These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).

In guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA), we identified a homozygous nonsense mutation that segregated with achalasia and alacrima, delayed developmental milestones, and gait abnormalities in a consanguineous Pakistani pedigree. Mutations in GMPPA were subsequently found in ten additional individuals from eight independent families affected by the combination of achalasia, alacrima, and neurological deficits. This autosomal-recessive disorder shows many similarities with triple A syndrome, which is characterized by achalasia, alacrima, and variable neurological deficits in combination with adrenal insufficiency. GMPPA is a largely uncharacterized homolog of GMPPB. GMPPB catalyzes the formation of GDP-mannose, which is an essential precursor of glycan moieties of glycoproteins and glycolipids and is associated with congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-dystroglycan. Surprisingly, GDP-mannose pyrophosphorylase activity was unchanged and GDP-mannose levels were strongly increased in lymphoblasts of individuals with GMPPA mutations. This suggests that GMPPA might serve as a GMPPB regulatory subunit mediating feedback inhibition of GMPPB instead of displaying catalytic enzyme activity itself. Thus, a triple-A-like syndrome can be added to the growing list of congenital disorders of glycosylation, in which dysregulation rather than mere enzyme deficiency is the basal pathophysiological mechanism.

Autosomal recessive familial amyotrophic lateral sclerosis (RFALS) is a rare form of ALS that usually presents at an early age with slow progression of symptoms. RFALS is clinically and genetically heterogeneous and the locus of RFALS type 3 was mapped to 2q33 (ALS2) in a single family. We now report linkage of a more-common form of RFALS to chromosome 15q15-q22 markers (ALS5) and show further genetic locus heterogeneity in RFALS. ALS5 is the locus for most families with RFALS and appears to be present in both North African and European populations.

Introduction: Stroke is a major cause of death with hypertension being identified as an important modifiable risk factor. Prompt identification of stroke symptoms and timely management is noted to be significant in lowering both morbidity and mortality. Baseline stroke knowledge in hypertensive patients is crucial to develop effectively targeted, and appropriate health promotion campaigns; thus, the main objectives of this study are to assess the awareness of stroke and to determine health-seeking practices among hypertensive patients. Materials and methods: A standardized questionnaire survey regarding awareness and practices about stroke among hypertensive patients was conducted in a tertiary care hospital of Islamabad. The sample size was calculated as 384. Results: Out of 384 patients evaluated, 80.5% had heard about stroke, 71.6% knew someone with stroke, and 76% identified the brain as the organ affected. Sudden onset numbness of limb (66.9%) and hypertension (93.5%) were common warning symptom and risk factor identified. 87.5% would take stroke patients to a hospital. Only 45.1% of the patients took their medications regularly, and 38% checked their blood pressure. Conclusion: Majority of hypertensive patients were aware of stroke but the awareness of risk factors and warning signs was poor. Stroke prevention practices were also sub-optimal. There is a need to increase knowledge regarding risk factors, which will benefit the community at large.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. It has been found to be associated with frontotemporal lobar degeneration (FTLD). In the present study, we have described homozygosity mapping and gene sequencing in a consanguineous autosomal recessive Pakistani family showing non-juvenile ALS without signs of FTLD. Gene mapping was carried out in all recruited family members using microsatellite markers, and linkage was established with sigma non-opioid intracellular receptor 1 (SIGMAR1) gene at chromosome 9p13.2. Gene sequencing of SIGMAR1 revealed a novel 3'-UTR nucleotide variation c.672*31A>G (rs4879809) segregating with disease in this family. The C9ORF72 repeat region in intron 1, previously implicated in a related phenotype, was excluded through linkage, and further confirmation of exclusion was obtained by amplifying intron 1 of C9ORF72 with multiple primers in affected individuals and controls. In silico analysis was carried out to explore the possible role of 3'-UTR variant of SIGMAR1 in ALS. The Regulatory RNA motif and Element Finder program revealed disturbance in miRNA (hsa-miR-1205) binding site due to this variation. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores due to this variation. Our results indicate that the 3'-UTR SIGMAR1 variant c.672*31A>G may have a role in the pathogenesis of ALS in this family.

BackgroundA principal caregiver (CG) is directly affected by patient’s health problems that lead to CG strain. Pakistan has an estimated 4.8% of the population suffering from strokes. The study objective was to evaluate the caregiver level of stress and the factors which make CGs more prone to stress and also to identify the predictive role of factors such as age, sex, educational, marital status on their burden.MethodsThis was a cross-sectional survey. 112 Participants were chosen on the basis of being directly involved in the care of patient and able to give consent for the study. Stroke patients had to have a more than 1 month history of stroke and treated in a tertiary care hospital. The severity of stress was rated using the Modified Caregiver Strain Index (MCSI).ResultsOut of a total of 112 stroke patients and their caregivers, 12 were exempted. Most of the CGs were between the ages 30–39 (48%) and male (70%). Out of the males, most were sons (89%). None of the female CGs was employed. The mean MCSI score was 13.8. Gender, age, marital status, and duration of care all did not have a significant effect on the total (P = 0.640, 0.848, 0.839, 0.110 respectively). Female gender (P = 0.0075) was a factor leading to increased emotional adjustments. Single CGs had increased changes in personal plans (P = 0.014), and married CGs found the behaviour of the patients less upsetting (P = 0.0425). There was no significant difference between the total (P = 0.906) or individual components between daughters and daughter-in-laws. Increased duration of care was significantly associated with decrease level of sleep disturbance (P = 0.026), physical strain (P = 0.050) and other demands on time (P = 0.044). Increase age of CG was associated with an increase feeling of being overwhelmed (P = 0.027).ConclusionThere is a need to identify the factors responsible for major CG stress by conducting similar studies and to define structured intervention for evaluating and preventing problems of caregivers.

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Validation study of the Mini-Mental State Examination in Urdu language for Pakistani populationObjective: This study was conducted primarily to validate and determine the optimal cutoff score in the diagnosis of dementia among Pakistani’s and study the effects of gender and education on the MMSE performance in our population.Methods: Four hundred participants took part in the study. Patient with dementia recruited from five major hospitals from Pakistan. The MMSE was translated into Urdu. Results: There were 61 men and 39 women in dementia group and 225 men and 75 women in the control group. The mean score of Urdu MMSE were lower in patients with dementia 18.5 ± 5.6 (range 0-30) as compared to the controls 26.8 ± 2.6 (range 7-30). This difference between groups was statistically significant (p<0.001). Educational based MMSE score below 15 yielded perfect sensitivity and specificity for the diagnosis of dementia.Conclusions: These finding confirm the influence of level of education on MMSE score and education stratified cutoff scores should be used while screening for cognitive impairment in this population.