Aromatic L-amino acid decarboxylase deficiency in countries in the Middle East: a case series and literature review.

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.

Expansion of the clinical and molecular spectrum of WWOX-related epileptic encephalopathy.

WWOX biallelic loss-of-function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX-related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

Case report: First case report of an Emirati child with a novel gene variant causing aromatic L-amino acid decarboxylase deficiency.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, neurometabolic disorder resulting from biallelic mutations in the dopa decarboxylase (DDC) gene. This is the first reported case of AADC deficiency in the United Arab Emirates (UAE) and describes an Emirati male patient who presented in the first few months of life with a severe phenotype of global hypotonia, developmental delay and oculogyric crisis. Following whole exome sequencing, a novel homozygous mutation in the DDC gene (c.1144G>T, p.Val382Phe) was reported and the patient underwent further testing, after which a diagnosis of AADC deficiency was confirmed. This mutation has not been previously described, but the clinical phenotype and corresponding biochemical profile confirmed that it is a pathogenic variant. The patient is currently managed at a tertiary referral center in the UAE and is treated in accordance with published guidance on AADC deficiency, including the recommended medical therapy combined with multidisciplinary care from a team of specialists. Some symptomatic improvements have been reported but at 5 years of age the patient continues to exhibit profound developmental delay, oculogyric crisis and is prone to recurrent respiratory infections. In order to improve outcomes for patients with AADC deficiency in the Middle Eastern region, there is an urgent need to raise the index of clinical suspicion, particularly among primary care physicians, pediatricians, and pediatric neurologists, and to improve access to diagnostic testing. This is particularly relevant at the current time, given the ongoing development of potentially disease-modifying gene therapy for AADC deficiency.

Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency.

BACKGROUND: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. METHODS: Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. RESULTS: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1 and HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. CONCLUSION: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome.

VPS26C homozygous nonsense variant in two cousins with neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features.

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, and 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.

Homozygous loss-of-function variants of TASP1, a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies.

We report four unrelated children with homozygous loss-of-function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure-to-thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5-11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.Thr234Met), affecting the active site of the encoded enzyme, and the fourth had a homozygous nonsense variant, c.199 C>T (p.Arg67*). TASP1 encodes taspase 1 (TASP1), which is responsible for cleaving, thus activating, the lysine methyltransferases KMT2A and KMT2D, which are essential for histone methylation and transcription regulation. The consistency of the phenotype, the critical biological function of TASP1, the deleterious nature of the TASP1 variants, and the overlapping features with Wiedemann-Steiner and Kabuki syndromes respectively caused by pathogenic variants in KMT2A and KMT2D all support that TASP1 is a disease-related gene.

Mitochondrial dynamics: Biological roles, molecular machinery, and related diseases.

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.

West syndrome, developmental and epileptic encephalopathy, and severe CNS disorder associated with WWOX mutations.

Mutations in the WWOX gene have been reported in a number of patients with various neurological disorders including spino-cerebellar ataxia, intellectual disability, epilepsy, and epileptic encephalopathy. We aimed to study the clinical, electrographic, and imaging features of two new cases with WWOX mutations and compare them to previously reported cases with WWOX mutations. We assessed two unrelated children from two consanguineous families who had severe neurological disorder including early-onset spastic quadriplegia, profound developmental delay, epilepsy, and West syndrome. Based on whole-exome sequencing, we identified homozygous null mutations in WWOX in both children, and further addressed the genotype-phenotype correlation. In addition, we provide a detailed review of the previously reported cases of WWOX-related neurological disorders and compare them to the children in this report. The findings in this report expand the clinical phenotype associated with WWOX mutations and confirm a well characterised severe central nervous system disorder in association with biallelic null mutations in WWOX. This syndrome consists of profound psychomotor delay, early-onset spastic quadriplegia, and refractory epilepsy including epileptic encephalopathy, acquired microcephaly, and growth restriction. This can be associated with progressive brain atrophy, suggestive of neurodegeneration. Identification of this phenotype by clinicians may help with early diagnosis and appropriate genetic counselling.

ATP13A2 novel mutations causing a rare form of juvenile-onset Parkinson disease.

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.

B3GALNT2-Related Dystroglycanopathy: Expansion of the Phenotype with Novel Mutation Associated with Muscle-Eye-Brain Disease, Walker-Warburg Syndrome, Epileptic Encephalopathy-West Syndrome, and Sensorineural Hearing Loss.

Mutations in B3GALNT2, 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 B3GALNT2-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 B3GALNT2. 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 B3GALNT2-related dystroglycanopathy. In this report, we also provide a detailed review of previously reported cases with B3GALNT2-related dystroglycanopathy and compare them to our reported child. In addition, we study the genotype-phenotype correlation in these cases.

Pediatric Multiple Sclerosis in the United Arab Emirates: Characteristics From a Multicenter Study and Global Comparison.

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.

Compound heterozygous variants in the multiple PDZ domain protein (MPDZ) cause a case of mild non-progressive communicating hydrocephalus.

