Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia.

OBJECTIVE: Exome sequences account for only 2% of the genome and may overlook mutations causing disease. To obtain a more complete view, whole genome sequencing (WGS) was analyzed in a large consanguineous family in which members displayed autosomal recessively inherited cerebellar ataxia manifesting before 2 years of age. METHODS: WGS from blood-derived genomic DNA was used for homozygosity mapping and a rare variant search. RNA from isolated blood leukocytes was used for quantitative polymerase chain reaction (PCR), RNA sequencing, and comparison of the transcriptomes of affected and unaffected family members. RESULTS: WGS revealed a point mutation in noncoding RNA RNU12 that was associated with early onset cerebellar ataxia. The U12-dependent minor spliceosome edits 879 known transcripts. Reverse transcriptase PCR demonstrated minor intron retention in all of 9 randomly selected RNAs from this group, and RNAseq showed splicing disruption specific to all U12-type introns detected in blood monocytes from affected individuals. Moreover, 144 minor intron-containing RNAs were differentially expressed, including transcripts for 3 genes previously associated with cerebellar neurodegeneration. INTERPRETATION: Interference with particular spliceosome components, including small nuclear RNAs, cause reproducible uniquely distributed phenotypic and transcript-specific effects, making this an important category of disease-associated mutation. Our approach to differential expression analysis of minor intron-containing genes is applicable to other diseases involving altered transcriptome processing. ANN NEUROL 2017;81:68-78.

W44X mutation in the WWOX gene causes intractable seizures and developmental delay: a case report.

BACKGROUND: WW domain containing oxidoreductase (WWOX) gene was cloned in 2000; alteration has been seen in many cancer cells. It acts as a tumor suppresser by blocking cell growth and causing apoptosis. WWOX protein showed different expression of mice brain and spinal cord, for which deletion causes seizure and early death. CASE PRESENTATION: Clinical and molecular characteristics of a consanguineous family show a homozygous mutation of WWOX gene at specific bases, causing a debilitating syndrome characterized by growth retardation, intractable epilepsy, intellectual disability, and early death. Using Whole Exome Sequencing (WES), a novel homozygous mutation in the WWOX gene is identified in a consanguineous Arab family from Qatar with two daughters who presented with intractable seizure and developmental delay. CONCLUSION: The study presents the importance of human WWOX gene for brain development and the association between gene mutation and epileptic encephalopathy. It also highlights the power of WES particularly in clinically challenging cases.

Nonsense mutation in the WDR73 gene is associated with Galloway-Mowat syndrome.

BACKGROUND: Neuroanatomical defects are often present in children with severe developmental delay and intellectual disabilities. Few genetic loci have been associated with disorders of neurodevelopment. Our objective of the present study was to analyse a consanguineous Arab family showing some of the hallmark signs of a rare cerebellar hypoplasia-related neurodevelopmental syndrome as a strategy for discovering a causative genetic mutation. METHODS: We used whole exome sequencing to identify the causative mutation in two female siblings of a consanguineous Arab family showing some of the hallmark signs of a cerebellar-hypoplasia-related neurodevelopmental disorder. Direct Sanger sequencing was used to validate the candidate mutations that cosegregated with the phenotype. Gene expression and loss of function studies were carried out in the zebrafish model system to examine the role of the candidate gene in neurodevelopment. RESULTS: Patients presented with severe global developmental delay, intellectual disability, hypoplasia of the cerebellum and biochemical findings suggestive of nephrotic disease. Whole exome sequencing of the two patients revealed a shared nonsense homozygous variant in WDR73 (p.Q235X (c.703C>T)) resulting in loss of the last 144 amino acids of the protein. The variant segregated according to a recessive mode of inheritance in this family and was absent from public and our inhouse databases. We examined the developmental role of WDR73 using a loss-of-function paradigm in zebrafish. There was a significant brain growth and morphogenesis defect in wdr73 knockdown embryos resulting in a poorly differentiated midbrain and cerebellum. CONCLUSIONS: The results provide new insight into the functional role of WDR73 in brain development and show that perturbation of its function in an inherited disorder in humans is associated with cerebellar hypoplasia as well as nephrotic disease, consistent with Galloway-Mowat Syndrome.

