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.

POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM# 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients' muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

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.

Long-term follow-up of patients with congenital myasthenic syndrome caused by COLQ mutations.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COlQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We present data on 15 COLQ -mutant CMS carrying 16 different mutations (9 novel ones identified) followed-up for an average period of 10 ears. The mean age at the first examination was 19 ears old (range from 3 to 48). We report relapses during short or long-term periods characterized by worsening of muscle weakness sometimes associated with respiratory crises. All the relapses ended spontaneously or with 3-4 DAP or ephedrine with no residual impairment. The triggering factors identified were esterase inhibitors, effort, puberty or pregnancy highlighting the importance of hormonal factors. There was no genotype-phenotype correlation. At the end of the follow-up, 80% of patients were ambulant and 87% of patients had no respiratory trouble in spite of severe relapses.

Impact of depression and disability on quality of life in Iranian patients with multiple sclerosis.

Multiple sclerosis (MS) can influence all aspects of a patient's health. This study determines the main factors affecting quality of life (QoL) in Iranian MS patients. QoL (Multiple Sclerosis Impact Scale; MSIS-29), disability (Expanded Disability Status Scale; EDSS) and depression (Beck Depression Inventory; BDI) were assessed in 106 MS patients. EDSS, clinical course and MS duration significantly correlated with physical MSIS-29. Depression highly correlated with both physical and psychological MSIS-29. Regression analyses showed that depression and EDSS predicted physical health. Psychological health was predicted by depression. These findings highlight that depression and physical disability strongly influence QoL in Iranian MS patients.

[Immunohematologic follow-up and transfusion safety in hematopoietic stem cells allografts]. / Le suivi immunohématologique et la sécurité transfusionnelle dans les allogreffes de cellules souches hématopoïétiques.

Since 1990, specific documentation is established between the immunohematology laboratory of the French EFS Lorraine-Champagne and the marrow transplantation unit of the CHU of Nancy, for patients undergoing hematopoietic stem cells transplantation. These documents and the standardization of the immunohematologic follow-up of those patients, have contributed to the improvement of the transfusion safety.

[Uni- and multifocal eosinophilic granulomas in adults. Diagnostic and therapeutic approaches. Apropos of 3 cases]. / Granulomes éosinophiles uni- et multifocaux de l'adulte. Approaches diagnostiques et thérapeutiques. A propos de trios observations. multifocal eosinophilic granulomas in adults. Diagnostic and therapeutic approaches. Apropos of 3 cases]

Unifocal and multifocal eosinophilic granuloma are Langerhans cell histiocytosis of unknown cause. Over the last 10 years, recent insights in pathogenesis and characterization of this pathology have been made. The authors report three cases of adult unifocal and multifocal eosinophilic granuloma. A review of literature underlines diagnostic features and therapeutic aspects of this disease.

[Immuno-hemolytic transfusion reactions. III. Report of 61 cases]. / Les accidents immuno-hémolytiques transfusionnels. III. Etude de 61 cas.

Blood transfusion is mainly bound to immunological and infectious risks. The immunological risk originates from an incompatibility between the blood of the donor and that of the recipient; this risk remains insufficiently assessed. A multicentre study has been carried out by the French Blood Transfusion Society and the National Institute for Blood Transfusion. Sixty-one accidents due to an erythrocyte incompatibility were found: 26 cases with ABO incompatibility, and 35 cases with alloantibodies of other blood group systems. For the former category of accidents, the most frequent cause was due to a failure in the realization of the bedside ABO check. For the latter, the main problem was the achievement and the interpretation of antibody screening. The long term follow-up shows no chronic after-effects of immunological accidents. For each accident, errors have been identified and analysed. It was proven that they all originate from health care establishments.

Associations of blood group-related antigens to FEV1, wheezing, and asthma.

Discordant results have been observed regarding the associations of chronic obstructive pulmonary diseases with secretor, Lewis, and ABO histo-blood groups, which are defined by glycosyltransferases. These enzymes build up oligosaccharide structures that play a role in the adhesion of environmental factors to epithelial cells. The objectives of the present study were to assess the role of all three systems, Lewis (Le), salivary ABH secretor (Se), and red cell blood group ABO, on lung function, wheezing, and asthma in a cohort of 228 coal miners studied cross-sectionally, considering the potential modifying effect of environmental factors on these associations. Asthma was significantly related to nonsecretor phenotype. Significantly lower lung function and higher prevalences of wheezing and asthma were observed in Lewis-negative or nonsecretor subjects of blood group O. Very low lung function values were observed in the small group of Lewis-negative nonsecretors who lack both Le and Se controlled fucoses (1% of Caucasians). Lewis-positive, salivary ABH secretors who have these two fucoses represent 70% of Caucasians. Among these subjects, lower lung function was observed in blood group A, and in a lesser extent in blood group B, i.e., with terminal alpha GaINAc or alpha Gal respectively, than in blood group O subjects. ABO, Lewis, and secretor phenotypes did not account for the potential genetic heterogeneity of subjects toward smoking, but alcohol consumption appeared to exert a protective effect on lung function in Lewis-negative subjects (10% of Caucasians). If confirmed in other populations, the magnitude of the effects observed regarding low lung function in Lewis-negative ABH nonsecretors, and the protective effect of Lewis negative on the deleterious effect of alcohol, may be of clinical importance. Further studies of the combined effects of various histo-blood group genetic systems seem worthwhile, particularly for airflow limitation, wheezing, and asthma, possibly with reference to susceptibility to infectious agents.