Publications by authors named "Brahim Tabarki"

63 Publications

Spinal Cord Involvement in Pediatric-Onset Metabolic Disorders With Mendelian and Mitochondrial Inheritance.

Front Pediatr 2020 14;8:599861. Epub 2021 Jan 14.

Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.

Previous reviews have described the features of brain involvement in pediatric-onset metabolic disorders with Mendelian and mitochondrial inheritance, but only a few have focused on spinal cord abnormalities. An increasing number of metabolic disorders with Mendelian and mitochondrial inheritance in children with predominant spinal cord involvement has been recognized. Spinal cord involvement may be isolated or may occur more frequently with brain involvement. Timely diagnosis and occasional genetic counseling are needed for timely therapy. Therefore, clinicians must be aware of the clinical, laboratory, and radiographic features of these disorders. In this review, we describe pediatric-onset metabolic disorders with Mendelian and mitochondrial inheritance and predominant spinal cord involvement. Furthermore, we provide an overview of these conditions, including background information and examples that require rapid identification, focusing on treatable conditions; that would be catastrophic if they are not recognized.
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http://dx.doi.org/10.3389/fped.2020.599861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841137PMC
January 2021

Acute Necrotizing Encephalopathy of Childhood: A Multicenter Experience in Saudi Arabia.

Front Pediatr 2020 9;8:526. Epub 2020 Oct 9.

Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

Acute necrotizing encephalopathy of childhood (ANEC) is a rapidly progressing encephalopathy characterized by fever, depressed level of consciousness, and seizures. Diagnosis depends on clinical presentation and characteristic neuroimaging findings of abnormal signal intensity involving the thalami as well as the supra and infra-tentorial areas. Treatment modalities are not well-established; empirical treatment with antibiotics and antiviral agents is the initial step, followed by steroids and immunoglobulin, as well as supportive care. Patients with ANEC have a variable prognosis, but mortality is very high. A retrospective chart review of patients diagnosed with ANEC in five tertiary centers from January 2015 to October 2018 was performed. Clinical and radiological findings, as well as the therapeutic approach and outcomes, were described. Twelve children were included ranging in age from 10 months to 6 years. All patients presented with preceding febrile illness, altered level of consciousness, and seizure. Radiological features showed abnormal signals in the thalami, and five patients (41.7%) had brainstem involvement. All patients received empirical treatment with antibiotics and antiviral agents. Ten patients (83.3%) received intravenous immunoglobulin (IVIG) and IV Methylprednisolone therapy. Outcomes were variable ranging from good outcomes with minimal neurological deficits to poor outcomes and death in 25% of cases. ANEC is a rare fulminant disease in children. The treatment is challenging. Early interventions with the use of IVIG and IV Methylprednisolone may change the outcome; however, further studies are needed to establish a consensus guideline for the management.
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http://dx.doi.org/10.3389/fped.2020.00526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581867PMC
October 2020

Epilepsy, neuropsychiatric phenotypes, neuroimaging findings, and genotype-neurophenotype correlation in 22q11.2 deletion syndrome.

Neurosciences (Riyadh) 2020 Aug;25(4):287-291

Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia.

Objective: To describe the epilepsy, neuropsychiatric manifestations, and neuroimaging findings in a group of patients with 22q11.2 DS, and to correlate the size of the deleted genetic material with the severity of the phenotype.

Methods: We retrospectively analyzed the medical records of 28 patients (21 pediatric patients and 7 adults) with a genetically confirmed diagnosis of 22q11.2 DS. Clinical data (epilepsy, neurological exam, neuropsychological and developmental assessment, and psychiatric disorders), neuroimaging, and cytogenetic tests were analyzed RESULTS: Of the 28 patients with 22q11.2 DS, 6 (21.4%) had epileptic seizures, 2 had symptomatic hypocalcemic seizures, 4 (14.2%) had a psychiatric disorder, which comprised of attention deficit hyperactivity disorder, autism spectrum disorder, psychosis, and mood disorder, and 17 (60.7%) had developmental delay. All patients with epilepsy had a developmental delay. Twelve patients underwent a neuropsychology assessment. Intellectual levels ranged from moderate intellectual disability (7/12, 58%) to average (5/12, 41.6%). Of the 16 patients, 6 (37.5%) had a normal brain, while 10 (62.5%) had abnormal neuroimaging findings. No significant correlation was found between the size of the deleted genetic material and the severity of the phenotype.

