Publications by authors named "Ayesha Hina"

10 Publications

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Prevalence of Clinical Spectrum of Cutaneous Adverse Drug Reactions in Patients Presenting at a Tertiary Care Hospital in Pakistan.

Cureus 2021 Apr 19;13(4):e14568. Epub 2021 Apr 19.

Biostatistics and Epidemiology, Aga Khan University Hospital, Karachi, PAK.

Introduction: Cutaneous adverse drug reactions (CADRs) are the most common adverse drug reactions reported in the literature. CADRs have resulted in disabling infirmities during hospitalization and complications following outdoor drug therapy. The pattern of CADRs and the responsible drugs usually changes with the introduction of newer drugs and evolving clinical practices. Moreover, several international studies showed variable prevalence, emphasizing the need for local data in light of different socioeconomic and demographic practices. Therefore, the purpose of this study is to evaluate the prevalence of adverse cutaneous drug reactions and identify the clinical spectrum and any potential risk factors.

Methodology: The current study is a descriptive cross-sectional study conducted at Aga Khan University Hospital, Pakistan. One hundred ninety-three patients who met the study inclusion criteria were included. Data were collected from patients on a proforma after taking informed consent. Quantitative data were presented as simple descriptive statistics giving mean and standard deviation, while qualitative variables were presented as frequency and percentages. Effect modifiers were controlled through stratification to highlight the effect of these on the outcome variable. The post-stratification chi-square test was applied and the p-value of ≤0.05 was statistically significant.

Results: A total of 193 patients who had cutaneous adverse drug reactions were included in the study. The mean age in this study was 47.78±8.33 years. One hundred eight (56%) were male and 85 (44%) were female. Out of 193 patients, 135 (69.9%), 50 (25.9%), 24 (12.4%), 12 (6.2%), 20 (10.4%), 11 (5.7%) and six (3.1%) had maculopapular rash, acneiform eruptions, Stevens-Johnson syndrome, erythema multiform, urticaria, fixed drug eruptions and toxic epidermal necrolysis, respectively.

Conclusion: CADRs are a common clinical presentation and awareness and knowledge about their diagnosis and prevention is important. It can be assumed that in our local setup, the clinical trends and medications causing ADRs are strikingly similar to those found in other countries. Physicians commonly come across these cases and they should be well aware of the clinical spectrum of skin reactions to enable early diagnosis and management.
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http://dx.doi.org/10.7759/cureus.14568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133508PMC
April 2021

Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence in an Inbred Population of Pakistan.

Diabetes 2020 07 29;69(7):1424-1438. Epub 2020 Apr 29.

Université de Lille, INSERM UMR1283, CNRS-UMR 8199-European Genomic Institute for Diabetes, and Lille University Hospital, Lille, France

Monogenic forms of obesity have been identified in ≤10% of severely obese European patients. However, the overall spectrum of deleterious variants (point mutations and structural variants) responsible for childhood severe obesity remains elusive. In this study, we genetically screened 225 severely obese children from consanguineous Pakistani families through a combination of techniques, including an in-house-developed augmented whole-exome sequencing method (CoDE-seq) that enables simultaneous detection of whole-exome copy number variations (CNVs) and point mutations in coding regions. We identified 110 (49%) probands carrying 55 different pathogenic point mutations and CNVs in 13 genes/loci responsible for nonsyndromic and syndromic monofactorial obesity. CoDE-seq also identified 28 rare or novel CNVs associated with intellectual disability in 22 additional obese subjects (10%). Additionally, we highlight variants in candidate genes for obesity warranting further investigation. Altogether, 59% of cases in the studied cohort are likely to have a discrete genetic cause, with 13% of these as a result of CNVs, demonstrating a remarkably higher prevalence of monofactorial obesity than hitherto reported and a plausible overlapping of obesity and intellectual disabilities in several cases. Finally, inbred populations with a high prevalence of obesity provide unique, genetically enriched material in the quest of new genes/variants influencing energy balance.
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http://dx.doi.org/10.2337/db19-1238DOI Listing
July 2020

Biochemical Screening of Intellectually Disabled Patients: A Stepping Stone to Initiate a Newborn Screening Program in Pakistan.

