Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1.

BACKGROUND AND OBJECTIVES: Pathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control. METHODS: We performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1-related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System (GMFCS) scores and a speech impairment score and were compared within and across clinically defined subgroups. RESULTS: We collected data of 71 individuals with STXBP1-related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (interquartile range 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including 2 individuals presenting with close to age-appropriate motor development. Twenty-nine of 61 individuals (48%) were able to walk unassisted, and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores (p = 0.02) than individuals with later epilepsy onset. DISCUSSION: We expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with epilepsy, in particular epileptic spasms, and neonatal or early-onset presented with less favorable motor and language functional outcomes compared with individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1-related disorders.

Functional outcome measures in young, steroid-naïve boys with Duchenne muscular dystrophy.

The purpose of this study was to quantitate motor performance in 196 genetically confirmed steroid-naïve boys with Duchenne muscular dystrophy (DMD), to evaluate the test-retest reliability of measures of motor performance in young DMD boys, and to assess correlations among the different functional outcomes including timed tests. Boys aged 4-7 years were recruited in the FOR-DMD study, a comparative effectiveness study of different steroid regimens in DMD. Eligible boys had to be able to rise from the floor independently and to perform pulmonary function testing consistently. The boys were evaluated with standardized assessments at the screening and baseline visits at 32 sites in 5 countries (US, UK, Canada, Italy, Germany). Assessments included timed rise from floor, timed 10 m walk/run, six-minute walk distance, North Star Ambulatory Assessment (NSAA) and forced vital capacity (FVC). Mean age at baseline was 5.9 years (range 4.1-8.1 years). Test-retest reliability was high for functional assessments, regardless of time lag between assessments (up to 90 days) and for the majority of age groups. Correlations were strong among the functional measures and timed tests, less so with FVC. Physiotherapy measures are reliable in a young, steroid-naïve population and rise from floor velocity appears to be a sensitive measure of strength in this population.

Clinical and Genetic Aspects of Juvenile Onset Pompe Disease.

Little is known about clinical symptomatology and genetics of juvenile onset Pompe disease (JOPD). The aims of this study were to analyze how these children are diagnosed, what clinical problems they have, and how phenotype is related to genotype. To accomplish this, we analyzed retrospectively data of 34 patients diagnosed after their first and before completion of their 18th birthday. Median age at diagnosis was 3.9 (range 1.1-17) years. Eight patients (23.5%) developed initial symptoms in the first year, 12 (35%) between 1 and 7 years, and 6 (18%) thereafter. Eight (23.5%) had no clinical symptoms at the time of diagnosis. Indications for diagnostics were a positive family history in three (9%), hyperCKemia in eight (23.5%), motor developmental delay in three (9%), and muscle weakness and/or pain in 17 (50%). Rare clinical signs were failure to thrive, recurrent diarrhea, and suspected hepatopathy with glycogen storage. Thirty-two different mutations were identified. Twenty-seven patients (79.5%) carried the milder c.32-13T > G mutation, known to be associated with a broad range of phenotypes. Three out of eight patients manifesting within the first year of life showed generalized muscle weakness, hypertrophic cardiomyopathy, and had to be ventilated during the course of disease, thereby demonstrating clinical overlap with infantile onset Pompe disease.These findings demonstrate that the phenotype of JOPD is broad and that the differential is not only restricted to neuromuscular disorders. Genotypic analysis was useful to delineate subjects with early onset JOPD from those with IOPD, but overall genotype-phenotype correlation was poor.

Making sense of missense variants in TTN-related congenital myopathies.

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Treatment with Nusinersen - Challenges Regarding the Indication for Children with SMA Type 1.

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

The Development of Extremely Premature Infants.

