Heba Y. El Khashab

Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

Purpose:Molecular karyotyping has rapidly become the test of choice in patients with neurocognitive phenotypes, but studies of its clinical utility have largely been limited to outbred populations. In consanguineous populations, single-gene recessive causes of neurocognitive phenotypes are expected to account for a relatively high percentage of cases, thus diminishing the yield of molecular karyotyping. The aim of this study was to test the clinical yield of molecular karyotyping in the highly consanguineous population of Saudi Arabia.Methods:We have reviewed the data of 584 patients with neurocognitive phenotypes (mainly referred from pediatric neurology clinics), all evaluated by a single clinical geneticist.Results:At least 21% of tested cases had chromosomal aberrations that are likely disease-causing. These changes include both known and novel deletion syndromes. The higher yield of molecular karyotyping in this study as compared with the commonly cited 11% can be explained by our ability to efficiently identify single-gene disorders, thus enriching the samples that underwent molecular karyotyping for de novo chromosomal aberrations. We show that we were able to identify a causal mutation in 37% of cases on a clinical basis with the help of autozygome analysis, thus bypassing the need for molecular karyotyping.Conclusion:Our study confirms the clinical utility of molecular karyotyping even in highly consanguineous populations.Genet Med 17 9, 719–725.

A newly recognized autosomal recessive syndrome affecting neurologic function and vision

Genetic factors represent an important etiologic group in the causation of intellectual disability. We describe a Saudi Arabian family with closley related parents in which four of six children were affected by a congenital cognitive disturbance. The four individuals (aged 18, 16, 13, and 2 years when last examined) had motor and cognitive delay with seizures in early childhood, and three of the four (sparing only the youngest child) had progressive, severe cognitive decline with spasticity. Two affected children had ocular malformations, and the three older children had progressive visual loss. The youngest had normal globes with good functional vision when last examined but exhibited the oculodigital sign, which may signify a subclinical visual deficit. A potentially deleterious nucleotide change (c.1A>G; p.Met1Val) in the C12orf57 gene was homozygous in all affected individuals, heterozygous in the parents, and absent in an unaffected sibling and >350 normal individuals. This gene has no known function. This family manifests a autosomal recessive syndrome with some phenotypic variability that includes abnormal development of brain and eyes, delayed cognitive and motor milestones, seizures, and a severe cognitive and visual decline that is associated with a homozygous variant in a newly identified gene.

Novel copy number variants and major limb reduction malformation: Report of three cases

Limb reduction malformations are highly heterogeneous in their clinical presentation and so, predicting the underlying mutation on a clinical basis can be challenging. Molecular karyotyping is a powerful genomic tool that has quickly become the mainstay for the study of children with malformation syndromes. We describe three patients with major limb reduction anomalies in whom pathogenic copy number variants were identified on molecular karyotyping. These include a patient with hypoplastic phalanges and absent hallux bilaterally with de novo deletion of 11.9 Mb on 7p21.1–22.1 spanning 63 genes including RAC1, another patient with severe Holt–Oram syndrome and a large de novo deletion 2.2 Mb on 12q24.13–24.21 spanning 20 genes including TBX3 and TBX5, and a third patient with acheiropodia who had a nullizygous deletion of 102 kb on 7q36.3 spanning LMBR1. We discuss the potential of these novel genomic rearrangements to improve our understanding of limb development in humans.

Mutation in GM2A Leads to a Progressive Chorea-dementia Syndrome.

Background The etiology of many cases of childhood-onset chorea remains undetermined, although advances in genomics are revealing both new disease-associated genes and variant phenotypes associated with known genes. Methods We report a Saudi family with a neurodegenerative course dominated by progressive chorea and dementia in whom we performed homozygosity mapping and whole exome sequencing. Results We identified a homozygous missense mutation in GM2A within a prominent block of homozygosity. This mutation is predicted to impair protein function. Discussion Although discovered more than two decades ago, to date, only five patients with this rare form of GM2 gangliosidosis have been reported. The phenotype of previously described GM2A patients has been typified by onset in infancy, profound hypotonia and impaired volitional movement, intractable seizures, hyperacusis, and a macular cherry red spot. Our findings expand the phenotypic spectrum of GM2A mutation-positive gangliosidosis to include generalized chorea without macular findings or hyperacusis and highlight how mutations in neurodegenerative disease genes may present in unexpected ways.

