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Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Background Homozygous frameshift mutation in RUBCN (KIAA0226), known to result in endolysosomal machinery defects, has previously been reported in a single Saudi family with autosomal recessive spinocerebellar ataxia (Salih ataxia, SCAR15, OMIM # 615705). The present report describes the clinical, neurophysiologic, neuroimaging, and genetic findings in a second unrelated Saudi family with two affected children harboring identical homozygous frameshift mutation in the gene. It also explores and documents an ancient founder cerebellar ataxia mutation in the Arabian Peninsula. Case presentation The present family has two affected males (aged 6.5 and 17 years) with unsteady gait apparent since learning to walk at 2.5 and 3 years, respectively. The younger patient showed gait ataxia and normal reflexes. The older patient had saccadic eye movement, dysarthria, mild upper and lower limb and gait ataxia (on tandem walking), and enhanced reflexes in the lower limbs. Cognitive abilities were mildly impaired in the younger sibling (IQ 67) and borderline in the older patient (IQ 72). Nerve conduction studies were normal in both patients. MRI was normal at 2.5 years in the younger sibling. Brain MRI showed normal cerebellar volume and folia in the older sibling at the age of 6 years, and revealed minimal superior vermian atrophy at the age of 16 years. Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers. Autozygosity mapping focused on smallest haplotype on chromosome 3 and mutation age analysis revealed the mutation occurred approximately 1550 years ago spanning about 62 generations. Conclusions Our findings validate the slowly progressive phenotype of Salih ataxia (SCAR15, OMIM # 615705) by an additional family. Haplotype sharing attests to a common founder, an ancient RUBCN mutation in the Arab population.

Background Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM #611105) is a genetic disease of the central nervous system characterized by lower limb spasticity, cerebellar ataxia and involvement of the dorsal column. The disease is caused by mutations in the DARS2 gene but has never been reported in sub-Saharan Africa so far. Case presentation Two siblings, aged 18 years and 15 years, from a consanguineous family presented with pyramidal signs and symptoms since infancy and developmental delay. Whole exome sequencing of the proband identified two compound heterozygous variants (NM_018122.4:c.1762C > G and c.563G > A) in DARS2 . Sanger sequencing confirmed the presence of the mutations and their segregation in trans in both patients and in their elder sister (aged 20 years), who showed only brisk reflexes and mild lower limb spasticity. Surprisingly, in contrast to her subtle clinical presentation, the elder sister had abnormal MRI features and serum lactate levels comparable to her ill sisters. Conclusion This report illustrates intra-familial phenotypic variation in LBSL and provides an example of a marked dissociation between the clinical and radiological phenotypes of the disease. This may have implications for the detection of mutation carriers in LBSL.

Background Neurodegeneration with brain iron accumulation (NBIA) refers to genetically heterogenous paediatric neurodegenerative disorders characterised by basal ganglia iron deposition. One major cause is recessive mutations in the PLA2G6 gene. While strabismus and optic nerve pallor have been reported for PLA2G6-related disease, the ophthalmic phenotype is not carefully defined. In this study we characterise the ophthalmic phenotype of PLA2G6-related NBIA. Methods Prospective cohort study. Results The eight patients were 4–26 years old when examined. All had progressive cognitive and motor regression first noted between 9 months and 6 years of age that typically first manifested as difficulty walking (ataxia). Ophthalmic examination was sometimes limited by cognitive ability. Four of eight had exotropia, 7/7 bilateral supraduction defect, 5/7 poor convergence, 6/8 saccadic pursuit, 4/8 saccadic intrusions that resembled square-wave jerks, and 8/8 bilateral optic nerve head pallor. All patients lacked Bell phenomenon. Conclusions Upgaze palsy, although not a previously reported finding, was confirmed in all patients (except in one for whom assessment could not be performed) and thus can be considered part of the phenotype in children and young adults. Other frequent findings not previously highlighted were abnormal convergence, saccadic pursuit, and saccadic intrusions. Optic nerve head pallor and strabismus, previously reported findings in the disease, were found in 100% and 50% of our cohort, respectively, and the strabismus in our series was always exotropia. Taken together, these clinical findings may be helpful in distinguishing PLA2G6-related neurodegeneration from the other major cause of NBIA, recessive PANK2 mutations.

The correct funding information is as follows: MAS and co-authors are thankful to the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia, for supporting the work through the research group project number RGP-VPP-301. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Background The presence of a clinical pharmacist in a hospital’s Emergency Department (ED) is important to decrease the potential for medication errors. To our knowledge, no previous studies have been conducted to evaluate the impact of implementing clinical pharmacy services in the ED in Qatar. Objective To characterize the contributions of clinical pharmacists in a short stay unit of ED in order to implement and scale-up the service to all ED areas in the future. Methods A retrospective study conducted for 7 months in the ED of Hamad General Hospital, Qatar. The intervention recommendations were made by clinical pharmacists to the physician in charge during medical rounds. Results A total of 824 documented pharmacist recommendations were analyzed. The interventions included the following: Providing information to the physician (24.4 %) and recommending medication discontinuation (22.0 %), dose adjustment (19.3 %), medication addition (16.0 %), changes in frequency of medications (7.6 %), medication resumption (5.7 %), and patient education (5.0 %). Conclusion Clinical pharmacists in the ED studied play an important role in patient care.

