Elevated level of creatine phosphokinase in newborn: Clinical significance and association with congenital muscle diseases.

OBJECTIVES: To establish the normal Creatine phosphokinase (CPK) range in newborns of all 3 modes of delivery and prove that high CPK level in neonates is not specific a indicator for muscular pathology. METHODS: This is a prospective cohort study that is conducted in King Abdulaziz Medical City and King Abdullah Specialized Children Hospital in Riyadh and included 504 term neonates who were born between March 2021 and August 2021. Two hundred and fifty three were males and 251 were females. Data and consents were managed and collected using 2 coordinators. RESULTS: Duration of the second stage of labor, age on the first CPK test and fetal gestational age were significantly correlated with CPK values (r=0.197, r=-0.234, r=0.274, respectively). The normal ranges for each delivery type were 334 U/L-2667U/L in normal spontaneous vaginal delivery, 265U/L-1182U/L in elective cesarean section, and 223U/L-3082 U/L in emergency cesarean section. CONCLUSION: The CPK was elevated in all neonates in all 3 modes of deliveries. An elevated levels of CPK in neonates is not a specific indicator for any congenital muscular pathology.

Effect of melatonin in children with neurodevelopmental disabilities and sleep disorders.

Objectives: The aim of this study is to assess the efficacy and side effects of melatonin use in a population of children with neurodevelopmental disabilities who had sleep disorders. Methods: This is a cross-sectional study conducted in the pediatric neurology clinic at King Abdulaziz Medical City. A designed questionnaire was given to the parents to inquire about the sleep characteristics of their children before and after using melatonin. The patients' demographic data were collected and different parameters before and after starting melatonin were compared. Categorical variables were summarized and reported in terms of frequency and percent (n%). Continuous variables were reported in terms of mean and standard deviation. Results: A total of 23 patients were enrolled in our study, of which 15 (65.22%) were male. The mean age was 5.83 ± 3.07 years. For melatonin dose, 9 (39.13%) received 1 mg, 8 (34.78%) received 2 mg, and 6 (26.09%) received over 3 mg. Regarding melatonin duration of use, 7 (30.43%) received melatonin for 0 to 6 months, 7 (30.43%) received it for 7 to 12 months, and 9 (39.13%) received it for over a year. Significant differences were observed in time taken to fall asleep (P =0.046), the number of times the child woke up at night (P =0.071), total sleep time within 24 hours (P =.011), and time taken to wake up (P =.007), while no significant difference was observed in the number of naps taken during the daytime (P =.801). There were no major side effects reported. Conclusion: Melatonin had a significant impact on total sleep time and quality during the pre and post assessment of children with neurodevelopmental disabilities and sleep disorders.

Pediatric intracranial hypertension. Experience from 2 Tertiary Centers.

OBJECTIVE: To review the experience of 2 tertiary centers in Saudi Arabia with intracranial hypertension (IH) in the pediatric population. METHODS: We retrospectively reviewed and analyzed pediatric patients diagnosed with IH from June 2002 to May 2017 in 2 institutes. RESULTS: We identified 53 patients (30 females and 23 males) with a mean age of 7 years at the time of presentation. Among them, 41 patients were younger than 12 years, and 12 were older. Obese and overweight patients constituted 27.00% (n = 14) of all cases, 8 (66.7%) of whom were older than 12 years. The most common presenting feature was papilledema followed by headache. Vitamin D deficiency, which constituted the most common associated condition, was identified in 12 (22.6%) patients. Acetazolamide was the treatment option in 98.11% of patients, and only 5.7% underwent surgical interventions. The length of follow-up ranged from 6 months to 8 years. CONCLUSION: Intracranial hypertension is rare in children and commonly seen in overweight females older than 12 years similar to adults. Patients younger than 12 years tend to develop secondary IH. More studies are needed to characterize the clinical presentation and guide the management plan.

Confirming the pathogenicity of NECAP1 in early onset epileptic encephalopathy.

Early onset epileptic encephalopathy (EOEE) has been used to encompass Ohtahara syndrome (early infantile epileptic encephalopathy [EIEE]), early myoclonic epilepsy, and many others. Multiple genes have been established to cause epileptic encephalopathy in the immature brain, and next-generation sequencing has accelerated the process of novel gene discovery. Many of the previously published candidate genes are still pending confirmatory reports or functional studies. Although most of the genes involved are ion channels (channelopathies), multiple other pathways have been implicated as well. NECAP1 is a key element in clathrin-mediated endocytosis and has been reported previously to cause EOEE in a Saudi family. We report another family with the same variant confirming the pathogenicity of this variant as a Saudi founder mutation, further delineate its phenotype, and propose that it causes EOEE instead of EIEE.

