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The phenotypic spectrum associated with heterozygous mutations in cartilage oligomeric matrix protein gene (COMP) range from a mild form of multiple epiphyseal dysplasia (MED) to pseudoachondroplasia (PSACH). However, the phenotypic effect from biallelic COMP variants is unclear. We investigated a large consanguineous Pakistani family with a severe form of PSACH in 2 individuals. Another 14 family members presented with a mild PSACH phenotype similar to MED. Using exome sequencing and subsequent segregation analysis, we identified homozygosity for a COMP missense variant [c.1423G>A; p.(D475N)] in the 2 severely affected individuals, whereas family members with the mild PSACH phenotype were heterozygous. Our observations show for the first time that a biallelic COMP variant may be associated with pronounced and widespread skeletal malformations suggesting an additive effect of the 2 mutated alleles.

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Autosomal recessive primary microcephaly (MCPH) is a rare and heterogeneous genetic disorder characterized by reduced head circumference, low cognitive prowess and, in general, architecturally normal brains. As many as 14 different loci have already been mapped. We recruited 35 MCPH families in Pakistan and could identify the genetic cause of the disease in 31 of them. Using homozygosity mapping complemented with whole-exome, gene panel or Sanger sequencing, we identified 12 novel mutations in 3 known MCPH-associated genes - 9 in ASPM, 2 in MCPH1 and 1 in CDK5RAP2. The 2 MCPH1 mutations were homozygous microdeletions of 164,250 and 577,594 bp, respectively, for which we were able to map the exact breakpoints. We also identified four known mutations - three in ASPM and one in WDR62. The latter was initially deemed to be a missense mutation but we demonstrate here that it affects splicing. As to ASPM, as many as 17 out of 27 MCPH5 families that we ascertained in our sample were found to carry the previously reported founder mutation p.Trp1326*. This study adds to the mutational spectra of four known MCPH-associated genes and updates our knowledge about the genetic heterogeneity of MCPH in the Pakistani population considering its ethnic diversity.

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The human genome project is one of the significant achievements that have provided detailed insight into our genetic legacy. During the last two decades, biomedical investigations have gathered a considerable body of evidence by detecting more than 2000 disease genes. Despite the imperative advances in the genetic understanding of various diseases, the pathogenesis of many others remains obscure. With recent advances, the laborious methodologies used to identify DNA variations are replaced by direct sequencing of genomic DNA to detect genetic changes. The ability to perform such studies depends equally on the development of high-throughput and economical genotyping methods. Currently, basically for every disease whose origen is still unknown, genetic approaches are available which could be pedigree-dependent or -independent with the capacity to elucidate fundamental disease mechanisms. Computer algorithms and programs for linkage analysis have formed the foundation for many disease gene detection projects, similarly databases of clinical findings have been widely used to support diagnostic decisions in dysmorphology and general human disease. For every disease type, genome sequence variations, particularly single nucleotide polymorphisms are mapped by comparing the genetic makeup of case and control groups. Methods that predict the effects of polymorphisms on protein stability are useful for the identification of possible disease associations, whereas structural effects can be assessed using methods to predict stability changes in proteins using sequence and/or structural information.

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Laurin-Sandrow syndrome (LSS) is a rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. The genetic basis of LSS is currently unknown. LSS shows phenotypic overlap with Haas-type polysyndactyly (HTS) regarding the digital phenotype. Here we report on five unrelated families with overlapping microduplications encompassing the Sonic hedgehog (SHH) limb enhancer ZPA regulatory sequence (ZRS) on chromosome 7q36. Clinically, the patients show polysyndactyly phenotypes and various types of lower limb malformations ranging from syndactyly to mirror image polydactyly with duplications of the fibulae. We show that larger duplications of the ZRS region (>80 kb) are associated with HTS, whereas smaller duplications (<80 kb) result in the LSS phenotype. On the basis of our data, the latter can be clearly distinguished from HTS by the presence of mirror image polysyndactyly of the feet with duplication of the fibula. Our results expand the clinical phenotype of the ZRS-associated syndromes and suggest that smaller duplications (<80 kb) are associated with a more severe phenotype. In addition, we show that these small microduplications within the ZRS region are the underlying genetic cause of Laurin-Sandrow syndrome.

