A Diagnostic Algorithm for Mitochondrial Disorders in Estonian Children.

Mitochondrial disorders are a heterogeneous group of disorders affecting energy production of the body. Different consensus diagnostic criteria for mitochondrial disorders in childhood are available - Wolfson, Nijmegen and modified Walker criteria. Due to the extreme complexity of mitochondrial disorders in children, we decided to develop a diagnostic algorithm, applicable in clinical practice in Estonia, in order to identify patients with mitochondrial disorders among pediatric neonatology and neurology patients. Additionally, it was aimed to evaluate the live-birth prevalence of mitochondrial disorders in childhood. During the study period (2003-2009), a total of 22 children were referred to a muscle biopsy in suspicion of mitochondrial disorder based on the preliminary biochemical, metabolic and instrumental investigations. Enzymatic and/or molecular analysis confirmed mitochondrial disease in 5 of them - an SCO2 gene (synthesis of cytochrome c oxidase, subunit 2) defect, 2 cases of pyruvate dehydrogenase complex deficiency and 2 cases of combined complex I and IV deficiency. The live-birth prevalence for mitochondrial defects observed in our cohort was 1/20,764 live births. Our epidemiological data correlate well with previously published epidemiology data on mitochondrial diseases in childhood from Sweden and Australia, but are lower than in Finland.

Use of botulinum neurotoxin A in uncontrolled salivation in children with cerebral palsy: a pilot study.

This study investigated the safety and efficacy of botulinum neurotoxin type-A (BNT-A) injections into the salivary glands for treatment of sialorrhea in children with cerebral palsy (CP) and assessed the clinical factors that affect treatment outcome. The parotid and submandibular glands of nine CP patients were injected with BNT-A 1.4 U/kg in each parotid gland, and 0.6 U/kg in each submandibular gland. All children had neurological disorders. Gross motor function classification system levels ranged from I to V. All children had moderate to severe intellectual disability. A telephone interview with one parent determined response to treatment. Drooling intensity and frequency were measured with the drooling severity and frequency scale. After BNT-A treatment, the patients were followed up for 6 months using self-assessed rating scales for drooling intensity, discomfort and treatment effect (drooling impact scale). All parents reported an improvement in sialorrhea in the first week. Drooling was very intensive at baseline, and moderate 2 weeks after treatment. Maximum response occurred at 2-8 weeks. The use of BNT-A in uncontrolled salivation in children with CP can be considered acceptable and effective. Malocclusion and anterior salivation are closely related clinical characteristics and should be taken into account when planning treatment.

Whole Xp Deletion in a Girl with Mental Retardation, Epilepsy, and Biochemical Features of OTC Deficiency.

Background: Females with a total or partial deletion of the short arm of the X chromosome have variable features of Turner syndrome, but mental retardation (MR) rarely occurs. The haploinsufficiency of deleted genes that escape X-inactivation may explain the occurrence of MR and autism. Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder and is inherited in an X-linked semi-dominant trait, and the OTC gene maps to Xp21. Methods: We report on a girl with MR, epilepsy and biochemical changes characteristic of OTC deficiency but no identifiable point mutation in the OTC gene. Standard G-banding cytogenetic analysis, whole genome karyotyping, and X-inactivation studies were performed to determine the genetic etiology of the OTC deficiency in the patient. Results: Cytogenetic analysis and molecular karyotyping using SNP array revealed a deletion of the whole short arm of the X chromosome (Xp22.33-p11.1). Inactivation studies also revealed a completely skewed X-inactivation. Conclusion: Our patient presented with MR, epilepsy, and some evidence of reduced OTC activity, but performed genetic studies gave no explanation for this phenotype. We hope that this case report contributes to the understanding of the underlying genetic factors of the manifestation of X-linked disorders in female patients.

The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation.

The urinary creatine:creatinine (Cr:Crn) ratio was measured in males from 49 families with a family history compatible with X-linked mental retardation (XLMR) in order to estimate the prevalence of SLC6A8 deficiency in Estonia. We identified 11 boys from 9 families with an increased urinary Cr:Crn ratio (18%). In three related boys, a hemizygous missense mutation (c.1271G>A; p.Gly424Asp) was identified. Their mother was heterozygous for the same mutation. Although many missense mutations have been described, the p.Gly424Asp mutation has not been previously reported. The clinical expression varied widely among affected males of this family. Patients 1 and 3 had relatively mild clinical expression (mild mental retardation (MR) and attention deficit disorder), but patient 2 had all typical clinical signs of SLC6A8 defect such as moderate MR, autistic features, expressive dysphasia and epilepsy. Among our patients, we saw significant problems in speech and language development combined with attention and behavioural difficulties. The number of false-positive biochemical results with increased urinary Cr:Crn ratio was higher (18%) in our study than in previous reports (1.8­10%). We therefore suggest that repeated biochemical testing should be performed before DNA sequencing analysis. Our study suggests that 2% (95% confidence limits: 0.05­11.1%) of this Estonian XLMR panel are due to mutations in the SLC6A8, which is similar to the prevalence reported in other populations. We therefore conclude that creatine transporter deficiency is a relatively common genetic disorder in males with sporadic or familiar MR and diagnostic screening of them should always include screening for SLC6A8 deficiency.