Joubert syndrome labeled as hypotonic cerebral palsy.

Joubert syndrome (JS) is a rare autosomal recessive disorder with cerebellar vermis hypoplasia and complex brainstem malformation. The diagnosis of cases can be difficult as the presentation can be similar to cases of cerebral palsy. We present a case of JS in an 18-month-old girl who presented to pediatric rehabilitation with a diagnosis of hypotonic cerebral palsy and abnormal eye movements. The brain MRI confirmed the typical brain malformations.

Decreasing Lens Irradiation on Brain Imaging: A Multi-CT Scanner Quality Improvement Project.

AIMS: Cataracts, a leading global cause of blindness, are associated with ionising radiation exposure. This audit aimed to enhance lens exclusion during non-contrast head computed tomography (CT) scans at Newham University Hospital (NUH) using two CT scanners. METHODS: A retrospective audit of non-contrast head CT scans at NUH excluded scans for trauma and imaging of orbital structures. A one-week audit in April 2023 assessed lens exclusion, compared to the Royal College of Radiologists (RCR) standards. A total of 101 consecutive scans were analysed and 63 (62%) scans were included in the final study. Thirty-eight percent of the scans were excluded according to the exclusion criteria of head, neck and facial traumas, orbital infections and papilledema. Results were presented, followed by a three-month radiographer re-education period, emphasizing gantry tilt and patient positioning. A reaudit in August 2023 evaluated outcomes. For the reaudit, 183 consecutive scans were analysed, with 131 (72%) scans included in the final study and 52 (28%) scans excluded according to the same exclusion criteria as the first audit. RESULTS: Lens exclusion in non-contrast head CT scans improved significantly from 0/63 (0%) compliance to 19/131 (14.50%) (p=0005) compliance with the standards. Variability in radiographer practices, 'near misses' and time constraints were identified as challenges. Staff turnover impacted compliance. CONCLUSION: This audit has shed light on a critical aspect of patient care in the field of radiology. This research underscores the importance of rigorous and standardised protocols in radiological procedures, particularly when it comes to protecting the lens of the eye. By enhancing lens exclusion during non-contrast head CT scans, we have taken a significant step in mitigating the risk associated with ionising radiation exposure. Although substantial improvements were made, achieving the RCR audit standard remained elusive. Ongoing re-education, reaudits and a multidisciplinary approach are necessary to optimise radiographer adherence and reduce ionising radiation exposure to the lens during head CT scans. This quality improvement project proves that continued emphasis on gantry tilt and patient positioning in radiographer education and training can make a significant difference in patient safety. As we move forward, let us remember that even small improvements can make a big difference in safeguarding the health and well-being of patients.

Obstructive hydrocephalus and facial nerve palsy secondary to vertebrobasilar dolichoectasia: Case Report.

BACKGROUND: Symptomatic hydrocephalus due to vertebrobasilar dolichoectasia is a rare occurrence. CASE DESCRIPTION: We report a patient who presented with acute confusion and vomiting. Neuroimaging revealed elongated and tortuous basilar artery indenting and elevating the floor of third ventricle causing obstructive hydrocephalus. Initially, the patient was treated with external ventricular drain and then with ventriculo-peritoneal shunt. CONCLUSION: We suggest prompt surgical intervention upon diagnosis as a first choice of treatment in order to avoid further complications.

W-pouch With Modified Non-isolated Extra Limb for Continence in Cutaneous Diversion After Radical Cystectomy.

