Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

No abstract

The outcomes of patient care are improved by adequate knowledge, practical skills, and positive attitude. Currently, there is a lack of data on medical research activities among resident doctors in Saudi Arabia. This study aimed to evaluate the perception, barriers, and research attitudes among various residency programs running in different cities of Saudi Arabia. A total of 434 surgical and medical residents participated in the current study. A cross-sectional study encompassing multiple training centers in the eastern province of Saudi. Convenient sampling technique was used to include all the working training residents. A self-administered questionnaire was formulated for data collection. Descriptive statistics were employed to analyze the data. The mean age of the residents with various specialties was 27.83 ± 2.41 years. Approximately 61.7% had participated in research, while 38.3% had never participated in any research. A total of 26% of junior and 44% of senior residents have one publication only. While 11% of junior and 9% of senior residents have three publications or more. Inadequate facilities for research, lack of baseline research skills, and personal commitments were the reasons which over 60% of respondents had agreed on. Institutional reasons: lack of professional supervisor support and lack of research curriculum in the training program was reported by 308 (71%) and 305(70.3%) residents, respectively. A lack of interest for research was prevailed more in males (19%) compared to females (14%) (OR 1.43, 95% CI: 0.86–2.38, p-value 0.17). A subset of residents had one or three publications, while some had none. A lack of baseline research skills and inadequate facilities for scientific explorations, time, and funds were the main constraints among training residents. However, several residents had a positive attitude toward research but fewer publications. Thus, training in medical research methodology should be obligatory in the residency curriculum in all specialties. Further research is needed.

assistance and protection from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 2. On preventing and treating health effects from acute, prolonged, and repeated nerve agent exposure, and the identification of medical countermeasures able to reduce or eliminate the longer term health effects of nerve agents, Toxicology (2018),