Front Neurol 2019 17;10:762. Epub 2019 Jul 17.

Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.

Inborn errors of metabolism (IEMs) are rare group of genetic disorders comprising of more than 1,000 different types. Around 200 of IEMs are potentially treatable through diet, pharmacological and other therapies, if diagnosed earlier in life. IEMs can be diagnosed early through newborn screening (NBS) programs, which are in place in most of the developed countries. However, establishing a NBS in a developing country is a challenging task due to scarcity of disease related data, large population size, poor economy, and burden of other common disorders. Since, not enough data is available for the prevalence of IEMs in Pakistan; therefore, in this study, we set out to find the prevalence of various treatable IEMs in a cohort of intellectually disabled patients suspected for IEMs, which will help us to initiate a NBS program for the most frequent IEMs in Pakistan. Therefore, a total of 429 intellectually disabled (IQ <70) patient samples were collected from Pakistan. A subset of 113 patient samples was selected based on the clinical information for the detailed biochemical screening. Advance analytical techniques like, Amino Acid Analyzer, GC-MS, UHPLC-MS, and MS/MS were used to screen for different treatable IEMs like aminoacidopathies, fatty acid β-oxidation disorders and mucopolysaccharidoses (MPS) etc. A total of 14 patients were diagnosed with an IEM i.e., 9 with homocystinuria, 2 with MPS, 2 with Guanidinoacetate methyltransferase (GAMT) deficiency and 1 with sitosterolemia. These IEMs are found frequent in the collected patient samples from Pakistan. Thus, present study can help to take an initiative step to start a NBS program in Pakistan, especially for the homocystinuria having highest incidence among aminoacidopathies in the studied patients, and which is amenable to treatment. This endeavor will pave the way for a healthier life of affected patients and will lessen the burden on their families and society.
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http://dx.doi.org/10.3389/fneur.2019.00762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650569PMC
July 2019

Biochemical screening of intellectually disabled and healthy children in Punjab, Pakistan: differences in liver function test and lipid profiles.

Int J Dev Disabil 2019 Jan 15;66(3):190-195. Epub 2019 Jan 15.

Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.

Inborn errors of metabolism (IEMs) are rare genetic disorders. Generally, IEMs are untreatable; however, some IEMs causing intellectual disability are potentially treatable if diagnosed earlier. In this study, levels of some clinically important biochemical parameters in intellectually disabled children suspected for IEMs were tested to see their association with intellectual disability, which could be helpful in preliminary screening. This comparative cross-sectional observational study was carried out from 2014 to 2017. Blood samples from 800 boys and girls (aged 4-24 years) were collected, of which 391 were healthy (IQ >90) and 409 were intellectually disabled (IQ <70) children with unknown cause. Clinically important (Liver and kidney enzymes etc.) biochemical parameters were analyzed in sera samples using commercial kits on semi-automated clinical chemistry analyzer. Serum analysis showed the levels of ALP ( < 0.00001), ASAT ( = 0.001), ALAT ( = 0.016), albumin ( < 0.001), uric acid ( < 0.001), cholesterol ( < 0.001), triglycerides ( < 0.001), and hemoglobin ( = 0.005) were significantly different between healthy and intellectually disabled children. Changes in the liver function test and lipid profile parameters were significantly different in children with intellectual disability; however, it requires further detailed analysis for complete characterization of these diseases.
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http://dx.doi.org/10.1080/20473869.2018.1533084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142844PMC
January 2019

Molecular genetic diagnosis of Wilson disease by ARMS-PCR in a Pakistani family.

Mol Biol Rep 2018 Dec 13;45(6):2585-2591. Epub 2018 Nov 13.

Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Jhang Road, P.O. Box. 577, Faisalabad, Pakistan.