Conclusion: 22q11.2DS patients are at high risk to develop epilepsy, neuropsychiatric manifestations, and structural brain abnormalities. This indicates that this defined genetic locus is crucial for the development of the nervous system, and patients with 22q11.2 DS have genetic susceptibility to develop epilepsy.
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http://dx.doi.org/10.17712/nsj.2020.4.20200045DOI Listing
August 2020

Problem-solving in clinical practice: breathing difficulty and muscle weakness following allogeneic haematopoietic stem cell transplantation.

Arch Dis Child Educ Pract Ed 2020 Sep 8. Epub 2020 Sep 8.

Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia

Acute weakness and dyspnoea are unusual presentation after allogeneic haematopoietic stem cell transplantation (HSCT) complicated by chronic graft-versus-host disease (GVHD). The differential diagnosis and management are challenging for the paediatrician. This case chronicles the diagnostic journey of a child who presented with weakness, dyspnoea and difficulty in speech, 2 years after allogeneic HSCT and GVHD and explores the approach to neurological manifestations in this context.
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http://dx.doi.org/10.1136/archdischild-2019-317281DOI Listing
September 2020

Evaluation of adherence to pediatric status epilepticus management guidelines in Saudi Arabia.

Neurosciences (Riyadh) 2020 Jul;25(3):182-187

Division of Pediatric Neurology, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia.

Objective: To assess compliance with the 2017 Saudi pediatric status epilepticus management guidelines and to printout the main obstacle for adherence to the guidelines.

Methods: A cross sectional study conducted in September 2019, using electronic survey. The survey sent to all the Pediatric Emergency physicians practicing in Kingdom of Saudi Arabia (KSA) through emails and WhatsApp and the questionnaire based on clinical scenario written in English language.

Results: One hundred and three (70%) of 147 physicians working in KSA and covering pediatric emergency departments responded to the survey. Only 20% of the physicians reported full compliance to all 4 guideline components; 57% reported that they were not aware of the published guidelines.

Conclusion: Pediatric emergency physicians reported poor compliance to the 2017 published guidelines for the treatment of children with convulsive status epilepticus in KSA.
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http://dx.doi.org/10.17712/nsj.2020.3.20190106DOI Listing
July 2020

KCNT1-related epilepsy: An international multicenter cohort of 27 pediatric cases.

Epilepsia 2020 04 13;61(4):679-692. Epub 2020 Mar 13.

Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

Objective: Through international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1-related epilepsy and explored genotype-phenotype correlations associated with frequently encountered variants.

Methods: A cross-sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics.

Results: Twenty-seven children (15 males, mean age = 40.8 months) were included. Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two-thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray-white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%-50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement. When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy.

Significance: Our cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common. Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence-based practice is still unavailable.
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http://dx.doi.org/10.1111/epi.16480DOI Listing
April 2020

Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn screening.

Ann Clin Transl Neurol 2019 10 26;6(10):2097-2103. Epub 2019 Sep 26.

Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

Background: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder mostly presented in children. The disorder is described as having subacute encephalopathy with confusion, dystonia, and dysarthria triggered by febrile illness that leads to neuroregression and death if untreated. Using biotin and thiamine at an early stage of the disease can lead to significant improvement.

Methods: BTBGD is a treatable disease if diagnosed at an early age and has been frequently reported in Saudi population. Keeping this in mind, the current study screened 3000 Saudi newborns for the SLC19A3 gene mutations using target sequencing, aiming to determine the carrier frequency in Saudi Population and whether BTBGD is a good candidate to be included in the newborn-screened disorders.

