Farooq Naeem

Identification of Mutations in TRAPPC9, which Encodes the NIK- and IKK-β-Binding Protein, in Nonsyndromic Autosomal-Recessive Mental Retardation

Mental retardation/intellectual disability is a devastating neurodevelopmental disorder with serious impact on affected individuals and their families, as well as on health and social services. It occurs with a prevalence of approximately 2%, is an etiologically heterogeneous condition, and is frequently the result of genetic aberrations. Autosomal-recessive forms of nonsyndromic MR (NS-ARMR) are believed to be common, yet only five genes have been identified. We have used homozygosity mapping to search for the gene responsible for NS-ARMR in a large Pakistani pedigree. Using Affymetrix 5.0 single nucleotide polymorphism (SNP) microarrays, we identified a 3.2 Mb region on 8q24 with a continuous run of 606 homozygous SNPs shared among all affected members of the family. Additional genotype data from microsatellite markers verified this, allowing us to calculate a two-point LOD score of 5.18. Within this region, we identified a truncating homozygous mutation, R475X, in exon 7 of the gene TRAPPC9. In a second large NS-ARMR/ID family, previously linked to 8q24 in a study of Iranian families, we identified a 4 bp deletion within exon 14 of TRAPPC9, also segregating with the phenotype and truncating the protein. This gene encodes NIK- and IKK-beta-binding protein (NIBP), which is involved in the NF-kappaB signaling pathway and directly interacts with IKK-beta and MAP3K14. Brain magnetic resonance imaging of affected individuals indicates the presence of mild cerebral white matter hypoplasia. Microcephaly is present in some but not all affected individuals. Thus, to our knowledge, this is the sixth gene for NS-ARMR to be discovered.

CC2D2A, Encoding A Coiled-Coil and C2 Domain Protein, Causes Autosomal-Recessive Mental Retardation with Retinitis Pigmentosa

Autosomal-recessive inheritance is believed to be relatively common in mental retardation (MR), although only four genes for nonsyndromic autosomal-recessive mental retardation (ARMR) have been reported. In this study, we ascertained a consanguineous Pakistani family with ARMR in four living individuals from three branches of the family, plus an additional affected individual later identified as a phenocopy. Retinitis pigmentosa was present in affected individuals, but no other features suggestive of a syndromic form of MR were found. We used Affymetrix 500K microarrays to perform homozygosity mapping and identified a homozygous and haploidentical region of 11.2 Mb on chromosome 4p15.33-p15.2. Linkage analysis across this region produced a maximum two-point LOD score of 3.59. We sequenced genes within the critical region and identified a homozygous splice-site mutation segregating in the family, within a coiled-coil and C2 domain-containing gene, CC2D2A. This mutation leads to the skipping of exon 19, resulting in a frameshift and a truncated protein lacking the C2 domain. Conservation analysis for CC2D2A suggests a functional domain near the C terminus as well as the C2 domain. Preliminary functional studies of CC2D2A suggest a possible role in Ca(2+)-dependent signal transduction. Identifying the function of CC2D2A, and a possible common pathway with CC2D1A, in correct neuronal development and functioning may help identify possible therapeutic targets for MR.

Mutations in the Alpha 1,2-Mannosidase Gene, MAN1B1, Cause Autosomal-Recessive Intellectual Disability

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 next-generation 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.

Prevalence and psychosocial risk factors of PTSD: 18 months after Kashmir earthquake in Pakistan

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.

Preliminary evaluation of culturally sensitive CBT for depression in Pakistan: findings from Developing Culturally-sensitive CBT Project (DCCP).

BACKGROUND There is sufficient research evidence in favour of cognitive therapy in western world. However, only limited research has been carried out on its effectiveness in other countries. It is suggested that adaptations in content, format and delivery are needed before CBT can be employed in non-western cultures. We describe a preliminary evaluation of culturally adapted CBT for depression in Pakistan. AIMS We aimed to evaluate the efficacy of this culturally adapted CBT using a therapist manual. METHOD In a randomized controlled trial we compared combination of CBT and antidepressants with antidepressants alone (treatment as usual) in primary care. Referred patients with ICD-10 diagnosis of depression were invited to participate and randomized to the intervention and control groups. Hospital Anxiety and Depression Scale (HADS) and Bradford Somatic Inventory (BSI) were used to measure changes in depression, anxiety and somatic symptoms. RESULTS Seventeen patients each were randomized to each arms of the trial. Except for financial status there were no differences between the two groups on various demographic variables. Patients receiving CBT showed statistically significant improvement on measures of depression (p < .001), anxiety (p < .001) and somatic symptoms (p < .000) as compared to antidepressant alone group. 82% patients attended six or more sessions of therapy. CONCLUSIONS A culturally sensitive manualized CBT was effective in reducing symptoms of depression and anxiety in Pakistan.

Predictors of Response to Cognitive Behaviour Therapy in the Treatment of Schizophrenia: A Comparison of Brief and Standard Interventions

Cognitive therapy is now widely recommended for the treatment of schizophrenia. However, little is known about factors predicting good outcome. We are describing separate sub-analyses of two randomized controlled trials of Cognitive Behaviour Therapy for schizophrenia. In one trial expert therapists provided therapy while in the second trial brief therapy was provided by trained nurses. In both trials psychopathology was assessed using the Comprehensive Psychopathological Rating Scale (CPRS) and the Health of the Nation Outcome Scale (HoNOS). Insight, delusions, hallucinations and negative and positive symptoms were also measured. In brief therapy trial higher levels of insight and high CPRS global impression score predicted good outcome in the CBT group. Analyses using similar variables did not reveal any specific predictors for good outcome in the second trial.

