Concurrent TNFRSF1A R92Q and pyrin E230K mutations in a child with multiple sclerosis

We report a 16-year-old female patient with a severe course of multiple sclerosis and concomitant symptoms suggestive of a hereditary autoinflammatory disease. Genetic analyses revealed that she inherited a TNFRSF1A R92Q mutation from her mother and a pyrin E230K mutation from her father. To our knowledge, this is the first report of a patient with severe childhood multiple sclerosis and mutations in two genes which predispose to hereditary autoinflammatory disorders. We speculate that these mutations contribute to early multiple sclerosis manifestation and enhance the inflammatory damage inflicted by the autoimmune response

Serum levels of matrix metalloproteinases-2 and-9 and their tissue inhibitors in inflammatory neuromuscular disorders

We monitored serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) before and during intravenously applied immunoglobulin (IVIG) therapy in 33 patients with chronic immune-mediated neuropathies and myopathies and 15 controls. Baseline MMP-2 and TIMP-2 serum levels were lower and MMP-9 and TIMP-1 serum levels higher in all patients compared to age-matched controls. Eight days after IVIG treatment, MMP-2, TIMP-2, and TIMP-1 serum levels increased, while MMP-9 serum levels decreased, indicating tissue repair. After 60 days, MMP-9 levels increased, MMP-2 approached normal levels, while TIMP-1 and TIMP-2 serum levels were below day 8 levels, indicating relapsing tissue damage. Comparing the MMP/TIMP results with the clinical courses, IVIG treatment tended to change MMP/TIMP levels in a way that paralleled clinical improvement and relapse. In sum, during a distinct time period, IVIG therapy seems to be able to modulate VIMP-mediated tissue repair. Copyright (c) 2006 S. Karger AG, Basel

Improved Respiratory Outcomes for X-Linked Myotubular Myopathy (XLMTM) with Gene Replacement Therapy, Resamirigene Bilparvovec (ASPIRO): Preliminary Results from ASPIRO, a Phase 1/2/3 Study

Astelas Gene Therapies

A recurrent single-amino acid deletion (p.Glu500del) in the head domain of ß-cardiac myosin in two unrelated boys presenting with polyhydramnios, congenital axial stiffness and skeletal myopathy

Abstract Background Alterations in the MYH7 gene can cause cardiac and skeletal myopathies. MYH7-related skeletal myopathies are extremely rare, and the vast majority of causal variants in the MYH7 gene are predicted to alter the rod domain of the of ß-cardiac myosin molecule, resulting in distal muscle weakness as the predominant manifestation. Here we describe two unrelated patients harboring an in-frame deletion in the MYH7 gene that is predicted to result in deletion of a single amino acid (p.Glu500del) in the head domain of ß-cardiac myosin. Both patients display an unusual skeletal myopathy phenotype with congenital axial stiffness and muscular hypertonus, but no cardiac involvement. Results Clinical data, MRI results and histopathological data were collected retrospectively in two unrelated boys (9 and 3.5 years old). Exome sequencing uncovered the same 3-bp in-frame deletion in exon 15 (c.1498_1500delGAG) of the MYH7 gene of both patients, a mutation which deletes a highly conserved glutamate residue (p.Glu500del) in the relay loop of the head domain of the ß-cardiac myosin heavy chain. The mutation occurred de novo in one patient, whereas mosaicism was detected in blood of the father of the second patient. Both boys presented with an unusual phenotype of prenatal polyhydramnios, congenital axial stiffness and muscular hypertonus. In one patient the phenotype evolved into an axial/proximal skeletal myopathy without distal involvement or cardiomyopathy, whereas the other patient exhibited predominantly stiffness and respiratory involvement. We review and compare all patients described in the literature who possess a variant predicted to alter the p.Glu500 residue in the ß-cardiac myosin head domain, and we provide in-silico analyses of potential effects on polypeptide function. Conclusion The data presented here expand the phenotypic spectrum of mutations in the MYH7 gene and have implications for future diagnostics and therapeutic approaches

Adjunctive lithium treatment in the prevention of suicidal behavior in patients with depression and comorbid personality disorders