Results: Using targeted gene sequencing, DNA from 3000 newborns Saudi was screened for the SLC19A3 gene mutations using standard methods. Screening of the SLC19A3 gene revealed a previously reported heterozygous missense mutation (c.1264A>G (p.Thr422Ala) in six unrelated newborns. No probands having homozygous pathogenic mutations were found in the studied cohort. The variant has been frequently reported previously in homozygous state in Saudi population, making it a hot spot mutation. The current study showed that the carrier frequency of SLC19A3 gene mutation is 1 of 500 in Saudi newborns.

Conclusion: For the first time in the literature, we determined the carrier frequency of SLC19A3 gene mutation in Saudi population. The estimated prevalence is too rare in Saudi population (at least one in million); therefore, the data are not in favor of including such very rare disorders in newborn screening program at population level. However, a larger cohort is needed for a more accurate estimate.
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http://dx.doi.org/10.1002/acn3.50898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801173PMC
October 2019

Metabolic and genetic disorders mimicking cerebral palsy.

Neurosciences (Riyadh) 2019 Jul;24(3):155-163

Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia.

Cerebral palsy is a syndrome that encompasses a large group of childhood movement and posture disorders that result from a lesion occurring in the developing brain. The clinical presentation of many metabolic and genetic conditions, particularly in highly consanguineous populations, can mimic cerebral palsy particularly at early age. The aim of this review article is to identify the clinical features that should alert the physician to the possibility of disorders that resemble cerebral palsy, the clinical and neuroimaging red flags, and highlight some metabolic and genetic conditions which may present with spasticity, ataxia and dyskinesia. In the case of metabolic or genetic disorder, making a precise diagnosis is particularly important for the possibility of treatment, accurate prognosis and genetic counseling.
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http://dx.doi.org/10.17712/nsj.2019.3. 20190045DOI Listing
July 2019

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.

Genet Med 2019 11 16;21(11):2521-2531. Epub 2019 May 16.

CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada.

Purpose: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established.

Methods: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease.

Results: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration.

Conclusion: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
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http://dx.doi.org/10.1038/s41436-019-0532-zDOI Listing
November 2019

The landscape of early infantile epileptic encephalopathy in a consanguineous population.

Seizure 2019 Jul 27;69:154-172. Epub 2019 Apr 27.

King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia. Electronic address:

Purpose: Epileptic encephalopathies (EE), are a group of age-related disorders characterized by intractable seizures and electroencephalogram (EEG) abnormalities that may result in cognitive and motor delay. Early infantile epileptic encephalopathies (EIEE) manifest in the first year of life. EIEE are highly heterogeneous genetically but a genetic etiology is only identified in half of the cases, typically in the form of de novo dominant mutations.

Method: This is a descriptive retrospective study of a consecutive series of patients diagnosed with EIEE from the participating hospitals. A chart review was performed for all patients. The diagnosis of epileptic encephalopathy was confirmed by molecular investigations in commercial labs. In silico study was done for all novel mutations. A systematic search was done for all the types of EIEE and their correlated genes in the literature using the Online Mendelian Inheritance In Man and PubMed databases.

Results: In this case series, we report 72 molecularly characterized EIEE from a highly consanguineous population, and review their clinical course. We identified 50 variants, 26 of which are novel, causing 26 different types of EIEE. Unlike outbred populations, autosomal recessive EIEE accounted for half the cases. The phenotypes ranged from self-limiting and drug-responsive to severe refractory seizures or even death.

Conclusions: We reported the largest EIEE case series in the region with confirmed molecular testing and detailed clinical phenotyping. The number autosomal recessive predominance could be explained by the society's high consanguinity. We reviewed all the EIEE registered causative genes in the literature and proposed a functional classification.
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http://dx.doi.org/10.1016/j.seizure.2019.04.018DOI Listing
July 2019

Distinct neuroimaging features of gene-related spastic paraplegia, a mimicker of cerebral palsy.

Arch Dis Child 2020 May 31;105(5):482. Epub 2019 Jan 31.

Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1136/archdischild-2018-316484DOI Listing
May 2020

Novel Homozygous Mutation of the AIMP1 Gene: A Milder Neuroimaging Phenotype With Preservation of the Deep White Matter.

Pediatr Neurol 2019 02 25;91:57-61. Epub 2018 Sep 25.

Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Electronic address:

Background: Mutations in AIMP1, which plays an important role in the development and maintenance of axon-cytoskeleton integrity and regulating neurofilaments, cause neurodegeneration of variable severity and white matter abnormalities.

Methods: From the patient records we analyzed the clinical evaluation, molecular genetics, neurodiagnostic, and neuroradiological investigations.

Results: We describe six members of a large consanguineous family with a phenotype of severe neurodegeneration in the form of developmental delays, progressive microcephaly, epilepsy, and failure to thrive. MRI showed callosal atrophy and T2 hyperintensity in the superficial white matter. The periventricular and deep white matter structures were, however, preserved. MR spectroscopy demonstrated N-acetylaspartate preservation without evidence of neuroinflammation. Exome sequencing showed a novel homozygous mutation of the AIMP1 gene in all individuals: c.917A>G (p.(Asp306Gly)).

Conclusions: This novel homozygous mutation of the AIMP1 gene is characterized by preserved development of the periventricular and deep white matter structures as demonstrated by MRI and MR spectroscopy correlation.
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http://dx.doi.org/10.1016/j.pediatrneurol.2018.09.010DOI Listing
February 2019

Embryopathy Associated With a Vitamin Therapy.

Pediatr Neurol 2018 12 4;89:73-74. Epub 2018 Aug 4.

Department of Radiology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1016/j.pediatrneurol.2018.07.012DOI Listing
December 2018

Autozygome and high throughput confirmation of disease genes candidacy.

Genet Med 2019 03 21;21(3):736-742. Epub 2018 Sep 21.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Purpose: Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases.

Methods: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines.

Results: We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders.

Conclusions: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.
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http://dx.doi.org/10.1038/s41436-018-0138-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752307PMC
March 2019

Genomic and phenotypic delineation of congenital microcephaly.

Genet Med 2019 03 14;21(3):545-552. Epub 2018 Sep 14.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM.

Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis.

Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1.

Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.
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http://dx.doi.org/10.1038/s41436-018-0140-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986385PMC
March 2019

FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance.

Mol Genet Metab 2018 11 29;125(3):281-291. Epub 2018 Jul 29.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address:

An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.
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http://dx.doi.org/10.1016/j.ymgme.2018.07.014DOI Listing
November 2018

Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy.

Brain Dev 2018 Oct 9;40(9):827-829. Epub 2018 Jun 9.

Divisions of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Electronic address:

Introduction: SLC13A5-related epileptic encephalopathy is a recently described autosomal recessive disorder that is characterized by infantile epilepsy and developmental delay. Seizures are markedly drug resistant and often induced by fever; they mainly occur in clusters, sometimes evolving into status epilepticus.

Methods And Results: We report the use of stiripentol as an adjunctive therapy in three siblings with drug-resistant SLC13A5-related epilepsy. The three patients showed remarkable improvement in the severity and frequency of seizures, status epilepticus, emergency department visits, and alertness.

Conclusion: These observations extend the use of stiripentol beyond the classical Dravet syndrome, and further studies on the use of this drug in drug-resistant epilepsy, mainly of genetic origin, are warranted.
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http://dx.doi.org/10.1016/j.braindev.2018.05.020DOI Listing
October 2018

Neurometabolic disorders and congenital malformations of the central nervous system.

Neurosciences (Riyadh) 2018 Apr;23(2):97-103

Divisions of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City,Riyadh, Kingdom of Saudi Arabia.

Both malformations of the central nervous system and neurometabolic disorders are common, mainly in highly consanguineous populations. Both metabolic pathways and developmental pathways are closely related and interact with each other. Neurometabolic disorders can lead to disturbances in brain development through multiple mechanisms that include deficits in energy metabolism, critical nutrient deficiency, accumulation of neurotoxic substrates, abnormality in cell membrane constituents, and interference in cell-to-cell signaling pathways. The anomalies observed include absent or hypoplastic corpus callosum, midline brain defects, and malformations of the cortex, the cerebellum and the brain stem. Early diagnosis of an underlying inherited neurometabolic disorders is critical for the institution of treatment, which may positively influence prognosis, and allow for proper genetic counseling. In this review, we discuss those disorders in which the structural brain malformation is a dominant feature, and propose a practical approach that will permit a physician to investigate, and treat these disorders.
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http://dx.doi.org/10.17712/nsj.2018.2.20170481DOI Listing
April 2018

PRUNE Syndrome Is a New Neurodevelopmental Disorder: Report and Review.

