Lahore Institute of Research and Development

Lahore, Pakistan

Lahore Institute of Research and Development

Lahore, Pakistan
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Kaufman L.,Center for Addiction and Mental Health | Ayub M.,Lahore Institute of Research and Development | Ayub M.,St Lukes Hospital | Ayub M.,Durham University | And 2 more authors.
Journal of Neurodevelopmental Disorders | Year: 2010

Intellectual disability (ID), also referred to as mental retardation (MR), is frequently the result of genetic mutation. Where ID is present together with additional clinical symptoms or physical anomalies, there is often sufficient information available for the diagnosing physician to identify a known syndrome, which may then educe the identification of the causative defect. However, where co-morbid features are absent, narrowing down a specific gene can only be done by 'brute force' using the latest molecular genetic techniques. Here we attempt to provide a systematic review of genetic causes of cases of ID where no other symptoms or co-morbid features are present, or non-syndromic ID. We attempt to summarize commonalities between the genes and the molecular pathways of their encoded proteins. Since ID is a common feature of autism, and conversely autistic features are frequently present in individuals with ID, we also look at possible overlaps in genetic etiology with non-syndromic ID. © 2010 The Author(s).

Ayub M.,Durham University | Ayub M.,Esk and Wear Valleys NHS Foundation Trust | Ayub M.,Lanchester Road Hospital | Poongan I.,Esk and Wear Valleys NHS Foundation Trust | And 7 more authors.
Child Psychiatry and Human Development | Year: 2012

A severe earthquake occurred in Kashmir in 2005. The epicentre was close to Muzzafarabad. We collected data on over 1,100 children 18 months after the earthquake to look at symptoms of PTSD and behavioural and emotional problems using well established questionnaires. We found that 64.8% of children had significant symptoms of PTSD. Girls were more likely to suffer from these symptoms. The proportion of children suffering from emotional and behaviour difficulties was 34.6%. This percentage was not different from other studies of children from Pakistan within areas which were not affected by the earthquake. The rate of emotional symptoms was higher in girls while hyperactivity was more frequent in boys. This pattern is similar to other studies from across the world. © Springer Science+Business Media, LLC 2011.

Naeem F.,Lahore Institute of Research and Development | Ayub M.,Esk and Wear Valleys NHS Foundation Trust | Ayub M.,Lanchester Road Hospital | Masood K.,Sheikh Zayed Medical College | And 6 more authors.
Journal of Affective Disorders | Year: 2011

Background: On average in a year 939 earthquakes of a magnitude between 5 and 8 on the Richter scale occur around the world. In earthquakes developing countries are prone to large-scale destruction because of poor structural quality of buildings, and preparedness for earthquakes. On 8th October 2005, a major earthquake hit the remote and mountainous region of northern Pakistan and Kashmir. We wanted to find out the rate of PTSD in a randomly selected sample of participants living in earthquake area and the correlates of the PTSD. Method: The study was conducted 18 months after the earthquake. We selected a sample of men and women living in the houses and tents for interviews. Using well established instruments for PTSD and general psychiatric morbidity we gathered information from over 1200 people in face to face interviews. We gathered information about trauma exposure and loss as well. Results: 55.2% women and 33.4% men suffered from PTSD. Living in a joint family was protective against the symptoms of PTSD. Dose of exposure to trauma was associated with the symptoms of PTSD. Living in a tent was associated with general psychiatric morbidity but not with PTSD. Limitations: We used questionnaire instead of interviews to detect the symptoms of psychiatric disorders. Conclusions: The symptoms of PTSD are common 18 months after the earthquake and they are specifically associated with the dose of trauma exposure. This may have implications for rehabilitation of this population. © 2010 Elsevier B.V.

Ayub M.,Durham University | Irfan M.,Lahore Institute of Research and Development | Maclean A.,University of Edinburgh | Naeem F.,St Mays Hospital | Blackwood D.,University of Edinburgh
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2013

A large family with a high prevalence of recurrent major depression and high average inbreeding coefficient was ascertained from rural Pakistan. Subjects were interviewed and diagnosed by a trained psychiatrist, 370 microsatellite markers were genotyped and the program FEstim was used for homozygosity mapping. Significant linkage was found on Chromosome 9 and Chromosome 6 after fine mapping. These regions on Chromosome 6 and 9 may harbor genes which predispose to depression. © 2012 Wiley Periodicals, Inc.

