Jehan suleiman - Academia.edu (original) (raw)

Papers by Jehan suleiman

Frontiers in Pediatrics, Aug 30, 2022

Clinical Genetics, Dec 26, 2019

In this report we describe two cousins with cognitive impairment, growth failure, skeletal abnorm... more In this report we describe two cousins with cognitive impairment, growth failure, skeletal abnormalities, and distinctive facial features. Genome sequencing failed to identify variants in known disease-associated genes explaining the phenotype. Extended comprehensive analysis of the two affected cousins'genomes, however, revealed that both share the homozygous nonsense variant c.178G>T (p.Glu60*) in the VPS26C gene. This gene encodes VPS26C, a member of the retriever integral membrane protein recycling pathway. The potential vital biological role of VPS26C, the nature of the variant which is predicted to result in loss-of-function, expression studies revealing significant reduction in the mutant transcript, the co-segregation of the homozygous variant with the phenotype in two affected individuals all support that VPS26C is a novel gene associated with a previously unrecognized syndrome characterized by neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features.

Clinical Genetics, Jun 25, 2018

We present 3 children with homozygous null variants in the PPP1R21 gene. A 3‐year‐old girl had pr... more We present 3 children with homozygous null variants in the PPP1R21 gene. A 3‐year‐old girl had profound developmental delay, hypotonia and weakness, poor feeding, recurrent chest infections and respiratory failure, rotatory nystagmus, absent reflexes, and a homozygous nonsense variant c.2089C>T (p.Arg697*). A 2‐year‐old boy had profound developmental delay, weakness and hypotonia, recurrent chest infections and respiratory distress, undescended testes, rotatory nystagmus, hyporeflexia, and a homozygous nonsense variant c.427C>T (p.Arg143*). An 11‐year‐old girl with profound developmental delay, weakness and hypotonia, stereotypic movements, growth failure, hyporeflexia, and a homozygous frameshift variant c.87_88delAG (p.Gly30Cysfs*4). In addition, these children shared common facial features (thick eyebrows, hypertelorism, broad nasal bridge, short nose with upturned nasal tip and broad low‐hanging columella, thick lips, low‐set ears, and coarse facies with excessive facial hair), and brain abnormalities (cerebellar vermis hypoplasia, ventricular dilatation, and reduced white matter volume). Although PPP1R21 has not yet been linked to human disease, the consistency in the phenotype of individuals from unrelated families, the nature of the variants which result in truncated proteins, and the expected vital role for PPP1R21 in cellular function, all support that PPP1R21 is a novel disease‐associated gene responsible for the phenotype observed in these individuals.

Journal of Child Neurology, Apr 1, 2018

We delineate the clinical characteristics, incidence, and prevalence of pediatric-onset multiple ... more We delineate the clinical characteristics, incidence, and prevalence of pediatric-onset multiple sclerosis in Abu Dhabi, United Arab Emirates, from 2010 to 2014. Eighty-two patients (65% female) were identified. Fifty-three (64.6%) were Emiratis (45 from Abu Dhabi and 8 from 5 other emirates) and 29 were expatriates. Mean age of onset was 15.9 years overall, 15.3 years in males and 16.3 years in females. Patients with onset before age 12 years presented with visual symptoms while those with onset after age 12 years presented with a mixture of visual, motor and sensory symptoms. Interferon beta-1a was the most frequently used disease-modifying therapy (48%). In Abu Dhabi Emirati nationals, the age-and sex-adjusted prevalences were 26/100 000 for males and 36/100 000 for females. The total incidence in Emirati nationals from 2010 to 2014 was 2.3/100 000 for ages 10 to 14 years and 7.2/100 000 for ages 15 to 19 years. By comparison with international cohorts, the incidence of pediatric-onset multiple sclerosis in Abu Dhabi is higher whereas gender distribution is similar.

