Expert Group Consensus on early diagnosis and management of infantile-onset pompe disease in the Gulf Region.

BACKGROUND: Infantile-onset Pompe disease (IOPD) is a rare and devastating, autosomal recessive lysosomal storage disorder that manifests immediately after birth. In severe IOPD cases, complete/almost-complete acid alpha-glucosidase enzyme deficiency is observed. Considering the rapid progression of the disease, timely diagnosis and treatment are important; even slight delays can remarkably alter the course of the disease. Enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase is safe and beneficial for IOPD patients. However, there is heterogeneity in the patient response to ERT. The factors influencing treatment effectiveness include the patient's age at the time of treatment initiation, pre-existing muscle damage, and cross-reactive immunologic material (CRIM) status at baseline. Immunomodulation along with ERT is the recently developed therapeutic approach that has been included in the therapeutic armamentarium of IOPD for optimizing clinical benefits, particularly in CRIM-negative IOPD patients. However, there is a dearth of published data on the early diagnosis and clinical position of the immunomodulation protocol along with ERT in the treatment of IOPD in the Gulf region. METHODS AND RESULTS: Expert panel meetings, involving six experts from the Kingdom of Saudi Arabia, Kuwait, Oman, Qatar, and the United Arab Emirates, were convened to develop consensus-based recommendations addressing current diagnostic and management challenges for patients with IOPD in the Gulf region. Furthermore, this consensus guideline may be implemented in clinical practice for the timely diagnosis and management of patients with IOPD. CONCLUSION: The expert consensus will help clinicians to make appropriate and timely decisions regarding immunomodulation initiation and ERT treatment in IOPD patients in the Gulf region.

The re-occurrence of dilated cardiomyopathy in propionic acidemia after liver transplantation requiring heart transplant, first case from Middle East.

Propionic acidemia is a rare autosomal recessive inborn error of metabolism. It is relatively common in Middle East. Dilated cardiomyopathy is one of the leading causes of morbidity and mortality for patients with propionic acidemia. Liver transplantation has been used for patient with frequent metabolic decompensations and was shown to be beneficial in propionic acidemia-related dilated cardiomyopathy. Up to our knowledge, there has been one reported case of recurrent dilated cardiomyopathy 3 years after liver transplantation. We report the first case, from Middle East, of recurrent dilated cardiomyopathy, 6 years after liver transplantation.

Point of Care Exome Sequencing Reveals Allelic and Phenotypic Heterogeneity Underlying Mendelian disease in Qatar.

The effectiveness of next generation sequencing at solving genetic disease has motivated the rapid adoption of this technology into clinical practice around the world. In this study, we use whole exome sequencing (WES) to assess 48 patients with Mendelian disease from 30 serial families as part of the "Qatar Mendelian Disease pilot program" - a coordinated multi-center effort to build capacity and clinical expertise in genetic medicine in Qatar. By enrolling whole families (parents plus available siblings), we demonstrate significantly improved discriminatory power for candidate variant identification over trios for both de novo and recessive inheritance patterns. For the same index cases, we further demonstrate that even in the absence of families, variant prioritization is improved up to 8-fold when a modest set of population-matched controls is used vs large public databases, stressing the poor representation of Middle Eastern alleles in presently available databases. Our in-house pipeline identified candidate disease variants in 27 of 30 families (90%), 23 of which (85%) harbor novel pathogenic variants in known disease genes, pointing to significant allelic heterogeneity and founder mutations underlying Mendelian disease in the Middle East. For 6 of these families, the clinical presentation was only partially explained by the candidate gene, suggesting phenotypic expansion of known syndromes. Our pilot study demonstrates the utility of WES for Middle Eastern populations, the dramatic improvement in variant prioritization conferred by enrolling population-matched controls and/or enrolling additional unaffected siblings at the point-of-care, and 25 novel disease-causing alleles, relevant to newborn and premarital screening panels in regional populations.

Human heterologous liver cells transiently improve hyperammonemia and ureagenesis in individuals with severe urea cycle disorders.

BACKGROUND: Urea cycle disorders (UCDs) still have a poor prognosis despite several therapeutic advancements. As liver transplantation can provide a cure, liver cell therapy (LCT) might be a new therapeutic option in these patients. METHODS: Twelve patients with severe UCDs were included in this prospective clinical trial. Patients received up to six infusions of cryopreserved human heterologous liver cells via a surgically placed catheter in the portal vein. Portal vein pressure, portal vein flow, and vital signs were monitored continuously. Calcineurin inhibitors and steroids were used for immunosuppression. In four patients, ureagenesis was determined with stable isotopes. Number and severity of hyperammonemic events and side effects of immunosuppression were analyzed during an observation period of up to 2 years. RESULTS: No study-related mortality was observed. The application catheter dislocated in two children. No significant side effects of catheter application or cell infusion were noted in the other ten patients. The overall incidence of infections did not differ significantly from a historical control group, and no specific side effects of immunosuppression were found. Seven patients were treated per protocol and could be analyzed for efficacy. Severe metabolic crises could be prevented in all of these patients, moderate crises in four of seven. Ureagenesis increased after cell infusion in all patients investigated. CONCLUSIONS: We found a favorable safety profile with respect to catheter placement, intraportal liver cell infusion, and immunosuppression. More than half of the children treated per protocol experienced metabolic stabilization and could be safely bridged to liver transplantation.