A dynamic trinucleotide repeat (TNR) expansion in the DMD gene.

Dystrophinopathies are allelic X-linked myopathies caused by large deletions/duplications or small lesions along the DMD gene. An unexpected dynamic trinucleotide (GAA) expansion, ranging from ∼59 to 82 pure GAA repeats, within the DMD intron 62, was revealed to segregate through three family generations. From the pedigree, two female patients were referred for DMD investigation due to chronic myopathy and a muscle biopsy compatible with dystrophinopathy. As the size of the GAA repeat is limited to 11-33 within the general population our findings may provide a novel insight towards a Trinucleotide Repeat Expansion. Whether this TNR has an impact on the reported phenotype remains to be resolved.

A series of Greek children with pure hereditary spastic paraplegia: clinical features and genetic findings.

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. Adult case series dominate the literature, and there have been only a few studies in children. The purpose of this study is to describe our experience with pediatric HSP in Greece. We report the clinical and genetic findings in our patients and aim to offer insights into the diagnostic difficulties of childhood-onset disease. A series of 15 Greek children affected by pure HSP underwent extensive diagnostic investigations. Molecular analysis included whole exome sequencing (WES) or consecutive screening of candidate genes ATL1, SPAST, REEP1, and CYP7B1. WES performed in three cases yielded previously reported mutations in ATL1 and CYP7B1, and a variant c.397C>T of unknown significance in SPG7. Candidate gene screening performed in the remaining patients identified previously reported mutations in ATL1 (2), SPAST (2), and REEP1 (1), and two novel mutations, c.1636G>A and c.1413+3_6delAAGT, in SPAST. In six cases, the mutations were inherited from their parents, while in three cases, the mutations were apparently de novo. Our data confirm the genetic heterogeneity of childhood-onset pure HSP, with SPG4/SPAST and SPG3A/ATL1 being the most frequent forms. De novo occurrence of HSP does not seem to be uncommon. Candidate gene studies guided by diagnostic algorithms and WES seem both to be reasonable genetic testing strategies.

Miller-Fisher syndrome in association with enterovirus infection.

Miller-Fisher is a rare syndrome of childhood that presents with external ophthalmoplegia, ataxia, and areflexia. It has been mainly associated with a preceding Campylobacter infection and less commonly with other bacterial or viral infections. This report describes, for the first time, a child with Miller-Fisher syndrome and documented Enterovirus infection, as it was proven by the isolation of Enterovirus from cerebrospinal fluid by polymerase chain reaction testing.

Inattention, hyperactivity, impulsivity--epidemiology and correlations: a nationwide greek study from birth to 18 years.

We examined the prevalence of inattention, hyperactivity, and impulsivity (attention-deficit hyperactivity disorder [ADHD]-like symptoms) at 7 and 18 years in a Greek birth cohort, and associated factors. Information was derived from a representative sample of 2695 Greek individuals followed-up from birth to18 years through 3 questionnaire surveys (1983, 1990, 2001). At 7 years, the prevalence of hyperactivity was 7%, inattention 9.5%, and impulsivity 7% for all children, while a significant decrease was observed at 18 years. Adverse perinatal factors, poor academic performance, fights or quarrels with peers, comorbidity, and a higher frequency of physical punishment and accidents during childhood were found to be associated with ADHD-like symptoms at 7 years. Factors identified to be related with these symptoms at 18 years included male gender, maternal stress, smoking during pregnancy, physical punishment, and psychological problems in childhood. These longitudinal findings provide significant information for health and educational planning in Greece and other countries.

Childhood optic neuritis clinical features and outcome.

AIM: To describe clinical features and outcome of a series of children with first-episode optic neuritis investigated in three paediatric neurology centres. METHODS: Databases were searched to identify children (<16 years) with optic neuritis and life table analysis was used. RESULTS: 44 children (female/male ratio 1.8) median age 10.9 years were followed up for median 1 year. Optic neuritis was unilateral in 43%. Maximal visual deficit was severe (<6/60) in 77%, with full recovery in 70%. Cumulative probability of developing MS (11/44) or NMO (3/44) at 2 years was 0.45. Relapsing optic neuritis was a strong predictor for development of MS or NMO. A positive MRI (>1 brain T2 hyperintense lesion) was a strong predictor for development of MS. DISCUSSION: Childhood optic neuritis is associated with severe visual deficit with good recovery. An initial abnormal MRI brain scan or relapsing optic neuritis should alert the clinician to MS or NMO diagnosis.

