Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia.

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

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. We also show our first results of mtDNA analysis obtained from standard WES reads. METHODS: Retrospective cases were selected from a database of 181 patients whose fibroblast cell cultures had been stored from 2003 to 2013. Prospective cases were selected during the period of 2014-2016 from patients referred to a clinical geneticist in whom an MD was suspected. We scored each patient according to the mitochondrial disease criteria (MDC) (Morava et al., 2006) after re-evaluation of their clinical data, and then performed WES analysis. RESULTS: A total of 28 patients were selected to the study group. A disease-causing variant was found in 16 patients (57%) using WES. An MD was diagnosed in four patients (14%), with variants in the SLC25A4, POLG, SPATA5, and NDUFB11 genes. Other variants found were associated with a neuromuscular disease (SMN1, MYH2, and LMNA genes), neurodegenerative disorder (TSPOAP1, CACNA1A, ALS2, and SCN2A genes), multisystemic disease (EPG5, NKX1-2, ATRX, and ABCC6 genes), and one in an isolated cardiomyopathy causing gene (MYBPC3). The mtDNA point mutation was found in the MT-ATP6 gene of one patient upon mtDNA analysis. CONCLUSIONS: The diagnostic yield of WES in our cohort was 57%, proving to be a very good effectiveness. However, MDs were found in only 14% of the patients. We suggest WES analysis as a first-tier method in clinical genetic practice for children with any multisystem, neurological, and/or neuromuscular problem, as nuclear DNA variants are more common in children with MDs; a large number of patients harbor disease-causing variants in genes other than the mitochondria-related ones, and the clinical presentation might not always point towards an MD. We have also successfully conducted analysis of mtDNA from standard WES reads, providing further evidence that this method could be routinely used in the future.

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. The incidence rate was the highest (141.9/100 000) in the age group from 5 to 9 years. Specific electroclinical syndromes were identified in 22.8% of cases. Structural or metabolic etiology was identified in 20.0% of cases, presumed genetic origin was identified in 33.9% of cases, and in 46.1% of cases the cause of epilepsy remained unknown. The incidence rate of childhood epilepsy in Estonia (86.3/100 000) is similar to the other European countries. In comparison with the results of the first epidemiological study of childhood epilepsy in Estonia (incidence rate 45/100 000; Beilmann et al), the incidence rate in this study is almost 2 times higher, what can be explained with better case collection and improved diagnostic modalities in Estonia.

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. We describe four patients with isolated chromosome 1p36 deletions. All patients shared white matter abnormalities, allowing us to narrow the critical region for white matter involvement to the deletion size of up to 2.5 Mb from the telomere. We hypothesise that there might be a gene(s) responsible for myelin development in the 1p36 subtelomeric region. Other significant clinical findings were progressive spastic paraparesis, epileptic encephalopathy, various skeletal anomalies, Prader-Willi-like phenotype, neoplastic changes - a haemangioma and a benign skin tumour, and in one case, sleep myoclonus, a clinical entity not previously described in association with 1p36 monosomy. Combined with prior studies, our results suggest that the clinical features seen in monosomy 1p36 have more complex causes than a classical contiguous gene deletion syndrome.

Newly-diagnosed pediatric epilepsy is associated with elevated autoantibodies to glutamic acid decarboxylase but not cardiolipin.

Glutamic acid decarboxylase autoantibodies (GADA) and anti-cardiolipin autoantibodies (ACA) have been detected in adult subjects with epilepsy, though the functional implications of these findings are a matter of debate. This study aimed to determine the prevalence of GADA and ACA and to investigate their clinical significance in pediatric subjects with newly-diagnosed epilepsy. For this purpose GADA and ACA were assessed by enzyme-linked immunosorbent assays in 208 pediatric patients with newly-diagnosed epilepsy and 128 controls. The clinical data (results of electroencephalography, magnetic resonance imaging, 6-month outcome etc.) was compared to antibody test results. Our study revealed GADA in 14 (6.7%) patients with epilepsy and in 1 (0.8%) control, which was a statistically significant difference (P=0.010; Chi-square test). The GADA-positive and -negative patients had similar clinical characteristics. The prevalence of ACA in patients with epilepsy (6.3%) was not significantly different than controls (2.6%). These results suggest that GADA is associated with epilepsy in a subgroup of newly-diagnosed pediatric patients. Further studies are required to determine the prognostic significance and pathogenic role of GADA among pediatric subjects with epilepsy.

