Prevalence of high-risk human papillomavirus in oral squamous cell carcinoma with or without chewing habits.

Oral cancer (OC) is the most common cancer in Pakistani males and the second most common in females. Major risk factors include peculiar chewing habits, human papillomavirus (HPV) infection and molecular pathways. However, less data is available for this avertible cancer regarding its association with high-risk HPV (HR-HPV) and chewing habits in this region. Therefore, this study was done to determine the prevalence of HR-HPV in oral squamous cell carcinoma (OSCC) and its correlation with p16 and chewing habits. Formalin-fixed paraffin-embedded (FFPE) biopsy specimens of 186 samples were tested for HR-HPV type 16/18 by PCR, followed by p16 immunostaining (IHC) in a subset of cases (n = 50). Appropriate statistical tests were applied to find the association between HR-HPV/p16 and peculiar chewing habits with significance criteria of p<0.05 with 95% CI. HR-HPV (type 16 &18) was present in seven out of 186 cases (3.8%). Of these seven cases, five were positive for HPV16, whereas two were positive for HPV16/18. The overall expression of p16 protein in 50 samples was 38% (n = 19), and among these 19-IHC positive samples, 26% were positive for HR-HPV DNA. No significant association was found between HR-HPV positivity and p16 and chewing habits (p>0.05). It was concluded that HR-HPV prevalence in OSCC was very low in our population, with no statistically significant correlation with p16 and chewing habits. These results suggest the role of HR-HPV as an independent risk factor in OSCC in the local setting.

Sequence variants in the BTD underlying biotinidase deficiency in families of Pakistani origin.

BACKGROUND: Biotinidase deficiency (BTD) is a rare autosomal recessive metabolic disease, which develops neurological symptoms because of the impaired biotin recycling. Pathogenic mutations on BTD gene cause BTD deficiency. The clinical features and mutation analysis of Pakistani children with BTD deficiency have rarely been described. Herein, for the first time, we report the clinical features, BTD gene mutations and biochemical analysis of seven symptomatic children with BTD deficiency from Pakistan. METHODS: Seven suspected BTD-deficient patients who presented abnormal organic acid profiles and clinical features were subjected to Sanger sequencing to identify pathogenic mutations in the BTD gene. The results were analyzed by Mutation Surveyor Software. RESULTS: All seven patients exhibited common biotinidase deficiency symptoms including hypotonia, developmental delay and seizures. Biochemical analysis shows marked excretion of 3-hydroxy isovalerate in all cases, followed by 3-hydroxy propionate and methyl citrate. Sanger sequencing revealed one frame-shift mutation, c.98_104delinsTCC (p.Cys33Phefs), and two missense mutations, c.1612C>A (p.Arg538Ser) and c.1330G>C (p.Asp444His). All mutations were in the homozygous state and classified as pathogenic in published studies and mutation databases. CONCLUSIONS: This study has validated the BTD variants as the underlying cause of biotinidase deficiency in which molecular testing of BTD is supported by urinary organic acid analysis and clinical diagnosis. Secondly, the strength of the local availability of this test in Pakistan will paved the way for the neonatal screening of biotinidase deficiency.

Spectrum of Cystic Fibrosis Conductance Regulator Gene Mutations Reported in Pakistani Descent Cystic Fibrosis Patients.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This study aims to determine the genotypic and phenotypic spectrum of the CFTR gene mutations reported in the literature for Pakistani-origin CF patients. Databases were searched for such studies from 1947-2019 for sample size, method of diagnosis, and CFTR gene mutations. The authors identified 12 studies reporting 33 CFTR gene mutations, both intronic as well as exonic in Pakistani origin patients. The most widely tested mutation was D508 with a frequency of 17%-60%. No hotspot zone was identified and not all reported mutations were causing disease. There is a need to identify common mutations in the Pakistani population to develop population-specific CFTR mutations panel. This will enable the researchers to perform phenotype-genotype correlation studies to improve the CF detection rate. Key Words: Cystic fibrosis, Pakistan, Mutations, CFTR.