BACKGROUND: Until now, there has been no comprehensive long-term study in Germany on the development of extremely premature infants up to school age. METHODS: From October 2004 to September 2008, in the German federal state of Lower Saxony, 437 infants born at a gestational age less than 28 weeks were followed up at the ages of 2 and 5 years, and some at the age of 10 years. The 5-year follow-up data were collated with the peri- and neonatological parameters and compared with the 2- and 10-year follow-up data. RESULTS: The mortality of extremely premature infants was 25.1%. Among the five-year-olds studied, 14.1% showed cognitive impairment and 17.4% had cerebral palsy. 40.4% manifested abnormalities of speech or language, 33.1% had behavioral abnormalities, and 72.5% received therapeutic interventions. Infants in whom severe brain damage was diagnosed by ultrasonography shortly after birth were more likely to develop cerebral palsy (odds ratio [OR] 38.28, 99% confidence interval [12.55; 116.80]) and to have impaired cognitive development (OR 7.36 [2.52; 21.51]). The likelihood of cognitive impairment was also higher among infants whose mothers had a lower level of education (OR 3.83 [1.68; 8.77]). 73.1% (242 out of 331) of the two-year-olds were in the same category of cognitive function at the 5-year follow-up; 82.4% (65 out of 79) of the 5-year-olds were in the same category of cognitive function at the 10-year follow-up. CONCLUSION: Many of these extremely premature infants had developmental disturbances, and many required therapeutic interventions. The risk factors revealed by this study may help identify patients who are in particular need of support, enabling targeted measures to be taken at the earliest possible stage in order to improve their cognitive and motor abilities. Nationwide, standardized follow-up at the age of 5 years would be desirable.

Intragenic duplication of EHMT1 gene results in Kleefstra syndrome.

BACKGROUND: Kleefstra syndrome is characterized by intellectual disability, muscular hypotonia in childhood and typical facial features. It results from either a microdeletion of or a deleterious sequence variant in the gene euchromatic histone-lysine N-methyltransferase 1 (EHMT1) on chromosome 9q34. RESULTS: We report on a 3-year-old girl with characteristic symptoms of Kleefstra syndrome. Array comparative genomic hybridization analysis revealed a 145 kilobases duplication spanning exons 2 to 10 of EHMT1. Sequence analysis characterized it as an intragenic tandem duplication leading to a frame shift with a premature stop codon in EHMT1. CONCLUSIONS: This is the first description of an intragenic duplication of EHMT1 resulting in Kleefstra syndrome.

A 3p interstitial deletion in two monozygotic twin brothers and an 18-year-old man: further characterization and review.

An increasing number of patients with 3p proximal deletions were reported in the previous decade, but the region responsible for the main features such as intellectual disability (ID) and developmental delay is not yet characterized. Here we report on two monozygotic twin brothers of 2 10/12 years and an 18-year-old man, all three of them displaying severe ID, psychomotoric delay, autistic features, and only mild facial dysmorphisms. Array CGH (aCGH), revealed a 6.55 Mb de novo interstitial deletion of 3p14.1p14.3 in the twin brothers and a 4.76 Mb interstitial deletion of 3p14.1p14.2 in the 18-year-old patient, respectively. We compared the malformation spectrum with previous molecularly well-defined patients in the literature and in the DECIPHER database (Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources; http://decipher.sanger.ac.uk/). In conclusion, the deletion of a region containing 3p14.2 seems to be associated with a relative concise phenotype including ID and developmental delay. Thus, we hypothesize that 3p14.2 is the potential core region in 3p proximal deletions. The knowledge of this potential core region could be helpful in the genetic counselling of patients with 3p proximal deletions, especially concerning their phenotype.

Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial.