Objective. Patients with both major depression and personality disorders have a high risk of suicidal behavior. Lithium is meant to have anti-suicidal properties in patients with affective disorders. The anti-suicidal effect of lithium in patients with affective disorders and comorbid personality disorders has not been investigated yet. Methods. A post-hoc analysis of a subsample of patients with depression and comorbid personality disorder (PD) and a recent suicide attempt (n = 19) from the prospective, placebo-controlled lithium intervention study (N = 167), was conducted. Results. Three patients in the lithium group (n = 8) and two patients in the placebo group (n = 11) presented a suicide attempt throughout the course of the study. No differences related to suicidal behavior could be detected between the placebo group and the group with lithium intervention. Conclusions. On the basis of the small sample size, among patients with comorbid PD, lithium does not seem to have an effect on suicidal behavior in contrast to patients with affective disorders without comorbid PD

Early-onset myopathies: Clinical findings, prevalence of subgroups and diagnostic approach in a single neuromuscular referral center in Germany.

BACKGROUND: Early-onset myopathies are a heterogeneous group of neuromuscular diseases with broad clinical, genetic and histopathological overlap. The diagnostic approach has considerably changed since high throughput genetic methods (next generation sequencing, NGS) became available. OBJECTIVE: We present diagnostic subgroups in a single neuromuscular referral center and describe an algorithm for the diagnostic work-up. METHODS: The diagnostic approach of 98 index patients was retrospectively analysed. In 56 cases targeted sequencing of a known gene was performed, in 44 patients NGS was performed using large muscle specific panels, and in 12 individuals whole exome sequencing (WES) was undertaken. One patient was diagnosed via array CGH. Clinical features of all patients are provided. RESULTS: The final diagnosis could be found in 63 out of 98 patients (64%) with molecular genetic analysis. In 55% targeted gene sequencing could establish the genetic diagnosis. However, this rate largely depended on the presence of distinct histological or clinical features. NGS (large myopathy-related panels and WES) revealed genetic diagnosis in 58.5% (52% and 67%, respectively). The genes detected by WES in our cohort of patients were all covered by the panels. Based on our findings we propose an algorithm for a practical diagnostic approach.Prevalences:MTM1- and LAMA2-patients are the two biggest subgroups, followed by SEPN1-, RYR1- and Collagen VI-related diseases. 31% of genetically confirmed cases represents a group with overlap between "congenital myopathies (CM)" and "congenital muscular dystrophies (CMD)". In 36% of the patients a specific genetic diagnosis could not be assigned. CONCLUSIONS: A final diagnosis can be confirmed by high throughput genetic analysis in 58.5% of the cases, which is a higher rate than reported in the literature for muscle biopsy and should in many cases be considered as a first diagnostic tool. NGS cannot replace neuromuscular expertise and a close discussion with the geneticists on NGS is mandatory. Targeted candidate gene sequencing still plays a role in selected cases with highly suspicious clinical or histological features. There is a relevant clinical and genetic overlap between the entities CM and CMD

Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness

Objective: We prospectively screened a large European cohort of patients presenting with hyperCKemia and/or limb-girdle muscular weakness (LGMW) for acid α-glucosidase (GAA) deficiency by dried blood spot (DBS) investigation. Methods: DBS were collected from 3,076 consecutive adult patients from 7 German and British neuromuscular centers. All specimens were investigated for GAA deficiency by fluorometry. Samples with reduced enzyme activity were subsequently investigated for GAA gene mutations. Results: Of 3,076 patients with DBS samples, 232 patients (7.6%) showed low GAA enzyme activity. Of these 232 patients, 55 (24%) presented with isolated hyperCKemia and 176 (76%) with hyperCKemia and LGMW. With both features present, 94% of the patients showed a low enzymatic activity. Mutational analysis found GAA gene mutations in 74 patients (2.4%); herein 70 patients were heterozygote for the common GAA gene splice-site mutation c.-32-13T>G. The most common clinical presentation in the confirmed Pompe cohort was a limb-girdle phenotype (85.3%) combined with ventilatory insufficiency (61%). Isolated hyperCKemia was found in 12%, while 2.7 had hyperCKemia and ventilatory insufficiency only. Conclusions: In a large cohort of unselected adult patients with hyperCKemia and/or LGMW, we found a prevalence of late-onset Pompe disease of 2.4%. Therefore, targeted screening of such a population should be encouraged in clinical practice