Tracking of overweight and obesity in Greek youth.

OBJECTIVES: The aim of this study was to determine the prevalence and tracking of overweight and obesity in a representative sample of Greek youth and the relation with child and parental factors. METHODS: Data were derived from 2 follow-ups of the Greek 1983 National Perinatal Survey by means of a questionnaire completed by parents in 1990 and parents/adolescents in 2001. Parent- and self-reported height and weight measurements were available for 7,219 participants aged 7, and 2,842 participants aged 18. RESULTS: The overall overweight/obesity prevalence was 24.3% at age 7, and 15.1% at age 18. The overweight prevalence increased from childhood to adolescence in boys (16.1 to 19.1%) and decreased in girls (19.2 to 8.0%), while the obesity prevalence showed a decrease in both boys (6.2 to 3.6%) and girls (5.8 to 1.0%). Overall, tracking of weight status was 73.7%. More boys (49.2%) remained overweight/obese than girls (24.7%). At age 7, overweight/ obesity was positively associated with male gender, paternal education, and urban residence. Overweight/obesity also correlated with male gender at age 18, and with parental weight status. CONCLUSIONS: The prevalence of overweight among Greek youth is high and showed an increase from childhood to adolescence in boys, and a decrease in girls.

Trihexyphenidyl for acute life-threatening episodes due to a dystonic movement disorder in Rett syndrome.

In Rett syndrome (RS), acute life-threatening episodes (ALTEs) are usually attributed to epilepsy or autonomic dysfunction but they can represent a movement disorder (MD). We describe three girls with RS who experienced ALTEs from an early age. These were long considered epileptic until video-EEG in Patients 1 and 3 revealed their non-epileptic nature. A primary dystonic mechanism was suspected and Patients 1 and 2 were treated with Trihexyphenidyl with significantly reduced frequency of the ALTEs. Patient 3 died before Trihexyphenidyl was tried. Trihexyphenidyl in RS patients with similar presentations can modify the dystonia and prevent ALTEs.

Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family.

Acute necrotizing encephalopathy (ANE) typically affects young, healthy children who develop rapid-onset severe encephalopathy triggered by viral infections. This disease is more commonly reported in Japan but occurs worldwide, although it remains under-recognized in Western countries. An autosomal dominant form, ANE1, was recently identified. We report the details of a 9-year-old Caucasian female who experienced recurrent ANE episodes at the ages of 9 months and 9 years. Brain magnetic resonance imaging findings were characteristic of ANE during both episodes, although more extensive in the recent episode, which resulted in severe neurological sequelae; influenza A was identified on bronchoalveolar lavage during this episode. Interestingly, there was evidence of peripheral polyneuropathy during the recent episode, which has not previously been described in sporadic ANE. Both the patient and her mother, who had also had postviral polyneuritis in the past, harbour a mutation in Ran-binding protein 2 (RANBP2); this occurred de novo in the mother and confers genetic susceptibility to ANE. Our case suggests that recurrent disease and/or an expanded clinical phenotype raises the possibility of ANE1; positive family history, although supportive, is not necessary as the mutation can occur de novo. Increased awareness may lead to earlier recognition and better treatment options.

White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene.

AIM: Mutations in the SLC16A2 gene have been implicated in Allan-Herndon-Dudley syndrome (AHDS), an X-linked learning disability* syndrome associated with thyroid function test (TFT) abnormalities. Delayed myelination is a non-specific finding in individuals with learning disability whose genetic basis is often uncertain. The aim of this study was to describe neuroimaging findings and neurological features in males with SLC16A2 gene mutations. METHOD: We reviewed brain magnetic resonance imaging (MRI) findings and neurological features in a cohort of five males aged between 1 year 6 months and 6 years (median 4y) from four families harbouring SLC16A2 gene mutations. RESULTS: The participants presented aged between 4 and 9 months with initial hypotonia and subsequent spastic paraparesis with dystonic posturing and superimposed paroxysmal dyskinesias. Dystonic cerebral palsy was the most common initial clinical diagnosis, and AHDS was suspected only retrospectively, considering the characteristically abnormal thyroid function tests, with high serum tri-iodothyronine (T(3)), as the most consistent finding. Brain MRI showed absent or markedly delayed myelination in all five participants, prompting the suspicion of Pelizaeus-Merzbacher disease in one patient. INTERPRETATION: Our findings indicate a consistent association between defective neuronal T(3) uptake and delayed myelination. SLC16A2 involvement should be considered in males with learning disability, an associated motor or movement disorder, and evidence of delayed myelination on brain MRI. Although dysmorphic features suggestive of AHDS are not always present, T(3) measurement is a reliable screening test.