Oral cancer: Clinicopathological features and associated risk factors in a high risk population presenting to a major tertiary care center in Pakistan.

Oral squamous cell carcinoma (OSCC) has the highest prevalence in head and neck cancers and is the first and second most common cancer in males and females of Pakistan respectively. Major risk factors include peculiar chewing habits like areca nut, betel quid, and tobacco. The majority of OSCC presents at an advanced stage with poor prognosis. On the face of such a high burden of this preventable cancer, there is a relative lack of recent robust data and its association with known risk factors from Pakistan. The aim of this study was to identify the socioeconomic factors and clinicopathological features that may contribute to the development of OSCC. A total of 186 patients diagnosed and treated at a tertiary care hospital, Karachi Pakistan were recruited. Clinicopathological and socioeconomic information was obtained on a structured questionnaire. Descriptive analysis was done for demographics and socioeconomic status (SES) while regression analysis was performed to evaluate the association between SES and chewing habits, tumor site, and tumor stage. The majority of patients were males and the mean age of OSCC patients was 47.62±12.18 years. Most of the patients belonged to low SES (68.3%) and 77.4% were habitual of chewing. Gender (male) and SES were significantly associated with chewing habits (p<0.05). Odds of developing buccal mucosa tumors in chewers (of any type of substance) and gutka users were 2 and 4 times higher than non-chewers respectively. Middle age, chewing habits, and occupation were significantly associated with late stage presentation of OSCC (p<0.05). In conclusion, male patients belonging to low SES in their forties who had chewing habits for years constituted the bulk of OSCC. Buccal mucosa was the most common site in chewers and the majority presented with late stage tumors.

Dedifferentiated Liposarcoma With Meningothelial-Like Whorls: Five Additional Cases and Review of the Literature.

Background. Diagnosis of dedifferentiated liposarcoma (DDL) can sometimes be challenging due to a wide variety of histological features. "Meningothelial-like" whorl is an uncommon histological feature of DDL, which is also observed in neural tumors and follicular dendritic cell sarcoma. This feature is frequently associated with metaplastic bone formation. We conducted this study to describe the clinicopathological features of DDL with meningothelial-like whorls that would aid in establishing accurate diagnosis. Material and Methods. Microscopic glass slides of 5 cases of DDL with meningothelial-like whorls, diagnosed between January 2010 and December 2019, were reviewed. Results. Paratesticular region was the most common site. Whorls occupied 10% to 75% of tumor area and ranged in size from <0.1 cm to >2 cm. In 1 case, these whorls coalesced to form large areas of dedifferentiation. The cells forming whorls were spindle to epithelioid shaped and lacked significant nuclear pleomorphism and increased mitoses. Metaplastic bone formation was observed in 4 cases and cartilage formation in 3 cases. p16 and α-smooth muscle actin (α-SMA) immunohistochemical stains were positive in 2 cases, when performed. MDM2 gene amplification was observed in all cases by fluorescence in situ hybridization technique. These tumors showed aggressive behavior, similar to that of DDL without meningothelial-like whorls. Two patients died, 1 developed recurrence, 1 presented as recurrent tumor, and 1 developed metastasis. Conclusion. Meningothelial-like whorls in DDL most likely represent an early stage of dedifferentiation. Presence of well-differentiated liposarcoma areas, metaplastic bone formation, positive expressions for p16 and α-SMA immunohistochemical stains, and MDM2 gene amplification are useful diagnostic clues. These tumors have the potential to behave aggressively.

Polymorphisms in the GC Gene for Vitamin D Binding Protein and Their Association with Vitamin D and Bone Mass in Young Adults.

