Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans

Pattern of lipid profile among type 2 diabetic patients

Diabetes mellitus is recognized as a serious global health problem and frequently associated with disabling and lifethreatening complications related to some modifiable risk factors. One of the modifiable factors is dyslipidemia. This study addressed the dyslipidemic status of 124 subjects with type 2 diabetes mellitus (T2DM) attending the outpatient department, Ibrahim General Hospital and Diabetic Care and Education Center Dhanmondi, Dhaka during the period from January to June 2010. The diagnosed diabetic subjects were interviewed and the biochemical investigation data were collected from record review. Three fourth of the respondents were female and majority (24.2%) of them were 46 to 50 years of age. Most of the respondents were graduates having neuclear families. The mean total cholesterol and triglyceride were found 181.7±43.0 mg/dl and 161.0±112.5 mg/dl respectively. According to NCEP ATP III (2001), 59.7% of the participants had high level of low density lipoproteins (LDL) and only 18% had desired level of high density lipoproteins (HDL). The mean (±SD) of LDL and HDL were 109.8±37.0 mg/dl and 41.0±7.9 mg/dl respectively. Men had elevated level of mean TG with wide variation (185.98±179.56 mg/dl) than women (151.63±72.16 mg/dl). The mean (±SD) of HDL was found lower in men than women (35.8 ± 6.3 vs. 42.9 ± 7.5 mg/dl, p< 0.05) though not significant. The study revealed that dyslipidemia (high TC, TG, LDL and low HDL) was prevalent among the T2DM subjects, which needs attention of equal importance to maintain within normal limit as with the control of hyperglycemia and hypertension. Ibrahim Med. Coll. J. 2012; 6(1): 12-1

In vivo evaluation of wound healing improvement of a new Schiff base derived bromine compound (CNBP) in rats

Background: The effect of delivered bromine vapor and also bromine substitutions are shown to play an important role in anti-inflammatory activity. The present study encompasses a broad in vivo study to size up healing activity of a novel dibromide substituted Schiff based compound against cutaneous wound model in Sprague Dawley (SD) rats. Methodology/principal findings: 2, 2′-[1, 2-Cyclohexanediylbis(nitriloethylidyne)] bis[4-bromophenol], CNBP, is synthesized through a Schiff base reaction applying the related ketone and diamine as the initiators. Four groups of six in each male SD rats are divided as negative group which are treated with gum acacia, positive control animals which are treated with topical dosage of Intrasite gel, and testing groups treated with low (10 mg/kg) and high (20 mg/kg) doses of CNBP. The excisional wounds are created on the posterior neck area of each group and the wound closure percentage was measured in the two separated days of the experiment. Moreover, the histopathological evaluation and determination of activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (GPx), and malondialdehyde (MDA) of the skin sections are performed. Furthermore, the immunohistochemistry consists of the evaluation of Hsp70 and BAX proteins. Conclusions/significance: The wound closure percentage showed a significant increase in high dose CNBP-treated group compared to the negative control. Histopathological evaluation of the skin sections showed that granulation tissue contained more proliferating fibroblast, collagen deposition, angiogenesis, and also less inflammatory cells in the high dose CNBP-treated group compared to the normal rats. In the treated groups with CNBP, SOD, CAT, and GPx activities were found significantly higher, however, the MDA level was shown to be lower (*P < 0.05; **P < 0.01; ***P < 0.001) than the negative control. At the molecular level, CNBP (20 mg/ml, HD) improved wound-healing process via down and up regulation of Bax and Hsp70 protein, respectively at the wound site. © 201

Effects of the copper (II) complex on parameters of renal function in AOM-induced colon cancer.

<p>The values are expressed as the mean ± the S.E.M. There were no statistically significant differences between the groups. <i>P</i><0.05 compared to cancer control group was considered to be significant.</p

Effects of the copper (II) complex on body weights in AOM-induced colon cancer.

<p>The values are expressed as the mean ± the S.E.M. There were no statistically significant differences between the groups. <i>P</i><0.05 was considered to be significant.</p

Effects of the copper (II) complex on antioxidant enzyme activities.

<p>A) Negative colon group, B) group exposed to AOM, C) group treated with 5-fluorouracil, D) group treated with 2.5 mg/kg copper (II) complex, E) group treated with 5 mg/kg copper (II) complex. All values are expressed as the means ± the standard error of mean. The mean difference was significant at p<0.05 compared to the cancer control group.</p

Effects of the copper (II) complex on liver function in AOM-induced colon cancer.

<p>The values are expressed as the mean ± the SEM There were no significant differences between groups. The significance value was set at P < 0.05 compared to the cancer control group. TB: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: g-glutamyl transferase.</p

Effects of the copper (II) complex on the regional distribution of colonic ACF in AOM-induced colonic cancer.

<p>The values are expressed as the mean ± the S.E.M. The significance value was set at P< 0.05 compared to the cancer control group.</p

Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans