Adult-onset very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD).

BACKGROUND AND PURPOSE: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a hereditary disorder of mitochondrial long-chain fatty acid oxidation that has variable presentations, including exercise intolerance, cardiomyopathy and liver disease. The aim of this study was to describe the clinical and genetic manifestations of six patients with adult-onset VLCADD. METHODS: In this study, the clinical, pathological and genetic findings of six adult patients (four from Iran and two from Serbia) with VLCADD and their response to treatment are described. RESULTS: The median (range) age of patients at first visit was 31 (27-38) years, and the median (range) age of onset was 26.5 (19-33) years. Parental consanguinity was present for four patients. Four patients had a history of rhabdomyolysis, and the recorded CK level ranged between 67 and 90 000 IU/l. Three patients had a history of exertional myalgia, and one patient had a non-fluctuating weakness. Through next-generation sequencing analysis, we identified six cases with variants in the ACADVL gene and a confirmed diagnosis of VLCADD. Of the total six variants identified, five were missense, and one was a novel frameshift mutation identified in two unrelated individuals. Two variants were novel, and three were previously reported. We treated the patients with a combination of L-carnitine, Coenzyme Q10 and riboflavin. Three patients responded favorably to the treatment. CONCLUSION: Adult-onset VLCADD is a rare entity with various presentations. Patients may respond favorably to a cocktail of L-carnitine, Coenzyme Q10, and riboflavin.

Increased number of regulatory T cells in esophageal tissue of patients with eosinophilic esophagitis in comparison to gastro esophageal reflux disease and control groups

Background: Eosinophilic esophagitis (EoE) is a primarily polygenic allergic disorder. Although most patients have IgE sensitization, it seems that non-IgE mediated responses mainly contribute to the pathogenesis of EoE. Regulatory T cells (Tregs) may have an important role in allergies. There are limited data on the association of Tregs and EoE. In this study, we enumerated and compared T lymphocytes and Tregs in esophageal tissue of patients with EoE, gastroesophageal reflux disease (GERD) and normal controls. Methods: Ten patients with EoE, ten patients with GERD and eight normal controls were included. Immunohistochemistry staining was used to enumerate T lymphocytes and Tregs. CD3+ cells were considered as T cells and FOXP3+, CD3+ cells were considered as Tregs. T cells and Tregs were counted in 10 high power fields (HPF) (×400) for each patient and the average of 10 HPFs was recorded. Results: The mean±SEM of Tregs in esophageal tissue of patients with EoE (10.90 ± 2.14cells/HPF) was significantly higher than the GERD (2.77 ± 0.66 cells/HPF) and control groups (0.37 ± 0.08 cells/HPF) (P < 0.001). Additionally, the mean ± SEM of T lymphocytes in esophageal tissue of patients with EoE (24.39 ± 3.86 cells/HPF) were increased in comparison to the GERD (10.07 ± 2.65 cells/HPF) and control groups (3.17 ± 0.93 cells/HPF) (P < 0.001). Conclusion: There is an increase in the number of esophageal T lymphocytes and regulatory T cells in patients with EoE compared to the GERD and control groups

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Increased number of regulatory T cells in esophageal tissue of patients with eosinophilic esophagitis in comparison to gastro esophageal reflux disease and control groups.

BACKGROUND: Eosinophilic esophagitis (EoE) is a primarily polygenic allergic disorder. Although most patients have IgE sensitization, it seems that non-IgE mediated responses mainly contribute to the pathogenesis of EoE. Regulatory T cells (Tregs) may have an important role in allergies. There are limited data on the association of Tregs and EoE. In this study, we enumerated and compared T lymphocytes and Tregs in esophageal tissue of patients with EoE, gastroesophageal reflux disease (GERD) and normal controls. METHODS: Ten patients with EoE, ten patients with GERD and eight normal controls were included. Immunohistochemistry staining was used to enumerate T lymphocytes and Tregs. CD3+ cells were considered as T cells and FOXP3+, CD3+ cells were considered as Tregs. T cells and Tregs were counted in 10 high power fields (HPF) (×400) for each patient and the average of 10 HPFs was recorded. RESULTS: The mean±SEM of Tregs in esophageal tissue of patients with EoE (10.90±2.14cells/HPF) was significantly higher than the GERD (2.77±0.66cells/HPF) and control groups (0.37±0.08cells/HPF) (P<0.001). Additionally, the mean±SEM of T lymphocytes in esophageal tissue of patients with EoE (24.39±3.86cells/HPF) were increased in comparison to the GERD (10.07±2.65cells/HPF) and control groups (3.17±0.93cells/HPF) (P<0.001). CONCLUSION: There is an increase in the number of esophageal T lymphocytes and regulatory T cells in patients with EoE compared to the GERD and control groups.

Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies.

BACKGROUND AND PURPOSE: Nemaline myopathy (NEM) has been associated with mutations in 12 genes to date. However, for some patients diagnosed with NEM, definitive mutations are not identified in the known genes, suggesting that there are other genes involved. This study describes compound heterozygosity for rare variants in ryanodine receptor type 3 (RYR3) gene in one such patient. METHODS AND RESULTS: Clinical examination of the patient at 22 years of age revealed a long narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear and subsarcolemmal areas, and within the cytoplasm. No likely pathogenic mutations in known NEM genes were identified. Copy number variation in known NEM genes was excluded by NEM-targeted comparative genomic hybridization array. Next-generation sequencing revealed compound heterozygous missense variants in the RYR3 gene. RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain and cauda equina samples. Immunofluorescence of human skeletal muscle revealed a 'single-row' appearance of RYR3, interspersed between the 'double rows' of ryanodine receptor type 1 (RYR1) at each A-I junction. CONCLUSION: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain, and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.

Improved diagnostic yield of neuromuscular disorders applying clinical exome sequencing in patients arising from a consanguineous population.

Neuromuscular diseases (NMDs) include a broad range of disorders affecting muscles, nerves and neuromuscular junctions. Their overlapping phenotypes and heterogeneous genetic nature have created challenges in diagnosis which calls for the implementation of massive parallel sequencing as a candidate strategy to increase the diagnostic yield. In this study, total of 45 patients, mostly offspring of consanguineous marriages were examined using whole exome sequencing. Data analysis was performed to identify the most probable pathogenic rare variants in known NMD genes which led to identification of causal variants for 33 out of 45 patients (73.3%) in the following known genes: CAPN3, Col6A1, Col6A3, DMD, DYSF, FHL1, GJB1, ISPD, LAMA2, LMNA, PLEC1, RYR1, SGCA, SGCB, SYNE1, TNNT1 and 22 novel pathogenic variants were detected. Today, the advantage of whole exome sequencing in clinical diagnostic strategies of heterogeneous disorders is clear. In this cohort, a diagnostic yield of 73.3% was achieved which is quite high compared to the overall reported diagnostic yield of 25% to 50%. This could be explained by the consanguineous background of these patients and is another strong advantage of offering clinical exome sequencing in diagnostic laboratories, especially in populations with high rate of consanguinity.