Genetic literacy among primary care physicians in a resource-constrained setting.

BACKGROUND: Genetic literacy among primary healthcare providers is crucial for appropriate patient care with the advances in genetic and genomic medicine. Studies from high-income countries highlight the lack of knowledge in genetics and the need to develop curricula for continuing professional development of non-geneticists. Scarce data is available from resource-constrained countries in Middle East and North Africa. Lebanon is a small country in this region characterized by high rates of consanguinity and genetic disorders like several surrounding countries, such as Jordan, Syria, and Turkey. METHODS: The primary aim of this study assessed the genetic literacy, self-perceived and actual knowledge as well as practices among primary care providers in Lebanon. The secondary aim identified their educational needs and proposed evidence-based continuing education programs. A cross-sectional survey-based study, using a self-administered questionnaire, was conducted targeting physicians from Family Medicine, Obstetrics and Gynecology, and Pediatrics. The questionnaire was divided into five sections: demographics, familiarity with genetic tests, self-reported and actual knowledge, genetic practices, and educational needs. Statistics were performed using SPSS v24. The Chi-square test was used for independent variables. Differences between mean scores were measured using paired sample t-tests for groups of two levels and one-way ANOVA for more than two. Multiple linear regression was used to study the variables associated with the knowledge score while controlling for other variables. RESULTS: The survey included 123 physicians. They were mostly familiar with karyotype as first-tier genetic test. Although 38% perceived their knowledge as good, only 6% scored as such in knowledge assessment. A better knowledge score was observed in academic institutions as well as in urban settings (p<0.05). One third never ordered any genetic testing, mostly due to poor knowledge. Almost all (98%) were ready to attend continuing professional development sessions in genetics. CONCLUSION: Our findings show the need to improve genetic literacy among healthcare frontliners, focusing on remote regions and nonacademic centers in Lebanon, a model for other resource-constrained country in the Middle East and North Africa region. This study advances recommendations for evidence-based genetic continuing education programs and highlighted the role of that the few genetic specialists can play in their successful implementation.

Mitochondrial depletion syndrome type 3: the Lebanese variant.

Introduction: Mitochondrial DNA depletion syndrome type 3 is an emerging disorder linked to variants in the deoxyguanosine kinase gene, which encodes for mitochondrial maintenance. This autosomal recessive disorder is frequent in the Middle East and North Africa. Diagnosis is often delayed due to the non-specificity of clinical presentation with cerebro-hepatic deterioration. The only therapeutic option is liver transplantation, although the value of this remains debatable. Methods: We describe the clinical, biochemical, and molecular profiles of Lebanese patients with this rare disorder. We also present a review of all cases from the Middle East and North Africa. Results: All Lebanese patients share a unique mutation, unreported in other populations. Almost half of patients worldwide originate from the Middle East and North Africa, with cases reported from only 7 of the 21 countries in this region. Clinical presentation is heterogeneous, with early-onset neurological and hepatic signs. Liver failure and lactic acidosis are constants. Several variants can be identified in each population; a unique c.235C>T p. (Gln79*) pathogenic variant is found in Lebanese patients. Outcome is poor, with death before 1 year of age. Conclusion: The pathogenic nonsense variant c.235C>T p. (Gln79*) in the deoxyguanosine kinase gene may be considered a founder mutation in Lebanon. Further genotypic delineation of this devastating disorder in populations with high consanguinity rates is needed.

Challenges of genetic diagnosis of inborn errors of metabolism in a major tertiary care center in Lebanon.

Background: Inborn errors of metabolism are rare genetic disorders; however, these are prevalent in countries with high consanguinity rates, like Lebanon. Patients are suspected, based on a combination of clinical and biochemical features; however, the final confirmation relies on genetic testing. Using next generation sequencing, as a new genetic investigational tool, carries several challenges for the physician, the geneticist, and the families. Methods: In this retrospective study, we analyzed the clinical, biochemical, and genetic profile of inborn errors of metabolism suspected patients, seen at a major tertiary care center in Lebanon, between 2015 and 2018. Genetic testing was performed using next generation sequencing. Genotype-phenotype correlation and diagnostic yield of each testing modality were studied. Results: Out of 211 patients genetically tested, 126 were suspected to have an inborn error of metabolism. The diagnostic yield of next generation sequencing reached 64.3%. Single gene testing was requested in 53%, whole exome sequencing in 36% and gene panels in 10%. Aminoacid disorders were mostly diagnosed followed by storage disorders, organic acidemias and mitochondrial diseases. Targeted testing was performed in 77% of aminoacid and organic acid disorders and half of suspected storage disorders. Single gene sequencing was positive in 75%, whereas whole exome sequencing diagnostic yield for complex cases, like mitochondrial disorders, reached 49%. Good clinical and biochemical correlation allowed the interpretation of variants of unknown significance and negative mutations as well as therapeutic management of most patients. Conclusion: Tailoring the choice of test modality, by next generation sequencing, to the category of suspected inborn errors of metabolism may lead to rapid diagnosis, shortcutting the cost of repeated testing. Whole exome sequencing as a first-tier investigation may be considered mainly for suspected mitochondrial diseases, whereas targeted sequencing can be offered upon suspicion of a specific enzyme deficiency. Timing and modality of gene test remain challenging, in view of the cost incurred by families.

