Dravet Syndrome: Diagnosis and Long-Term Course

AbstractDravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures. Non-convulsive status epilepticus and epileptic encephalopathy are common. Development is normal in the first year of life, but most individuals eventually suffer from intellectual impairment. Dravet syndrome is associated with mutations in the sodium channel alpha1 subunit gene (SCN1A) in 70-80% of individuals. SCN1A mutation results in inhibition of the GABAergic inhibitory interneurons, leading to excessive neuronal excitation. The “interneuron hypothesis” is the current most accepted pathophysiological mechanism of Dravet syndrome. The mortality rate is increased significantly in Dravet syndrome. Ataxia, a characteristic crouched gait and Parkinson’s symptoms may develop in some individuals. It is likely that Dravet syndrome is underdiagnosed in adults with treatment-resistant epilepsy. Early diagnosis is important to avoid anti-seizure medications that exacerbate seizures.

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Dravet syndrome associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors

Brain Communications ◽

10.1093/braincomms/fcab033 ◽

2021 ◽

Author(s):

Ciria C Hernandez ◽

XiaoJuan Tian ◽

Ningning Hu ◽

Wangzhen Shen ◽

Mackenzie A Catron ◽

...

Keyword(s):

Gabaa Receptor ◽

De Novo ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

First Year ◽

Genes Encoding ◽

Genetic Landscape ◽

Clonic Seizures ◽

Trafficking Defects ◽

First Year Of Life

Abstract Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic-clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABAA receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABAA receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p.L215P; c.640C>T, p.R214C; c.859G>A; V287I; c.641G>A, p.R214H) and GABRG2 (c.269C>G, p.T90R; c.1025C>T, p.P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p.F331S; c.542A>T, p.Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABAA receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p.T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.

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Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1804764115 ◽

2018 ◽

Vol 115 (34) ◽

pp. E8077-E8085 ◽

Cited By ~ 46

Author(s):

Kay L. Richards ◽

Carol J. Milligan ◽

Robert J. Richardson ◽

Nikola Jancovski ◽

Morten Grunnet ◽

...

Keyword(s):

Disease Onset ◽

Intractable Epilepsy ◽

Premature Death ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

First Year ◽

Inhibitory Interneurons ◽

Loss Of Function ◽

Intracerebroventricular Infusion ◽

First Year Of Life

Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.

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CARDIOLOGICAL PROBLEMS IN THE LONG-TERM PERIOD IN CHILDREN AFTER AORTIC COARCTATION SURGERY TREATMENT IN THE FIRST YEAR OF LIFE

PEDIATRIA Journal named after G N SPERANSKY ◽

10.24110/0031-403x-2018-97-3-24-28 ◽

2018 ◽

Vol 97 (3) ◽

pp. 24-28

Author(s):

M.R. Tumanyan ◽

◽

A.A. Svobodov ◽

E.G. Levchenko ◽

A.G. Anderson ◽

...

Keyword(s):

Aortic Coarctation ◽

First Year ◽

First Year Of Life

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Muenke syndrome: long-term outcome of a syndrome-specific treatment protocol

Journal of Neurosurgery Pediatrics ◽

10.3171/2019.5.peds1969 ◽

2019 ◽

Vol 24 (4) ◽

pp. 415-422 ◽

Cited By ~ 2

Author(s):

Bianca K. den Ottelander ◽

Robbin de Goederen ◽

Marie-Lise C. van Veelen ◽

Stephanie D. C. van de Beeten ◽

Maarten H. Lequin ◽

...

Keyword(s):

Treatment Protocol ◽

First Year ◽

Ventricular Size ◽

Term Outcome ◽

Long Term Outcome ◽

Skull Growth ◽

Muenke Syndrome ◽

First Year Of Life

OBJECTIVEThe authors evaluated the long-term outcome of their treatment protocol for Muenke syndrome, which includes a single craniofacial procedure.METHODSThis was a prospective observational cohort study of Muenke syndrome patients who underwent surgery for craniosynostosis within the first year of life. Symptoms and determinants of intracranial hypertension were evaluated by longitudinal monitoring of the presence of papilledema (fundoscopy), obstructive sleep apnea (OSA; with polysomnography), cerebellar tonsillar herniation (MRI studies), ventricular size (MRI and CT studies), and skull growth (occipital frontal head circumference [OFC]). Other evaluated factors included hearing, speech, and ophthalmological outcomes.RESULTSThe study included 38 patients; 36 patients underwent fronto-supraorbital advancement. The median age at last follow-up was 13.2 years (range 1.3–24.4 years). Three patients had papilledema, which was related to ophthalmological disorders in 2 patients. Three patients had mild OSA. Three patients had a Chiari I malformation, and tonsillar descent < 5 mm was present in 6 patients. Tonsillar position was unrelated to papilledema, ventricular size, or restricted skull growth. Ten patients had ventriculomegaly, and the OFC growth curve deflected in 3 patients. Twenty-two patients had hearing loss. Refraction anomalies were diagnosed in 14/15 patients measured at ≥ 8 years of age.CONCLUSIONSPatients with Muenke syndrome treated with a single fronto-supraorbital advancement in their first year of life rarely develop signs of intracranial hypertension, in accordance with the very low prevalence of its causative factors (OSA, hydrocephalus, and restricted skull growth). This illustrates that there is no need for a routine second craniofacial procedure. Patient follow-up should focus on visual assessment and speech and hearing outcomes.