Boy with celiac disease, malformations, and ring chromosome 13 with deletion 13q32-->qter.

We describe a 2(1/2)-year-old boy with a ring chromosome 13 with distal deletion of 13q32-->qter and celiac disease.

The high frequency of coeliac disease among children with neurological disorders.

In the present study we have explored antigliadin (AGA) and antireticulin (ARA) antibody tests for the serological screening for coeliac disease (CD) of 206 children with neurological disorders. IgA- or/and IgG-type AGA was discovered in 17 (8.3%) patients and IgA-type ARA in one (0.5%) patient. A small intestinal biopsy was performed in all 18 antibody-positive patients, and villous atrophy compatible with CD was revealed in three cases (patients with either epilepsy, retardation of psychomotor development or Down's syndrome). The CD prevalence rate of 14.6 per 1000 (95% CI 7.0-22.2) found in the present study was higher than could have been anticipated on the basis of the results of our previous population studies, which indicate that CD occurs more frequently among children with neurological disorders (OR = 37.6; 95% CI 9.7-146.9). Whether this finding reflects certain immunopathogenic links between CD and particular neurological diseases needs to be studied further. In this study, we were unable, using indirect immunofluorescence testing, to demonstrate the presence of autoantibodies against brain tissue in CD and AGA-positive patients.

Prevalence of childhood epilepsy in Estonia.

PURPOSE: To establish the prevalence rate (PR) and main characteristics of childhood epilepsy in Estonia. METHODS: We performed a population-based case ascertainment of all the possible sources of medical care in seven counties of Estonia from January 1995 to December 1997. Only cases of patients from 1 month to 19 years of age with active epilepsy (i.e., at least one seizure during the last 5 years, regardless of treatment) were included. All patients were examined by a pediatric neurologist. RESULTS: Five hundred sixty cases met the study criteria on the prevalence day, December 31, 1997. The total PR was 3.6 per 1,000 population (boy/girl ratio, 1.2:1.0). The PR was the highest-4.3 per 1,000-in the 5-to-9-year-old age group. The prevalence declined markedly in children age 14 years and on. The correlation between age and PR was negative (-0.542, p < 0.0001) by regression analyses. The most frequent seizure types in the total group were primarily generalized seizures-PR 2. 1/1,000 [rate ratio (RR) 1.4, 95% confidence interval (CI) 1.2, 1.6]. The predominance of generalized seizures was significant in those younger than 10 years. In 14.8% of cases, there was a history of epilepsy among first- and second-degree relatives. Benign rolandic epilepsy-PR 0.2/1,000-was the most frequent among idiopathic syndromes, and Lennox-Gastaut syndrome-PR 0.08/1,000-was the most frequent among cryptogenic ones. Perinatal factors-PR 0.8/1,000 were the most frequently found cause of epilepsy. In 304 cases (54.2%), additional medical problems existed. CONCLUSIONS: The prevalence of childhood epilepsy was comparable with that found in developed countries. Generalized seizures predominated, and the main cause was perinatal factors.

Incidence of childhood epilepsy in Estonia.

The aim of this study has been to establish the incidence rate (IR) and main characteristics of childhood epilepsy in Estonia. A population-based prospective study was performed from January 1st 1995 to December 31st 1997 in seven counties (population of children 161202). Only cases occurring in the age range of 1 month to 19 years with active epilepsy were included. Two hundred and sixteen cases met the study criteria. The total age-adjusted IR was 45/100000. The IR was the highest, 73/100000, in the age group from 1 month to 4 years. The IR declined markedly after the age of 15 years. Primarily generalized seizures demonstrated a higher IR, 25/100000, than partial seizures, the IR of which was 20/100000. The IR of symptomatic epileptic syndromes was 16/100000, that of cryptogenic, 15.5/100000 and that of idiopathic, 13/100000. The cumulative incidence of epilepsy through age 19 was 0.13%. A family history of epilepsy was present in 13.9% of cases. In 40.7% of cases the cause of epilepsy was identified. Adverse perinatal events were the most frequent etiological factors: in 25%, IR 11/100000. In 103 cases (47.6%) additional medical problems were disclosed. Strong negative univariate association was noted between partial seizures and idiopathic etiology (OR 0.37, 95%CI 0.18, 0.72; P = 0.002) and between partial seizures and motor disability (OR 0.43, 95%CI 0.24, 0.78; P = 0.003). The incidence of childhood epilepsy in Estonia was comparable with developed countries. Generalized seizures predominated. Perinatal factors were the main causes. The idiopathic etiology and motor disability of cryptogenic and symptomatic cases were associated with generalized seizures.