Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.

PURPOSE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. METHODS: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. RESULTS: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. CONCLUSION: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.

Epilepsy in patients with insulin-dependent diabetes and relation to glutamic acid decarboxylase 65.

OBJECTIVE: To report if the association of epilepsy in pediatric patients (below the age of 15 years) with Insulin-dependent Diabetes (IDDM) at King Fahad Medical City (KFMC) is higher than the prevalence of epilepsy in the same age group (who have no IDDM) in our community. Consequently, we would determine if there is a relationship between the presence of epilepsy in diabetic children and the presence of positive antiGAD65 antibodies. METHODS: This cohort study included 305 pediatric patients below the age of 15 years with Insulin-dependent Diabetes Mellitus (IDDM). They were randomly recruited at the Pediatric Endocrinology Clinic in KFMC. The patients` caregivers were given a questionnaire between December 2015 till March 2019 to determine the seizure disorder history. There was also a retrospective review of 214 patients` files for anti-GAD 65 positivity. RESULTS: Our study found a significant relation between the presence of epilepsy in children with IDDM. Therefore, we could confirm the relationship between the existence of epilepsy in children with IDDM and having positive GAD65 antibodies. CONCLUSION: Our study supports the presence of consistent relation between having IDDM and having epilepsy in children and between the latter and the presence of positive GAD65 antibodies.

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

Anti-N-methyl-d-aspartate Receptor Encephalitis: A Case Series and Review of the Literature.

Anti-NMDAR (N-methyl-d-aspartate receptor) encephalitis is a potentially severe form of encephalitis associated with antibodies against NR1 and NR2 subunits of the NMDAR. Anti-NMDAR encephalitis is a treatable cause of encephalitis. An underlying tumor should be actively looked for as this is also considered to be a paraneoplastic syndrome. We report two children with anti-NMDAR encephalitis with a literature review of current evidence in diagnosing and managing this rare condition. Resection of the tumor, glucocorticoids, intravenous immunoglobulin, and plasma exchange often result in improvement, usually within four weeks. Outcome corresponds with the rapidity of commencing appropriate treatment.

Immunogenicity of a Meningococcal B Vaccine during a University Outbreak.

BACKROUND: In December 2013, a multicomponent meningococcal serogroup B (4CMenB) vaccine was used before licensure on the basis of special consideration by the Food and Drug Administration to respond to an outbreak of Neisseria meningitidis B at a U.S. university. Data suggested that vaccination would control the outbreak because isolates expressed antigens that were closely related to the vaccine antigens (factor H-binding protein [fHbp] and neisserial heparin-binding antigen). We quantified the immune responses induced by 4CMenB during the outbreak. METHODS: We conducted a seroprevalence survey among students to assess vaccination status and collect serum specimens to quantify titers of serum bactericidal antibodies (SBA) with an assay that included human complement (hSBA). We compared the proportion of vaccinated and unvaccinated participants who were seropositive for the outbreak strain and for one closely related reference strain (44/76-SL, which included fHbp) and one mismatched reference strain (5/99, which included neisserial adhesin A), both of which were used in vaccine development. Seropositivity was defined as an hSBA titer of 4 or higher. RESULTS: Among the 499 participants who received two doses of the 4CMenB vaccine 10 weeks apart, 66.1% (95% confidence interval [CI], 61.8 to 70.3) were seropositive for the outbreak strain, although the geometric mean titer was low at 7.6 (95% CI, 6.7 to 8.5). Among a random subgroup of 61 vaccinees who also received two doses but did not have a detectable protective response to the outbreak strain, 86.9% (95% CI, 75.8 to 94.2) were seropositive for the 44/76-SL strain, for which there was a geometric mean titer of 17.4 (95% CI, 13.0 to 23.2), whereas 100% of these vaccinees (95% CI, 94.1 to 100) were seropositive for the 5/99 strain and had a higher geometric mean titer (256.3; 95% CI, 187.3 to 350.7). The response to the outbreak strain was moderately correlated with the response to the 44/76-SL strain (Pearson's correlation,0.64; P<0.001) but not with the response to the 5/99 strain (Pearson's correlation,-0.06; P=0.43). CONCLUSIONS: Eight weeks after the second dose of the 4CMenB vaccine was administered, there was no evidence of an hSBA response against the outbreak strain in 33.9% of vaccinees, although no cases of meningococcal disease caused by N. meningitidis B were reported among vaccinated students. (Funded by Princeton University and others.).

Incidence of autism in high risk neonatal follow up.

