevent mental deterioration in LD, we propose that perampanel should be administered from the early stage of LD.

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Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novoGRIN2Amutation

Epilepsia ◽

10.1111/epi.12663 ◽

2014 ◽

Vol 55 (7) ◽

pp. e75-e79 ◽

Cited By ~ 19

Author(s):

Sunita Venkateswaran ◽

Ken A. Myers ◽

Amanda C. Smith ◽

Chandree L. Beaulieu ◽

Jeremy A. Schwartzentruber ◽

...

Keyword(s):

Exome Sequencing ◽

Developmental Delay ◽

Whole Exome Sequencing ◽

Intractable Epilepsy ◽

Global Developmental Delay ◽

Whole Exome

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Beneficial effects of the ketogenic diet on drug-resistant epileptic encephalopathy associated with a de novo NBEA pathogenic variant

Epileptic Disorders ◽

10.1684/epd.2021.1327 ◽

2021 ◽

Vol 23 (5) ◽

pp. 739-743

Author(s):

Silvia Schiavoni ◽

Carlotta Spagnoli ◽

Susanna Rizzi ◽

Grazia Gabriella Salerno ◽

Daniele Frattini ◽

...

Keyword(s):

Ketogenic Diet ◽

De Novo ◽

Epileptic Encephalopathy ◽

Pathogenic Variant ◽

Drug Resistant ◽

Beneficial Effects

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Mutations in NOTCH3 Gene may Promote the Clinical Presentation of Spinocerebellar Ataxia Type 37 Caused by Mutations in DAB1 Gene

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.668312 ◽

2021 ◽

Vol 8 ◽

Author(s):

Zhao-Wei Wang ◽

Li-Ping Wang ◽

Ye Du ◽

Qi Liu

Keyword(s):

Spinocerebellar Ataxia ◽

Sanger Sequencing ◽

Autosomal Dominant ◽

Bioinformatics Analysis ◽

Clinical Presentation ◽

Cerebellar Atrophy ◽

Gene Mutations ◽

Brain Magnetic Resonance Imaging ◽

Diagnostic Methods ◽

Spinocerebellar Ataxia Type

Background: Autosomal dominant spinocerebellar ataxia type 37 (SCA37) and Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) result from DAB1 and NOTCH3 gene mutations, respectively.Methods: In addition to conventional diagnostic methods, next-generation sequencing (NGS) and Sanger sequencing were performed to define and confirm the DAB1 and NOTCH3 gene mutation for a Chinese pedigree. Bioinformatics analysis was also applied for the mutated DAB1 and NOTCH3 protein using available software tools.Results: Brain magnetic resonance imaging shows diffuse leukoencephalopathy and cerebellar atrophy in the proband. NGS and Sanger sequencing identified two novel heterozygous mutations: NM_021080:c.318T > G (p.H106Q) in the DAB1 gene and NM_000435:c.3298C > T (p.R1100C) in the NOTCH3 gene. Bioinformatics analysis suggested that the DAB1 and NOTCH3 gene mutations are disease-causing and may be responsible for the phenotypes.Conclusion: This is the first report of a pedigree with both SAC37 and CADASIL phenotypes carrying corresponding gene mutations. Mutations in the NOTCH3 gene may promote the clinical presentation of spinocerebellar ataxia type 37 caused by mutations in the DAB1 gene. In addition to general examinations, it is vital for physicians to apply molecular genetics to get an accurate diagnosis in the clinic, especially for rare diseases.

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