Rafiq M.A.,Center for Addiction and Mental Health | Kuss A.W.,Max Planck Institute for Molecular Genetics | Kuss A.W.,University of Greifswald | Puettmann L.,Max Planck Institute for Molecular Genetics | And 25 more authors.
American Journal of Human Genetics | Year: 2011

We have used genome-wide genotyping to identify an overlapping homozygosity-by-descent locus on chromosome 9q34.3 (MRT15) in four consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability (NS-ARID) and one in which the patients show additional clinical features. Four of the families are from Pakistan, and one is from Iran. Using a combination of nextgeneration sequencing and Sanger sequencing, we have identified mutations in the gene MAN1B1, encoding a mannosyl oligosaccharide, alpha 1,2-mannosidase. In one Pakistani family, MR43, a homozygous nonsense mutation (RefSeq number NM-016219.3: c.1418G>A [p.Trp473*]), segregated with intellectual disability and additional dysmorphic features. We also identified the missense mutation c. 1189G>A (p.Glu397Lys; RefSeq number NM-016219.3), which segregates with NS-ARID in three families who come from the same village and probably have shared inheritance. In the Iranian family, the missense mutation c.1000C>T (p.Arg334Cys; RefSeq number NM-016219.3) also segregates with NS-ARID. Both missense mutations are at amino acid residues that are conserved across the animal kingdom, and they either reduce k cat by ∼1300-fold or disrupt stable protein expression in mammalian cells. MAN1B1 is one of the few NS-ARID genes with an elevated mutation frequency in patients with NS-ARID from different populations. © 2011 by The American Society of Human Genetics. All rights reserved.

Bernkopf M.,Laboratory of Molecular Biology and Tumorcytogenetics | Webersinke G.,Laboratory of Molecular Biology and Tumorcytogenetics | Tongsook C.,University of Graz | Koyani C.N.,Medical University of Graz | And 18 more authors.
Human Molecular Genetics | Year: 2014

We describe the characterization of a gene for mild nonsyndromic autosomal recessive intellectual disability (ID) in two unrelated families, one from Austria, the other from Pakistan.Genome-wide single nucleotide polymorphism microarray analysis enabled us to define a region of homozygosity by descent on chromosome 17q25. Whole-exome sequencing and analysis of this region in an affected individual from the Austrian family identified a 5 bp frameshifting deletion in the METTL23 gene. By means of Sanger sequencing of METTL23, a nonsense mutation was detected in a consanguineous ID family from Pakistan for which homozygosity-by-descent mapping had identified a region on 17q25. Both changes lead to truncation of the putative METTL23 protein, which disrupts the predicted catalytic domain and alters the cellular localization. 3D-modelling of the protein indicates that METTL23is strongly predicted to function as an S-adenosyl-methionine (SAM)-dependent methyltransferase. Expression analysis of METTL23 indicated a strong association with heat shock proteins, which suggests that these may act as a putative substrate for methylation by METTL23. A number of methyltransferases have been described recently in association with ID. Disruption of METTL23 presented here supports the importance of methylation processes for intact neuronal function and brain development. © The Author 2014. Published by Oxford University Press.

Law R.,Campbell Family Mental Health Research Institute | Dixon-Salazar T.,University of California at San Diego | Dixon-Salazar T.,Howard Hughes Medical Institute | Jerber J.,University of California at San Diego | And 29 more authors.
American Journal of Human Genetics | Year: 2014

Dendritic spines represent the major site of neuronal activity in the brain; they serve as the receiving point for neurotransmitters and undergo rapid activity-dependent morphological changes that correlate with learning and memory. Using a combination of homozygosity mapping and next-generation sequencing in two consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability, we identified truncating mutations in formin 2 (FMN2), encoding a protein that belongs to the formin family of actin cytoskeleton nucleation factors and is highly expressed in the maturing brain. We found that FMN2 localizes to punctae along dendrites and that germline inactivation of mouse Fmn2 resulted in animals with decreased spine density; such mice were previously demonstrated to have a conditioned fear-learning defect. Furthermore, patient neural cells derived from induced pluripotent stem cells showed correlated decreased synaptic density. Thus, FMN2 mutations link intellectual disability either directly or indirectly to the regulation of actin-mediated synaptic spine density. © 2014 The American Society of Human Genetics.