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review.

Background: Hereditary tyrosinemia type 1 is a rare genetic disorder leading to liver cirrhosis and hepatocellular carcinoma. Few decades ago, dietary measures and ultimately liver transplant constituted the only treatment modalities. Nowadays, early diagnosis and therapy with nitisinone can reverse the clinical picture. In developing countries, diagnostic and therapeutic challenges may affect the outcome of this disease. The choice of the treatment modality may depend on the economic status of each country. Few reports on the long-term outcome of hereditary tyrosinemia type 1 are available from developing and Arab countries. Methods: A retrospective study of charts of Lebanese patients diagnosed with tyrosinemia type 1 and followed, at the American University of Beirut, during a 12-year period was performed. Clinical presentation and liver biochemical profile at diagnosis were analyzed, along with therapeutic modalities and long-term outcome. Results: Twenty-two children were diagnosed and followed during the study period. Median age at diagnosis was 7 months (range: one day to 35 months). Most of the patients presented with hepatomegaly and jaundice. Four patients were referred for atypical presentations with developmental delay and seizures, secondary to undiagnosed hypoglycemia episodes. Around half of the patients presented with failure to thrive. Transaminitis, cholestasis and increased α-fetoprotein level were variably present at diagnosis (36% to 50%). All patients had elevated plasma tyrosine and urinary succinylacetone levels. Genetic testing was performed in 9%. Only one third could be treated with nitisinone. Liver transplant was electively performed in 9% of cases, to overcome the long-term cost of nitisinone. One third of the patients died between the age of 1 month and 11 years. Surviving patients are still candidates for liver transplant. Conclusion: Our experience reflects the challenges of diagnosis and treatment of hereditary tyrosinemia type 1 in a developing country. In the absence of specific neonatal screening, early diagnosis relies mostly on the clinical awareness of the physician. Long-term nitisinone use may be deterred by its high cost and liver transplantation carries risks of surgical complications. New, effective, and less expensive treatments are needed, especially for developing countries.

Kidney and Metabolic Phenotypes in Glycogen Storage Disease Type-I Patients.

Patients and Methods: A retrospective chart review of 32 GSD- I patients, followed at the American University of Beirut Medical Center, between 2007 and 2018 was conducted. Diagnosis was confirmed by enzymatic and/or genetic studies. Clinical presentation, growth, and kidney outcome were assessed. All patients were evaluated for body mass index, blood parameters of metabolic control including uric acid, alanine, lactic acid, and triglycerides in blood. Kidney evaluation included creatinine clearance, microalbuminuria, citraturia, and calciuria as well as urine microalbumin/creatinine ratio. Results: Almost one third of GSD-I patients developed microalbuminuria. This was detected below 7 months of age in 36% of patients who required early treatment with ACEI with significant reduction in albuminuria. Kidney stones were present in 6% and were associated with hypercalciuria and hypocitraturia. Poor metabolic control reflected by hyperuricemia, lactic acidosis, and hyperalaninemia were noted only in patients who developed microalbuminuria. Conclusion: Glomerular injury may appear in early infancy in poorly controlled patients. Adequate metabolic control and ACEI therapy may improve kidney outcome in GSD I patients. Plasma alanine appears to be a promising and reliable marker reflecting metabolic control in GSD-I patients.

Diagnosis and management of symptomatic profound biotinidase deficiency in a tertiary care center in Lebanon.

Neonatal screening for biotinidase deficiency is still lacking in several countries worldwide, although this neurocutaneous disorder is treatable and preventable. Therefore, unscreened patients are diagnosed when symptomatic; treatment with Biotin is known to reverse cutaneous symptoms and improve neurological outcome. We describe a series of five symptomatic patients diagnosed with profound biotinidase deficiency and followed at a tertiary care center in Lebanon, for a variable period from 16 months to 11 years. Adjustment of Biotin therapy is correlated to clinical response and biochemical profile including 3-hydroxyisovalerylcarnitine on dried blood spots and urine organic acids. A previously unreported mutation is also reported in a patient who displayed an unusual outcome with reversible hearing loss on Biotin therapy. Clinical responsiveness to Biotin may be related to the underlying genetic mutation, although no clear genotype-phenotype correlation in biotinidase deficiency is proven. Furthermore, in the absence of systematic newborn screening for this disorder in several countries, identification of a reliable blood biomarker of Biotin responsiveness is warranted for better management of late diagnosed symptomatic patients.