Neuropediatrics, May 23, 2018

Mutations in , encoding a glycosyltransferase enzyme involved in α-dystroglycan glycosylation, ha... more Mutations in , encoding a glycosyltransferase enzyme involved in α-dystroglycan glycosylation, have been recently associated with dystroglycanopathy, a well-recognized subtype of congenital muscular dystrophy (CMD). Only a few cases have been reported with -related dystroglycanopathy with variable severity ranging from mild CMD to severe muscle-eye-brain disease. Here, we describe a child with a novel homozygous nonsense mutation in . The affected child has severe neurological disease since birth, including muscle disease manifested as hypotonia, muscle weakness, and wasting with elevated creatine kinase, eye disease including microphthalmia and blindness, brain disease with extensive brain malformations including massive hydrocephalus, diffuse cobblestone-lissencephaly, deformed craniocervical junction, and pontocerebellar hypoplasia. The clinical and radiologic findings are compatible with a diagnosis of severe muscle-eye-brain disease and more specifically Walker-Warburg syndrome. A more distinct aspect of the clinical phenotype in this child is the presence of refractory epilepsy in the form of epileptic spasms, epileptic encephalopathy, and West syndrome, as well as sensorineural hearing loss. These findings could expand the phenotype of -related dystroglycanopathy. In this report, we also provide a detailed review of previously reported cases with -related dystroglycanopathy and compare them to our reported child. In addition, we study the genotype-phenotype correlation in these cases.

Brain & Development, Oct 1, 2018

Parkinson disease is a common neurodegenerative disease that typically starts around the age of 6... more Parkinson disease is a common neurodegenerative disease that typically starts around the age of 60 years; however, juvenile-onset disease can occur rarely. Although Parkinson disease is typically sporadic; in rare occasions, it can be caused by a single gene defect that is inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Herein, we describe a 10-year-old child who had juvenile-onset parkinsonism with rigidity, bradykinesia, dystonia, gait disturbance, and cognitive impairment. Whole exome sequencing showed compound heterozygosity for two previously unreported novel mutations in ATP13A2 (PARK9): a paternally inherited c.1321A>T (p.I441F) and a maternally inherited c.3205G>A (p.A1069T). ATP13A2 mutations are rare cause of autosomal recessive juvenile-onset Parkinson disease. Family co-segregation study and the clinical phenotype support that p.I441F and p. A1069T are indeed disease-causing mutations.

European Journal of Pediatrics, May 4, 2023

In the original published version of the above article, the DDC gene variant for patient 8 was in... more In the original published version of the above article, the DDC gene variant for patient 8 was incorrect in Fig. 4. This was given as c.245G > A; Homozygous; p.R82Q. This should be c.479G > A; Homozygous; p.R160Q. The text corresponding to Fig. 4 has also been corrected to "Six missense variants leading to a single amino acid substitution were reported for 12 patients across exons 2 (n = 1), 3 (n = 3), 5 (n = 1), 11 (n = 2) and 13 (n = 5)." The original article has been corrected.

European Journal of Pediatrics, Mar 16, 2023

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited neurometabolic disorder... more Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited neurometabolic disorder that can lead to severe physical and developmental impairment. This report includes 16 patients from the Middle East and is the largest series of patients with confirmed AADC deficiency from this region reported to date. The patients displayed a range of signs and symptoms at presentation and almost all failed to reach major motor milestones. Missed and delayed diagnoses were common leading to the late introduction of targeted treatments. Eight unique variants were identified in the DDC gene, including six missense and two intronic variants. A previously undescribed variant was identified: an intronic variant between exons 13 and 14 (c.1243-10A>G). The patients were mostly treated with currently recommended medications, including dopamine agonists, vitamin B6, and monoamine oxidase inhibitors. One patient responded well, but treatment outcomes were otherwise mostly limited to mild symptomatic improvements. Five patients had died by the time of data collection, confirming that the condition is associated with premature mortality. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age. Conclusions: Delays in the diagnosis of AADC deficiency are common. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age. What is Known: • Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disorder that can lead to severe physical and developmental impairment. • Currently recommended medications provide mostly mild symptomatic improvements. What is New: • The clinical presentation of sixteen patients with confirmed AADC deficiency varied considerably and almost all failed to reach major motor milestones. • There is an urgent need for earlier diagnosis, given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age.

