5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2.

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.

Further evidence for the pathogenicity of 15q24 microduplications distal to the minimal critical regions.

DNA copy number alterations in 15q24 have repeatedly been reported in patients exhibiting mild to moderate developmental delay and dysmorphic features. To date, mainly microdeletions have been described, and comparison of overlapping regions allowed the definition of minimal critical regions (MCRs) for microdeletions as well as microduplications. These MCRs are associated with distinct phenotypes. Recently, a family with a new microduplication distal to these MCRs was reported. However, for this alteration the typical phenotypical consequences could not yet be determined. Here we present another family with a nearly identical microduplication exhibiting a broad clinical spectrum including developmental delay, autistic traits and dysmorphic features. Our data suggest that microduplications adjacent and distal to the known MCRs are variable in expressivity and are associated with distinct features. They might represent a novel and recurrent microduplication syndrome.

A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro.

The GABRA1 gene encodes one of the most conserved and highly expressed subunits of the GABAA receptor family. Variants in this gene are causatively implicated in different forms of epilepsy and also more severe epilepsy-related neurodevelopmental syndromes. Here we study functional consequences of a novel de novo missense GABRA1 variant, p.(Ala332Val), identified through exome sequencing in an individual affected by early-onset syndromic epileptic encephalopathy. The variant is localised within the transmembrane domain helix 3 (TM3) and in silico prediction algorithms suggested this variant to be likely pathogenic. In vitro assessment revealed unchanged protein levels, regular assembly and forward trafficking to the cell surface. On the functional level a significant left shift of the apparent GABA potency in two-electrode voltage clamp electrophysiology experiments was observed, as well as changes in the extent of desensitization. Additionally, apparent diazepam potency was left shifted in radioligand displacement assays. During prenatal development mainly alpha2/3 subunits are expressed, whereas after birth a switch to alpha1 occurs. The expression of alpha1 in humans is upregulated during the first years. Thus, the molecular change of function reported here supports pathogenicity and could explain early-onset of seizures in the affected individual.

Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion.

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.

Behavioral and emotional problems in children with epilepsy.

The principal purpose of this study was to assess behavioral and emotional problems in children with epilepsy to investigate if specific behavioral and emotional problems are associated with specific medical epilepsy-related factors. The Child Behavior Checklist (CBCL) was used to assess parent-reported behavioral and emotional problems in 108 5- to 18-year-old children with various epilepsy syndromes. Specific medical epilepsy-related factors, such as etiology, age at onset, seizure symptoms, prognosis, seizure frequency, electroencephalography (EEG), and anticonvulsive therapy, were recorded during a regular follow-up examination in our pediatric outpatient epilepsy clinic, and 22.2% of our patients showed moderate to severe behavioral or emotional problems as measured by the Child Behavior Checklist total score. Higher Child Behavior Checklist scores were associated with such specific medical epilepsy-related factors as etiology, age at onset, and polypharmacy. Higher scores on the Social Problem scale were associated with symptomatic epilepsy syndromes and an earlier age at onset. Higher scores on the Social Problems, Attention Problems, and Aggressive Behavior scales were associated with anticonvulsive polytherapy. There were no statistically significant associations between the Child Behavior Checklist scores and seizure symptoms and frequency and EEG at the time of evaluation. The demonstrated frequency of behavioral and emotional problems in children with epilepsy suggests the necessity to address psychosocial issues during the course of clinical treatment.

Changes in body mass index during long-term topiramate therapy in paediatric epilepsy patients--a retrospective analysis.

STUDY OBJECTIVE: To assess the effect of topiramate (TPM) on body mass index (BMI) in paediatric epilepsy patients and to examine predictors of weight loss. DESIGN: Retrospective, observational study. SETTING: University clinic epilepsy outpatient department. SUBJECTS: Patients below age 18 years who received TPM for at least 12 months. MEASUREMENTS AND MAIN RESULTS: Changes in BMI (kg/m2) standard deviation scores (S.D.S.) from baseline to the follow-up periods of 12, 24 and 36 months were evaluated. The repeated measures t-test for paired samples, revealed significant decreases for BMI S.D.S. at 12 months (P = 0.004; n = 53) and 24 months (P = 0.044; n = 35), but no significant decrease at 36 months (n = 21). Analysis of variance revealed a predictor value of sex for BMI S.D.S. at 12 months (females more likely to lose weight; P = 0.037) and a predictor value of baseline BMI for BMI S.D.S. at 24 months (patients with a higher baseline BMI were more likely to lose weight; P = 0.047). CONCLUSION: Weight loss is common in paediatric epilepsy patients who receive TPM and is sustained for at least one year. The pattern of weight loss differs according to sex and baseline BMI.

Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy--the Austrian experience.

PURPOSE: To evaluate the long-term efficacy/tolerability of the ketogenic diet (KD) in paediatric drug-resistant epilepsies. METHODS: Data from children who were treated between 1999 and 2008 and had continuous follow-up of at least 6 months after initiation of the KD were analysed retrospectively. Response was defined as > or = 50% seizure reduction. Treatment effects on EEG, developmental outcome and the "outcome-predictive" value of various clinical factors were also assessed. RESULTS: 50 children (22 boys; mean age 4.5 years+/-3.55) were included. Mean follow-up was 3.93+/-2.95. 50% of the patients were responders, 48% of them became seizure free. 50% were non-responders, 20% of them deteriorated. In responders, EEG background activity improved significantly (p=0.014) and a significantly lower rate of epileptic discharges (p=0.009) was seen after 6 months. In addition, neurological examination findings demonstrated significant developmental progress (p=0.038). Favourable treatment outcome was associated with a shorter disease duration (p=0.025) and generalised tonic clonic seizures (p=0.059). No further significant outcome predictors were detected. However, response was 44% in patients with infantile spasms, 62.5% in those with Dravet syndrome and 50% in Lennox-Gastaut-syndrome. Side effects occurred in 28%, but discontinuation of the KD was not required in any case. They most often observed with concomitant topiramate (p=0.001) and valproate (p=0.046). CONCLUSION: Despite the retrospective nature of the study and the inhomogeneous patient sample, we found good long-term effects of the KD on seizure frequency, EEG and neurological development.