OBJECTIVE: To report the functional results of continent cutaneous ileal urinary diversion using modified W-pouch with non-isolated extra limb for continence. PATIENTS AND METHODS: From January 2013 to January 2016, 21 patients with muscle-invasive bladder cancer with median (interquartile range) of 59 (56.5-62.5) years old underwent radical cystectomy with pelvic lymphadenectomy; they then had an ileal continent cutaneous pouch constructed from W-pouch with non-isolated extra limb for continence. The technique entails the creation of a detubularized ileal W-pouch with extra limb fashioned from 59 cm of the terminal ileum. This extra limb is not isolated from the pouch. The proximal part of this limb is tailored and fixed in a subserous extramural tunnel for continence, whereas the distal part is left continuous with the pouch. The median (interquartile range) of follow up was 12 (8-17) months. Evaluation of the technique included operative time, continence efficiency, overall complications, and quality of life questionnaire for the patients. RESULTS: The median (interquartile range) of operative time of the operation was 4.7 (3.9-5.4) hours. The median (interquartile range) of operative time of the cutaneous pouch creation was 39 (33-43) minutes. No perioperative mortality had occurred. The incidence of continence was 95.2%. The overall complications were 42.8%, and most of them were grade 1 or 2 on Clavien-Dindo classification system. CONCLUSION: Modification of W-pouch with non-isolated extra limb as continent cutaneous pouch can simplify the technique and shorten the operative time with efficient continence, less side effects, and good quality of life.

Neuro-imaging evaluation after the first afebrile seizure in children: A retrospective observational study.

PURPOSE: To evaluate the role of neuro-imaging in children presenting with the first afebrile seizure and determine factors that influence the outcome of imaging in a large paediatric emergency centre. METHOD: This is a retrospective review of the medical records of all patients presenting with the first non-febrile seizure to a large paediatric emergency centre in the state of Qatar. Seizure classification followed the current ILAE classification system. Imaging was undertaken in our tertiary hospital and all images were reviewed by experienced neuro-radiologists. Student t test was used for statistical analysis. RESULTS: Ninety-six children underwent neuro-imaging following the first afebrile seizure. Of them, thirty-two patients (33%) were reported to have abnormalities. Children below the age of two demonstrated a significantly higher percentage of abnormal imaging (59%); (p=0.002). Children presenting with prolonged seizures showed a high percentage of imaging abnormalities (58%); (p=0.003). Children with focal seizures demonstrated a higher percentage of imaging abnormality compared to those presenting with generalized seizures (35% vs 31%). This difference did not reach statistical significance. CONCLUSION: Children below the age of two demonstrated significantly higher percentages of abnormal imaging (59%), as did children presenting with status epilepticus (58%). Neuro-imaging should be considered in infants and those with focal or prolonged seizures. Neuro-imaging informed decision making in 6-8% of children.

Loss-of-Function Mutation in APC2 Causes Sotos Syndrome Features.

Sotos syndrome, characterized by intellectual disability and characteristic facial features, is caused by haploinsufficiency in the NSD1 gene. We conducted an etiological study on two siblings with Sotos features without mutations in NSD1 and detected a homozygous frameshift mutation in the APC2 gene by whole-exome sequencing, which resulted in the loss of function of cytoskeletal regulation in neurons. Apc2-deficient (Apc2-/-) mice exhibited impaired learning and memory abilities along with an abnormal head shape. Endogenous Apc2 expression was downregulated by the knockdown of Nsd1, indicating that APC2 is a downstream effector of NSD1 in neurons. Nsd1 knockdown in embryonic mouse brains impaired the migration and laminar positioning of cortical neurons, as observed in Apc2-/- mice, and this defect was rescued by the forced expression of Apc2. Thus, APC2 is a crucial target of NSD1, which provides an explanation for the intellectual disability associated with Sotos syndrome.

Lingual mucosal graft in treatment of Peyronie disease.

OBJECTIVE: To evaluate the use of lingual mucosal graft (LMG) as a substitute for tunica albuginea in the treatment of Peyronie disease (PD). PATIENTS AND METHODS: Seventeen patients, reporting normal erectile function, with PD interfering with sexual function were operated on by plaque excision and grafting with LMG. Preoperative assessment included: the International Index of Erectile Function-5 score, penile duplex, and penile curvature angle measurement. Postoperative erectile function and penile deformity were assessed every 3 months for 9-18 months. RESULTS: Mean age of the patients was 52 (± 4.7) years and mean angle of deformity was 60° (± 5.1). Donor site complications occurred in the form of mild transient swelling, numbness, and pain. Postoperative assessment showed complete penile straightening in 15 patients with mild curvature recurrence (<20°) in 2 patients at the third month. De novo mild erectile dysfunction was reported by 1 patient who responded to low-dose phosphodiesterase type 5 inhibitor. Patients' and partners' satisfaction was reported in 16 (94%) patients. These results remained stable until the end of the follow-up period. CONCLUSION: LMG seems to be a valuable substitute for tunica albuginea in cases of PD. It is readily available and shows early graft take. It also proved safety, reliability, feasibility, and a satisfactory short-term outcome for the treatment of PD.