OBJECTIVE: To identify DBP gene rs4588 and rs7041 polymorphisms and associate with participants' serum 25(OH)D and BMD levels. STUDY DESIGN: Cross-sectional descriptive study design. PLACE AND DURATION OF STUDY: Section of Chemical Pathology and Molecular Pathology, Department of Pathology and Laboratory Medicine, The Aga Khan University, Karachi, from July 2014 to September 2015. METHODOLOGY: Blood samples from 98 young adults, out of 101 samples collected, were genotyped for GC rs4588 and rs7041 polymorphisms by polymerase chain reaction-based restriction fragment length polymorphism assay. Questionnaires were administered to obtain information on demographics and anthropometric characteristics, BMD was assessed with heel ultrasound and 25(OH)D was measured using a Chemiluminescence immunoassay. RESULTS: High prevalence of vitamin D deficiency was noted in the study population n=87 (86.1%) having median (IQR) 25(OH)D levels of 14.9 (20.9) ng/ml, in males and 12.1 (51.8) ng/ml in females. The C/C genotype of SNP rs4588 had the highest proportion n=50 (51%), whereas for rs7041 genotype G/T was most frequently observed n=53 (54%) in subjects. Highest 25(OH)D levels were observed within the homozygous genotypes C/C median 25(OH)D 14.0 (49.6) and G/G (median 25(OH)D 14.9 (37.1) ng/ml. Statistically significant relationship was noted between rs7041 genotype G/T and BMD (p 0.037). CONCLUSION: Hypovitaminosis D was frequently found in young adults. Furthermore, G/T variant of rs7041 polymorphism was associated with lower 25(OH)D serum levels.

MLPA Analyses Reveal a Spectrum of Dystrophin Gene Deletions/Duplications in Pakistani Patients Suspected of Having Duchenne/Becker Muscular Dystrophy: A Retrospective Study.

Introduction: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are inherited X-linked recessive genetic disorders caused by defects in the dystrophin gene. Abnormality in the dystrophin protein causes progressive muscle damage and weakness leading to long-term disability. Objective: To investigate the spectrum of dystrophin gene variants (deletions and duplications) in Pakistani patients suspected of having DMD/BMD or of being DMD/BMD carriers. Methods: A single center (Aga Khan University Hospital, Karachi, Pakistan) retrospective review of 46 cases was conducted to characterize dystrophin gene variants (deletion/duplication) in DMB/BMD patients using the multiplex ligation-dependent probe amplification-based method to provide coverage for all 79 exons. Results: Dystrophin gene deletions were identified in 40 of 46 cases, whereas duplications were present in 6 of 46 cases. The majority of the deletions were present between exons 45 and 52 followed by the region between exons 8 and 18. The most frequently deleted was exon 46 (8%) followed by exon 49 (7%). Dystrophin gene duplications were clustered between exons 3 and 7. The average deletion or duplication size was five exons for both kinds of variants. Conclusions: The applicability of exon skipping drugs depends on the specific mutational frequencies within populations. Our data suggest that for the Pakistani patients, multiple exon skipping between exons 46 and 49 could potentially be a target for exon skipping therapy. However, a larger nationwide study is required to further identify the predominant deletion/duplication dystrophin gene variants present in the population.

Distribution of Chromosomal Abnormalities Commonly Observed in Adult Acute Myeloid Leukemia in Pakistan as Predictors of Prognosis

