Chronic granulomatous disease is an inherited disorder in which phagocytes lack a functional NADPH oxidase and cannot produce superoxide anions. The most common form is caused by mutations in
CYBB
...encoding gp91
phox
. We investigated 24 CGD patients and their families. Twenty-one mutations in
CYBB
were classified as X91
0
, X91
+
or X91
−
variants according to cytochrome
b
558
expression. Point mutations in encoding regions represented 50 % of the mutations found in
CYBB
, splice site mutations 27 %, deletions and insertions 23 %. Eight mutations in
CYBB
were novel leading to X91
0
CGD cases. Two of these were point mutations: c493G>T and a double mutation c625C>G in exon 6 and c1510C>T in exon 12 leading to a premature stop codon at Gly165 in gp91
phox
and missense mutations His209Arg/Thr503Ile respectively. Two novel splice mutations in 5′intronic regions of introns 1 and 6 were found. A novel deletion/insertion c1024_1026delCTG/insT results in a frameshift introducing a stop codon at position 346 in gp91
phox
. The last novel mutation was the insertion of a T at c1373 leading to a frameshift and a premature stop codon at position 484 in gp91
phox
. For the first time the precise size of two large mutations in
CYBB
was determined by array-comparative genomic hybridization and carriers’ status were evaluated by multiplex ligation-dependent probe amplification assay. No clear correlation between clinical severity and
CYBB
mutations could be established. Of three mutations in
CYBA, NCF1 and NCF2
leading to rare autosomal recessive CGD, one nonsense mutation c29G>A in exon 1 of
NCF2
was new.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The binding of FasL to Fas, 2 homotrimeric transmembrane proteins, induces recruitment of adaptor proteins and cysteinyl aspartic proteases to form a signaling multimolecular complex essential in ...delivering a successful death signal.1 Autoimmune lymphoproliferative syndrome (ALPS) is a prototypic disorder of impaired apoptosis in human subjects characterized by chronic benign noninfectious lymphoproliferation, autoimmune manifestations largely directed against blood cells, and accumulation of double-negative CD3+ T-cell receptor (TCR) α/β+ CD4− CD8− T cells (DNT cells) that typically does not exceed 2.5% of T lymphocytes in healthy adults.2 Other reliable immunologic biomarkers include polyclonal hypergammaglobulinemia and high serum or plasma levels of either IL-10, IL-18, soluble Fas ligand (sFasL), or vitamin B12.3 Different causative genes involved in the Fas-FasL apoptotic pathway have been reported in patients with ALPS. Phenotypic B-cell abnormalities associated with antibody deficiency have been previously reported in patients with ALPS and underlie the clinical and immunologic overlap between ALPS and common variable immunodeficiency.5 FAS sequencing revealed the presence in patients 1, 2, and 3 of a novel homozygous missense mutation, c.1017A>G, that leads to the substitution of a highly conserved asparagine located at position 266 of the protein in the death domain with serine (Fig 1, B and D). ...a previous study showed normal Fas expression and function in an asymptomatic heterozygous mother bearing the same mutation.6 Haploinsufficiency, which has been demonstrated to be the underlying pathophysiologic mechanism in patients with ALPS with heterozygous extracellular FAS mutations, could also be suggested from the behavior of homozygous cells of patient...
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Mitochondrial diseases include a wide group of clinically heterogeneous disorders caused by a dysfunction of the mitochondrial respiratory chain and can be related to mutations in nuclear or ...mitochondrial DNA genes. In the present report, we performed a whole mitochondrial genome screening in two patients with clinical features of mitochondrial diseases. Mutational analysis revealed the presence of two undescribed heteroplasmic mitochondrial variations, the m.3911A > G (E202G) variant in the MT-ND1 gene found in two patients (P1 and P2) and the m.12058A > C (E433D) pathogenic variant in the MT-ND4 gene present only in patient P2 who had a more severe phenotype. These two substitutions were predicted to be damaging by several bioinformatics tools and lead to amino acid changes in two conserved residues localized in two important functional domains of the mitochondrial subunits of complex I. Furthermore, the 3D modeling suggested that the two amino acid changes could therefore alter the structure of the two subunits and may decrease the stability and the function of complex I. The two described pathogenic variants found in patient P2 could act synergically and alter the complex I function by affecting the proton pumping processes and the energy production and then could explain the severe phenotype compared to patient P1 presenting only the E202G substitution in ND1.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset ...and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Mitochondrial diseases are a clinically heterogeneous group of multisystemic disorders that arise as a result of various mitochondrial dysfunctions. Autosomal recessive aARS deficiencies represent a ...rapidly growing group of severe rare inherited mitochondrial diseases, involving multiple organs, and currently without curative option. They might be related to defects of mitochondrial aminoacyl t-RNA synthetases (mtARS) that are ubiquitous enzymes involved in mitochondrial aminoacylation and the translation process. Here, using NGS analysis of 281 nuclear genes encoding mitochondrial proteins, we identified 4 variants in different mt