Outcome of Nonketotic Hyperglycinemia in Lebanon: 14-Year Retrospective Review.

Nonketotic hyperglycinemia is a rare inborn error of glycine metabolism characterized by a severe metabolic encephalopathy with drug-resistant seizures. Here, we report the outcome of nonketotic hyperglycinemia in a cohort of patients diagnosed and followed-up at a tertiary care reference center in Lebanon, between 2000 and 2014.Eight out of 12 patients with nonketotic hyperglycinemia were retrospectively reviewed. The remainders were excluded for incomplete data. The majority of cases presented with seizures and hypsarrhythmia or burst suppression patterns. Half of the patients died. Survival varied between 7 days and 18 years. Seizures remained unresponsive with poor outcome, despite standard supportive care and antiepileptic therapy; however, two patients were responsive to ketogenic diet and one of them became seizure-free.Scarce data on the outcome of nonketotic hyperglycinemia patients from the Middle East and North Africa region are available. The ketogenic diet, in combination with standard therapies, appears to be effective in controlling the seizures in this devastating disorder. Larger multicenter studies are still needed to establish the role of the ketogenic diet in nonketotic hyperglycinemia.

Pamidronate Rescue Therapy for Hypercalcemia in a Child With Williams Syndrome.

A 15-month-old male infant diagnosed with Williams Syndrome (WS) was admitted with severe hypercalcemia and nephrocalcinosis. Intravenous hydration and furosemide failed to yield an appreciable and sustainable fall in serum calcium, while the injection of pamidronate achieved a significant decrease in serum calcium in a short period of time. This bisphosphonate could be considered as a second-line treatment for refractory hypercalcemia in WS.

Treatable Genetic Metabolic Epilepsies.

OPINION STATEMENT: In the absence of a culprit epileptogenic lesion, pharmacoresistant seizures should prompt the physician to consider potentially treatable metabolic epilepsies, especially in the presence of developmental delays. Even though the anti-seizure treatment of the epilepsies remains symptomatic and usually tailored to an electroclinical phenotype rather than to an underlying etiology, a thorough metabolic workup might reveal a disease with an etiology-specific treatment. Early diagnosis is essential in the case of treatable metabolic epilepsies allowing timely intervention. Despite the advances in genetic testing, biochemical testing including cerebrospinal fluid studies are still needed to expedite the diagnostic workup and potential therapeutic trials. The diagnostician should have a high index of suspicion despite potential clinical digressions from seminal publications describing the initial cases, as these index patients may represent the most severe form of the condition rather than its most common presenting form. The often gratifying developmental outcome and seizure control with early treatment calls for a prompt diagnostic consideration of treatable metabolic diseases; even though relatively rare or potentially only seemingly so.

Epileptic and electroencephalographic manifestations of guanidinoacetate-methyltransferase deficiency.

AIM: Describe the seizure-related manifestations of guanidinoacetate methyltransferase (GAMT) deficiency in two new cases and compare these to the related literature. METHODS: We reviewed the clinical and electroencephalographic manifestations of two siblings with GAMT deficiency. We also performed a thorough literature review of all cases of GAMT deficiency, using the PubMed database, and compared our findings to those previously reported. RESULTS: One sibling presented with Lennox-Gastaut syndrome while the second had manifestations of late-onset West syndrome. Based on a literature search, we found that the clinical picture of GAMT deficiency has been described in a total of 58 cases, including our two patients, 45 of whom had at least some description of EEG and/or seizure manifestation. Epilepsy was present in 81%, with age at onset usually between 10 months and 3 years. Drug resistance was observed in approximately 45%. Initial seizures were febrile, tonic, or tonic-clonic. Drop attacks and generalised seizures were the most frequent seizure type. Absence and febrile seizures also occurred. Less frequently, focal seizures and late-onset infantile spasms (one prior case) were observed. Multifocal spikes and generalised <3-Hz-spike slow waves were common while only one prior single case report of hypsarrhythmia was described. Lennox-Gastaut syndrome was common, while progressive myoclonic epilepsy was also, less frequently, reported. CONCLUSIONS: To our knowledge, this is the second report of the occurrence of West syndrome in GAMT deficiency. The majority of patients with GAMT deficiency have seizures and approximately half are drug-resistant. Late-onset of hypsarrhythmia and/or epileptic spasms could potentially prove to be a distinctive, albeit infrequent, feature of this treatable metabolic disorder.

