Mehnaz Atiq

Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients

BackgroundSengers syndrome is an autosomal recessive condition characterized by congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the acylglycerol kinase (AGK) gene have been recently described as the cause of Sengers syndrome in nine families.MethodsWe investigated the clinical and molecular features of Sengers syndrome in seven new families; five families with the severe and two with the milder form.ResultsSequence analysis of AGK revealed compound heterozygous or homozygous predicted loss-of-function mutations in all affected individuals. A total of eight different disease alleles were identified, of which six were novel, homozygous c.523_524delAT (p.Ile175Tyrfs*2), c.424-1G > A (splice site), c.409C > T (p.Arg137*) and c.877 + 3G > T (splice site), and compound heterozygous c.871C > T (p.Gln291*) and c.1035dup (p.Ile346Tyrfs*39). All patients displayed perinatal or early-onset cardiomyopathy and cataract, clinical features pathognomonic for Sengers syndrome. Other common findings included blood lactic acidosis and tachydyspnoea while nystagmus, eosinophilia and cervical meningocele were documented in only either one or two cases. Deficiency of the adenine nucleotide translocator was found in heart and skeletal muscle biopsies from two patients associated with respiratory chain complex I deficiency. In contrast to previous findings, mitochondrial DNA content was normal in both tissues.ConclusionWe compare our findings to those in 21 previously reported AGK mutation-positive Sengers patients, confirming that Sengers syndrome is a clinically recognisable disorder of mitochondrial energy metabolism.

Impact of prior antibiotic use in culture-negative endocarditis: review of 86 cases from southern Pakistan

BACKGROUND A large number of patients treated at our hospital for endocarditis have negative cultures. Taking into consideration the fact that many of these patients receive antibiotics prior to referral, we decided to study culture-negative endocarditis in Pakistan. METHODS The medical records of all patients admitted to the Aga Khan University Hospital, Pakistan, for the period from 1988 to 2001, with an underlying diagnosis of infective endocarditis (IE) and negative cultures, were reviewed. RESULTS Of the 159 patients diagnosed with IE by revised Duke criteria, 86 (54.1%) had persistent negative cultures. More than half of these patients (52%) had received antibiotics before being referred to our center. Patients with culture-negative endocarditis were less likely to be classified as definite endocarditis by revised Duke criteria (p<0.001, 95% CI 0.07-0.3) or to have large vegetations (p=0.021, 95% CI 0.05-0.5), and more likely to have a mitral valve prolapse (p=0.003, 95% CI 1.6-2.3). Definite endocarditis (p=0.042, 95% CI 1.02-7.4), heart failure (p=0.008, 95% CI 1.4-12.7), renal failure (p=0.017, 95% CI 1.16-40.7), embolism (p=0.019, 95% CI 1.2-38.8), and neurological complications (p=0.02, 95% CI 1.16-9.2) were associated with an increased mortality. CONCLUSION Culture-negative endocarditis is very common among patients with IE in Pakistan. The presentation, laboratory findings, and complications are similar to those for culture-positive endocarditis. It is postulated that previous antibiotic treatment is the most common cause of culture-negative endocarditis in our hospital.

Risk factors predisposing to congenital heart defects.

Introduction: Congenital heart disease (CHD) is associated with multiple risk factors, consanguinity may be one such significant factor. The role of consanguinity in the etiology of CHD is supported by inbreeding studies, which demonstrate an autosomal recessive pattern of inheritance of some congenital heart defects. This study was done to find out the risk factors for CHD. Methods: A case-control study was done on pediatric patients at a tertiary care hospital, Aga Khan University Hospital, located in Karachi, Pakistan. A total of 500 patients, 250 cases and 250 controls were included in the study. Results: Amongst the 250 cases (i.e. those diagnosed with CHD), 122 patients (48.8%) were born of consanguineous marriages while in the controls (i.e. non-CHD) only 72 patients (28.9%) showed a consanguinity amongst parents. On multivariate analysis, consanguinity emerged as an independent risk factor for CHD; adjusted odds ratio 2.59 (95% C. I. 1.73 - 3.87). Other risk factors included low birth weight, maternal co-morbidities, family history of CHD and first born child. On the other hand, medications used by the mother during the index pregnancy, maternal age and gender of the child did not significantly increase the risk of developing CHD. Conclusions: Analyses of our results show that parental consanguinity, family history of CHD, maternal co-morbidities, first born child and low birth weight are independent risk factors for CHD.