Molecular Genetics and Metabolism, Dec 1, 2018

Mitochondria are dynamic organelles that undergo fusion, fission, movement, and mitophagy. These ... more Mitochondria are dynamic organelles that undergo fusion, fission, movement, and mitophagy. These processes are essential to maintain the normal mitochondrial morphology, distribution, and function. Mitochondrial fusion allows the exchange of intramitochondrial material, whereas the fission process is required to replicate the mitochondria during cell division, facilitate the transport and distribution of mitochondria, and allow the isolation of damaged organelles. Mitochondrial mobility is essential for mitochondrial distribution depending on the cellular metabolic demands. Mitophagy is needed for the elimination of dysfunctional and damaged mitochondria to maintain a healthy mitochondrial population. The mitochondrial dynamic processes are mediated by a number of nuclear-encoded proteins that function in mitochondrial transport, fusion, fission, and mitophagy. Disorders of mitochondrial dynamics are caused by pathogenic variants in the genes encoding these proteins. These diseases have a high clinical variability, and range in severity from isolated optic atrophy to lethal encephalopathy. These disorders include defects in mitochondrial fusion (caused by pathogenic variants in MFN2, OPA1, YME1L1, MSTO1, and FBXL4), mitochondrial fission (caused by pathogenic variants in DNM1L and MFF), and mitochondrial autophagy (caused by pathogenic variants in PINK1 and PRKN). In this review, the molecular machinery and biological roles of mitochondrial dynamic processes are discussed. Subsequently, the currently known diseases related to mitochondrial dynamic defects are presented.

European Journal of Paediatric Neurology, May 1, 2015

Background In patients with glycine receptor antibodies (GlyRAb), a range of neurological syndrom... more Background In patients with glycine receptor antibodies (GlyRAb), a range of neurological syndromes that includes Stiff Person Syndrome (SPS) and its more severe variant Progressive Encephalitis with Rigidity and Myoclonus (PERM) have recently been reported in a predominantly adult cohort (Carvajal-Gonzalez et al., Brain 2014;137(Pt 8):2178–92). Objectives To report the clinical features and outcome of children with GlyR-Ab. Methods Cases were identified from samples sent to the Nuffield Department of Clinical Neurology, Oxford for a range of neuronal surface antibody testing. Results Six girls with a mean age of 8 years (median 7.5; range 1–15) were identified (2 London, 1 Oxford, and 3 Australia). The children presented with refractory focal seizures (n=2), or cognitive/behavioural changes (n=4) of whom two had tremor and gait abnormalities and one features of PERM. During the course of the illness, seizures featured in 5 patients and cognitive/behavioural changes in all. Electroencephalogram (EEG) during the illness revealed features of encephalopathy (n=3) and focal/multifocal epileptiform discharges (n=2). Two children had early imaging features of brain inflammation, and in another 2, global atrophy were identified on serial imaging despite normal acute scans. GlyR-Abs were detected in the serum (n=6) and/or CSF (n=2). Co-occurrence of low levels ( Conclusions The paediatric phenotype is predominated by female sex, seizures, and, where PERM occurs, it is associated with additional features. The clinical relevance of GlyR antibodies needs to be determined, to help guide therapies.

