Clinical, Molecular, and Computational Analysis in two cases with mitochondrial encephalomyopathy associated with SUCLG1 mutation in a consanguineous family.

Deficiency of the mitochondrial enzyme succinyl COA ligase (SUCL) is associated with encephalomyopathic mtDNA depletion syndrome and methylmalonic aciduria. This disorder is caused by mutations in both SUCL subunits genes: SUCLG1 (α subnit) and SUCLA2 (ß subnit). We report here, two Tunisian patients belonging to a consanguineous family with mitochondrial encephalomyopathy, hearing loss, lactic acidosis, hypotonia, psychomotor retardation and methylmalonic aciduria. Mutational analysis of SUCLG1 gene showed, for the first time, the presence of c.41T > C in the exon 1 at homozygous state. In-silico analysis revealed that this mutation substitutes a conserved methionine residue to a threonine at position 14 (p.M14T) located at the SUCLG1 protein mitochondrial targeting sequence. Moreover, these analysis predicted that this mutation alter stability structure and mitochondrial translocation of the protein. In Addition, a decrease in mtDNA copy number was revealed by real time PCR in the peripheral blood leukocytes in the two patients compared with controls.

Mitochondrial genes modulate the phenotypic expression of congenital scoliosis syndrome caused by mutations in the TBXT gene.

BACKGROUND: Congenital scoliosis (CS) is a spinal disorder caused by genetic-congenital vertebral malformations and may be associated with other congenital defects or may occur alone. It is genetically heterogeneous and numerous genes contributing to this disease have been identified. In addition, CS has a wide range of phenotypic and genotypic variability, which has been explained by the intervention of genetic factors like modifiers and environment genes. The aim of the present study was to determine the possible cause of CS in a Tunisian patient and to examine the association between mtDNA mutations and mtDNA content and CS. METHODS: Here we performed Whole-Exome Sequencing (WES) in a patient presenting clinical features suggestive of severe congenital scoliosis syndrome. Direct sequencing of the whole mitochondrial DNA (mtDNA) was also performed in addition to copy number quantification in the blood of the indexed case. In silico prediction tools, 3D modeling and molecular docking approaches were used. RESULTS: The WES revealed the homozygous missense mutation c.512A > G (p.H171R) in the TBXT gene. Bioinformatic analysis demonstrated that the p.H171R variant was highly deleterious and caused the TBXT structure instability. Molecular docking revealed that the p.H171R mutation disrupted the monomer stability which seemed to be crucial for maintaining the stability of the homodimer and consequently to the destabilization of the homodimer-DNA complex. On the other hand, we hypothesized that mtDNA can be a modifier factor, so, the screening of the whole mtDNA showed a novel heteroplasmic m.10150T > A (p.M31K) variation in the MT-ND3 gene. Further, qPCR analyses of the patient's blood excluded mtDNA depletion. Bioinformatic investigation revealed that the p.M31K mutation in the ND3 protein was highly deleterious and may cause the ND3 protein structure destabilization and could disturb the interaction between complex I subunits. CONCLUSION: We described the possible role of mtDNA genetics on the pathogenesis of congenital scoliosis by hypothesizing that the presence of the homozygous variant in TBXT accounts for the CS phenotype in our patient and the MT-ND3 gene may act as a modifier gene.

Disseminated BCG infection revealing a severe combined immunodeficiency: A case report.

INTRODUCTION: Bacillus Calmette Guerin (BCG) vaccine, which is administered to all newborns in Tunisia, can lead to serious complications ranging from local disease to disseminated disease in a group of patients with primary immunodeficiency diseases. CASE REPORT: A 3-month-old boy presented with persistent fever, hepato-splenomegaly and multiple osteolytic lesions. He was diagnosed with severe combined immunodeficiency disease and disseminated BCG infection. Despite anti-tubercular therapy combined with intravenous immunoglobulin, the evolution was fatal. CONCLUSION: The case highlights the possible risk of such rare yet lethal complication of BCG vaccine. In suspected cases of primary immunodeficiency disease, inoculation of BCG should be postponed until appropriate screening tests exclude such diagnosis to prevent serious complications.

Malignant hyperthermia in a 4-year-old girl during anesthesia induction with sevoflurane and succinylcholine for congenital ptosis surgery.