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Cenani-Lenz syndrome (CLS) is a rare autosomal recessive developmental disorder of the limbs. The disorder is characterized by complete syndactyly with metacarpal fusions and/or oligodactyly sometimes accompanied by radioulnar synostosis. The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth abnormalities are frequent features as well as lower limb involvement. CLS was recently associated with mutations in the low-density lipoprotein receptor-related protein 4 (LRP4) gene and dysregulated canonical WNT signaling. We have identified a large consanguineous Pakistani pedigree with 9 members affected by CLS. The affected individuals present with a consistent expression of the syndrome restricted to the limbs and kidneys. Symptoms from the lower limb are mild or absent and there were no radioulnar synostosis or craniofacial involvement. Genetic analysis using autozygosity mapping and sequencing revealed homozygosity for a novel missense mutation c.2858T > C (p.L953P) in the LRP4 gene. The mutation is located in a region encoding the highly conserved low-density lipoprotein receptor repeat class B domain of LRP4. Our findings add to the genotype-phenotype correlations in CLS and support kidney anomalies as a frequent associated feature.

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Autosomal recessive primary microcephaly (MCPH) is caused by mutations in at least eight different genes involved either in cell division or DNA repair. Most mutations are identified in consanguine families from Pakistan, Iran and India. To further assess their genetic heterogeneity and mutational spectra, we have analyzed 57 consanguine Pakistani MCPH families. In 34 MCPH families, we detected linkage to five out of the eight well-characterized disease loci and identified mutations in 27 families, leaving seven families without mutations in the coding exons of the presumably underlying MCPH genes. In the MCPH cohort 23 families could not be linked to any of the known loci, pointing to remarkable locus heterogeneity. The majority of mutations were found in ASPM followed by WDR62, CENPJ, CEP152 and MCPH1. One ASPM mutation (p.Trp1326*) was found in as many as eight families suggesting a Pakistani founder mutation. One third of the families were linked to ASPM followed by WDR62 confirming previous data. We identified three novel ASPM mutations, four novel WDR62 mutations, one novel MCPH1 mutation and two novel CEP152 mutations. CEP152 mutations have not been described before in the Pakistani population.

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Cervical and vaginal epithelia are primary barriers against HIV type I (HIV-1) entry during male-to-female transmission. Cervical mucus (CM) is produced by the endocervix and forms a layer locally as well as in the vaginal compartment in the form of cervicovaginal mucus (CVM). To study the potential barrier function of each mucus type during HIV-1 transmission, we quantified HIV-1 mobility in CM and CVM ex vivo using fluorescent microscopy. Virions and 200-nm PEGylated beads were digitally tracked and mean-squared displacement was calculated. The mobility of beads increased significantly in CVM compared with CM, consistent with the known decreased mucin concentration of CVM. Unexpectedly, HIV-1 diffusion was significantly hindered in the same CVM samples in which bead diffusion was unhindered. Inhibition of virus transport was envelope-independent. Our results reveal a previously unknown activity in CVM that is capable of impeding HIV-1 mobility to enhance mucosal barrier function.

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BACKGROUND: We report cascade testing of a large Pakistani family for beta-thalassemia alleles. The family was still practicing consanguineous marriages and was at risk of having more affected births. OBJECTIVE: The objective of this study was to show that identification of disease carriers in families with index cases in order to create awareness about disease and provide genetic counseling would result in reduction of the frequency of beta-thalassemia in Pakistan. METHODS: In this large family with an index case, 27 available living members were tested for beta-thalassemia. Carriers of the disease were detected by measuring hemoglobin indices, and amplification refractory mutation system polymerase chain reaction was used for mutation analysis. Genetic counseling was provided to members of this family. RESULTS: There were already 3 marriages between the carrier members and 1 between a carrier and noncarrier in this large family; 12 (44.4%) members were found to carry the mutant gene, representing a very high carrier rate compared to the 5.4% carrier frequency of beta-thalassemia in the general population of Pakistan. The family was counseled for prevention of affected births. The initially reluctant family gradually became cooperative and seriously attended the genetic counseling sessions. CONCLUSION: Cascade testing is more practical than general population screening in a country with limited health facilities where consanguineous marriages are practiced. This report emphasizes the need of extensive testing within families with index cases to identify the carriers of beta-thalassemia in order to reduce disease occurrence through awareness and genetic counseling.