The live-birth prevalence of mucopolysaccharidoses in Estonia.

Previous studies on the prevalence of mucopolysaccharidoses (MPS) in different populations have shown considerable variations. There are, however, few data with regard to the prevalence of MPSs in Fenno-Ugric populations or in north-eastern Europe, except for a report about Scandinavian countries. A retrospective epidemiological study of MPSs in Estonia was undertaken, and live-birth prevalence of MPS patients born between 1985 and 2006 was estimated. The live-birth prevalence for all MPS subtypes was found to be 4.05 per 100,000 live births, which is consistent with most other European studies. MPS II had the highest calculated incidence, with 2.16 per 100,000 live births (4.2 per 100,000 male live births), forming 53% of all diagnosed MPS cases, and was twice as high as in other studied European populations. The second most common subtype was MPS IIIA, with a live-birth prevalence of 1.62 in 100,000 live births. With 0.27 out of 100,000 live births, MPS VI had the third-highest live-birth prevalence. No cases of MPS I were diagnosed in Estonia, making the prevalence of MPS I in Estonia much lower than in other European populations. MPSs are the third most frequent inborn error of metabolism in Estonia after phenylketonuria and galactosemia.

A novel c.2T > C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability.

Mutations in the KDM5C gene (lysine (K)-specific demethylase 5C gene; also known as JARID1C and SMCX; MIM 314690) were recently associated with X-linked intellectual disability (XLID). To date only two case reports and five studies that screen for mutations in the KDM5C gene have been published, with 21 mutations reported. Herein we present a large family with XLID caused by a novel mutation c.2T > C in the start codon of the KDM5C gene, presumably leading to loss of gene translation. Six sibs out of seven (two sons and four sisters) and their mother carry this mutation. Two affected males presented the distinctive clinical phenotype, characterized by moderate short stature, clumsy gait, ataxia, increased muscle tone and brisk tendon reflexes. They constantly bore a happy and smiling facial expression, with a protruding tongue. We hereby offer the first thorough description of five affected females with the KDM5C gene mutation. Most frequent clinical features were short stature, facial dysmorphism and developmental problems. X-chromosome inactivation study showed completely skewed inactivation pattern of mutation-carrying chromosome in all affected female patients.

Magnetic resonance imaging in children with bilateral spastic forms of cerebral palsy.

We analyzed the relationship between magnetic resonance image findings in children with bilateral spastic cerebral palsy and its stages of severity in term and preterm children. Magnetic resonance image findings of 102 children (66 male and 36 female) with bilateral spastic cerebral palsy (median age, 2.5 years; range, 3 months to 15 years) were reevaluated. The study group consisted of children with confirmed perinatal asphyxia. Hypoxic-ischemic events were diagnosed in 64% of the children. Significant abnormalities relevant to cerebral palsy were evident on imaging in 85/102 (83%) children (in 77% of term and 93% of preterm children). Enlargement of the ventricles alone (48%) or accompanied by periventricular white-matter damage (25%) was the most frequent finding in term and preterm children, but was more highly expressed in preterm children (P < 0.05). White-matter damage was more often found in preterm children (P < 0.05). Enlargement of the lateral ventricles and periventricular leukomalacia may be attributable to ischemic damage to the neonatal brain. Significant correlations were found between magnetic resonance image findings and severity of cerebral palsy (P < 0.05). Detection of brain abnormalities in children with cerebral palsy may prove useful in prognoses as well as in medical consultations and management.

A female with Angelman syndrome and unusual limb deformities.

This report presents the case of a 13-year-old female with Angelman syndrome caused by 15q11-13 microdeletion demonstrating unusual marked limb deformities with generalized osteoporosis, delayed bone age, and brachydactyly type B. The radiographs of her femur, tibia, fibula, ulna, and radius revealed curved deformities in the distal diaphysis-metaphysis areas and generalized osteoporosis. This can be explained by the patient's severe disability, delayed puberty, presumed nutritional and environmental deficits, or rickets. In addition, she had shortening of the distal phalanges of all fingers, the absence of some epiphyses of the distal phalanges, and hypertrophic and curved III metacarpal bones. These clinical findings could not be explained by classical rickets or osteoporosis, but can be classified as brachydactyly type B. To our knowledge, such marked limb deformities and brachydactyly have not previously been described in patients with Angelman syndrome.