PubMed | Im Neueheimerfeld, Lahore Institute of Research and Development, University of Education of Pakistan, Campbell Family Mental Health Research Institute and 3 more.
Type: Journal Article | Journal: Journal of human genetics | Year: 2016

We have used single-nucleotide polymorphism microarray genotyping and homozygosity-by-descent (HBD) mapping followed by Sanger sequencing or whole-exome sequencing (WES) to identify causative mutations in three consanguineous families with intellectual disability (ID) related to thyroid dyshormonogenesis (TDH). One family was found to have a shared HBD region of 12.1Mb on 8q24.21-q24.23 containing 36 coding genes, including the thyroglobulin gene, TG. Sanger sequencing of TG identified a homozygous nonsense mutation Arg2336*, which segregated with the phenotype in the family. A second family showed several HBD regions, including 6.0Mb on 2p25.3-p25.2. WES identified a homozygous nonsense mutation, Glu596*, in the thyroid peroxidase gene, TPO. WES of a mother/father/proband trio from a third family revealed a homozygous missense mutation, Arg412His, in TPO. Mutations in TG and TPO are very rarely associated with ID, mainly because TDH is generally detectable and treatable. However, in populations where resources for screening and detection are limited, and especially where consanguineous marriages are common, mutations in genes involved in thyroid function may also be causes of ID, and as TPO and TG mutations are the most common genetic causes of TDH, these are also likely to be relatively common causes of ID.

PubMed | The Hospital for Sick Children, Institute of Human Genetics and, Lahore Institute of Research and Development, University Institute of Mental Health and 9 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

There are two known mRNA degradation pathways, 3 to 5 and 5 to 3. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a splice site variant (c.636+1G>A) that results in an in-frame insertion of 45 nucleotides and a missense variant (c.947C>T; p.Thr316Met). DCPS decaps the cap structure generated by 3 to 5 exonucleolytic degradation of mRNA. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS. In another family, we identified a homozygous mutation (c.161T>C; p.Phe54Ser) in EDC3 in two affected children. EDC3 stimulates DCP2, which decaps mRNAs at the beginning of the 5 to 3 degradation pathway. In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. We show that individuals with biallelic mutations in these genes of seemingly central functions are viable and that these possibly lead to impairment of neurological functions linking mRNA decapping to normal cognition. Our results further affirm an emerging theme linking aberrant mRNA metabolism to neurological defects.

Naeem F.,Lahore Institute of Research and Development | Gobbi M.,University of Southampton | Ayub M.,Tees Esk and Wear Valley NHS Foundation Trust | Kingdon D.,University of Southampton
International Journal of Mental Health Systems | Year: 2010

Background: Psychological therapies especially Cognitive Behaviour Therapy (CBT) are used widely in the West to help patients with psychiatric problems. Cognitive Behaviour Therapy has an established evidence base for the treatment of different emotional disorders. In spite of these developments in the developed world, patients in most developing countries hardly benefit from non pharmacological interventions. Although a significant number of psychologists are trained in Pakistan each year, psychological interventions play only a minor role in treatment plans in Pakistan. We conducted interviews with psychologists in Pakistan, to explore their experiences and their views on "providing CBT in Pakistan". These interviews were conducted as part of a project whose focus was to try to develop culturally-sensitive CBT in Pakistan.Methods: In depth semi structured interviews were conducted with 5 psychologists working in psychiatry departments in Lahore, Pakistan.Results: All the psychologists reported that psychotherapies, including CBT, need adjustments for use in Pakistan, although they were not able to elicit on these in details. Four major themes were discovered, hurdles in therapy, therapy related issues, involvement of the family and modification in therapy. The biggest hurdles in therapy were described to be service and resource issues.Conclusions: For CBT to be acceptable, accessible and effective in Non Western cultures numerous adjustments need to be made, taking into consideration; factors related to service structure and delivery, patient's knowledge and beliefs about health and the therapy itself. Interviews with the psychologists in these countries can give us insights which can guide development of therapy and manuals to support its delivery. © 2010 Naeem et al; licensee BioMed Central Ltd.

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