This study was conducted to identify the genetic basis of retinal dystrophies in consanguineous Pakistani families. We recruited two families with retinitis pigmentosa (RP) displaying visual ...difficulties, including nyctalopia and constricted visual fields. Linkage analysis and Sanger sequencing resulted in the identification of a previously reported nonsense mutation, c.847C > T, in exon 5 of
in one family and a novel four-base pair deletion in exon 4 of
, c.delAGAA4218_4221, leading to premature protein termination in the second family. Here, we report two RP-causing mutations extending the genetic heterogeneity of the disease.
To find out prevalence of Diabetic Retinopathy in general population of three districts in Pakistan.
A community based cross-sectional survey was conducted in three large districts of Pakistan namely ...Rawalpindi in Punjab, Peshawar in Khyber Pakhtoonkhwa and Hyderabad in Sindh between January 2013 and August 2015. Lady Health Workers identified individuals at high risk for diabetes based on pre-defined criteria. High risk population was tested for dysglycemia. Fundoscopic evaluation for evidence of DR was performed in all individuals with a random blood glucose >190mg/dl. Individuals with the evidence of DR were referred to affiliated tertiary care ophthalmology departments.
A total of 42,629 individuals reported at the project sites and 63% (n=26,859) were female. Fifty one percent (n=21,989) individuals met high risk criteria. Out of these 21,989 individuals, dysglycemia was found in 3,869 (17.6%). Fundoscopy showed evidence of DR in 1,042 (27%) individuals. Amongst high risk population, dysglycemia was significantly more common in females as compared to males. The frequency of DR in dysglycemic patients was comparable across both gender groups.
The prevalence of DR in Pakistani population is alarmingly high. This preventable cause of blindness is largely undiagnosed in our population and a simple integrated model based on primary health care facilities can help identify and treat a large population of DR patients.
South Asian population has a particularly high prevalence of thyroid disorders mainly due to iodine deficiency and goitrogen use. There is no data available for prevalence of thyroid disorders in the ...general population living in nonmountainous regions of Pakistan.
A total of 2335 residents of Pak Pattan, Punjab, Pakistan were interviewed about demographic, dietary, medical and environmental history as well as screened for goiter. Individuals of all ages and either gender were included.
Median age was 34 (10-88) years and 1164 (49.9%) were males. Median monthly income was 49 (3.9-137) USD. Six hundred and sixty-nine (28.7%) subjects had palpable goiter. 77.5% (n = 462) and 22.5% (n = 133) had World Health Organization Grade I and Grade II goiters respectively, further screened by measuring thyroid-stimulating hormone (TSH). In subjects with TSH <0.4 mg/dL, free T3 and free T4 levels were measured. In 185 goiter subjects when TSH was measured, 50% (n = 93) were euthyroid, 48% (n = 89) were hyperthyroid, and one subject each was hypothyroid and subclinically hyperthyroid. 29/89 hyperthyroid subjects underwent radionuclide scanning. Twelve subjects had heterogeneous uptake consistent with multinodular goiter, 12 subjects had diffuse uptake, two had cold nodules and two had hyperfunctioning single nodules. Goiter was significantly more common among females, unmarried individuals and individuals drinking tube well (subterranean) water. Goiter was less common among those who consumed daily milk, daily ghee (hydrogenated oil), spices, chilies, and turmeric.
In our study population, goiter was endemic with very high prevalence of hyperthyroidism. Turmeric use was association with reduced goitrogenesis. Further studies to assess iodine sufficiency, thiocyanate exposure and autoimmunity need to be conducted. Masses consuming high goitrogen diets should be educated to incorporate turmeric, spices and green chilies in their cooking recipes, to reduce the risk of goiter development. In addition, use of iodized salt in their daily diet cannot be overemphasized.
Sir, This is in response to the letter to the editor by Elahi et al., titled "Reluctance in use of iodized salt for elimination of iodine deficiency" to our original article titled "Turmeric use is ...associated with reduced goitrogenesis:
Intellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing ...(ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5, c.344_345delGA (p.Arg115Asnfs∗19) and c.571_572delAA (p.Lys191Valfs∗10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function.
Background End-stage renal disease frequently leads to increased cardiovascular mortality. Cardiovascular autonomic neuropathy (CAN) may be predictive of cardiac arrhythmias and sudden cardiac death ...in patients with end-stage renal disease. Methods A total of 70 patients with end-stage renal disease were included in the study. The assessment of cardiac dysautonomia was based on the four standardized tests performed at the baseline and, again, at the end of the study. The criteria for CAN included at least two abnormal test results. Results Fifty of 70 patients completed the study and were followed-up after one year. Out of the 50 patients, 44 (88%) had CAN at baseline. Twelve (24%) patients died at the one-year follow-up. Sudden cardiac death was reported in seven out of 12 (58%) patients. All seven patients who died had high dysautonomia scores (three abnormal tests) at the baseline. There was a significantly higher percentage of patients with all four abnormal tests amongst patients who died of any cause (56% vs. 17%; RR 6.07, 95% CI 1.29-28.49; p-value 0.02) or due to sudden cardiac death (43% vs. 10.5%; RR 6.37, 95% CI 1.03-39.36; p-value 0.04). All five patients who did not have CAN at the baseline developed this abnormality on repeat testing after one year. Conclusion The prevalence of CAN in patients with end-stage renal disease on maintenance hemodialysis was significantly higher. CAN was an independent predictor of all-cause and cardiovascular mortality, which highlights it as a risk stratification tool in patients with end-stage renal disease.
