FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance.

An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.

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.

Type III spinal muscular atrophy mimicking muscular dystrophies.

Types III and IV spinal muscular atrophy represent a diagnostic challenge due to the great variability in their presentation. We report a series of eight patients with type III spinal muscular atrophy who were followed for a long time for possible muscular dystrophy or myopathy, confirming its clinical heterogeneity and propensity to delayed diagnosis. Clinical examination revealed heterogeneous findings, where the diagnosis of type III spinal muscular atrophy was not immediately apparent in many patients as their clinical and laboratory abnormalities were consistent with muscular dystrophy or myopathy. The presence of dystrophic features such as hypertrophy of the calves, weakness of the limb girdle, high serum creatine kinase levels, and myopathic histopathology should not divert attention from the possibility of spinal muscular atrophy. It is strongly recommended to give variable presentations enough thought and to consider the autosomal recessive type III spinal muscular atrophy in the diagnostic evaluation.