Diagnostic challenges of aminoacidopathies and organic acidemias in a developing country: a twelve-year experience.

BACKGROUND: Diagnosis of aminoacidopathies and organic acidemias constitutes a real challenge in a developing country with high consanguinity rate and no systematic newborn screening. We report a twelve-year experience with the identification of these disorders in Lebanon, based on their clinical and biochemical profiles. METHODS: In this retrospective study, we reviewed clinical presentation and biochemical investigations of 294 patients. Traditional chromatographic methods were used for analyses. Findings were linked to the identified disorders. RESULTS: Out of 2921 patients, presenting to our metabolic program with neurological, digestive, family history and/or other symptoms suggestive of aminoacidopathy or organic acidemia, 294 patients were included with confirmed amino or organic acid disorder. The overall analytical yield was 10%. Aminoacidopathies were three-fold higher than organic acidemias. Phenylketonuria and methylmalonic acidemia were the most frequent. The majority of patients (79%) were symptomatic (median age: 14months, range: 1day-44years), mainly with neurological manifestations (87%). Intellectual disability was mostly due to phenylketonuria (73%). Chronic liver failure was frequent in maple syrup urine disease (53%). Plasma amino and urine organic acid chromatography were diagnostic in 8.8% and 3.9% of analyzed cases, respectively. Change in chromatographic technique from reversed-phase to ion-exchange enhanced the detection of many aminoacidopathies. CONCLUSIONS: In the absence of newborn screening, the majority of aminoacidopathy and organic acidemia cases are still diagnosed clinically. This study emphasizes the importance of clinical awareness and accurate biochemical analyses as key tools for diagnosis in countries like ours, and the necessity for a comprehensive national newborn screening program.

Spectrum of mutations in Lebanese patients with phenylalanine hydroxylase deficiency.

Phenylketonuria is an autosomal recessive inborn error of metabolism resulting from phenylalanine hydroxylase deficiency. Genetic basis of phenylalanine hydroxylase deficiency has been reported in various European and Asian countries with few reports available in Arab populations of the Mediterranean region. This is the first pilot study describing phenotype and genotype of 23 Lebanese patients with phenylketonuria. 48% of the patients presented mainly with neurological signs at a mean age of 2 years 9 months, as newborn screening is not yet a nationwide policy. 56.5% of the patients had classical phenylketonuria. Thirteen different mutations were identified: splice site 52%, frameshift 31%, and missense 17% with no nonsense mutations. IVS10-11G>A was found mainly in Christians at high relative frequency whereas Muslims carried the G352fs and R261Q mutations. A rare splice mutation IVS7+1G>T, not described before, was identified in the homozygous state in one family with moderate phenylketonuria phenotype. Genotype-phenotype correlation using Guldberg arbitrary value method showed high consistency between predicted and observed phenotypes. Calculated homozygosity rate was 0.07 indicating the genetic heterogeneity in our patients. Our findings underline the admixture of different ethnicities and religions in Lebanon that might help tracing back the PAH gene flux history across the Mediterranean region.

Experience with hyperphenylalaninemia in a developing country: unusual clinical manifestations and a novel gene mutation.

We report our experience in a cohort of patients with hyperphenylalaninemia in a tertiary care referral center in Lebanon. Forty-one sequential patients were studied: 34 classical phenylketonuria (PKU), 3 hyperphenylalaninemia (non-PKU), and 4 biopterin metabolism defects. The majority of cases were clinically diagnosed at variable ages with variable neurological outcomes. Only 29.3% were detected by neonatal screening. Two unusual cases were observed in the context of inadequate treatment in 1 and delayed therapy in the other: a newborn with PKU developed severe keratomalacia; and a 5-year-old girl with dihydropteridine reductase deficiency due to a novel mutation identified in the quinoid dihydropteridine reductase gene developed Lennox-Gastaut syndrome and white matter changes with periventricular cysts. Part of our experience parallels that in the West. However, the clinical manifestations observed in our patients emphasize the importance of a national newborn screening program with efficient management of diagnosed cases.

Two new familial severe infantile spasm syndromes in males.

We describe two new familial severe infantile spasm syndromes (ISSs) unrelated to Aristaless-related homeobox (ARX) gene mutation. Family A contains two male siblings each with dysmorphism, profound psychomotor delay, gastroesophageal reflux, infantile spasms, hypsarrhythmia, prominent independent central apneas, and early death. Family B contains two male siblings with dysmorphism, profound psychomotor delay, ambiguous genitalia, macular hypoplasia, neurosensory hearing deficit, gastroesophageal reflux, infantile spasms, no hypsarrhythmia, apneas, and early death in one sibling. Etiologic workup and ARX gene sequencing were negative. This indicates that several familial ISSs exist but are not genetically characterized.