Perrault syndrome (PS) is a genetically heterogeneous disorder characterized by primary ovarian insufficiency (POI) in females and sensorineural hearing loss in males and females. In many PS ...subjects, causative variants have not been found in the five reported PS genes. The objective of this study was to identify the genetic cause of PS in an extended consanguineous family with six deaf individuals. Whole exome sequencing (WES) was completed on four affected members of a large family, and variants and co‐segregation was confirmed by Sanger sequencing. All hearing impaired individuals, including the proband, are homozygous for a pathogenic variant of CLDN14, but this only explains the deafness. The PS proband is also homozygous for a frameshift variant (c.1453_1454delGA, p.(Glu485Lysfs*5)) in exon 7 of SGO2 encoding shugoshin 2, which is the likely cause of her concurrent ovarian insufficiency. In mouse, Sgol2a encoding shugoshin‐like 2a is necessary during meiosis in both sexes to maintain the integrity of the cohesin complex that tethers sister chromatids. Human SGO2 has not previously been implicated in any disorder, but in this case of POI and perhaps others, it is a candidate for unexplained infertility.
Summary Introduction We conducted this study to determine the frequency of malaria and dengue–malaria co-infection in patients admitted to our hospital as ‘probable’ cases of dengue fever during the ...2012 outbreak of dengue, and to ascertain whether dengue–malaria co-infection was more severe than either infection alone. Methods This cross-sectional observational study was conducted at Jinnah Hospital Lahore, Pakistan between August and November 2012. Patients with 2–10 days of fever and with two or more of the following: myalgia, arthralgia, retro-orbital pain, headache, skin rash, and hemorrhagic manifestations plus thrombocytopenia and leukopenia, were classified as probable cases of dengue fever and were subjected to reverse transcriptase (RT)-PCR and/or dengue-specific IgM by ELISA. The diagnosis of malaria was established on thick and thin blood film microscopy. Severe disease was defined by the presence of an altered level of consciousness, World Health Organization grade ≥2 bleeding, jaundice, circulatory shock, hemoglobin <50 g/l, platelet count <50 × 109 /l, serum creatinine >265 μmol/l, or death. Results There were 85 probable cases of dengue fever. Sixty-four (75%) were male and the median age was 22 years (range 12–90 years). Of 52 patients for whom results of diagnostic tests for both dengue and malaria were available, five (10%) had isolated dengue infection, 18 (35%) isolated Plasmodium infection, and 17 (33%) dengue–malaria co-infection. Thirty-five out of 52 (67%) probable cases had malaria and 17 out of 22 (77%) dengue-specific IgM reactive patients had concurrent malaria. Patients with isolated malaria had significantly lower median hemoglobin concentrations (124.5 g/l vs. 144.0 g/l, p = 0.04) and median hematocrit (36.0 vs. 41.7, p = 0.02) at presentation than cases of isolated dengue. Patients with dengue–malaria co-infection had a significantly lower rate of jaundice than those with isolated dengue (0% vs. 40%, p = 0.04). The frequency of severe disease was comparable amongst the three groups; this was seen in five (100%) cases of isolated dengue, 17 (94%) cases of isolated malaria, and 16 (94%) cases of dengue–malaria co-infection. Conclusions The rate of isolated malaria and dengue–malaria co-infection was high in probable cases of dengue fever in our study. Except for jaundice, we could not find any significant between-group differences in the severity of the disease.
To identify the genetic origins of autosomal recessive congenital cataracts (arCC) in the Pakistani population.
Based on the hypothesis that most arCC patients in consanguineous families in the ...Punjab areas of Pakistan should be homozygous for causative mutations, affected individuals were screened for homozygosity of nearby highly informative microsatellite markers and then screened for pathogenic mutations by DNA sequencing. A total of 83 unmapped consanguineous families were screened for mutations in 33 known candidate genes.
Patients in 32 arCC families were homozygous for markers near at least 1 of the 33 known CC genes. Sequencing the included genes revealed homozygous cosegregating sequence changes in 10 families, 2 of which had the same variation. These included five missense, one nonsense, two frame shift, and one splice site mutations, eight of which were novel, in EPHA2, FOXE3, FYCO1, TDRD7, MIP, GALK1, and CRYBA4.
The above results confirm the usefulness of homozygosity mapping for identifying genetic defects underlying autosomal recessive disorders in consanguineous families. In our ongoing study of arCC in Pakistan, including 83 arCC families that underwent homozygosity mapping, 3 mapped using genome-wide linkage analysis in unpublished data, and 30 previously reported families, mutations were detected in approximately 37.1% (43/116) of all families studied, suggesting that additional genes might be responsible in the remaining families. The most commonly mutated gene was FYCO1 (14%), followed by CRYBB3 (5.2%), GALK1 (3.5%), and EPHA2 (2.6%). This provides the first comprehensive description of the genetic architecture of arCC in the Pakistani population.
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes ...have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.
PDF