OBJECTIVE: To detect autism spectrum disorder (ASD) cases within the High Risk Neonatal Follow up Program (HRNFP), as an indicator of the prevalence of ASD and associated risk factors in the Kingdom of Saudi Arabia (KSA). METHODS: We conducted this retrospective medical chart review in a tertiary care hospital in Riyadh, KSA. All patients admitted to the HRNFP were seen at 3 years corrected age between January 2012 and December 2013. Patients diagnosed with ASD from the HRNFP were referred to the King Fahad Medical City (KFMC) Autism Program for further assessment. The following potential risk factors for ASD were documented: low birth weight, gestational age less than 33 weeks, and male gender. RESULTS: In 2012, 59 patients were evaluated in the HRNFP. Three cases were diagnosed with ASD, with an ASD incidence rate of 5.1% (95% confidence interval [CI] calculated by adjusted Wald method: 1.2-14.5%). In 2013, 48 patients were evaluated and 2 cases were diagnosed with ASD, with an ASD incidence rate of 4.2% (95% CI: 0.4%-14.8%). The total ASD incidence rate during the 2-year study period was 4.7% (95% CI: 1.7%-10.8%). Factors associated with a higher likelihood of ASD were: male gender, low birth weight, and gestational age less than 33 weeks. CONCLUSION: Compared with the community, the prevalence of ASD was higher in the HRNFP. Further investigation is required to evaluate risk factors.

Acute hemiplegia as a rare presentation of infantile Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) usually presents in a symmetrical ascending fashion of weakness. We present a 6-month-old male infant who presented to our emergency room with acute left-sided limb weakness and head lag 3 days after a febrile upper respiratory tract infection. A diagnosis of GBS was established by confirming high cerebrospinal fluid protein, motor nerve reduced amplitude, and prolonged conductions, and MRI T2 high signal intensity affecting the ventral roots of the spinal cord. He showed remarkable clinical and neurophysiological improvement after intravenous immunoglobulin and intensive physiotherapy. The occurrence of infantile acute hemiplegia as a presentation of GBS is rare. This report highlights the importance of considering GBS in the differential diagnosis so that early effective treatment may be started.

Limbic encephalitis in a child: an atypical presentation.

BACKGROUND: Limbic encephalitis is a rare disorder with a generally subacute onset evolving over days to weeks. Patients present with a variable combination of memory loss, seizures, and psychiatric disturbance, and it is not rare for patients to be initially misdiagnosed. PATIENT: We describe a previously healthy 12-year-old boy who developed his first seizures at 8 years of age. He had a total of eight prolonged focal seizures, each followed by a month of behavioral changes and short-term memory loss. There was no family history of seizures or other neurological disorders, and he had an otherwise unremarkable neonatal and medical history. RESULTS: Magnetic resonance imaging during each episode of seizures showed alternating unilateral brain hemispheric involvement consistent with limbic encephalitis that was followed by resolution for a total of six times. Despite a negative laboratory evaluation for a large panel of paraneoplastic antibodies, the clinical scenario and exclusion of other possible disorders made recurrent limbic encephalitis the most likely diagnosis. CONCLUSION: Limbic encephalitis is a rare disorder that is diagnosed primarily on the basis of clinical criteria and is often associated with the presence of a paraneoplastic antibody. However, lack of a positive paraneoplastic antibody in a patient with a triad of seizure, behavioral changes, and short-term memory loss does not exclude the diagnosis. The unique presentation in a seronegative patient may indicate an unrecognized antibody.

Infantile osteopetrosis, craniosynostosis, and Chiari malformation type I with novel OSTEM1 mutation.

We report a case of a 9-month-old Arab infant, with novel OSTEM mutation and unpublished triad of osteopetrosis (OP), craniosynostosis (CS), and Chiari malformation type I (CM1). The index presented with progressive irritability, abnormal movements, following an accidental fall. The history revealed early onset of irritability, progressive visual loss, and global developmental delay, more prominent at the gross motor level and a suspected congenital cytomegalovirus infection. The pregnancy was uneventful with subsequent unremarkable delivery. The parents are Arabs'first cousins with no apparent symptoms or signs of bone disease. Three dimensional brain computed tomography (CT) showed ventriculomegaly, thick calvaria, and CS of the coronal and sagittal sutures. Patient had signs of left lower motor neuron facial palsy, and CT of petrous bones confirms the presence of osteopetrotic petrous with slim mastoid portions of the facial nerve canals both sides. Brain magnetic resonance imaging showed CM1. Skeletal survey showed sclerotic skeleton. He needed ventriculoperitoneal shunt and died at 18 months of age. Molecular testing for OSTEM1 gene revealed novel homozygous mutation that segregated from his parents. This novel OSTEM1 gene novel mutation and the combination of OP, infantile CS, and CM1 is to our knowledge never been reported.