KIF16B is a candidate gene for a novel autosomal-recessive intellectual disability syndrome.

Intellectual disability (ID) and global developmental delay are closely related; the latter is reserved for children under the age of 5 years as it is challenging to reliably assess clinical severity in this population. ID is a common condition, with up to 1%-3% of the population being affected and leading to a huge social and economic impact. ID is attributed to genetic abnormalities most of the time; however, the exact role of genetic involvement in ID is yet to be determined. Whole exome sequencing (WES) has gained popularity in the workup for ID, and multiple studies have been published examining the diagnostic yield in identification of the disease-causing variant (16%-55%), with the genetic involvement increasing as intelligence quotient decreases. WES has also accelerated novel disease gene discovery in this field. We identified a novel biallelic variant in the KIF16B gene (NM_024704.4:c.3611T > G) in two brothers that may be the cause of their phenotype.

Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases.

Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process required to produce various ISC-containing proteins. These ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid, an essential cofactor of respiratory chain complexes. Defects in ISC biogenesis lead to multiple mitochondrial dysfunction syndromes including: ISCA2 with infantile onset leukodystrophy. Recently, a founder mutation, c.229G > A, p.Gly77Ser in ISCA2 was reported to cause Multiple Mitochondrial Dysfunction Syndrome type 4. In a retrospective review of children diagnosed with the ISCA2 defect, we were able to identify ten new patients who were not reported previously with the identical founder mutation. High CSF glycine levels and elevated glycine peaks on MR spectroscopy were demonstrated in all tested probands. All patients were between 3 and 7 months of age with a triad of neurodevelopmental regression, nystagmus and optic atrophy and leukodystrophy. MRI findings were typical in the patients with diffuse, abnormal white matter signal in the cerebrum, cerebellum, brain stem and spinal cord. The patients ended up in a vegetative state, and often premature death due to respiratory infections. We alert clinicians to consider the ISCA2 defect as a differential diagnosis of infantile onset leukodystrophies affecting the brain as well as the spinal cord, especially in the presence of elevated CSF glycine or elevated glycine peaks in MR spectroscopy.

Phenotypic and Molecular Spectrum of Aicardi-Goutières Syndrome: A Study of 24 Patients.

BACKGROUND: Aicardi-Goutières syndrome is a rare genetic neurological disorder with variable clinical manifestations. Molecular detection of specific mutations is required to confirm the diagnosis. The aim of this study was to review the clinical and molecular diagnostic findings in 24 individuals with Aicardi-Goutières syndrome who presented during childhood in an Arab population. MATERIALS AND METHODS: We reviewed the records of 24 patients from six tertiary hospitals in different Arab countries. All included patients had a molecular diagnosis of Aicardi-Goutières syndrome. RESULTS: Six individuals with Aicardi-Goutières syndrome (25%) had a neonatal presentation, whereas the remaining patients presented during the first year of life. Patients presented with developmental delay (24 cases, 100%); spasticity (24 cases, 100%); speech delay (23 cases, 95.8%); profound intellectual disability (21 cases, 87.5%); truncal hypotonia (21 cases, 87.5%); seizures (eighteen cases, 75%); and epileptic encephalopathy (15 cases, 62.5%). Neuroimaging showed white matter abnormalities (22 cases, 91.7%), cerebral atrophy (75%), and small, multifocal calcifications in the lentiform nuclei and deep cerebral white matter (54.2%). Homozygous mutations were identified in RNASEH2B (54.2%), RNASEH2A (20.8%), RNASEH2C (8.3%), SAMHD1 (8.3%), TREX1 (4.2%), and heterozygous mutations in IFIH1 (4.2%), with c.356A>G (p.Asp119Gly) in RNASEH2B being the most frequent mutation. Three novel mutations c.987delT and c.625 + 1G>A in SAMHD1 gene and c.961G>T in the IFIHI1 gene were identified. CONCLUSIONS: This is the largest molecularly confirmed Aicardi-Goutières syndrome cohort from Arabia. By presenting these clinical and molecular findings, we hope to raise awareness of Aicardi-Goutières syndrome and to demonstrate the importance of specialist referral and molecular diagnosis.

Clinical exome sequencing: results from 2819 samples reflecting 1000 families.