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INTRODUCTION: Parkinson's disease is an idiopathic disorder of the extrapyramidal system. It has a worldwide prevalence but data from developing countries is scanty. We describe the clinical spectrum of the disease from Pakistan, a developing country. METHODS: Patients with Parkinson's disease, over a period of 11 years, were identified by ICD-9 coding system of the hospital medical records. Demographical characteristics, clinical features, laboratory investigations and radiological investigations were recorded and analysed. RESULTS: A total of 80 patients were identified. 50 (63 percent) were males and 30 (37 percent) were females. Mean age of onset of the disease was 54 years. 47 (59 percent) patients had onset of illness during the sixth or seventh decade of life. Mean duration of illness at the time of presentation was five years. Rigidity, bradykinesia, tremors, hypomimia, primitive reflexes, difficulty in performing fine work and walking difficulty were the most common clinical features. 52 (65 percent) patients had stage I or II (Hoehn-Yahr staging) disease at the time of presentation. 56 (70 percent) patients had predominantly unilateral symptoms. 15 (19 percent) patients had cognitive impairment. Cognitive decline was more common in the elderly and in patients with disease duration of longer than ten years. CONCLUSION: Parkinson's disease is more common in males. Tremor, rigidity, walking difficulty, bradykinesia and difficulty in performing fine work are the commonest clinical features. Disease severity increases with duration of the disease. Cognitive impairment is not uncommon in these patients and is associated with disease duration and age of onset of the illness.

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INTRODUCTION: Pneumonia is a common complication after acute stroke. It affects the outcome adversely. However, data regarding microbiology of stroke-associated pneumonia and its effect on outcome is scarce. METHODS: Stroke-associated pneumonia was identified through chart review of all ICD-9 identified adult stroke patients admitted to our hospital over a period of four years (1998-2001). The demographical, laboratory, radiological, microbiological data and outcome of patients with stroke-associated pneumonia were recorded and analysed. RESULTS: 443 patients with stroke were admitted over the four-year period and 102 (23 percent) had stroke-associated pneumonia. Their ages range from 28 to 100 (mean 64+/-14) years. 69 (68 percent) were men. Median length of stay was nine days compared to four days for all stroke patients. 68 (67 percent) patients manifested pneumonia within 48 hours and 34 (33 percent) after 48 hours of admission. Yield of tracheal aspirate cultures was 38 percent and that of chest radiographs was 25 percent. Pseudomonas aeruginosa and Staphylococcus aureus were the most common organisms (12 percent each) followed by Streptococcus pneumoniae and Klebsiella pneumoniae (4 percent each). Patients with infiltrates on chest radiographs were more likely to have positive tracheal aspirate cultures (p-value is 0.003). 35 patients (34 percent) expired during hospital stay. Positive chest radiographs and tracheal aspirates were independent predictors of prolonged hospital stay (p-value is less than 0.005). CONCLUSION: Pneumonia is a common medical complication of stroke. It is associated with a high mortality and prolongs the hospital stay. The yield of chest radiographs and tracheal aspirates is low. However, these are independent predictors of prolonged hospital stay. Pseudomonas aeruginosa and Staphylococcus aureus are most common organisms in stroke-associated pneumonia.