Neurology, Apr 10, 2018

Developmental Medicine & Child Neurology, Dec 8, 2014

Epilepsia, Mar 28, 2013

SummaryPurposeAntibodies against neuronal surface proteins are increasingly recognized in autoimm... more SummaryPurposeAntibodies against neuronal surface proteins are increasingly recognized in autoimmune central nervous system (CNS) disorders in which seizures are the main or an important feature. The disorders include antibody‐associated limbic encephalitis and N‐methyl‐D‐aspartate receptor (NMDAR)encephalitis; however, seizures of autoimmune etiology may exist beyond the spectrum of these recognized syndromes. Because these seizures are potentially treatable with immune therapy, guidelines are needed to help in their early recognition.MethodsWe describe 13 representative children seen at our tertiary institution over a period of 3.5 years with suspected autoimmune epilepsy. Autoimmune epilepsy was suspected clinically when there was any of the following: (1) recognizable syndromes such as NMDAR encephalitis or limbic encephalitis, (2) evidence of CNS inflammation in cerebrospinal fluid or on magnetic resonance imaging (MRI), (3) the presence of other autoimmune diseases, or (4) positive response to immunotherapy. We tested these patients for neuronal surface antibodies (voltage gated potassium channel [VGKC]‐complex, leucine rich glioma inactivated 1 [LGI1], contactin‐associated protein‐like 2 [CASPR2], and NMDAR) and glutamic acid decarboxylase (GAD) antibodies. We modified the J Neurol Neurosurg Psychiatry, 83, 2012, 638 guidelines that were designed to classify adults with neuronal surface antibody syndromes (NSAS), to be more appropriate for children with suspected autoimmune epilepsy. Using the modified guidelines, the 13 patients were classified into definite, probable, possible, unlikely, or unknown autoimmune epilepsy according to the presence of neuronal surface or GAD antibodies, and the response to immune therapy when given.Key FindingsOf the 13 patients, 11 were females, and the mean age was 6 years (range 1–13 years). Three patients had classical NMDAR encephalitis, two had VGKC encephalitis, two had limbic encephalitis with negative antibodies, three had epilepsy with other autoimmune diseases (one with high titer GAD antibodies), two had fever‐induced refractory epileptic encephalopathy in school‐aged children (FIRES), and one epileptic encephalopathy associated with VGKC antibodies. Seven patients of the 13 children with suspected autoimmune epilepsy were positive for neuronal surface antibodies (NMDAR, n = 3; VGKC‐complex, n = 3; and GAD, n = 1). Immunotherapy was given to nine cases, and a positive response was more common in patients with positive neuronal surface antibodies (5/5) compared to those with negative antibodies (2/4). Applying the proposed guidelines, the classification of autoimmune epilepsy was definite in five, probable in one, possible in three, unlikely in two, and unknown in two patients.SignificanceNeuronal surface antibodies and GAD antibodies are present in a proportion of children with suspected autoimmune epilepsy and may define a treatable subgroup of childhood epilepsy. The proposed guidelines can be useful in the recognition of children with seizures of autoimmune etiology.

Journal of the Neurological Sciences, Oct 1, 2013

Clinical Genetics, Sep 7, 2017

The advancement in genomic sequencing has greatly improved the diagnostic yield for neurodevelopm... more The advancement in genomic sequencing has greatly improved the diagnostic yield for neurodevelopmental disorders and led to the discovery of large number of novel genes associated with these disorders. WDR45B has been identified as a potential intellectual disability gene through genomic sequencing of two large cohorts of affected individuals. In this report we present six individuals from three unrelated families with homozygous pathogenic variants in WDR45B: c.799C>T (p.Q267*) in one family and c.673C>T (p.R225*) in two families. These individuals shared a similar phenotype including profound development delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations. Neuroimaging showed ventriculomegaly, reduced cerebral white matter volume, and thinning of cerebral gray matter. The consistency in the phenotype strongly supports that WDR45B is associated with this disease.

Clinical Genetics, 2018

We report a 20p12.1 homozygous deletion including exons 5‐10 of the TASP1 gene in an infant with ... more We report a 20p12.1 homozygous deletion including exons 5‐10 of the TASP1 gene in an infant with developmental delay, acquired microcephaly, distinctive facial features, and multiple congenital anomalies involving skeletal, cardiac, and renal systems. TASP1 encodes taspase 1 which is responsible for cleaving, thus activating, a number of transcription factors including the mixed lineage leukemia 1 (MLL1). Taspase 1‐deficient mice showed early lethality, skeletal abnormalities, and growth failure, which support a potentially causal role of TASP1 deletion in this infant. Furthermore, the infant reported here had many of the features seen in Wiedemann‐Steiner syndrome which is caused by MLL1 defects. Such observation further supports that TASP1 is a novel disease‐related gene that is associated with a disease phenotype overlapping with Wiedemann‐Steiner syndrome as both are caused by defects in the same pathway.

European Journal of Pediatrics

American Journal of Medical Genetics Part A