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Comparing Long‐Term Outcomes in Tracheostomy Placed in the First Year of Life

The Laryngoscope ◽

10.1002/lary.29440 ◽

2021 ◽

Author(s):

Jordan R. Salley ◽

Yann‐Fuu Kou ◽

Gopi B. Shah ◽

Romaine F. Johnson

Keyword(s):

First Year ◽

Long Term Outcomes ◽

First Year Of Life

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Efficacy and safety of fenfluramine in the treatment of Dravet syndrome - literature review

Journal of Education, Health and Sport ◽

10.12775/jehs.2022.12.01.008 ◽

2022 ◽

Vol 12 (1) ◽

pp. 106-116

Author(s):

Martyna Stefaniak ◽

Zofia Pietrzak ◽

Piotr Dzikowski ◽

Emilia Nowicka ◽

Michał Obel ◽

...

Keyword(s):

Oral Solution ◽

Dravet Syndrome ◽

First Year ◽

Efficacy And Safety ◽

Anti Epileptic Drug ◽

Drug Regimens ◽

Pulmonary Arterial ◽

First Year Of Life ◽

Patients Experience ◽

Oral Doses

Dravet Syndrome is a severe, drug-resistant, and rare epileptiform disorder that is typically presented in the first year of life in an otherwise healthy child. It is characterized by prolonged seizures that are often resistant to current anti-epileptic drug regimens, which made them poorly controlled, and almost 50% of patients experience at least four tonic-clonic seizures per month. There are three new medicines: stiripentol, cannabidiol, and fenfluramine, with documented efficacy and safety as adjunctive therapies in pharmacoresistant Dravet syndrome treatment. This study aimed to assess the efficacy and safety of fenfluramine in the treatment of Dravet syndrome. Our study material consisted of publications, which were found in PubMed, Google Scholar, and Embase databases. In order to find the proper publications, the search has been conducted with the use of a combination of keywords like: “fenfluramine”, “Dravet syndrome”, “epilepsy treatment”, “Dravet syndrome pediatric patients”. The first step was to find proper publications from the last 10 years. The second step was to carry out an overview of the found publications. Results of mentioned studies proved that in Dravet syndrome, fenfluramine provided a significantly greater reduction in convulsive seizure frequency compared with placebo. No patient developed valvular heart disease or pulmonary arterial hypertension, the side effects that occurred during its use were mild and the drug was generally well-tolerated. The bioequivalence and tolerability of single oral doses of fenfluramine hydrochloride oral solution in the fed and fasted states support drug administration without regard to meals. Fenfluramine may represent a new important treatment option for Dravet syndrome.

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THE NEPHROTIC SYNDROME IN THE FIRST YEAR OF LIFE

PEDIATRICS ◽

10.1542/peds.25.6.967 ◽

1960 ◽

Vol 25 (6) ◽

pp. 967-976

Author(s):

R. A. Parker ◽

Carolyn F. Piel

Keyword(s):

Nephrotic Syndrome ◽

Cortical Area ◽

Clinical Course ◽

Renal Pathology ◽

Electrolyte Imbalance ◽

First Year ◽

Renal Lesions ◽

Susceptibility To Infection ◽

First Year Of Life

The clinical course of nephrosis in five infants with onset of disease before 7 months of age is presented, together with evaluation of renal lesions seen at necropsy. The problems of the management of nephrosis susceptibility to infection and water and electrolyte imbalance were found to be exaggerated by the young age of the patients. The renal pathology observed in these five infants consisted of persistence of immature glomeruli and dilatation of the tubules in the cortical area. Later, the immature glomeruli and associated tubules appear to atrophy and the remaining glomeruli to hypertrophy. Long-term adrenocorticosteroid therapy seems to be contraindicated, not only on the basis of the pathologic changes, but because it greatly exaggerates the problems of management and does not effect a remission of the disease.

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