Wilson disease is a rare autosomal recessive disorder caused by mutations in the ATP7B gene causing hepatic and neurological damage due to copper accumulation. Early diagnosis and treatment could lead to improved survival of patients. Patients are best treated at pre-symptomatic stages but early diagnosis of Wilson disease is challenging owing to complex diagnosis. Evidence based genetic counseling requires characterization of underlying mutations in Wilson disease families. The aim was to characterize the causative mutation(s) in a Pakistani Wilson disease family by custom developed ARMS-PCR assay. A proband (19 years old boy) having Wilson disease with evidence of K-F ring, severe neurological and psychiatric manifestations and clinical findings supported by biochemical abnormalities was followed. Following screening for 12 putative mutations in ATP7B, we identified a homozygous mutation (p.Cys271*, c.813C > A) in proband by T-ARMS-PCR assay and validated by Sanger DNA sequencing. Furthermore, on screening of his family members, a younger sister (aged 9 years) was found to have the same homozygous mutation even though she was clinically asymptomatic except for a light K-F ring. Parents were heterozygous for this mutation and an elder brother was homozygous normal. Molecular diagnosis by PCR based assays (M-ARMS-PCR and T-ARMS-PCR) is cost effective, reliable, and efficient for preliminary screening of mutations in the ATP7B gene in developing countries like Pakistan, which can be successfully applied to Wilson disease families for genetic testing and follow-up evidence based genetic counseling.
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http://dx.doi.org/10.1007/s11033-018-4426-yDOI Listing
December 2018

An Overview of Traditional and Novel Therapeutic Options for the Management of Phenylketonuria.

Crit Rev Eukaryot Gene Expr 2018 ;28(2):177-185

Department of Pediatrics, DHQ Hospital, Faisalabad Medical University, Faisalabad, Pakistan.

Phenylketonuria (PKU) is an autosomal recessive disorder caused by the deficiency of phenylalanine hydroxylase enzyme that catalyzes the conversion of L-phenylalanine to L-tyrosine using tetrahydrobiopterin (BH4) as a cofactor. Among aminoacidopathies, PKU is one of the most prevalent disorders in different populations. It may be caused by deficiency of BH4 or mutations in PAH. About 98% of PKU patients have mutations in the PAH, while the remaining have BH4 deficiency. If PKU is diagnosed earlier in life using advance analytical techniques (e.g., high performance liquid chromatography, mass spectrometry, and polymerase chain reaction), then it is potentially treatable by special diets (L-phenylalanine-free medical formula). However, some complications such as vitamin B12 deficiency, cardiovascular problems, and neurodevelopmental problems have been reported in PKU patients when they ate special diets for a long period. Hence, special diet alone is not a good option for proper treatment. Next generation therapies require structure-function based development. For therapies which target PAH gene (e.g., gene therapy, RNAi, gene editing), a lot of research has yet to be done. Treatment with BH4 therapy is safe and effective but only in BH4-responsive PKU patients. Therefore, research efforts should be focused on the development of more targeted pharmacological and genetic therapies especially PAH gene therapy, which can reduce the burden or deleterious effects of this disease in affected patients.
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http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2018023073DOI Listing
August 2019

Loss-of-function mutations in ADCY3 cause monogenic severe obesity.

Nat Genet 2018 02 8;50(2):175-179. Epub 2018 Jan 8.

Centre National de la Recherche Scientifique (CNRS) UMR 8199, Institut Pasteur de Lille, University of Lille, Lille, France.

Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin-melanocortin pathway in controlling energy balance, appetite and body weight . The majority of loss-of-function mutations (mostly recessive or co-dominant) have been identified in genes that are directly involved in leptin-melanocortin signaling. These genes, however, only explain obesity in <5% of cases, predominantly from outbred populations . We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity. These data suggested that new monogenic forms of obesity could also be identified in this population. Here we identify and functionally characterize homozygous mutations in the ADCY3 gene encoding adenylate cyclase 3 in children with severe obesity from consanguineous Pakistani families, as well as compound heterozygous mutations in a severely obese child of European-American descent. These findings highlight ADCY3 as an important mediator of energy homeostasis and an attractive pharmacological target in the treatment of obesity.
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http://dx.doi.org/10.1038/s41588-017-0023-6DOI Listing
February 2018

Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options.