The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease

Background Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects. Methods We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with RMND1 mutations. In addition, we reviewed all the previously published cases to determine the genotype–phenotype correlates and performed survival analysis to identify prognostic factors. Results We identified 14 new cases from 11 pedigrees that harbour recessive RMND1 mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, p.(Leu435Phe); c.830+1G>A and c.1317+1G>T. Together with all previously published cases (n=32), we show that congenital sensorineural deafness, hypotonia, developmental delay and lactic acidaemia are common clinical manifestations with disease onset under 2 years. Renal involvement is more prevalent than seizures (66% vs 44%). In addition, median survival time was longer in patients with renal involvement compared with those without renal disease (6 years vs 8 months, p=0.009). The neurological phenotype also appears milder in patients with renal involvement. Conclusions The clinical phenotypes and prognosis associated with RMND1 mutations are more heterogeneous than that were initially described. Regular monitoring of kidney function is imperative in the clinical practice in light of nephropathy being present in over 60% of cases. Furthermore, renal replacement therapy should be considered particularly in those patients with mild neurological manifestation as shown in our study that four recipients of kidney transplant demonstrate good clinical outcome to date.

Infective endocarditis in patients with congenitally malformed hearts: characterization of the syndrome in a developing country.

OBJECTIVE Cardiac surgery for correction or palliation of congenital cardiac disease in infancy and childhood remains a privilege that is rarely accessible to two-thirds of the worlds population. This imbalance has created a unique spectrum of illness in patients with underlying congenital cardiac disease and complicating infective endocarditis in developing countries, including Pakistan. In this study, we characterize endocarditis as seen in such patients presenting in Karachi. PATIENTS AND SETTINGS We reviewed retrospectively patients admitted to Aga Khan University with underlying congenitally malformed hearts and endocarditis between 1991 and 2004. RESULTS We identified 48 patients with endocarditis according to the modified Duke Criterions, with just over half the cases (54%) classified as definite endocarditis. Of the patients, 23 (49%) patients were more than 16 years old. Uncorrected left-to-right-shunts, tetralogy of Fallot, and congenital mitral valvar disease were the most common underlying defects. Patients with cyanotic defects, particularly of the complex type, were underrepresented (4%). Only 11 (22.9%) of the patients had a previous palliative or corrective surgery. In one-third of the patients (16), streptococcal species were identified as the microbiologic cause of endocarditis, and 22 (45.8%) had culture-negative endocarditis. In contrast, Staphylococcus aureus and enterococci caused endocarditis in only one patient each. There were no differences in mortality or complications between cyanotic and acyanotic congenital defects. Surgery was performed in nine (18.7%) patients with endocarditis, and of these, 13 (27.1%) died. CONCLUSIONS In contrast to the developed world, endocarditis in the developing countries, such as Pakistan, complicates uncorrected left-to-right shunts and tetralogy of Fallot, probably because patients with complex cyanotic defects fail to survive long after birth due to the lack of available surgery. Almost half of patients had culture-negative endocarditis, likely related to several factors.

Estimation of pulmonary vascular resistance with Doppler diastolic gradients.

This study was undertaken to determine the diastolic Doppler echocardiographic correlates of pulmonary vascular resistance calculated on cardiac catheterization in patients with secondary pulmonary arterial hypertension. Thirty-eight consecutive patients with congenital heart disease, pulmonary artery hypertension and pulmonary regurgitation were studied. Continuous-wave Doppler-derived pulmonary artery diastolic gradients were measured at 3 points on the pulmonary regurgitant diastolic velocity slope: peak diastolic, end-diastolic (at the R wave on the electrocardiogram), and mid-diastolic (midway between the peak and end-diastolic points). Catheterization data included oximetry, measurements of pressure in the cardiac chambers and great arteries, and calculation of pulmonary vascular resistance index. Doppler-derived peak, mid, and end-diastolic pulmonary regurgitation gradients correlated best with catheterization-measured pulmonary artery systolic, mean and diastolic pressures, respectively. The best Doppler correlate of pulmonary vascular resistance index was the pulmonary artery end-diastolic gradient. Clinically useful information can be obtained from Doppler pulmonary artery diastolic gradients measured on the pulmonary regurgitant diastolic velocity slope, which can estimate the pulmonary arterial pressure as well as pulmonary vascular resistance obtained on cardiac catheterization.