Ineffectiveness of topiramate and levetiracetam in infantile spasms non-responsive to steroids. Open labeled randomized prospective study.

OBJECTIVE: To compare the effectiveness of 2 novel antiepileptic drugs, topiramate and levetiracetam, as a second line treatment for infantile spasm when oral steroids fail. METHODS: Forty infants under 2 years with clinically- and EEG-proven infantile spasms that did not respond to prednisone (2mg/kg/day in 2 divided doses) were recruited and randomized into 2 groups. They were randomly assigned to either topiramate (group 1; 1mg/kg/day for 3 days then increased by 1mg/kg/day every third day up to 6mg/kg/day) or levetiracetam (group 2; 10mg/kg/day for 5 days and then increased by 10mg/kg/day every 5 days up to 60mg/kg/day). The study was conducted in the Pediatric Neurology Department at the National Neuroscience Institute of King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia between January 2008 and December 2010. RESULTS: Of the 20 patients included in the final data analysis, 11 (55%) were administered topiramate and 9 (45%) levetiracetam. Eighteen patients did not respond to the first drug, and subsequently to the other drug when crossed-over. Two patients with infantile spasm responded to either one drug without crossover. Their EEGs improved with time. CONCLUSION: The present study demonstrated the ineffectiveness of topiramate and levetiracetam suggesting current treatment modalities are grossly inadequate underscoring the urgent need for more research efforts to overcome current deficiencies. Two patients with cryptogenic infantile spasm responded to treatment suggesting the potential for treatment of such patients with these 2 drugs, and merits further multicenter investigation.

Serum TGF-ß, Serum MMP-1, and HOMA-IR as non-invasive predictors of fibrosis in Egyptian patients with NAFLD.

BACKGROUND/AIM: Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent cause of chronic liver disease worldwide. A number of these patients progress to nonalcoholic steatohepatitis (NASH) which carries significant morbidity and mortality. The aim of this study is to evaluate the diagnostic value of serum levels of transforming growth factor beta-1 (TGF-ß1) matrix metalloproteinase-1 (MMP-1), and insulin resistance as predictors of fibrosis in Egyptian NAFLD patients. PATIENTS AND METHODS: Fifty patients with NAFLD and different stages of fibrosis were studied. Serum levels of TGF-ß1, MMP-1, and fasting serum insulin were measured; calculation of the homeostasis model assessment for insulin resistance (HOMA-IR) was done. RESULTS: TGF-ß1 gives a sensitivity of 100% and specificity of 94.4% for stage 1 fibrosis, 100% and 93.9%, respectively, for stage 2 fibrosis, and 97.7% and 100%, respectively, for stage 3 fibrosis. MMP-1 showed sensitivity and specificity of 88% and 81.8%, respectively, for stage 2 fibrosis, 90.9% and 55.56%, respectively, for stage 3 fibrosis, but it is of no diagnostic value in stage 1 fibrosis. CONCLUSION: Serum TGF-ß1, MMP-1, and insulin resistance (HOMA-IR) proved to be potentially useful noninvasive markers in predicting fibrosis in NASH patients.

Incidence of kidney stones with topiramate treatment in pediatric patients.

PURPOSE: We ran this study to assess the incidence of nephrolithiasis in a group of children on topiramate (TPM) therapy for at least 1 year. METHODS: In this retrospective observational surveillance study, we reviewed the medical charts of children on TPM for at least 1 year seen at the pediatric neurology department during the period from 2005 to 2010 at King Fahad Medical City. Children with a normal baseline ultrasound report were included. Follow-up ultrasound reports after at least 1 year were collected. However, patients with any evidence of chronic illness or medications that may affect the kidney functions in addition to those who are not compliant with the prescribed dose were excluded. Family history of renal stones, symptoms suggestive of urologic disorders, and comorbidities were recorded. KEY FINDINGS: Medical charts of 96 children on TPM with a mean age of 6.9 (±3.8) years were reviewed; 52 (54.2%) of the children were male. The follow-up ultrasound showed that five children (5.2%) had developed kidney stones. The occurrence of kidney stones was found in four female patients (80%) versus one male (20%) (p > 0.05). SIGNIFICANCE: Long-term use of TPM may result in increased incidence of asymptomatic kidney stones in the pediatric population. Hence, routine baseline and follow-up ultrasound of the urinary system should be recommended during the use of TPM in children.

Cognitive and behavioral development profile of a Saudi girl with Fragile X syndrome.

This report presents an ideal case of a girl with Fragile X syndrome. There is positive family history of the same condition. The analysis revealed low average IQ with attention deficit, shyness, and social withdrawal. The report shows that girls with Fragile X might have only mild cognitive deficits that enable them to adapt and succeed in society.