Flank free modified supine position: A new modification for supine percutaneous nephrolithotomy.

OBJECTIVES: Percutaneous nephrolithotomy (PCNL) is the standard management for large and/or complex urolithiasis, but the standard patient position for PCNL is undecided. With the patient prone PCNL has several drawbacks, while when supine, as described previously, PCNL has mechanical limitations. We describe a modification that aims to overcome these limitations and provide easy access comparable to that in the prone position. PATIENTS AND METHODS: This prospective study was carried out at the Urology Department, Zagazig University, Egypt, from October 2008 to March 2011, and included 78 patients (48 men and 30 women). First the patient was placed supine and then in the 'flank-free modified' supine position. The distance between the last rib and the iliac crest in the posterior axillary line was measured in both positions. RESULTS: The mean age of the patients was 40.8 years, the mean (SD) stone diameter was 3.4 (0.7) cm, the number of right/left stones was 34/44, and mean body mass index was 28.8 kg/m(2). The mean (SD) increase in the distance between the last rib and the iliac crest in the posterior axillary line in the flank free modified supine position vs. the previous supine position was 12 (0.8) mm. CONCLUSION: The flank-free modified supine position increases the distance between the last rib and the iliac crest, and, together with the absence of a cushion under the flank, provides ample space for puncture, dilatation, multiple tracts and manoeuvrability of the system with the nephroscope.

Neurocysticercosis in Qatari patients: case reports.

Neurocysticercosis is the most common parasitic infection of the central nervous system. It is a major cause of seizures in developing countries, especially in the Indian subcontinent and most of Asia, Latin America and Africa. It is increasing in prevalence in Muslim countries, especially in the Gulf region reflecting the demographics of these countries which rely heavily on labourers from highly endemic areas. Infections among Muslims in non-endemic regions are increasing. We describe one prospective case report of a Qatari male who presented with seizures and was found to have neurocysticercosis, and three retrospective cases of this infection among Qatari Muslims, who were admitted to a tertiary care hospital over the past 10 years.

Evaluation of transvaginal slings using different materials in the management of female stress urinary incontinence.

PURPOSE: To evaluate tailored polypropylene (prolene) mesh, anterior rectus sheath, and vaginal wall slings positioned under the mid-urethra, to treat stress urinary incontinence (SUI) in women, as SUI is a common pathological condition causing considerable distress and compromising social, physical, psychological, and sexual health, and for which surgical treatment remains controversial. PATIENTS AND METHODS: This prospective randomised study included 32 patients with SUI, evaluated by SEAPI (Stress, Emptying, Anatomy, Protection, and Instability) symptom score and urodynamics. According to sling material, 12 patients had tailored prolene mesh, 12 had anterior rectus sheath and eight had anterior vaginal wall slings. Operative variables (intraoperative bleeding, duration, complications and hospital stay) were documented, and postoperative complications and continence status were assessed. The follow-up was 12-18 months. RESULTS: Patients who received tailored prolene mesh slings had a lower operative duration and hospital stay, and less intraoperative bleeding. Postoperative complications, e.g. urinary retention and urgency, were <12%, with no significant differences. There was no significant difference among the three studied groups in the success rate (75%, 67% and 75%). CONCLUSIONS: Tailored prolene mesh, anterior rectus sheath and the vaginal wall sling are good alternatives to treat SUI in women, with comparable results in a short-term follow up. The surgeon's experience and the patient's clinical circumstances should be considered when choosing a sling material, as success rates are comparable, being slightly better for the prolene sling in operative duration, bleeding and hospital stay.