SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model.

The Birth Prevalence of Spinal Muscular Atrophy: A Population Specific Approach in Estonia.

Rare diseases are an important population health issue and many promising therapies have been developed in recent years. In light of novel genetic treatments expected to significantly improve spinal muscular atrophy (SMA) patients' quality of life and the urgent need for SMA newborn screening (NBS), new epidemiological data were needed to implement SMA NBS in Estonia. We aimed to describe the birth prevalence of SMA in the years 1996-2020 and to compare the results with previously published data.

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in , encoding a K48/K63 linkage-specific deubiquitylase.

Trait impulsivity in Juvenile Myoclonic Epilepsy.

Objective: Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta-analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) moderated by specific seizure characteristics; and (iii) associated with psychiatric adverse effects of antiepileptic drugs (AEDs).

Long-term neurodevelopmental outcome after perinatal arterial ischemic stroke and periventricular venous infarction.

Background: Long-term follow-up data after different vascular types of ischemic perinatal stroke is sparse. Our aim was to study neurodevelopmental outcomes following neonatal and presumed perinatal ischemic middle cerebral artery territory stroke (arterial ischemic stroke, AIS) and periventricular venous infarction (PVI).

Methods: A prospective consecutive cohort of 40 term-born children with perinatal stroke (21 AIS, 19 PVI) was identified through the Estonian Paediatric Stroke Database.

Effectiveness of whole exome sequencing in unsolved patients with a clinical suspicion of a mitochondrial disorder in Estonia.

Objective: Reaching a genetic diagnosis of mitochondrial disorders (MDs) is challenging due to their broad phenotypic and genotypic heterogeneity. However, there is growing evidence that the use of whole exome sequencing (WES) for diagnosing patients with a clinical suspicion of an MD is effective (39-60%). We aimed to study the effectiveness of WES in clinical practice in Estonia, in patients with an unsolved, but suspected MD.

Epilepsy after perinatal stroke with different vascular subtypes.

Objective: With an incidence up to 63 per 100,000 live births, perinatal stroke is an important cause of childhood epilepsy. The aim of the study was to find the prevalence of and predictive factors for epilepsy, and to describe the course of epilepsy in children with perinatal stroke with different vascular subtypes.

Methods: Patients were retrieved from the Estonian Paediatric Stroke Database with follow-up time at least 24 months.

Incidence of Childhood Epilepsy in Estonia.

The aim of this prospective epidemiological study was to establish the incidence rate of childhood epilepsy in Estonia, to describe the clinical spectrum and to identify etiology of childhood epilepsy. The overall incidence rate was 86.3/100 000.

Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency.

Variants in the SPATA5 gene were recently described in a cohort of patients with global developmental delay, sensorineural hearing loss, seizures, cortical visual impairment and microcephaly. SPATA5 protein localizes predominantly in the mitochondria and is proposed to be involved in mitochondrial function and brain developmental processes. However no functional studies have been performed.

Resting-State Functional Connectivity and Cognitive Impairment in Children with Perinatal Stroke.

Perinatal stroke is a leading cause of congenital hemiparesis and neurocognitive deficits in children. Dysfunctions in the large-scale resting-state functional networks may underlie cognitive and behavioral disability in these children. We studied resting-state functional connectivity in patients with perinatal stroke collected from the Estonian Pediatric Stroke Database.

Mutations in GABRB3: From febrile seizures to epileptic encephalopathies.

Objective: To examine the role of mutations in GABRB3 encoding the β subunit of the GABA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes.

Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs.

Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families.

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies.

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood.

CDKL5 Gene-Related Epileptic Encephalopathy in Estonia: Four Cases, One Novel Mutation Causing Severe Phenotype in a Boy, and Overview of the Literature.

