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Background Ritscher–Schinzel syndrome (RSS) is a clinically heterogeneous disorder characterised by distinctive craniofacial features in addition to cerebellar and cardiac anomalies. It has been described in different populations and is presumed to follow autosomal recessive inheritance. In an effort to identify the underlying genetic cause of RSS, affected individuals from a First Nations (FN) community in northern Manitoba, Canada, were enrolled in this study. Methods Homozygosity mapping by SNP array and Sanger sequencing of the candidate genes in a 1Mb interval on chromosome 8q24.13 were performed on genomic DNA from eight FN RSS patients, eight of their parents and five unaffected individuals (control subjects) from this geographic isolate. Results All eight patients were homozygous for a novel splice site mutation in KIAA0196. RNA analysis revealed an approximate eightfold reduction in the relative amount of a KIAA0196 transcript lacking exon 27. A 60% reduction in the amount of strumpellin protein was observed on western blot. Conclusions We have identified a mutation in KIAA0196 as the cause of the form of RSS characterised in our cohort. The ubiquitous expression and highly conserved nature of strumpellin, the product of KIAA0196, is consistent with the complex and multisystem nature of this disorder.

Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA.

Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo. Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of \"sitters\" (cohort 1) and an ambulatory group of \"walkers\" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures. At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007). This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials. Clinicaltrials.gov NCT00227266.

Spinal muscular atrophy is a common genetic disease of the motor neuron (frequency of eight cases per 100,000 live births) with a high mortality during infancy and no known treatment. Death is caused by severe and progressive restrictive lung disease. New information regarding the nature and function of the SMN protein and the availability of new pharmacologic agents now make it possible to consider clinical trials in this disease. Rehabilitation and proper management of medical complications have improved both the quality and duration of life for children with spinal muscular atrophy.

Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

Legionella pneumophila is a strict intracellular pathogen that causes an acute form of pneumonia in humans, called Legionnaires' disease. L. pneumophila enters human macrophages through a unique \"coiling phagocytosis\" mechanism and replicates within the phagosome by inhibiting fusion to endosomes and lysosomes. These replicative phagosomes are morphologically distinct and are associated with endoplasmic reticulum membranes and dotted with ribosomes. The mechanism by which L. pneumophila modulates the fusogenic properties of the phagosome and survives intracellularly remains unknown. In contrast to their human and guinea pig counterparts, mouse macrophages are not permissive to L. pneumophila replication with the exception of mice of the A/J strain, where inflammatory peritoneal macrophages and alveolar macrophages are highly permissive to L. pneumophila replication in vitro (1000-fold increase in viable bacteria during a 72-h infection). The characteristics of L. pneumophila replication observed in A/J macrophages, including the unique inhibition of phagosome maturation, are similar to those observed in human cells. Segregation analyses in informative backcross populations derived from susceptible (A/J) and resistant (C57BL/6J) progenitors have indicated that permissiveness of A/J macrophages to intracellular replication of L. pneumophila is determined by a single recessive gene designated Lgn1, which maps on Chromosome (Chr) 13. Understanding the molecular mechanism of action of Lgn1 may provide important clues on the intracellular survival strategy of L. pneumophila, and possibly on a new antimicrobial mechanism of the macrophage effective against L. pneumophila. (DBO)

Disruptions to hypothalamic-pituitary-adrenal (HPA) axis function have been associated with varying forms of psychopathology in children. Studies suggesting children with ADHD have blunted HPA function have been complicated by the prevalence of comorbid diagnoses and heterogeneity of ADHD. The goals of this research were to assess the relations between waking and stress-response salivary cortisol levels and comorbid disruptive behavior (DBD) and anxiety (AnxD) disorders and problems in boys with ADHD, and to examine whether cortisol levels varied across ADHD subtypes. One hundred seventy elementary school-age boys with ADHD provided salivary cortisol at waking and in reaction to venipuncture. Parent reports were used to assess boys' psychiatric diagnoses and severity of behavioral problems. Boys' comorbid AnxD and anxiety problems were associated with greater cortisol reactivity, whereas boys' comorbid DBD and oppositional problems predicted diminished adrenocortical activity. Reactive cortisol increases were greatest in boys with ADHD and comorbid AnxD, but without DBD. ADHD subtypes were not differentially associated with waking, pre-stress baseline, or reactive cortisol levels. However, comorbid DBD predicted decreased cortisol reactivity in boys with inattentive and hyperactive subtypes of ADHD, but not in boys with combined subtype of ADHD. The results clarify previous patterns of distinct and divergent dysregulations of HPA function associated with boys' varying kinds of psychopathology. [PUBLICATION ABSTRACT]

In humans, loss or mutation of the Survival Motor Neuron (SMN) gene is responsible for proximal spinal muscular atrophy (SMA), the second most common autosomal recessive disease of child-hood after cystic fibrosis. This lethal neuropathy affects 1/10,000 live-born children. It is characterized by degeneration of the alpha -motor neurons in the spinal cord, which causes proximal, symmetrical limb and trunk muscle weakness that progresses to paralysis. Since SMA is clinically heterogeneous, patients are classified on the basis of age at onset and disease severity, Type I SMA children are the most severely affected. They have onset of symptoms prior to 6 months, are never able to sit, and rarely live beyond 2 years of age. Type II and III SMA are milder forms and show onset of symptoms between 6 months and 17 years. Because of a 500-kb inverted duplication on Chr 5q13, the SMN gene is present in two copies designated centromeric SMN (cenSMN) and telomeric SMN. The genes span similar to 30 kb, are highly homologous, and their ubiquitous transcripts differ by only four nucleotides, which are silent polymorphisms. Individuals lacking cenSMN are normal, whereas SMA patients have no detectable telSMN (>95%) or small intragenic mutations. Analysis of mRNA indicated that the human SMN genes are alternatively spliced and that telSMN produces three times the amount of full-length transcript ( similar to 90%) compared with cenSMN. SMN protein is found in both the nucleus and cytoplasm and is present at high levels in brain, kidney, and liver in normal tissues. There is only one copy of the SMN gene in rodents. The absence of alternative splicing in the mouse and rat suggests that only the product for the full-length SMN transcript is required for normal development. Recently, SMN protein was shown to be essential for spliceosomal snRNP biogenesis and, consistent with this housekeeping function, complete loss of Smn leads to embryonic death prior to uterine implantation. Despite these advances, it is not clear why defects in telSMN specifically affect motor neurons. One might speculate that motor neurons have a high requirement for full-length SMN protein, which is not met when the telSMN locus is disrupted. Alternatively, SMN may possess an additional function specific to motor neurons, and loss of this function causes SMA. To address these questions in vivo, it will be necessary to produce viable mice that harbor hypomorphic Smn alleles and/or Smn alleles that can be disrupted conditionally. To facilitate this process, we present the entire nucleotide sequence, genomic organization, a panel of unique probes that span the Smn gene, as well as our gene targeting experience at the Smn locus. We have also analyzed the 5' region of Smn and show that it contains a functional promoter.