Background Early childhood years are very important and crucial periods for developing different developmental milestones. Hearing loss is considered to be one of the most commonly detectable problems, which often goes unnoticed or not given proper attention due to the lack of screening modalities or the inability of parents or guardians to recognize it in early stages. Therefore, it is necessary to determine the pattern of differences pertaining to hearing loss among pre-school children of various age groups to better approach this issue in a systemic and fundamental manner, so that better care and treatment can be provided to children suffering from deafness. Methods This study involved a descriptive, retrospective chart review in two hospital settings, and it was conducted at the department of physiology (neurophysiology) of King Abdulaziz and King Khalid University Hospitals at the King Saud University (KSU) in Riyadh during the period of 2012-2017. A total of 324 pre-school Saudi children from the age of two to five years were involved and tested by brainstem auditory evoked potentials (BAEPs) to assess deafness. Results A total of 324 patients underwent the BAEP test; of them, 199 (61.4%) were males and 125 (38.6%) were females. Regarding the age groups, the most common age group was that of two-year-olds with 117 (36.1%) participants, followed by three-year-olds with 80 (24.7%) children, four-year-olds with 73 (22.5%) patients, and five-year-olds with 54 (16.7%) participants. Furthermore, there were 220 (67.9%) patients with sensorineural hearing loss (SNHL), 92 (28.4%) with conductive hearing loss (CHL), four (1.2%) with mixed hearing loss (MHL), and eight (2.5%) with normal audiometry. The normal hearing threshold was determined to be 20 dB, and the mean value for the hearing threshold of the SNHL in the right ear was found to be 43.45 ± 25.85, while the left-ear mean value was 44.54 ± 28.78. The mean value of the hearing threshold in CHL of the right ear was 50.96 ± 22.23, while that of the left ear was 47.85 ± 22.74. Lastly, the mean value of the hearing threshold in MHL of the right ear was 80.00 ± 21.21, while that of the left ear was 73.75 ± 18.87. Conclusion SNHL was the most common type (67.9%) of pre-school hearing loss in Saudi Children attending the neurophysiology clinic at KSU hospitals between 2012-2017, while MHL constituted the most severe cases.Background Early childhood years are very important and crucial periods for developing different developmental milestones. Hearing loss is considered to be one of the most commonly detectable problems, which often goes unnoticed or not given proper attention due to the lack of screening modalities or the inability of parents or guardians to recognize it in early stages. Therefore, it is necessary to determine the pattern of differences pertaining to hearing loss among pre-school children of various age groups to better approach this issue in a systemic and fundamental manner, so that better care and treatment can be provided to children suffering from deafness. Methods This study involved a descriptive, retrospective chart review in two hospital settings, and it was conducted at the department of physiology (neurophysiology) of King Abdulaziz and King Khalid University Hospitals at the King Saud University (KSU) in Riyadh during the period of 2012-2017. A total of 324 pre-school Saudi children from the age of two to five years were involved and tested by brainstem auditory evoked potentials (BAEPs) to assess deafness. Results A total of 324 patients underwent the BAEP test; of them, 199 (61.4%) were males and 125 (38.6%) were females. Regarding the age groups, the most common age group was that of two-year-olds with 117 (36.1%) participants, followed by three-year-olds with 80 (24.7%) children, four-year-olds with 73 (22.5%) patients, and five-year-olds with 54 (16.7%) participants. Furthermore, there were 220 (67.9%) patients with sensorineural hearing loss (SNHL), 92 (28.4%) with conductive hearing loss (CHL), four (1.2%) with mixed hearing loss (MHL), and eight (2.5%) with normal audiometry. The normal hearing threshold was determined to be 20 dB, and the mean value for the hearing threshold of the SNHL in the right ear was found to be 43.45 ± 25.85, while the left-ear mean value was 44.54 ± 28.78. The mean value of the hearing threshold in CHL of the right ear was 50.96 ± 22.23, while that of the left ear was 47.85 ± 22.74. Lastly, the mean value of the hearing threshold in MHL of the right ear was 80.00 ± 21.21, while that of the left ear was 73.75 ± 18.87. Conclusion SNHL was the most common type (67.9%) of pre-school hearing loss in Saudi Children attending the neurophysiology clinic at KSU hospitals between 2012-2017, while MHL constituted the most severe cases.