Cyclin-dependent kinase-like 5 () gene mutations have mainly been found in females with early infantile epileptic encephalopathy (EIEE), severe intellectual disability, and Rett-like features. To date, only 22 boys have been reported, presenting with far more severe phenotypic features. We report the first cases of gene-related EIEE in Estonia diagnosed using panels of epilepsy-associated genes and describe the phenotype-genotype correlations in three male and one female patient.

Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies.

Objective: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations.

Methods: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected.

Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy.

The CACNA1A gene encodes the transmembrane pore-forming alpha-1A subunit of the Cav 2.1 P/Q-type voltage-gated calcium channel. Several heterozygous mutations within this gene, including nonsense mutations, missense mutations, and expansion of cytosine-adenine-guanine repeats, are known to cause three allelic autosomal dominant conditions-episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6.

De novo exonic mutation in MYH7 gene leading to exon skipping in a patient with early onset muscular weakness and fiber-type disproportion.

Here we report on a case of MYH7-related myopathy in a boy with early onset of muscular weakness and delayed motor development in infancy. His most affected muscles were neck extensors showing a dropped head sign, proximal muscles of lower limbs with positive Gower's sign, and trunk muscles. Brain and spinal cord MRI scans, echocardiography, and laboratory analyses including creatine kinase and lactate did not reveal any abnormalities.

Presumed Perinatal Stroke: Risk Factors, Clinical and Radiological Findings.

It is unknown why some infants with perinatal stroke present clinical symptoms late during infancy and will be identified as infants with presumed perinatal stroke. The risk factors and clinical and radiological data of 42 infants with presumed perinatal stroke (69% with periventricular venous infarction and 31% with arterial ischemic stroke) from the Estonian Pediatric Stroke Database were reviewed. Children with presumed perinatal stroke were born at term in 95% of the cases and had had no risk factors during pregnancy in 43% of the cases.

Clinical Phenotype of De Novo Mutation: Case Report and Review of Literature.

Mutations in the guanine nucleotide-binding protein (G protein), α activating activity polypeptide O () gene have recently been described in 6 patients with early infantile epileptic encephalopathies. In the present study, we report the phenotype and the clinical course of a 4-year-old female with an epileptic encephalopathy (Ohtahara syndrome) and profound intellectual disability due to a de novo mutation (c.692A>G; p.

De novo deletion of HOXB gene cluster in a patient with failure to thrive, developmental delay, gastroesophageal reflux and bronchiectasis.

We report a female patient with a complex phenotype consisting of failure to thrive, developmental delay, congenital bronchiectasis, gastroesophageal reflux and bilateral inguinal hernias. Chromosomal microarray analysis revealed a 230 kilobase deletion in chromosomal region 17q21.32 (arr[hg19] 17q21.

Mosaicism for maternal uniparental disomy 15 in a boy with some clinical features of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is caused by the lack of paternal expression of imprinted genes in the human chromosomal region 15q11.2-q13.2, which can be due to an interstitial deletion at 15q11.

Monosomy 1p36 - a multifaceted and still enigmatic syndrome: four clinically diverse cases with shared white matter abnormalities.

Monosomy 1p36 is the most common subtelomeric deletion syndrome seen in humans. Uniform features of the syndrome include early developmental delay and consequent intellectual disability, muscular hypotonia, and characteristic dysmorphic facial features. The gene-rich nature of the chromosomal band, inconsistent deletion sizes and overlapping clinical features have complicated relevant genotype-phenotype correlations.

De novo SCN8A mutation identified by whole-exome sequencing in a boy with neonatal epileptic encephalopathy, multiple congenital anomalies, and movement disorders.

Epileptic encephalopathies represent a clinically and genetically heterogeneous group of disorders, majority of which are of unknown etiology. We used whole-exome sequencing of a parent-offspring trio to identify the cause of early infantile epileptic encephalopathy in a boy with neonatal seizures, movement disorders, and multiple congenital anomalies who died at the age of 17 months because of respiratory illness and identified a de novo heterozygous missense mutation (c.3979A>G; p.