Biochem Genet 2018 Apr 1;56(1-2):7-21. Epub 2017 Nov 1.

DHQ Hospital, Faisalabad Medical University, Faisalabad, Pakistan.

Inborn errors of metabolism (IEMs) are a group of inherited metabolic disorders which are caused by mutations in the specific genes that lead to impaired proteins or enzymes production. Different metabolic pathways are perturbed due to the deficiency or lack of enzymes. To date, more than 500 IEMs have been reported with most of them being untreatable. However, fortunately 91 such disorders are potentially treatable, if diagnosed at an earlier stage of life. IEMs have been classified into different categories and one class of IEMs, characterized by the physiological disturbances of amino acids is called as aminoacidopathies. Out of 91 treatable IEM, thirteen disorders are amino acid related. Aminoacidopathies can be detected by chromatography and mass spectrometry based analytical techniques (e.g., HPLC, GC-MS, LC-MS/MS) for amino acid level changes, and through genetic assays (e.g., PCR, TaqMan Genotyping, DNA sequencing) at the mutation level in the corresponding genes. Hence, this review is focused to describe thirteen common aminoacidopathies namely: Phenylketonuria (PKU), Maple Syrup Urine Disease (MSUD), Homocystinuria/Methylene Tetrahydrofolate Reductase (MTHFR) deficiency, Tyrosinemia type II, Citrullinemia type I and type II, Argininosuccinic aciduria, Carbamoyl Phosphate Synthetase I (CPS) deficiency, Argininemia (arginase deficiency), Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome, N-Acetylglutamate Synthase (NAGS) deficiency, Ornithine Transcarbamylase (OTC) deficiency, and Pyruvate Dehydrogenase (PDH) complex deficiency. Furthermore, the etiology, prevalence and commonly used analytical techniques for screening of aminoacidopathies are briefly described. This information would be helpful to researchers and clinicians especially from developing countries to initiate newborn screening programs for aminoacidopathies.
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http://dx.doi.org/10.1007/s10528-017-9825-6DOI Listing
April 2018

Genetic variants in LEP, LEPR, and MC4R explain 30% of severe obesity in children from a consanguineous population.

Obesity (Silver Spring) 2015 08 14;23(8):1687-95. Epub 2015 Jul 14.

Department of Genomics of Common Disease, Imperial College London, London, UK.

Objective: Single gene mutations leading to severe obesity have so far been identified in 3-5% cases in European populations. However, prevalence of these pathogenic mutations has not systematically been examined in specific consanguineous populations. Here we describe the incidence of obesity-associated mutations through a step-wise sequence analysis, in a cohort of 73 Pakistani children with severe obesity from consanguineous families.

Methods: Initially, all subjects were screened for mutations in coding regions of leptin (LEP) and melanocortin 4 receptor (MC4R) genes by direct sequencing. Subjects negative for mutation in these genes were screened using microdroplet PCR enrichment and NGS. Genomic structural variation was assessed by genotyping. Serum leptin, insulin, and cortisol were determined by ELISA.

Results: Among 73 children with severe obesity (BMI SDS > 3.0), we identified 22 probands and 5 relatives, carrying 10 different loss-of-function homozygous mutations in LEP, leptin receptor (LEPR), and MC4R genes, including 4 novel variants. Hypercortisolemia was significantly emphasized in LEP mutation carriers.

Conclusions: The prevalence of pathogenic mutations in genes known to directly influence leptin-melanocortin signaling is 30% in our cohort. The results of this study emphasize the desirability of undertaking systematic and in-depth genetic analysis of cases with severe obesity in specific consanguineous populations.
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http://dx.doi.org/10.1002/oby.21142DOI Listing
August 2015
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