Spinal muscular atrophy genetic epidemiology and the case for premarital genomic screening in Arab populations.

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal autosomal recessive disorder for which several treatment options, including a gene therapy, have become available. SMA incidence has not been well-characterized in most Arab countries where rates of consanguinity are high. Understanding SMA disease epidemiology has important implications for screening, prevention, and treatment in those populations. METHODS: We perform SMA diagnostic testing in a clinical multi-national patient cohort (N = 171) referred for hypotonia and/or muscle weakness. In addition, we carry out genetic newborn screening for SMA on 1502 healthy Emirati newborns to estimate the carrier frequency and incidence of the disease in the United Arab Emirates. RESULTS: Patients referred for SMA genetic testing are mostly Arabs (82%) representing 18 countries. The overall diagnostic yield is 33.9%, which is higher (>50%) for certain nationalities. Most patients (71%) has two SMN2 copies and earlier disease onset. For the first time, we estimate SMA carrier frequency (1.3%) and incidence of the disease (1 in 7122 live births) in the United Arab Emirates. Using birth and marriage rates in two Arab populations (United Arab Emirates and Saudi Arabia), as well as disease incidence in both countries, we show that, besides preventing new cases, premarital genetic screening could potentially result in around $8 to $324 million annual cost savings, respectively, relative to postnatal treatment. CONCLUSIONS: The SMA carrier frequency and incidence we document suggests high potential benefit for universal implementation of premarital genomic screening for a wide range of recessive disorders in Arab populations.

The occurrence of spinal muscular atrophy, a fatal genetic nerve and muscle disease, has been poorly studied in most Arab countries. Individuals who carry a single mutated gene copy (carriers) may be more likely to marry other carriers in regions where marriage rates amongst relatives, who share similar genetics, are high. Here we report the results of a newborn testing program for this disease in 1502 Emiratis and calculate the presence of carriers (1/79) and occurrence of disease (1/7122) in this population. Using this new information along with the annual birth and marriage rates in the United Arab Emirates and Saudi Arabia, we make the case that premarital genomic screening (carrier testing) is the best way to prevent this and other similarly inherited disorders in the Arab population.

Trivial Neck Bite Resulting in a Stroke in an 18-Month-Old Child: A Case Report.

Stroke is often viewed as a diagnosis found In the elderly with or without comorbidities, but it is vital to not rule it out in a pediatric patient presenting with signs and symptoms of stroke. Here, we present a case of an 18-month-old boy who arrived at the emergency department with left arm weakness and left-sided seizures a few minutes after a right-sided trivial neck bite that was initially overlooked by the parents until symptoms occurred. Urgent imaging further with a computed tomography scan of the brain revealed a hypodense lesion in the area covering the lateral part of the frontal lobe, insula, and parietal cortex of the right hemisphere. Subsequent CT cervical-cerebral angiogram revealed normal aortic arch, carotid, and vertebral arteries with no dissection, stenosis, or occlusion. However, there was a 4 mm-long occlusion of the M2 segment of the right middle cerebral artery (MCA) suggestive of emboli and subsequent low attenuation of the brain parenchyma in the anterior aspect of the right MCA vascular territory corresponding with the infarction. The objective of this case report is to educate and inform both parents and medical professionals regarding the risk of neurological damage that can occur with minor head and neck trauma that is often overlooked and therefore the importance of ruling it out with necessary imaging modalities.

Gene transfer therapy in children with spinal muscular atrophy: A single-center experience with a cohort of 25 children.

INTRODUCTION/AIMS: New therapeutic strategies to increase survival motor neuron protein levels in spinal muscular atrophy (SMA) have focused on replacing the SMN1 gene. Onasemnogene abeparvovec was approved by the US Food and Drug Administration in 2019 for treatment of children with SMA less than 2 years of age. Postmarketing studies are limited, especially outside of Europe and the United States. Herein we describe a single-center experience with onasemnogene abeparvovec from the Middle East. METHODS: Between November 17, 2020 and January 31, 2022, 25 children with SMA received onasemnogene abeparvovec at our center in the United Arab Emirates. Data were collected on patients' demographics, age at diagnosis, SMA type, genetic information, relevant medical history, laboratory investigations, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) functional assessment scores at baseline and 1 and 3 months after gene therapy. RESULTS: Onasemnogene abeparvovec was well tolerated. Significant improvements in CHOP-INTEND scores were observed after the therapy. Elevation of liver enzymes and thrombocytopenia were the most common adverse events, but were transient and managed with high-dose corticosteroids. There were no life-threatening adverse events or deaths reported during the 3-month follow-up period. DISCUSSION: The study findings concurred with those of previously published studies. Side effects of gene transfer therapy are well tolerated, although serious complications can arise. In such cases, persistent transaminitis for example, steroid dose escalation is warranted with close observation of the patient's clinical status and lab values. Combination therapy should be explored as an alternative to gene transfer therapy only.

The genomic landscape of rare disorders in the Middle East.

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant. RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

Gene Therapy for Duchenne Muscular Dystrophy: Unlocking the Opportunities in Countries in the Middle East and Beyond.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder which leads to progressive muscle degeneration and weakness. Most patients die from cardiac or respiratory failure. Gene transfer therapy offers a promising approach to treating this disorder. OBJECTIVE: Given the genetic disease burden, family size, and the high consanguinity rates in the Middle East, our objective is to address current practices and challenges of DMD patient care within two countries in this region, namely the United Arab Emirates and Kuwait, and to outline readiness for gene therapy. METHODS: An expert panel meeting was held to discuss the DMD patient journey, disease awareness, current management of DMD, challenges faced and recommendations for improvement. Opportunities and challenges for gene therapy in both countries were also deliberated. A pre-meeting survey was conducted, and the results were used to guide the discussion during the meeting. RESULTS: DMD awareness is poor resulting in a delay in referral and diagnosis of patients. Awareness and education initiatives, along with an interconnected referral system could improve early diagnosis. Genetic testing is available in both countries although coverage varies. Corticosteroid therapy is the standard of care however there is often a delay in treatment initiation. Patients with DMD should be diagnosed and managed by a multi-disciplinary team in centers of excellence for neuromuscular disorders. Key success factors to support the introduction of gene therapy include education and training, timely and accessible genetic testing and resolution of reimbursement and cost issues. CONCLUSION: There are many challenges facing the management of DMD patients in the United Arab Emirates and Kuwait and most likely other countries within the Middle East. Successful introduction of gene therapy to treat DMD will require careful planning, education, capacity building and prioritization of core initiatives.

Sensing Technologies for Autism Spectrum Disorder Screening and Intervention.

This paper reviews the state-of-the-art in sensing technologies that are relevant for Autism Spectrum Disorder (ASD) screening and therapy. This disorder is characterized by difficulties in social communication, social interactions, and repetitive behaviors. It is diagnosed during the first three years of life. Early and intensive interventions have been shown to improve the developmental trajectory of the affected children. The earlier the diagnosis, the sooner the intervention therapy can begin, thus, making early diagnosis an important research goal. Technological innovations have tremendous potential to assist with early diagnosis and improve intervention programs. The need for careful and methodological evaluation of such emerging technologies becomes important in order to assist not only the therapists and clinicians in their selection of suitable tools, but to also guide the developers of the technologies in improving hardware and software. In this paper, we survey the literatures on sensing technologies for ASD and we categorize them into eye trackers, movement trackers, electrodermal activity monitors, tactile sensors, vocal prosody and speech detectors, and sleep quality assessment devices. We assess their effectiveness and study their limitations. We also examine the challenges faced by this growing field that need to be addressed before these technologies can perform up to their theoretical potential.