Hypermanganesemia with Dystonia Type 2: A Potentially Treatable Neurodegenerative Disorder: A Case Series in a Tertiary University Hospital.

IMPORTANCE: Hypermanganesemia with dystonia type 2 is a rare autosomal recessive neurodegenerative disorder characterized by the loss of previously acquired milestones, dystonia, parkinsonian features, a high serum manganese level, and characteristic neuroimaging findings such as bilateral and symmetrically increased T1 and decreased T2/fluid-attenuated inversion recovery signal intensity in the basal ganglia. This condition is secondary to a mutation in the SLC39A14 gene. OBJECTIVE: To present a series of three cases of hypermanganesemia with dystonia type 2, which was genetically confirmed secondary to a mutation in the SLC39A14 gene, and to describe the treatment and clinical course in these cases. DESIGN: A retrospective case series. SETTING: University, Tertiary hospital. PARTICIPANTS: Three unrelated pediatric patients with hypermanganesemia with dystonia type 2, genetically confirmed to be secondary to a mutation in the SLC39A14 gene. EXPOSURES: Chelation therapy using calcium disodium edetate. MAIN OUTCOME(S) AND MEASURE(S): The response to chelation therapy based on clinical improvements in motor and cognition developments. RESULTS: All three patients were started on chelation therapy using calcium disodium edetate, and two of them showed an improvement in their clinical course. The chelation therapy could alter the course of the disease and prevent deterioration in the clinical setting. CONCLUSIONS AND RELEVANCE: Early diagnosis and intervention with chelating agents, such as calcium disodium edetate, will help change the outcome in patients with hypermanganesemia with dystonia type 2. This finding highlights the importance of early diagnosis and treatment in improving the outcomes of patients with treatable neurodegenerative disorders.

Case Report: The Genetic Diagnosis of Duchenne Muscular Dystrophy in the Middle East.

The timely and accurate genetic diagnosis of Duchenne muscular dystrophy (DMD) enables prompt initiation of disease management and genetic counseling and optimal patient care. Despite the existence of best practice guidelines for the diagnosis of DMD, implementation of these recommendations in different parts of the world is challenging. Here, we present 4 unique case studies which illustrate the different diagnostic pathways of patients with DMD in Middle Eastern countries and highlight region-specific challenges to achieving timely and accurate genetic diagnosis of DMD. A lack of disease awareness and consequential failure to recognize the signs and symptoms of DMD significantly contributed to the delayed diagnoses of these patients. Additional challenges included limited available funding for genetic testing and a lack of local specialist and genetic testing centers, causing patients and their families to travel vast distances for appointments in some countries. Earlier and more accurate genetic diagnosis of DMD in this region would allow patients to benefit from effective disease management, leading to improvements in health-related quality of life.

The Leukodystrophy Spectrum in Saudi Arabia: Epidemiological, Clinical, Radiological, and Genetic Data.

Background: Leukodystrophies (LDs) are inherited heterogeneous conditions that affect the central nervous system with or without peripheral nerve involvement. They are individually rare, but collectively, they are common. Thirty disorders were included by the Global Leukodystrophy Initiative Consortium (GLIA) as LDs. Methods: We conducted a retrospective chart review of a consecutive series of patients diagnosed with different types of LD from four large tertiary referral centers in Riyadh, Saudi Arabia. Only those 30 disorders defined by GLIA as LDs were included. Results: In total, 83 children from 61 families were identified and recruited for this study. The male-to-female ratio was 1.5:1, and a consanguinity rate of 58.5% was observed. An estimated prevalence of 1:48,780 or 2.05/100,000 was observed based on the clinical cohort, whereas a minimum of 1:32,857 or 3.04/100,000 was observed based on the local genetic database. The central region of the country exhibited the highest prevalence of LDs (48.5%). The most common LD was metachromatic leukodystrophy (MLD), and it accounted for 25.3%. The most common disorder based on carrier frequency was AGS. Novel variants were discovered in 51% of the cases, but 49% possessed previously reported variants. Missense variants were high in number and accounted for 73% of all cases. Compared with other disorders, MLD due to saposin b deficiency was more common than expected, Pelizaeus-Merzbacher-like disease was more prevalent than Pelizaeus-Merzbacher disease, and X-linked adrenoleukodystrophy was less common than expected. The mortality rate among our patients with LD was 24%. Conclusion: To the best of our knowledge, this is the largest cohort of patients with LD from Saudi Arabia. We present epidemiological, clinical, radiological, and genetic data. Furthermore, we report 18 variants that have not been reported previously. These findings are of great clinical and molecular utility for diagnosing and managing patients with LD.