Objectives: The heterogenous response to treatment in acute myeloid leukemia (AML) can be attributed largely to the difference in cytogenetic features identified in between cases. Cytogenetic analysis in acute leukemia is now routinely used to assist patient management, particularly in terms of diagnosis, disease monitoring, prognosis and risk stratification. Knowing about cytogenetic profile at the time of diagnosis is important in order to take critical decisions in management of these patients. The study was conducted to determine the distribution of cytogenetic abnormalities in Pakistani adult patients with AML in order to have insights regarding behavior of the disease. Methods: A retrospective analysis of all the cases of AML (≥15years old) diagnosed at Aga Khan University from January 2011 to December 2016 was performed. Cytogenetic analysis was made for all cases using the trypsin-Giemsa banding technique. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature (ISCN) criteria. Results: A total of 321 patients were diagnosed with AML during the study period, of which 288 samples successfully yielded metaphase chromosomes. The male to female ratio was 1.7:1. A normal karyotype was present in 61% (n=176) of the cases whereas, 39% (n=112) had an abnormal karyotype. Of the abnormal cases, t (8;21) (q22;q22) and t (15;17) (q22;q12) were identified in 8.3% and 4.9% cases respectively. Adverse prognostic cytogenetic subgroups including complex karyotype, monosomy 7 and t(6;9)(p23;q34) were identified in 9%, 1% and 0.7% patients respectively. Conclusions: This largest cytogenetic data in adult AML from Pakistan showed comparable prevalence of favorable prognostic karyotype to international data. The prevalence of specific adverse prognostic karyotype was low.

Frequency of ALK Rearrangement by FISH Testing and its Correlation with ALK-IHC in Adenocarcinoma of Primary Lung Origin

Anaplastic lymphoma kinase (ALK) gene can be oncogenic either by forming fusion with other genes, amplification of the gene or by having mutations. ALK rearrangement can either be detected by standard "fluorescence in situ hybridization (FISH)" or "immunohistochemistry (IHC)". Objective of this study was to record the prevalence of ALK rearrangement in adenocarcinoma of Primary Lung origin and compare it with ALK-IHC staining. Data of 64 patients of lung adenocarcinoma from 2015-2017 was analyzed. All of the FFPE biopsies were tested for EGFR (qPCR) followed by ALK rearrangement (by FISH and IHC) on EGFR negative samples. Out of 64 samples, 21.8% (14) showed EGFR mutations and 14% (7/50) were positive for ALK rearrangement when checked by FISH. In IHC testing for ALK (FISH positive) 8% (4/50) showed positivity. In conclusion ALK-FISH positive cases are higher than other studies likely due to the relatively small sample size. FISH testing was found to be more sensitive than IHC; one reason may be the low level of ALK. Our study warrants that currently FISH remains the gold standard for screening of ALK gene rearrangements.

Anaplastic lymphoma kinase protein positive diffuse large B cell lymphoma; A developing world experience.

Anaplastic lymphoma kinase (ALK) positive diffuse large B-cell lymphoma (ALK+DLBCL) is a rare, distinct and aggressive subtype of non-Hodgkin's lymphoma (NHL). These tumors are considered to be derived from post-germinal center B cells but peculiarly their distinction is based on the fact that they are ALK-positive neoplastic B cells but lack expression of B cell markers (CD19,CD20, CD79a), T cell markers (CD3, CD5) and CD30. Its broad differential diagnosis and similarities to plasmablastic lymphoma, immunoblastic DLBCL, Anaplastic large-cell lymphoma (ALCL) of T-null cell lineage, and poorly differentiated/anaplastic carcinoma pose a grave challenge to physicians with conventional costly treatment for DLBCL failing to yield any clinical or prognostic significance in ALK+DLBCL. In this article we present 7 cases which were reported at Aga Khan University Hospital, Department of Pathology and Laboratory Medicine from 2009 to 2015 and a review of literature on ALK+ DLBCL, which according to the best of our knowledge is the second largest reported series and the first from South Asian subcontinent.

Assessment of WT1 Expression as a Marker of Treatment Outcome in Karyotype Normal Acute Myeloid Leukemia Patients in Pakistan.