Successful Surgical Intervention of Total Anomalous Pulmonary Venous Drainage in the Third Decade of Life

Total anomalous pulmonary venous drainage (TAPVD) accounts for approximately 1.5% of all congenital heart diseases. It is usually diagnosed in the neonatal period and is rarely seen in adults. We report an unusual case of a patient with TAPVD who was successfully treated at the age of 28 years. We believe that this is the oldest person in the South Asian literature to undergo surgical correction of TAPVD.

Dissecting aneurysm of the interventricular septum due to rupture of the sinus of valsalva

Aneurysm of the sinus of Valsalva is a rare congenital cardiac anomaly. It occurs as an outpouching that progresses like a windsock, and it may rupture producing aortic regurgitation, cardiac tamponade, congestive heart failure, conduction abnormalities, and stroke. We describe a case of rupture of the sinus of Valsalva into the interventricular septum producing a large dissecting aneurysm. Despite the location, it did not produce a conduction abnormality.

Clinicodemographic features and outcome of acute myocarditis in children admitted at tertiary care hospital

BACKGROUND Myocarditis is an inflammatory disorder of myocardium associated with high mortality and morbidity. It is often difficult to diagnose because it can either be asymptomatic or mimic other illnesses. This study is conducted to evaluate clinicodemographic features and outcome of acute myocarditis in children admitted at a tertiary care hospital. METHODS Medical records of all children aged 1month to 16years who were admitted between 2005 and 2013 at Aga Khan University Hospital, Karachi and discharged with a diagnosis of myocarditis were reviewed retrospectively. Clinical and demographic features, management and outcome were recorded. RESULTS Records of a total of 62 patients with the diagnosis of myocarditis were reviewed retrospectively between 2005 and 2013. Median age of patients was 12.5months with 28 (45%) females and 34 (55%) males. The main presenting complaint observed was irritability (73%) and least common symptom was abdominal pain (23%) while the most frequently occurring examination finding was tachycardia (90%). Length of the hospital stay was 8±4.7days with 21 (34%) admissions in the ward and 41 (66%) in intensive care unit. CONCLUSION The most frequent presentation in our study was irritability, followed by difficulty in breathing while the least common symptom was abdominal pain. Tachycardia was the commonest clinical sign observed so it is important to look for heart rate and rhythm in a sick child with irritability.

Sarcoidosis with Arteriovenous Malformation in a 15-Year-Old Girl – The Rarest of the Rare

Introduction Sarcoidosis is an uncommon multi-system disorder with many possible complications. Arteriovenous malformations (AVMs) are a rare vascular complication of sarcoidosis. Case description A 15-year-old girl presented to the Pediatric Clinic at AKUH with pulmonary, hepatic, joint, and skin manifestations. Physical examination and investigations pointed toward sarcoidosis, including raised erythrocyte sedimentation rate, angiotensin converting enzyme (ACE), and alanine transaminase (ALT). An incidental finding of pulmonary arteriovenous malformation (PAVM) was noticed on echocardiography. She responded to oral corticosteroids, her ACE and ALT levels improved. There was lack of indication for pulmonary angio-embolization for her PAVM. On a 3-year follow-up, her condition improved and she is clinically well. Discussion Pulmonary arteriovenous malformation is an extremely rare complication of sarcoidosis, especially among the pediatric population. Hence, this is the first reported case of its kind. The relation between sarcoidosis and PAVM is difficult to establish; however, there are some theories. This condition may be treated depending on the symptoms. Since our patient did not have any significant symptoms of PAVM, she was treated for the underlying disease, i.e., sarcoidosis. Conclusion While dealing with patients having multi-system disorders like sarcoidosis, one must be very vigilant so as not to miss out on any complication. Regular follow-up visits should be scheduled to rule out new complications and to monitor the past ones.