Child Neurol Open 2018 11;5:2329048X17752237. Epub 2018 Jan 11.

Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

PRUNE syndrome, or neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (OMIM#617481), is a new rare autosomal recessive neurodevelopmental disease that is caused by homozygous or compound heterozygous mutation in on chromosome 1q21. Here, We report on 12-month-old and 30-month-old girls from 2 unrelated Saudi families with typical presentations of PRUNE syndrome. Both patients had severe developmental delay, progressive microcephaly, and dysmorphic features. Brain magnetic resonance imaging showed slight thinning in the corpus callosum, mild frontal brain atrophy, and delayed myelination in one of the patients. Both patients had the same missense mutation in (c.383G>A, p.Arg128Gln), which was not reported before in a homozygous state. We compared our patients to previously reported cases. In conclusion, We suggest that clinicians consider PRUNE syndrome in any child presenting with dysmorphic features, developmental delay, progressive microcephaly, central hypotonia, peripheral spasticity, delayed myelination, brain atrophy, and a thin corpus callosum.
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http://dx.doi.org/10.1177/2329048X17752237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768269PMC
January 2018

Neuroregression, coarse features, and oligosaccharides in urines.

Neurosciences (Riyadh) 2017 10;22(4):325-327

Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946386PMC
http://dx.doi.org/10.17712/nsj.2017.4.20170193DOI Listing
October 2017

SLC19A3 Gene Defects Sorting the Phenotype and Acronyms: Review.

Neuropediatrics 2018 04 29;49(2):83-92. Epub 2017 Sep 29.

Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

Thiamine metabolism dysfunction syndrome type 2 is also known by other terms including: " gene defect," "biotin-responsive basal ganglia disease" (BBGD), and "biotin-thiamine-responsive basal ganglia disease" (BTBGD). The worldwide incidence and prevalence of this disorder are unknown, but the syndrome has primarily been reported in Saudi Arabia (52% of reported cases). It is caused by a defect in thiamine transporter 2 (hTHTR2), which is encoded by the gene. The clinical presentations of these syndromes are heterogeneous and are likely related to the age of onset. They can be classified into three major categories: classical childhood BBGD; early-infantile Leigh-like syndrome/atypical infantile spasms; and adult Wernicke's-like encephalopathy. These variable phenotypes have common features in that all are triggered by stressors, such as fever, trauma, or vaccinations. Affected brain areas include the basal ganglia, cerebral cortex, thalamus, and periaqueductal regions. Free thiamine is a potential biomarker for diagnosis and monitoring of treatment. Definitive diagnosis is usually made by molecular testing for the gene defect, and treatment consists of thiamine alone or in combination with biotin for life. In this report, we review all reported cases of the gene defect, discuss the history, epidemiology, metabolic pathways, clinical phenotypes, biochemical abnormalities, brain pathology, diagnosis, genetic issues, and treatment of this devastating disorder. Finally, we recommend instituting an international registry to further the basic scientific and clinical research to elucidate multiple unanswered questions about gene syndromes.
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http://dx.doi.org/10.1055/s-0037-1607191DOI Listing
April 2018

Expanding the genetic heterogeneity of intellectual disability.

Hum Genet 2017 11 22;136(11-12):1419-1429. Epub 2017 Sep 22.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.
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http://dx.doi.org/10.1007/s00439-017-1843-2DOI Listing
November 2017

Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors.

Ann Neurol 2017 Sep 30;82(3):317-330. Epub 2017 Aug 30.

Division of Child Neurology, Sant Joan de Déu Hospital, University of Barcelona, Barcelona, Spain.

Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317-330.
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http://dx.doi.org/10.1002/ana.24998DOI Listing
September 2017

Congenital disorders of glycosylation: The Saudi experience.