BACKGROUND: Congenital hydrocephalus (CH) results from the accumulation of excessive amounts of cerebrospinal fluid (CSF) in the brain, often leading to severe neurological impairments. However, the adverse effects of CH can be reduced if the condition is detected and treated early. Earlier reports demonstrated that some CH cases are caused by mutations in L1CAM gene encoding the neural cell adhesion molecule L1. On the other hand, recent studies have implicated the multiple PDZ domain (MPDZ) gene in some severe forms of CH, inherited in an autosomal recessive pattern. METHODS: In this study, whole-exome and Sanger sequencing were performed on a 9 months old Emirati child clinically diagnosed by CH. In addition, in silico, cellular, and molecular assays have been conducted to confirm pathogenicity of the identified variants and to establish disease mechanism. RESULTS: Whole exome sequencing revealed two compound heterozygous novel variants (c.394G > A and c.1744C > G) in the affected child within the MPDZ gene. Segregation analysis revealed that each of the parents is heterozygous for one of the two variants and therefore passed that variant to their child. The outcome of the in silico and bioinformatics analyses came in line with the experimental data, suggesting that the two variants are most likely disease causing. CONCLUSIONS: The compound heterozygous variants identified in this study are the most likely cause of CH in the affected child. The study further confirms MPDZ as a gene underlying some CH cases.

Correction to: Expanding the genetic heterogeneity of intellectual disability.

Variant nomenclature discrepancy was identified in the article.

17q23.2q23.3 de novo duplication in association with speech and language disorder, learning difficulties, incoordination, motor skill impairment, and behavioral disturbances: a case report.

BACKGROUND: Chromosomal rearrangements involving 17q23 have been described rarely. Deletions at 17q23.1q23.2 have been reported in individuals with developmental delay and growth retardation, whereas duplications at 17q23.1q23.2 appear to segregate with clubfoot. Dosage alterations in the TBX2 and TBX4 genes, located in 17q23.2, have been proposed to be responsible for the phenotypes observed in individuals with 17q23.1q23.2 deletions and duplications. In this report, we present the clinical phenotype of a child with a previously unreported de novo duplication at 17q23.2q23.3 located distal to the TBX2 and TBX4 region. CASE PRESENTATION: We report a 7.5-year-old boy with speech and language disorder, learning difficulties, incoordination, fine motor skill impairment, infrequent seizures with abnormal EEG, and behavior disturbances (mild self-inflicted injuries, hyperactivity-inattention, and stereotyped hand movements). Chromosomal microarray revealed a 2-Mb duplication of chromosome 17q23.2q23.3. Both parents did not have the duplication indicating that this duplication is de novo in the child. CONCLUSIONS: The duplicated region encompasses 16 genes. It is possible that increased dosage of one or more genes in this region is responsible for the observed phenotype. The TANC2 gene is one of the genes in the duplicated region.It encodes a member of the TANC (tetratricopeptide repeat, ankyrin repeat and coiled-coil containing) family which includes TANC1 and TANC2. These proteins are highly expressed in brain and play major roles in synapsis regulation. Hence, it is suggestive that TANC2 is the likely candidate gene responsible for the observed phenotype as an increased TANC2 dosage can potentially alter synapsis, resulting in neuronal dysfunction and the neurobehavioral phenotype observed in this child with 17q23.2q23.3 duplication.

Expanding the genetic heterogeneity of intellectual disability.

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.

A novel de novo mutation in DYNC1H1 gene underlying malformation of cortical development and cataract.

Mutations in DYNC1H1, the gene encoding the largest cytoplasmic dynein, have been associated with a wide spectrum of neurodegenerative disorders. In this study, we describe a child in whom a novel de novo likely pathogenic variant in the motor domain of DYCN1H1 was identified through whole exome sequencing. The affected child presented with severe neurological symptoms and more extensive cortical malformations compared to previously reported cases with mutations in this gene, including diffuse pachygyria-lissencephaly and bilateral symmetric subcortical gray matter heterotopia. A more distinct aspect of the phenotype in this child is the presence of cataract in infancy. So far, only acquired bilateral cataract in adulthood has been described in this disorder in a patient with a much milder neurological phenotype. These findings could extend the phenotype associated with defective DYNC1H1 and suggest a possible important role in human ocular development.

The recognition and treatment of autoimmune epilepsy in children.

There is emerging interest in autoimmune epilepsy, which represents a small but potentially treatable form of epilepsy. Most insights into autoimmune epilepsy derive from the recent descriptions of autoimmune encephalitis that takes two general forms: a focal encephalitis (such as limbic) or a diffuse encephalitis (such as anti-N-methyl-D-aspartate receptor [NMDAR] encephalitis). The features of autoimmune epilepsy include acute or subacute onset of seizures, usually in the context of encephalopathy, and inflammation of the central nervous system on testing cerebrospinal fluid or magnetic resonance imaging. Neuronal antibodies associated with autoimmune encephalitis and seizures in children include NMDAR, voltage-gated potassium channel complex, glycine receptor, γ-Aminobutyric acid type A receptor (GABA(A)R), γ-Aminobutyric acid type B receptor (GABA(B)R), and glutamic acid decarboxylase antibodies. These antibodies support the diagnosis of autoimmune epilepsy, but are not essential for diagnosis. When autoimmune epilepsy is suspected, first-line immune therapy with corticosteroids in addition to intravenous immunoglobulin or plasma exchange should be considered. Second-line therapy with rituximab or cyclophosphamide can be considered if the syndrome is severe. A response to immune therapy supports the diagnosis of autoimmune epilepsy. Neuronal antibodies are increasingly found in patients with focal epilepsy of unknown cause who do not have 'encephalitis'. Recent epidemiological studies support the link between epilepsy and autoimmune diseases. Future studies need to define the spectrum of autoimmune epilepsy and focus on early identification and treatment.