Can we be optimistic about asthma in childhood? A Greek cohort study.

OBJECTIVE: To examine the prevalence and natural course of asthma from childhood to adolescence in a population-based, Greek birth cohort and to identify associated factors. METHODS: Longitudinal information on asthma symptoms, physician diagnosed and treated, was available for 2133 children at 7 and 18 years of age. RESULTS: The prevalence of current asthma was 9.0% and 5.0% at 7 and 18 years, respectively. The prevalence of lifetime asthma was 26.3% at 18 years. More than half of the children (58.2%) with early onset asthma were asymptomatic at 7 years and only 7.6% continued to have symptoms during adolescence. However, in 48.2% of those with late onset asthma, symptoms persisted up to 18 years. Logistic regression analyses showed that male gender, family history of atopy, active adolescent smoking and maternal smoking were significantly positively associated with lifetime asthma at 18 years. In addition, smoking during pregnancy was associated with an increased risk for persistence of asthma symptoms at 18 years. Asthma during childhood and active adolescent smoking were positively associated, and daily consumption of fruit and vegetables was negatively associated with current asthma at 18 years of age. Finally, children who were breastfed had a lower risk for lifetime asthma at 7 years. CONCLUSION: The prevalence of asthma symptoms at 7 and 18 years of age was low throughout Greece. Our results suggest that, among others, nutrition is an important correlate of asthma in Greek children.

Parental stress affects the emotions and behaviour of children up to adolescence: a Greek prospective, longitudinal study.

Systematic research about the continuity of mental health problems from childhood to adolescence is limited, but necessary to design effective prevention and intervention strategies. We used a population-based representative sample of Greek adolescents, followed-up from birth to the age of 18 years, to assess early influences on and the persistence of mental health problems in youth. We examined the role of peripartum, early development and parental characteristics in predicting mental health problems in childhood and adolescence. Results suggest a strong relationship between behavioural problems in childhood and adolescence for both genders, while emotional problems were more likely to persist in boys. Age and sex-specific models revealed significant positive associations between higher scores on the behavioural and emotional problems scales and higher frequency of accidents in preschool years, physical punishment in early childhood, lack of parental interest in child's school and activities, and perceived maternal stress in all children. Perceived paternal stress was associated with higher scores on the Total and Internalizing problems scales in the total population. Our results suggest that early interventions are necessary as mental health problems strongly persist from childhood to late adolescence. The adverse effects of parental stress and poor care-giving practices on child's psychopathology need to be recognised and improved.

Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

The generation gap in numbers: parent-child disagreement on youth's emotional and behavioral problems: a Greek community based-survey.

OBJECTIVE: To evaluate discrepancies between parent and child reports on youth's emotional and behavioral problems in a representative, community based sample of Greek 18-year-olds, and to identify associated factors. METHODS: A total of 2,927 completed pairs of parent-child questionnaires were studied, including the child behavior checklist (CBCL) and the youth self-report (YSR). Linear regression analysis was used to identify both child and parental characteristics significantly associated with parent/child disagreement on scores for youth's Internalising, Externalising and Total problems scales for both genders separately. RESULTS: Although there was a strong correlation between scores on the YSR and CBCL corresponding scales, parent/child discrepancies were more likely to occur when the later: had good academic performance, were dissatisfied from their self-image or their life. Parental factors that influence discrepancies in parent/child scale scores were: low paternal education for both genders, father being the informant for boys, and maternal stress and lack of awareness of leisure activities for girls. CONCLUSION: The associations found highlight the contributions of both parents and children to the discrepancies on emotional and behavioral problems in adolescence. This study may facilitate constructive parenting practices through generations.

A novel GLRA1 mutation in a recessive hyperekplexia pedigree.

We report the identification of a novel Y228C mutation within the M1 trans-membrane domain of the GLRA1 subunit of the glycine receptor responsible for a severe recessive hyperekplexia phenotype in a Kurdish pedigree.