Am J Med Genet A 2017 Oct 25;173(10):2614-2621. Epub 2017 Jul 25.

Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

We retrospectively reviewed Saudi patients who had a congenital disorder of glycosylation (CDG). Twenty-seven Saudi patients (14 males, 13 females) from 13 unrelated families were identified. Based on molecular studies, the 27 CDG patients were classified into different subtypes: ALG9-CDG (8 patients, 29.5%), ALG3-CDG (7 patients, 26%), COG6-CDG (7 patients, 26%), MGAT2-CDG (3 patients, 11%), SLC35A2-CDG (1 patient), and PMM2-CDG (1 patient). All the patients had homozygous gene mutations. The combined carrier frequency of CDG for the encountered founder mutations in the Saudi population is 11.5 per 10,000, which translates to a minimum disease burden of 14 patients per 1,000,000. Our study provides comprehensive epidemiologic information and prevalence figures for each of these CDG in a large cohort of congenital disorder of glycosylation patients.
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http://dx.doi.org/10.1002/ajmg.a.38358DOI Listing
October 2017

Pediatric acute transverse myelitis.

Neurosciences (Riyadh) 2017 07;22(3):233-234

Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia. E-mail:

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946371PMC
http://dx.doi.org/10.17712/nsj.2017.3.20170294DOI Listing
July 2017

The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.

Authors:
Dorota Monies Mohamed Abouelhoda Moeenaldeen AlSayed Zuhair Alhassnan Maha Alotaibi Husam Kayyali Mohammed Al-Owain Ayaz Shah Zuhair Rahbeeni Mohammad A Al-Muhaizea Hamad I Alzaidan Edward Cupler Saeed Bohlega Eissa Faqeih Maha Faden Banan Alyounes Dyala Jaroudi Ewa Goljan Hadeel Elbardisy Asma Akilan Renad Albar Hesham Aldhalaan Shamshad Gulab Aziza Chedrawi Bandar K Al Saud Wesam Kurdi Nawal Makhseed Tahani Alqasim Heba Y El Khashab Hamoud Al-Mousa Amal Alhashem Imaduddin Kanaan Talal Algoufi Khalid Alsaleem Talal A Basha Fathiya Al-Murshedi Sameena Khan Adila Al-Kindy Maha Alnemer Sami Al-Hajjar Suad Alyamani Hasan Aldhekri Ali Al-Mehaidib Rand Arnaout Omar Dabbagh Mohammad Shagrani Dieter Broering Maha Tulbah Amal Alqassmi Maisoon Almugbel Mohammed AlQuaiz Abdulaziz Alsaman Khalid Al-Thihli Raashda A Sulaiman Wajeeh Al-Dekhail Abeer Alsaegh Fahad A Bashiri Alya Qari Suzan Alhomadi Hisham Alkuraya Mohammed Alsebayel Muddathir H Hamad Laszlo Szonyi Faisal Abaalkhail Sulaiman M Al-Mayouf Hamad Almojalli Khalid S Alqadi Hussien Elsiesy Taghreed M Shuaib Mohammed Zain Seidahmed Ibraheem Abosoudah Hana Akleh Abdulaziz AlGhonaium Turki M Alkharfy Fuad Al Mutairi Wafa Eyaid Abdullah Alshanbary Farrukh R Sheikh Fahad I Alsohaibani Abdullah Alsonbul Saeed Al Tala Soher Balkhy Randa Bassiouni Ahmed S Alenizi Maged H Hussein Saeed Hassan Mohamed Khalil Brahim Tabarki Saad Alshahwan Amira Oshi Yasser Sabr Saad Alsaadoun Mustafa A Salih Sarar Mohamed Habiba Sultana Abdullah Tamim Moayad El-Haj Saif Alshahrani Dalal K Bubshait Majid Alfadhel Tariq Faquih Mohamed El-Kalioby Shazia Subhani Zeeshan Shah Nabil Moghrabi Brian F Meyer Fowzan S Alkuraya

Hum Genet 2017 08 9;136(8):921-939. Epub 2017 Jun 9.

Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.
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http://dx.doi.org/10.1007/s00439-017-1821-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502059PMC
August 2017