ARS
in three patients from unrelated Tunisian families, with clinical features of mitochondrial disorders. Two homozygous variants were found in
KARS
(c.683C>T) and
AARS2
(c.1150-4C>G), respectively in two patients, while two heterozygous variants in
EARS2
(c.486-7C>G) and
DARS2
(c.1456C>T) were concomitantly found in the third patient. Bio-informatics investigations predicted their pathogenicity and deleterious effects on pre-mRNA splicing and on protein stability. Thus, our results suggest that
mtARS
mutations are common in Tunisian patients with mitochondrial diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: Bacillus Calmette-Guérin (BCG) vaccine is a widely used vaccine. Management of local BCG complications differs between clinicians, and the optimal approach remains unclear. Aims: We aim ...to describe the epidemiological, clinical and therapeutic aspects of the BCG vaccine side effects in Sfax. Patients and Methods: This was a retrospective study of all the cases of BCG vaccine adverse reactions recorded in the Dermatology and Paediatrics Departments of Hedi Chaker University Hospital of Sfax over a period of 10 years (2005-2015). Results: Twenty cases of BCG adverse reactions were notified during the study period. Actually, 80% of the patients presented local adverse reactions. The outcome was good in all the followed patients. The rate of disseminated BCG disease was 20%. Biological tests of immunity showed a primary immunodeficiency in three cases, whereas the outcome was fatal in two cases. Conclusion: BCG vaccine adverse reactions range from mild to severe. However, the management of benign local reactions remains unclear. Disseminated BCG disease must alert clinicians to the possibility of a primary immunodeficiency.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Leigh syndrome (LS) and Leigh-like spectrum are the most common infantile mitochondrial disorders characterized by heterogeneous neurologic and metabolic manifestations. Pathogenic variants in SLC ...carriers are frequently reported in LS given their important role in transporting various solutes across the blood–brain barrier. SLC19A3 (THTR2) is one of these carriers transporting vitamin-B1 (vitB1, thiamine) into the cell. Targeted NGS of nuclear genes involved in mitochondrial diseases was performed in a patient belonging to a consanguineous Tunisian family with LS and revealed a homozygous c.1264 A > G (p.T422A) variant in
SLC19A3
. Molecular docking revealed that the p.T422A aa change is located at a key position interacting with vitB1 and causes conformational changes compromising vitB1 import. We further disclosed decreased plasma antioxidant activities of CAT, SOD and GSH enzymes, and a 42% decrease of the mtDNA copy number in patient blood.
Altogether, our results disclose that the c.1264 A > G (p.T422A) variant in SLC19A3 affects vitB1 transport, induces a mtDNA depletion and reduces the expression level of oxidative stress enzymes, altogether contributing to the LS phenotype of the patient.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Miliary tuberculosis (TB) is a severe form of disseminated TB. In pediatrics, many cases are missed because the symptomatology of TB mimics common childhood diseases.
We present the case of a ...6-year-old girl with no remarkable history who had recurrent fever for 3 months. She was initially diagnosed with, and treated for, refractory multisystem inflammatory syndrome in children (MIS-C). When the study was extended to other differential diagnoses, thoraco-abdominopelvic computed tomography revealed miliary pulmonary nodules in addition to lymph nodes and spleen lesions. Magnetic resonance imaging of the brain revealed multiple tuberculomas. The tuberculin test results were positive. The course of the disease was favorable under quadruple therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The
PIGO
gene encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor serving to attach various proteins to ...their cell surface. These proteins are intrinsic for normal neuronal and embryonic development. In the current research work, a clinical investigation was conducted on a patient from a consanguineous family suffering from epileptic encephalopathy, characterized by severe seizures, developmental delay, hypotonia, ataxia and hyperphosphatasia. Molecular analysis was performed using Whole Exome Sequencing (WES). The molecular investigation revealed a novel homozygous variant c.1132C > T in the
PIGO
gene, in which a highly conserved Leucine was changed to a Phenylalanine (p.L378F). To investigate the impact of the non-synonymous mutation, a 3D structural model of the PIGO protein was generated using the AlphaFold protein structure database as a resource for template-based tertiary structure modeling. A structural analysis by applying some bioinformatic tools on both variants 378L and 378F models predicted the pathogenicity of the non-synonymous mutation and its potential functional and structural effects on PIGO protein. We also discussed the phenotypic and genotypic variability associated with the PIGO deficiency. To our best knowledge, this is the first report of a patient diagnosed with infantile epileptic encephalopathy showing a high elevation of serum alkaline phosphatase level. Our findings, therefore, widen the genotype and phenotype spectrum of GPI-anchor deficiencies and broaden the cohort of patients with
PIGO
associated epileptic encephalopathy with an elevated serum alkaline phosphatase level.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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