Currently, there is an effort to predict relapse by follow-up monitoring of MRD and subsequently to begin the treatment of the patients during their clinical and hematological remission prior to overt hematological relapse. Expression of WT1 in AML is known to be independently associated with significant inferior response to therapy and short survival outcome. Follow-up monitoring of WT1 gene expression during or after therapy would be a valuable predictive marker for early recurrence or relapse of AML disease. This pilot study evaluated newly diagnosed and post-induction or consolidation chemotherapy of AML patients who were registered with the Oncology Clinics of the Aga Khan University Hospital, Karachi. High WT1 burden (> 5000 copies/ml) in 2 patients was indicative of early recurrence of the disease along with shorter disease-free and overall survival. Low WT1 expression (< 200 copies/ml) in 2 patients after induction and consolidation therapy, respectively, was suggestive of better prognosis.

R990G polymorphism of calcium sensing receptor gene is associated with high parathyroid hormone levels in subjects with vitamin D deficiency: a cross-sectional study.

Single nucleotide polymorphisms (SNPs), R990G and A986S of the calcium sensing receptor (CaSR) gene, are shown to influence response of parathyroid hormone (PTH) in subjects with optimal vitamin D levels. This cross-sectional study was conducted in subjects with vitamin D deficiency (VDD) to observe associations between CaSR polymorphisms, plasma iPTH, and serum calcium levels. Adult females (n = 140) with known VDD, intact parathyroid hormone (iPTH), and calcium levels were recruited for genotype analysis. The frequencies of the 986 alleles GG, GT, and TT were 68%, 25%, and 7%, respectively, whereas the frequencies of the 990 alleles AA, AG, and GG were 80%, 8.9%, and 11.1%, respectively. The subjects with GG genotype of R990G polymorphism had higher iPTH levels (148.65 versus 91.47 and 86.1 pg/mL for GG versus AA, AG, resp., P = 0.008) and lower calcium levels (8.4 versus 9.04 and 9.07 mg/dL for GG versus AA, AG, resp., P = 0.002). No such association of A986S polymorphism with plasma iPTH or serum calcium levels was observed in the present study. Patients with VDD bearing the GG genotype of R990G SNPs are prone to have higher iPTH levels and lower calcium.

Cyclooxygenase-2 polymorphisms and breast cancer associated risk in Pakistani patients.

UNLABELLED: Prostaglandins produced by Cyclooxygenase-2 enzyme have been implicated to have a role in breast carcinogenesis. Several single nucleotide polymorphisms (SNPs) linked to COX-2 enzyme are reported to modulate its expression. The aim of the present study was to examine association of these SNPs to breast cancer risk in Pakistani patients. METHODS: In this case-control study, three sequence variants rs689465, rs689466, rs20417 in the promoter region of COX-2 were screened to evaluate the association with breast cancer risk. A total of 150 breast cancer patients and 101 healthy control genomic DNA were genotyped for rs689456, rs689466, rs20417 and their genotypes distribution in cases and control were compared using Pearson chi square test. Risk association was analyzed through odd ratio calculated by logistic regression. RESULTS: A screening analysis of COX-2 SNPs in 101 healthy controls showed distribution of Minor allelic frequency distribution of SNPs as follows : rs689465 (0.12), rs689466 (0.15), rs20417 (0.23). Further analyses revealed that their observed genotype frequencies were consistent with Hardy Weinberg equilibrium and strong linkage disequilibrium was identified between rs20417, rs689465 and rs689466. The Combined allele variants analysis showed that Haplotype rs68965G- 689466A-20417C (OR 2.909; CI 95 %1.3776.327; P = 0.007) was significantly associated with breast cancer. CONCLUSIONS: Our results indicate no strong association between three most frequent COX-2 SNPs rs689465 rs689466, rs20417 studied with breast cancer risk in the single locus analysis. However, our data suggested that combined COX-2 SNP haplotype have a role in breast cancer associated risk in Pakistani patients.

Distribution of EGFR mutations commonly observed in primary lung adenocarcinomas in Pakistan as predictors for targeted therapy.