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OBJECTIVE AND BACKGROUND: Moyamoya disease is an idiopathic vasculopathy of circle of Willis. Stroke is a common presentation. We describe clinical and radiological features of moyamoya disease in four patients. SETTING: Tertiary care center in a metropolitan city. MATERIALS AND METHODS: Patients with moyamoya disease were identified by ICD-9 coding system of the hospital medical records. Demographic characteristics, clinical features/presentation, laboratory investigations and radiological investigations were recorded and analyzed. RESULTS: Four patients (three children and one adult) presented with hemiparesis. One patient expired during hospital stay. Two patients underwent surgery (synangiosis). EEGs of three patients showed focal abnormalities. Neuroimaging showed ischemic infarctions in all patients. Findings on four vessel digital substraction angiography and/or magnetic resonance angiography were compatible with moyamoya disease. CONCLUSION: Moyamoya disease should be considered in all young patients, especially children, presenting with stroke.

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OBJECTIVE: The aim of this study was to obtain data on predisposing factors, causative organisms and their associated mortality and complications related to acute bacterial meningitis. METHODS: The chart review of all patients in whom acute bacterial meningitis was diagnosed at The Aga Khan University Hospital from January 1995 through December 2001. RESULTS: One hundred ninety-four patients were included in study. There were 146 males and 48 females. The mean age of our study population was 41 +/- 12.3 years. One hundred and ninety (97.9%) patients had community-acquired meningitis; only 4 (2.0%) patients developed meningitis nosocomially. The two most common predisposing factors were diabetes mellitus (13.9%) and otitis media (7.7%) among all 194 patients. A significant proportion of patients with complications had diabetes mellitus (24.6%, p < 0.001). CSF and blood cultures were positive in 53 (27.3%) and 42 (21.6%) patients respectively; there was no statistical difference found. The most common organisms isolated were Streptococcus pneumoniae in 35 (36.8%) patients followed by Neisseria meningitides in 30 (31.5%) patients. Approximately 68% of positive cultures yielded S. pneumoniae and N. meningitides (p < 0.0001). The overall mortality rate was 22.1%. The mortality rate for Streptococcus pneumoniae was 17.1%. The highest mortality was observed in patients with Pseudomonal meningitis where all four patients expired followed by mortality rate of 85.7% in Escherichia coli afflicted patients (p < 0.001). Complications occurred in 73 (37.6%) patients with persistent complications in 31 (42.4%) patients. Complications resolved in 34 (46.5%) patients. The most common complications were seizures (12.8%) and cranial nerve palsies (11.3%). Seizures were more likely to occur in older patients (p < 0.05) whereas hydrocephalus was more common in younger patients (p < 0.05). CONCLUSION: Bacterial Meningitis remains a serious disease associated with substantial morbidity and mortality. Most cases are community acquired with S. Pneumoniae being the most common pathogen. Old age, diabetes mellitus, a positive culture, seizures as a complication and late stage in the disease are the important predictors of a poor outcome.

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OBJECTIVE: Frequency of ischemic stroke subtypes is influenced by ethnic and geographic variables. Our objective was to identify various stroke subtypes and its determinants at a tertiary care hospital. METHODS: We prospectively collected data on ischemic stroke subtypes admitted to The Aga Khan University Hospital in Karachi. RESULTS: A total of 596 patients were enrolled in 22 months in the Aga Khan Universtiy Stroke Registry. These included 393 patients with Ischemic stroke, 126 patients with intracerebral hemorrhage, 50 patients with subarachnoid hemorrhage and others. The ischemic stroke group was classified according to the TOAST criteria and comprised of lacunar 168/393 (42.7%); large artery atherosclerosis 106/393 (26.9%); cardioembolic 24/393 (6.1%); undetermined 80/393 (20.3%); and other determined types 15/393 (3.8%). The high proportion of lacunar strokes in our population may be due to high burden of inadequately treated hypertension and diabetes. Clear cut cardioembolic stroke was relatively infrequent in our population. CONCLUSION: Lacunar stroke is the most common subtype of stroke in our patient population. This is most likely secondary to uncontrolled hypertension.