Angry Wives, Abusive Husbands: Relationship Between Domestic Violence and Psychosocial Variables

BACKGROUND A small number of studies conducted in Pakistan have shown high rates of domestic violence. None of the studies, however, discussed associated psychosocial factors. We interviewed a group of women to look at violence and associated psychosocial factors. We wanted to see if self-esteem, quality of relationships, social support, stressful life events, psychiatric symptoms, and different measures of anger were associated with domestic violence. METHODOLOGY In a cross-sectional survey of women presenting to primary care physicians, we used Womens Experience with Battering and Domestic Abuse Checklist to measure domestic violence. The Relationship Assessment Scale, Oslo Social Support Scale, State Trait Anger Inventory, and Evaluative Belief Scale were used to look at the correlates of violence. We used the information in a regression model to identify independent predictors of violence in this sample. RESULTS More than half of the women reported experiencing battering and/or violence. Women in abusive relationships reported unhappiness with their intimate relationships and had high scores on 1 subscale of anger. Living in extended families was protective against violence. CONCLUSIONS We were able to replicate findings that women in abusive relationships are not satisfied with the relationships with their partners. Living in extended families was protective against violence. Community studies may provide a better design to look at the association between abuse and poverty, literacy, self-esteem, and social support.

Schizophrenia medication adherence in a resource-poor setting: randomised controlled trial of supervised treatment in out-patients for schizophrenia (STOPS)

BACKGROUND Most people with schizophrenia in low- and middle-income (LAMI) countries receive minimal formal care, and there are high rates of non-adherence to medication. AIMS To evaluate the effectiveness of an intervention that involves a family member in supervising medication administration - supervised treatment in out-patients for schizophrenia (STOPS) - in improving treatment adherence and clinical outcomes. METHOD Individuals (n = 110) with schizophrenia or schizoaffective disorders were allocated to STOPS or to treatment as usual (TAU) and followed up for 1 year. The primary outcome was adherence to the treatment regimen. Positive and Negative Syndrome Scale for Schizophrenia and Global Assessment of Functioning scores were also assessed. RESULTS Participants in the STOPS group had better adherence (complete adherence: 37 (67.3%) in STOPS v. 25 (45.5%) in TAU; P<0.02) and significant improvement in symptoms and functioning. CONCLUSIONS STOPS may be useful in enhancing adherence to treatment for schizophrenia in LAMI countries.

Brief culturally adapted CBT for psychosis (CaCBTp): A randomized controlled trial from a low income country

Evidence for the effectiveness of Culturally adapted CBT for psychosis in Low And Middle Income Countries (LAMIC) is limited. Therefore, brief Culturally adapted CBT for psychosis (CaCBTp) targeted at symptoms of schizophrenia for outpatients plus treatment as usual (TAU) is compared with TAU. A total of 116 participants with schizophrenia were recruited from 2 hospitals in Karachi, Pakistan, and randomized into two groups with 1:1 allocation (CaCBTp plus TAU=59, TAU=57). A brief version of CaCBTp (6 individual sessions with the involvement of main carer, plus one session for the family) was provided over 4months. Psychopathology was measured using Positive and Negative Syndrome Scale of Schizophrenia (PANSS), Psychotic Symptom Rating Scales (PSYRATS), and the Schedule for Assessment of Insight (SAI) at baseline and end of therapy. Participants in treatment group, showed statistically significant improvement in all measures of psychopathology at the end of the study compared with control group. Participants in treatment group showed statistically significant improvement in Positive Symptoms (PANSS, Positive Symptoms Subscale; p=0.000), Negative Symptoms (PANSS, Negative Symptoms subscales; p=0.000), Delusions (PSYRATS, Delusions Subscale; p=0.000), Hallucinations (PSYRATS, Hallucination Subscale; p=0.000) and Insight (SAI; p=0.007). The results suggest that brief, Culturally adapted CBT for psychosis can be an effective treatment when provided in combination with TAU, for patients with schizophrenia in a LAMIC setting. This is the first trial of CBT for psychosis from outside the western world. These findings need replicating in other low and middle income countries.

Psychiatric morbidity and domestic violence: a survey of married women in Lahore

ObjectiveA number of studies have looked at the prevalence rates of psychiatric disorders in the community in Pakistan over the last two decades. However, a very little information is available on psychiatric morbidity in primary health care. We therefore decided to measure prevalence of psychiatric disorders and their correlates among women from primary health care facilities in Lahore.MethodsWe interviewed 650 women in primary health care settings in Lahore. We used a semi-structured interview and questionnaires to collect information during face-to-face interviews.ResultsNearly two-third of the women (64.3%) in our study were diagnosed to have a psychiatric problem, while one-third (30.4%) suffered with Major Depressive Disorder. Stressful life events, verbal violence and battering were positively correlated with psychiatric morbidity and social support, using reasoning to resolve conflicts and education were negatively correlated with psychiatric morbidity.ConclusionThe prevalence of psychiatric disorders is in line with the prevalence figures found in community studies. Domestic violence is an important correlate which can be the focus of interventions.