A Study on Herpes Simplex Encephalitis in 18 Children, Including 3 Relapses

Background: Herpes Simplex Virus (HSV) is the most common cause of acute sporadic focal encephalitis. Early Diagnosis is, therefore, crucial for predicting outcome. Improved laboratory technology and improved neuroimaging accessibility have enhanced our ability to diagnose this condition. Aims: To assess the reliability of different investigative tools in diagnosing and subsequent management of herpes simplex encephalitis (HSE); as well as the impact of infection and its relapse on the outcome of a cohort of 18 children evaluated during a period of 13 years. Methods: This combined prospective and retrospective study describes the clinical, laboratory, electroencephalographic and diagnostic imaging studies; and outcome in a cohort of 18 children with HSE over a period of 13 years. It also details the clinical and diagnostic features of 3 patients who relapsed. Results: The commonest initial presenting symptoms and signs were fever (100%), seizures (72%) irritability (50%) and weakness/hemiparesis (39%). Cerebrospinal fluid (CSF) pleocytosis was found in 62%, red blood cells (RBCs) >10x10 6 /L in 81% and raised proteins (>0.59g/L) in 52%. Examination for herpes simplex virus (HSV) by polymerase chain reaction (PCR) was positive in 50% (6/12). Electroencephalographic changes were universally abnormal (17/17; 100%) and periodic lateralization discharges (PLEDS) were seen in 35% (6/17). During the acute stage (days 1-8 from symptom onset), magnetic resonance imaging (MRI) revealed abnormalities in 91% (10/11), cranial computed tomography (CT) in 50% (5/10) and single photon emission computed tomography (SPECT), within 3days from onset of symptoms) had significant association with poor outcome (P = 0.002). Initial negative PCR results may become positive on subsequent CSF specimen. Conclusion: Diagnosis of HSE requires combined clinical, laboratory, electroencephalographic and neuroimaging studies. Negative results of PCR do not exclude the infection and should not interrupt the treatment. Early diagnosis and initiation of treatment minimize the devastating effect of HSE. Full course treatment with acyclovir for 21 days is also crucial for prognosis and prevention of subsequent relapse.

Auto-immune anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis: three case reports

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a recently identified auto-immune disorder characterised by severe memory deficit, a decreased level of consciousness, seizures, autonomic dysfunction and movement disorders. Three girls with the disorder are reported; they were aged 4 years, 5 years and 10 months. The 10-month-old infant who is one of the youngest patients reported with anti-NMDAR encephalitis worldwide, had MRI features suggestive of herpes simplex encephalitis (known to trigger anti-NMDAR encephalitis), but CSF PCR for herpes simplex was negative. All the patients presented with seizures, behavioural change, regression of speech, dystonia and choreo-athetosis. Anti-NMDAR antibodies were detected in all patients’ sera and cerebrospinal fluid (CSF). Intravenous immunoglobulin, corticosteroids and rituximab were administered at different intervals. Cases 1 and 2 made a full recovery, but case 3 has mild motor and speech delay. Patients who present with encephalopathy, seizures and movement disorders should be tested for anti-NMDAR antibodies in serum and CSF in addition to being screened for herpes simplex encephalitis.

Duane retraction syndrome in a patient with Duchenne muscular dystrophy

ABSTRACT Purpose: We describe the clinical features of a boy with bilateral Duane retraction syndrome (DRS), Duchenne muscular dystrophy (DMD), and other medical problems. Methods: The child was followed-up for five years; his chart was reviewed, including the results of a muscle biopsy and genetic testing. Multiplex ligation-dependent probe amplification (MLPA) was used to interrogate deletions/duplications in the dystrophin gene. Results: The proband had bilateral DRS with otherwise normal ocular motility; he also had developmental delay, mild mental retardation, and seizures. Clinical diagnosis of DMD included progressive proximal weakness, highly elevated creatine kinase levels, and a muscle biopsy showing significant dystrophic changes including contracted, degenerative, and regenerative fibers, and negative dystrophin immunostaining. MLPA documented duplication of exons 3 and 4 of the dystrophin gene. Conclusions: This boy is the third patient to be reported with DRS and DMD, the second with bilateral DRS and the only one with other neurologic features. Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS) in DMD, leaving open the question of whether this co-occurrence is the result of the genetic muscle abnormality, CNS effects caused by dystrophin mutations, or chance.