BACKGROUND: Duchenne muscular dystrophy is a rare X-linked progressive disease characterised by loss of ambulation at about age 10 years, with death in early adulthood due to respiratory and cardiac insufficiency. Steroids are effective at slowing the progression of muscle weakness; however, their use is limited by side-effects, prompting the search for alternatives. We assessed the effect of ciclosporin A as monotherapy and in combination with intermittent prednisone for the treatment of ambulant patients with this disorder. METHODS: Our study was a parallel-group, placebo-controlled, double-blind, multicentre trial at trial sites of the German muscular dystrophy network, MD-NET, over 36 months. Ambulant patients with Duchenne muscular dystrophy who were aged 5 years or older were randomly assigned to receive either ciclosporin A (3·5-4·0 mg/kg per day) or matching placebo. Allocation was done centrally with computer-generated random numbers. Patients and investigators were masked to the allocated treatment. After 3 months of treatment, both groups were also given intermittent prednisone for a further 12 months (0·75 mg/kg, alternating 10 days on with 10 days off). All patients who received at least one dose of study drug or placebo were included in the primary analysis. The primary outcome measure was manual muscle strength measured on the Medical Research Council (MRC) scale. This trial is registered with the German clinical trial register DRKS, number DRKS00000445. FINDINGS: 77 patients were randomly assigned to the ciclosporin A group and 76 to the placebo group; 73 patients on ciclosporin A and 73 on placebo received at least one dose and were available for efficacy analyses. 3 months of treatment with ciclosporin A alone did not show any significant improvement in primary outcome measures (mean change in the proportion of a possible total MRC score [%MRC] was -2·6 [SD 6·0] for patients on ciclosporin A and -0·8 [4·9] for patients on placebo; adjusted group difference estimate -0·88, 97·5% CI -2·6 to 0·9; p=0·26). The combination of ciclosporin A with intermittent steroids was not better than intermittent steroids alone over 12 months (mean change in %MRC was 0·7 [7·1] for patients on ciclosporin A and -0·3 [7·9] for patients on placebo; adjusted group difference estimate -0·85, -3·6 to 1·9; p=0·48). Numbers of adverse events (75 in patients on ciclosporin A and 74 on placebo) and serious adverse events (four with ciclosporin A and four with placebo) did not differ significantly between groups. INTERPRETATION: Ciclosporin A alone or in combination with intermittent prednisone does not improve muscle strength or functional abilities in ambulant boys with Duchenne muscular dystrophy, but is safe and well tolerated. FUNDING: German Federal Ministry of Education and Research, Action Benni and co eV, Novartis Pharma AG, and Deutsche Gesellschaft für Muskelkranke eV.

Normality of cardiopulmonary capacity in children operated on to correct congenital heart defects.

BACKGROUND: One of the main goals of corrective surgery of congenital heart defects in children is the improvement of quality of life, which in young children is predominantly determined by exercise capacity. It is not known whether this goal can be achieved in school-aged children who have undergone cardiac surgery in infancy. OBJECTIVES: To determine if primary school-aged children who underwent surgery to correct congenital heart defects in infancy are physically as fit as their peers. METHODS: We examined 84 children with congenital heart defects, aged 4 to 11 years, after surgical repair. Fifty-two children had simple defects (ie, atrial or ventricular septal defect, coarctation of the aorta). Thirty-two children had complex defects (ie, tetralogy of Fallot, pulmonary atresia with ventricular septal defect). All patients underwent exercise testing performed on a specially modified bicycle ergometer. Ninety-eight sex- and age-matched healthy children served as the control group. RESULTS: There was no gender difference, either in healthy children or in the group with congenital heart defects, regarding exercise testing and that the healthy children reached a mean +/- SD normalized maximal performance of 2.8 +/- 0.3 W/kg. The same range was found for the children who had undergone surgery to correct simple heart defects. The children operated on to correct complex heart defects showed significantly impaired mean normalized maximal performance, although this tended to be lower in the group that had pulmonary atresia with a ventricular septal defect than in the group with tetralogy of Fallot (mean normalized maximal performance, 1.9 W/kg vs 2.3 W/kg). CONCLUSIONS: The goal of normal exercise capacity in childhood after heart surgery is achieved in those with simple heart defects only. In children with complex heart defects impaired exercise performance persists, depending on the severity of the heart defect and probably on chronotropic incompetence.

Effectiveness of creatine monohydrate in mitochondrial encephalomyopathies.

The mitochondrial encephalomyopathies are chronic progressive disorders affecting predominantly the neuromuscular system. Symptoms are induced by insufficient energy supply resulting from a deficiency of oxidative phosphorylation. We studied one male and four female patients with genetically proven mitochondrial encephalomyopathy. Their ages ranged from 7 to 19 years (two with Kearns-Sayre syndrome, one patient with neuronal muscle weakness, ataxia, and retinitis pigmentosa syndrome, and two patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), using a retrospective study method. We studied the effect of creatine supplementation (0.08 g-0.35 g/kg body weight/day; 9 months to 4 years, 10 months) and measured skeletal muscle power analysis (bicycle ergometer). After creatine supplementation all patients demonstrated an increase in their maximum performance (W) (+4% - +30%; mean: +12.1%). These results indicate an improved aerobic oxidative function of mitochondria after creatine administration in patients with mitochondrial encephalomyopathies. Continuous physical exercise was improved to a greater extent than instantaneous activity.