Genetics of ataxia telangiectasia in a highly consanguineous population.

Ataxia telangiectasia (AT) is a rare autosomal recessive multisystemic disorder. It usually presents in toddler years with progressive ataxia and oculomotor apraxia, or less commonly, in the late-first or early-second decade of life with mixed movement disorders. Biallelic mutations in ataxia telangiectasia mutated gene (ATM) cause AT phenotype, a disease not well documented in Saudi Arabia, a highly consanguineous society. We studied several Saudi AT patients, identified ATM variants, and investigated associated clinical features. We included 17 patients from 12 consanguineous families. All patients had comprehensive clinical and radiological assessment, and most were examined through whole-exome sequencing (WES). Selected individuals were analyzed using various genetic approaches. We identified five different ATM variants in our patients: three previously reported mutations, and two novel variants. Nearly all patients had classical AT presentation except for two patients with a milder phenotype. Among the three known variants, a deletion causing truncation (c.381delA resulting in p.(Val128Ter)) was identified in 13 patients. Two patients harboured the other two truncating variants, (c.9001_9002delAG resulting in p.Ser3001Phefs*6) and (c.9066delA resulting in p.Glu3023Alafs*10) and two patients had novel compound heterozygous variants (NM_000051.3:Paternal Allele:c.8762C > G;p.Thr2921Arg and Maternal Allele:c.1057T > C;p.Cys353Arg). We speculate that c.381delA is a founder mutation in our population. This study provides a genotype-phenotype relationship in a previously unstudied consanguineous population. Our findings contribute to improve local clinical care, therapy, and genetic counseling.

Molecular and clinical spectra of FBXL4 deficiency.

F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.

Patient demographics and characteristics from an ambispective, observational study of patients with duchenne muscular dystrophy in Saudi Arabia.

Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder that is characterized by progressive muscle weakness, resulting in disability and premature death. Onset of symptoms typically occurs at 2-3 years of age, and disease progression is managed through treatment with corticosteroids. The aim of this interim analysis is to increase disease awareness and improve patient management in Saudi Arabia (SA) through the use of data from an ongoing ambispective, observational, multicenter study evaluating characteristics of patients aged 1-14 years with genetically confirmed DMD in SA. This interim analysis examined the secondary outcomes from the study-the demographics and clinical characteristics of patients included retrospectively [data recorded (enrollment visit) between January 2014 and September 2020] and prospectively between September 2020 and April 2021. The primary outcome-the list of DMD gene mutations for the study population-will be reported at a later date. There were 177 eligible patients. Mean, standard deviation (SD) age at enrollment was 7.5 (3.0) years. Median (min, max) age at diagnosis was 7.0 (1.3, 13.8) years. At enrollment, 28.9% of patients were full-time wheelchair users, 50.0% of ambulatory patients could run, and 63.9% could climb stairs. The mean (SD) ages of patients at enrollment who were unable to run and climb stairs were 8.0 (2.7) and 7.6 (3.0) years, respectively. Speech delay (19.4%) and learning difficulties (14.9%) were the most commonly reported intellectual impairments. Physical therapy (84.2%) was the most common choice for initial management of DMD. Only 40.7% of patients received corticosteroid therapy as part of their initial management plan, rising to 59.1% at enrollment. Devices were given to 28.8% of patients for initial management, most commonly ankle-foot orthoses (26.0%) and wheelchairs (6.2%). This analysis reports data from the largest study to date to capture demographics and clinical characteristics of DMD patients in SA. The interim results show a relatively late DMD diagnosis age compared with that in other countries, and a need for improved adherence to international DMD standard of care guidelines. Therefore, there is an urgent requirement for improved DMD education and awareness among healthcare professionals and the public in SA.