Malignant hyperthermia (MH) is a rare pharmacogenic disorder of skeletal muscle calcium regulation, resulting from general anesthesia that can be fatal. Most cases are caused by administration of volatile anesthetics or depolarizing muscle relaxants. It has been generally reported that both of sevoflurane and succinylcholine can induce the delayed onset of MH. Here, we report a case of malignant hyperthermia in a four-year-old girl during anesthesia induction for unilateral congenital ptosis surgery, two minutes after sevoflurane and succinylcholine administration. The crisis was atypical but early recognized and managed by administration of dantrolene with symptomatic treatment.

Acute appendicitis complicating pregnancy: a 33 case series, diagnosis and management, features, maternal and neonatal outcomes.

The occurrence of acute appendicitis during pregnancy may pose diagnostic and therapeutic difficulties. In fact pregnancy can make the clinical diagnosis delicate and the use of morphological examinations is still subject to controversy. The debates concerning the ideal surgical approach during pregnancy continue. On the other hand, in some cases the occurrence of acute appendicitis, especially in its complicated form, which is frequent in pregnant women, exposes to obstetrical complications and an increased risk of premature delivery We aims to describe the clinical and management features of acute appendicitis in pregnant women and the maternal and neonatal outcomes and carry out a review of the literature on this topic. It is a retrospective analysis of a series of 33 cases of appendicitis in pregnant women who were diagnosed and managed, in collaboration between the departments of General and digestive surgery, Gynecology and Obstetrics and Anaesthesia at Farhat Hached Universitary Hospital Sousse Tunisia between January 2005 and December 2015. The average age of the patients was 29 (20-40). Fourteen patients were in the first trimester, twelve in the 2nd and seven in the third trimester. The main symptom was pain in the right iliac fossa. The mean delay between consultation and surgery was 2.7 days. Twenty five patients had a preoperative ultrasound. Eight of the 33 pregnant patients presented complicated appendicitis with localized or generalized peritonitis. Thirty patients underwent laparotomic appendectomy: 28 with a Mc Burney incision and 2 with a midline incision and only three patients underwent laparoscopy. Preventive tocolysis was given to 14 patients, maternal mortality was null. Twenty four pregnancies were followed until delivery: one case of premature birth and one case of preterm labor were observed. Pregnancy makes it difficult to diagnose appendicitis, which explains the high rate of complicated acute appendicitis in our series. An early treatment improves maternal and fetal outcome.

Whole mitochondrial genome analysis in two families with dilated mitochondrial cardiomyopathy: detection of mutations in MT-ND2 and MT-TL1 genes.

Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathy and heart failure. These mutations were described in the mt-tRNA genes and in the mitochondrial protein-coding genes. The aim of this study was to identify the genetic defect in two patients belonging to two families with cardiac dysfunction associated to a wide spectrum of clinical phenotypes. The sequencing analysis of the whole mitochondrial DNA in the two patients and their parents revealed the presence of known polymorphisms associated to cardiomyopathy and two pathogenic mutations in DNA extracted from blood leucocytes: the heteroplasmic m.3243A > G mutation in the MT-TL1 gene in patient A; and the homoplasmic m.5182C > T mutation in the ND2 gene in patient B. Secondary structure analysis of the ND2 protein further supported the deleterious role of the m.5182C > T mutation, as it was found to be involved an extended imbalance in its hydrophobicity and affect its function. In addition, the mitochondrial variants identified in patients A and B classify both of them in the same haplogroup H2a2a1.

Chediak-higashi syndrome presented as accelerated phase: case report and review of the literature.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease, characterized by partial oculocutaneous albinism, recurrent pyogenic infections (skin, mucosa and respiratory system), and neurologic deficit. The hallmark of this syndrome is the presence of abnormal intracytoplasmic giant granules in all granule containing cells including leukocytes in blood and bone marrow. A majority (85 %) of patients with CHS develop an accelerated phase consisting of a lymphoproliferative syndrome with hemophagocytosis and infiltration of most tissues. This phase is characterized by fever, jaundice, hepatosplenomegaly, lymphadenopathy, pancytopenia and neurological abnormalities. In this paper, we report a case of CHS presented as accelerated phase in a 9-month-old girl child.