BACKGROUND: Acquired genetic alterations and presence of sensitizing mutations in the tyrosine kinase domain of EGFR and other signaling molecules have been found in different subsets of primary lung adenocarcinoma. The commonest EGFR mutations are small in frame deletions of exon 19 and a point mutation (L858R) in exon 21, having a combined occurrence of around 90%. The objective of this study was to determine the frequency and types of EGFR mutations in primary lung adenocarcinomas in Pakistan. MATERIALS AND METHODS: EGFR mutations in tumor samples were screened by multiplex real time PCR. Briefly, DNA from formalin fixed paraffin-embedded tissue was amplified with primers and probes specific to 43 different EGFR mutations in a Cobas z 480 instrument. The assay detects mutations in four exons (18-21) of the EGFR gene. RESULTS: Out of 94 patients, 65 were males and 29 females with a M:F ratio of 2.2: 1. The median age was 62 years (range, 28 - 85 years). In our biopsy samples 70 (74%) cases were of primary lung adenocarcinoma, whereas 24 (26%) were confirmed metastatic adenocarcinoma of primary lung origin. EGFR mutation was positive in 29% of the patients. The highest frequency of L858R was observed in 48% of these, followed by deletion in exon 19 (44%). In addition, other rare mutations such as compound G718X:S768I and insertions in exon 20 insertion were detected in approximately 4% of the patients. CONCLUSIONS: This study showed that Del 19 and L858R are the most frequent mutations in Pakistani lung adenocarcinoma patients and around 29% of the patients were found eligible for erlotinib therapy.

Estimating window period blood donations for human immunodeficiency virus Type 1, hepatitis C virus, and hepatitis B virus by nucleic acid amplification testing in Southern Pakistan.

BACKGROUND: Recently, strategic planning was initiated by the National Blood Transfusion Services Pakistan to improve its blood bank facilities. Emphasis has been placed on appropriate screening of blood products. Located in the southern region, Aga Khan University Hospital is a 700-bed tertiary care academic institute with comprehensive blood banking. Screening of blood donors has been based on verbal screening and serologic testing to date. Additionally, the need of implementing nucleic acid testing (NAT) was considered in 2011 because of an upsurge in hepatitis epidemiology. The aim of this study was to analyze the efficacy of this additional donor screening program and to evaluate the impact of NAT on the yield and residual risk of transfusion-transmissible viral infections. STUDY DESIGN AND METHODS: A total of 42,830 blood donations collected between 2011 and 2012 were screened for routine serologic assays. Only serologically negative donors (n=41,304) were tested for NAT. The frequency of viral infections was evaluated through serologic techniques and NAT yield for viral agents was estimated for computing window period donors. Residual risk per million donors was computed for viral infections in seronegative blood donors. RESULTS: Serologic work-up showed 1571 abnormal screening results in 1526 blood donors with the following results: hepatitis C virus antibodies (anti-HCV; n=708), hepatitis B surface antigen (n=555), human immunodeficiency virus antibodies (anti-HIV; n=29), malaria (n=30), VDRL (n=249), and coinfection (n=45). Thirty-five NAT-reactive samples were identified: HIV-1, one; HCV, 27; and hepatitis B virus (HBV), seven. Incident rates per 10(5) donors were highest for HCV (453.3) followed by HBV (171.5) and HIV (72.2). Calculated residual risk per million donors was highest at 1 in 10,900 for HBV, intermediate at 1 in 13,900 for HCV, and least at 1 in 62,600 for HIV. CONCLUSION: Incidence rates and estimated residual risk indicate that the current risk of transfusion-transmitted viral infections attributable to blood donation is relatively high in this country. The study recommends the parallel use of both serology and NAT screening of donated blood in countries that have high seroprevalence of these viral infections.

Ewing's sarcoma arising from the adrenal gland in a young male: a case report.