Pediatric resident's perception of night float system compared to 24 hours system, a prospective study.

BACKGROUND: The study aims to evaluate the perceptions of pediatric residents under the night float (NF) on-call system and its impact on well-being, education, and patient safety compared with the traditional 24-h on-call system. METHODS: The study is prospective in nature and conducted on two pediatric resident training centers who apply the NF on-call system as a pilot project. Senior residents (PGY-3 and PGY-4) enrolled in the two training centers were invited to participate before and 6 months after the implementation of the change in the on-call system. A self-administered online questionnaire was distributed. Responses were rated using a five-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). The items covered three main domains, namely, residents' well-being, ability to deliver healthcare, and medical education experience. Pre- and post-intervention scores were presented as means and compared by t-test for paired samples. RESULTS: A total of 42 residents participated in the survey (female = 24; 57.1%). All participants were senior residents; 25 (59.6%) were third-year residents (PGY-3), whereas 17 (40.4%) were fourth-year residents (PGY-4). The participants reported that many aspects of the three domains were improved with the introduction of the NF system. The system was perceived to exert less adverse health effect on the residents (mean: 2.37 ± 1.01) compared with the 24-h on-call system (mean: 4.19 ± 0.60; P < 0.001). In addition, the NF system was perceived to lead to less exposure to personal harm and result in less negative impact on quality of care, better work efficiency, reduced potential for medical errors, more successful teaching, and less disruptions to other rotations compared with the 24 h on-call system (P < 0.001). CONCLUSION: The perception of senior residents toward the 24-h on-call system pertains to negative impacts on well-being, education, and patient safety compared with on-call systems with restrictive duty hours, such as the NF system, which is perceived to be less harmful, to exert positive impacts on the quality of delivered healthcare services, and more useful from pedagogic aspect.

Acute Necrotizing Encephalopathy of Childhood: A Multicenter Experience in Saudi Arabia.

Background: Acute necrotizing encephalopathy of childhood (ANEC) is a rapidly progressing encephalopathy characterized by fever, depressed level of consciousness, and seizures. Diagnosis depends on clinical presentation and characteristic neuroimaging findings of abnormal signal intensity involving the thalami as well as the supra and infra-tentorial areas. Treatment modalities are not well-established; empirical treatment with antibiotics and antiviral agents is the initial step, followed by steroids and immunoglobulin, as well as supportive care. Patients with ANEC have a variable prognosis, but mortality is very high. Methods: A retrospective chart review of patients diagnosed with ANEC in five tertiary centers from January 2015 to October 2018 was performed. Clinical and radiological findings, as well as the therapeutic approach and outcomes, were described. Results: Twelve children were included ranging in age from 10 months to 6 years. All patients presented with preceding febrile illness, altered level of consciousness, and seizure. Radiological features showed abnormal signals in the thalami, and five patients (41.7%) had brainstem involvement. All patients received empirical treatment with antibiotics and antiviral agents. Ten patients (83.3%) received intravenous immunoglobulin (IVIG) and IV Methylprednisolone therapy. Outcomes were variable ranging from good outcomes with minimal neurological deficits to poor outcomes and death in 25% of cases. Conclusion: ANEC is a rare fulminant disease in children. The treatment is challenging. Early interventions with the use of IVIG and IV Methylprednisolone may change the outcome; however, further studies are needed to establish a consensus guideline for the management.

Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.

BACKGROUND: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. METHODS: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. RESULTS: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1). CONCLUSIONS: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.