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OBJECTIVE: The risk of stroke and death associated with carotid endarterctomy is operator dependant. Data regarding risks of this procedure are not available in Pakistan and therefore it is difficult to make accurate risk benefit analysis for individual patients. Our objective was to determine safety of carotid endarterectomy at an academic tertiary care center in Pakistan. METHODS: Patients who underwent carotid endarterectomy (CEA) at our hospital during a ten-year period were identified through ICD-9 coding system of the hospital medical records. Demographic features, associated medical problems and immediate postoperative complications were recorded and analyzed. RESULTS: Sixty-three carotid endarterectomies were performed on 59 patients. Ages range from 43 to 80 (mean 61 +/- 8) years; 53 were male and 10 were female. Common associated diseases among these patients were hypertension; 38 (64.4%), ischemic heart disease; 26 (44%), diabetes mellitus; 24 (40.7%), dyslipidemia; 19 (32.2%) and renal insufficiency; 13 (22%). Most common complication was neuropraxia (transient neuropathy); 5 (7.9%), followed by pneumonia and stroke; each in 3 (4.8%) patients. None of the strokes related to the surgical procedure were disabling. Two of the patients who had stroke, recovered fully within 17 weeks and one recovered partly but was independent in all daily activities of living (ADLs). One patient died following simultaneous coronary artery bypass graft (CABG) and CEA. The risk of stroke or death for patients undergoing CEA was high with simultaneous CABG (3/11, 27%) and low for patients undergoing CEA alone (1/52, 2%). CONCLUSION: Carotid endarterectomy is a safe procedure in patients with symptomatic carotid stenosis at our hospital and should be performed, when indicated.

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Although Plasmodium vivax usually causes benign uncomplicated malaria, it can occasionally result in severe disease with life-threatening, end-organ involvement generally seen with falciparum malaria. We report a case of cerebral malaria caused by P. vivax and review the literature on this subject.

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OBJECTIVE: To study the risk factors, etiology and management of ischemic stroke in young adults in a South Asian population. METHODS: Retrospective study conducted at a large tertiary hospital in Karachi. One hundred and eighteen patients between fifteen and forty-five years admitted over a five year period with a diagnosis of ischemic infarct constituted the study population. The study variables included the full clinical spectrum, spanning historical, laboratory, radiological and outcome parameters. RESULTS: Forty-three percent of patients were hypertensive and 30% were diabetic. The combination of diabetes and hypertension was found in 19.5% of patients, intra-cranial and carotid artherosclerosis in 22% and embolism in 11% of the cases. The in-hospital mortality was 11%. The outcome was excellent in 27%, good in 50% and poor in 23% of patients. CONCLUSION: The risk factors for artherosclerosis and the contribution of intra and extra-cranial artherosclerosis were found to be much higher than those from the Western Hemisphere.

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Neuropeptide Y, cholecystokinin (tetra- and octasulphated peptides) and substance P were measured in lumbar cerebrospinal fluid obtained from patients with various neurologic disorders such as Parkinson's disease, cerebrovascular disorders, multiple sclerosis, tuberculous meningitis and aseptic meningitis. These results are statistically compared with healthy results. The results accumulated showed that the data collected can provide the vital information necessary for designing drug therapy.

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BACKGROUND: The present study focuses on the role of carotid doppler ultrasonography (CDUS) in the diagnosis and management of carotid stenosis in young stroke patients. METHODS: The findings of carotid doppler in 45 ischemic stroke patients between 15-45 years of age were reviewed retrospectively. The variables of interest for this study included risk factors for atherosclerotic disease, primary abnormality detected on carotid doppler ultrasonography (ulceration vs. stenosis), degree of stenosis and the type of plaque (soft vs. calcified). RESULTS: The prevalence of hypertension and diabetes was 50% and 35% respectively. The rate of carotid stenosis in the study population was found to be 31%. The degree of stenosis was mild in 35% and moderate in 21%. High-grade stenosis was found in 21% of patients. The plaque was soft in the majority of cases (43%). CONCLUSION: The proportion of carotid stenosis in young stroke patients was relatively high compared with previous studies. This may be due to an increase in the risk factors for atherosclerotic disease in developing countries.

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