We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.

Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases.

BACKGROUND: Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive neurometabolic disorder. It is characterized by sub acute encephalopathy with confusion, seizure, dysarthria and dystonia following a history of febrile illness. If left untreated with biotin, the disease can progress to severe quadriparesis and even death. METHOD: A retrospective chart review of 18 patients with BBGD from two tertiary institutions describing their clinical, magnetic resonance imaging and molecular findings was conducted. RESULT: Eighteen children from 13 families seen over a period of nine years (2003-2012) were included. (Age range: 14month to 23 years, M: F: 1:1). The clinical features included sub acute encephalopathy, ataxia (n= 18), seizures (n= 13) dystonia (n=12) ,dysarthria (n= 9), quadriparesis and hyperreflexia (n=9). Magnetic resonance imaging demonstrated abnormal signal intensity with swelling in the basal ganglia during acute crises (n= 13/13) and atrophy of the basal ganglia and necrosis during follow up (n= 13/13). One-third of the present patients showed the recurrence of acute crises while on biotin therapy alone, but after the addition of thiamine, crises did not recur. All of the patients have a homozygous missense mutation in exon 5 of the SLC19A3 gene. The frequency of acute crises, delay in diagnosis and initiation of treatment significantly influenced the outcome. On follow up, four patients died, two had spastic quadriplegia, six had normal outcome and the rest had speech and motor dysfunctions. CONCLUSION: Clinicians should suspect BBGD in any child presenting with sub acute encephalopathy, abnormal movement and MRI findings as described above. Both biotin and thiamine are essential for disease management. Since biotin alone could not prevent the recurrence of crises in some patients, a more appropriate term to describe the disease would be biotin-thiamine-responsive basal ganglia disease (BTBGD).

A novel chronic childhood sensory predominant neuropathy.

Chronic childhood neuropathies are predominantly hereditary in origin. Specific distinct clinical entities have been described, however, occasionally children with an unusual clinical phenotype are encountered in practice. We describe four children (3 males, 1 female) of Lebanese Moslem descent all sharing a common great-great-grandparent pairing with such a novel clinical spectrum. The three males were first cousins, each the product of a different parental consanguineous (i.e., parents second cousins) mating, whereas the female was a third cousin to each of the males whose parents were also second cousins. Each child presented early in life with developmental delay with associated hypotonia and areflexia. All had a sensorineural hearing loss documented and two of the patients were dysmorphic in facial appearance. Nerve conduction studies highlighted a sensory axonal neuropathy and sural nerve biopsy undertaken in two patients confirmed an axonal neuropathy. Detailed genetic and metabolic testing was negative. Followed into later childhood, each child continued to manifest motoric impairment, unsteadiness, areflexia, and cognitive disability. These children appear to provide evidence for a novel autosomal recessive inherited chronic predominantly sensory neuropathy that shares core clinical features with observed variability in associated symptoms.

Pediatric migraine equivalents: occurrence and clinical features in practice.

Migraine equivalents of infancy, childhood, and adolescence are recognized periodic, paroxysmal syndromes without associated headache that are thought to be migrainous in etiology. Five such equivalents are presently recognized. Their clinical features and relative frequency in ambulatory pediatric neurology practice have not been well documented. Utilizing a comprehensive, standardized computer database, the occurrence of these migraine equivalents in a single pediatric neurology practice together with their observed clinical features were documented over an 8-year period. Of a total of 5,848 patients in the database, of whom 1,106 were migraineurs, 108 patients (1.8% of total, 9.8% of migraineurs) were identified to have migraine equivalents. The following distribution among migraine equivalents was observed: benign paroxysmal torticollis 11 (10.2% of patients with migraine equivalents), benign paroxysmal vertigo 41 (38%), abdominal migraine/cyclical vomiting 20 (18.5%), acephalgic migraine 31 (28.7%), and acute confusional migraine 5 (4.6%). In each type, with the exception of benign paroxysmal torticollis and acute confusional migraine, females clearly predominated, and in all types a strong positive family history of migraine was elicited (68%-100%). There was variation in the age of onset of a particular equivalent with considerable overlap observed. Coexisting more typical migraines were observed in from 10% (benign paroxysmal torticollis) to 70% (abdominal migraines/cyclical vomiting) of the cases. In conclusion, pediatric migraine equivalents occur with relative frequency in ambulatory practice, possessing discrete clinical features that have a clear relationship to more typical migrainous phenomena.