BACKGROUND: Ewing's sarcoma uncommonly arises from extraosseous soft tissue or parenchymal organs. Primary adrenal Ewing's Sarcoma, although very rare, is extremely aggressive and commonly fatal. CASE PRESENTATION: A 17 year old Pakistani male was referred to the outpatient oncology clinic at our center with a three month history of concomitant pain, swelling and dragging sensation in the right hypochondrium. Abdominal examination revealed a large, firm mass in the right hypochondrium extending into the right lumbar region and epigastrium. His genital exam was unremarkable and there were no stigmata of hepatic or adrenal disease.Computed tomography scans revealed a large peripherally enhancing mass in the hepatorenal area, biopsy of which showed a neoplastic lesion composed of small round blue cells which exhibited abundance of glycogen and stained diffusely positive for CD99 (MIC2 antigen). Fluorescence in situ hybridization demonstrated gene rearrangement at chromosome 22q12 which confirmed the diagnosis of Ewing's sarcoma. Staging scans revealed pulmonary metastasis and hence he was commenced on systemic chemotherapy. CONCLUSION: This case report highlights the importance of keeping Ewing's sarcoma in mind when a young patient presents with a large non-functional adrenal mass.

Crimean-Congo hemorrhagic fever nosocomial infection in a immunosuppressed patient, Pakistan: case report and virological investigation.

Crimean-Congo hemorrhagic fever (CCHF) is endemic in the Baluchistan province, Pakistan. Sporadic outbreaks of CCHF occur throughout the year especially in individuals in contact with infected livestock. Nosocomial transmission remains a risk due to difficulties in the diagnosis of CCHF and limited availability of facilities for the isolation of suspected patients. Rapid diagnosis of CCHF virus infection is required for early management of the disease and to prevent transmission. This study describes the case of a 43-year-old surgeon who contracted CCHF during a surgical procedure in Quetta, Baluchistan and who was transferred to a tertiary care facility at the Aga Khan University Hospital, Karachi within 1 week of contracting the infection. Diagnosis of CCHF was made using a rapid real-time reverse transcription polymerase chain reaction (RT-PCR) assay for CCHF viral RNA. The patient had chronic hepatitis B and hepatitis D infection for which he had previously received a liver transplant. He proceeded to develop classic hemorrhagic manifestations and succumbed to the infection 14 days post-onset of disease. There was no further nosocomial transmission of the CCHF during the hospital treatment of the surgeon. Early diagnosis of CCHF enables rapid engagement of appropriate isolation, barrier nursing and infection control measures thus preventing nosocomial transmission of the virus.

Spinal muscular atrophy: clinical spectrum and genetic mutations in Pakistani children.

BACKGROUND: In Pakistan the rate of consanguineous marriages is high, thus, the chance of incidence of autosomal recessive disorders is likely to be high. The aim of this study is to investigate the clinical characteristics and genetics of spinal muscular atrophy (SMA) in children who presented to Aga Khan University, Karachi. MATERIALS AND METHODS: This study was a retrospective review of the medical charts of children (neonate: 15 years) with discharge diagnosis of SMA during last 10 years. Demographic features, consanguinity, and diagnostic analysis (including genetic analysis) were noted. RESULTS: During the study period 67 children had a discharge diagnosis of SMA. Werdnig Hoffman disease (SMA type I) was the commonest variant seen in 37 (56%) children. Overall 68% were infants. High parental consanguinity was observed in 68% of the study cohort. The history of delayed development and undiagnosed early death was observed in the families of 19 children. Genetic testing was performed in 22 (33%) children. Survival motor neuron (SMN) 1 gene deletion was found in 19 (86%) of the 22 patients in whom the gene analysis was done and 13 (68%) were also positive for neuronal apoptosis inhibitory proteins (NAIP) deletion. CONCLUSION: SMA is not an uncommon neurodegenerative disorder in Pakistan and SMA type I was the most common type. SMN1 gene deletion was the most common genetic deletion found in this study. In addition, family history of developmental delay and frequent early deaths highlights the need for implementation of prenatal diagnosis for early detection, effective control, and management of this disorder in Pakistan.