Frizzle Frazzled

An otherwise healthy 12-year-old boy originally from Palestine was referred for refractory papilledema secondary to familial IIH. He has a history of fully accommodative esotropia with onset age 2-3. At age 9, elevated optic nerves prompted a neuro-ophthalmic referral. Best corrected visual acuities were subnormal at 20/60 OU. Optic disc drusen were confirmed on fundus autofluorescence but superimposed by papilledema with obscuration of the retinal vessels OD>OS. MRI findings were consistent with elevated intracranial pressure (Figure 1). Lumber puncture showed normal spinal fluid constituents and an opening pressure of 24 cm H2O. He was diagnosed with familial idiopathic intracranial hypertension because his 9-year-old sister presented at the same time with similar neuro-ophthalmic findings and headaches that resolved after lumbar puncture. Oral acetazolamide 375 mg TID (15 mg/kg/day) improved the optic nerve appearance and his visual acuity on follow up. Subsequently, gains in visual acuity reverted to baseline, and his disc appearance worsened. OCT of the macula showed abnormal foveal contour and intraretinal fluid, felt consistent with refractory papilledema. Repeat opening pressure read 26 cm H2O. A second opinion was obtained for consideration of optic nerve sheath fenestration. Subnormal visual acuities of 20/50 OD and 20/40 OS with best correction of +14.00sphere OD and +13.25+0.50x090 OS were noted. Goldmann perimetry showed constricted fields OU with an enlarged blind spot OD and a superonasal defect OS (Figure 2). Examination showed normal anterior segments, 2+ vitreous cells, and nerve fiber layer thickening with blurred optic disc margins and blunted foveal reflexes OU (Figure 3). Scattered, faint tessellated pigmentary changes were noted throughout the mid-peripheral retinae. The patient was discontinued from acetazolamide under consideration of an alternative diagnosis. Fluorescein angiography subsequently showed no leakage from the optic nerve heads but window defects in the inferonasal mid-periphery. A confirmatory diagnostic test was obtained

Frizzle Frazzled

An otherwise healthy 12-year-old boy originally from Palestine was referred for refractory papilledema secondary to familial IIH. He has a history of fully accommodative esotropia with onset age 2-3. At age 9, elevated optic nerves prompted a neuro-ophthalmic referral. Best corrected visual acuities were subnormal at 20/60 OU. Optic disc drusen were confirmed on fundus autofluorescence but superimposed by papilledema with obscuration of the retinal vessels OD>OS. MRI findings were consistent with elevated intracranial pressure (Figure 1). Lumber puncture showed normal spinal fluid constituents and an opening pressure of 24 cm H2O. He was diagnosed with familial idiopathic intracranial hypertension because his 9-year-old sister presented at the same time with similar neuro-ophthalmic findings and headaches that resolved after lumbar puncture. Oral acetazolamide 375 mg TID (15 mg/kg/day) improved the optic nerve appearance and his visual acuity on follow up. Subsequently, gains in visual acuity reverted to baseline, and his disc appearance worsened. OCT of the macula showed abnormal foveal contour and intraretinal fluid, felt consistent with refractory papilledema. Repeat opening pressure read 26 cm H2O. A second opinion was obtained for consideration of optic nerve sheath fenestration. Subnormal visual acuities of 20/50 OD and 20/40 OS with best correction of +14.00sphere OD and +13.25+0.50x090 OS were noted. Goldmann perimetry showed constricted fields OU with an enlarged blind spot OD and a superonasal defect OS (Figure 2). Examination showed normal anterior segments, 2+ vitreous cells, and nerve fiber layer thickening with blurred optic disc margins and blunted foveal reflexes OU (Figure 3). Scattered, faint tessellated pigmentary changes were noted throughout the mid-peripheral retinae. The patient was discontinued from acetazolamide under consideration of an alternative diagnosis. Fluorescein angiography subsequently showed no leakage from the optic nerve heads but window defects in the inferonasal mid-periphery. A confirmatory diagnostic test was obtained

Frizzle Frazzled

An otherwise healthy 12-year-old boy originally from Palestine was referred for refractory papilledema secondary to familial IIH. He has a history of fully accommodative esotropia with onset age 2-3. At age 9, elevated optic nerves prompted a neuro-ophthalmic referral. Best corrected visual acuities were subnormal at 20/60 OU. Optic disc drusen were confirmed on fundus autofluorescence but superimposed by papilledema with obscuration of the retinal vessels OD>OS. MRI findings were consistent with elevated intracranial pressure (Figure 1). Lumber puncture showed normal spinal fluid constituents and an opening pressure of 24 cm H2O. He was diagnosed with familial idiopathic intracranial hypertension because his 9-year-old sister presented at the same time with similar neuro-ophthalmic findings and headaches that resolved after lumbar puncture. Oral acetazolamide 375 mg TID (15 mg/kg/day) improved the optic nerve appearance and his visual acuity on follow up. Subsequently, gains in visual acuity reverted to baseline, and his disc appearance worsened. OCT of the macula showed abnormal foveal contour and intraretinal fluid, felt consistent with refractory papilledema. Repeat opening pressure read 26 cm H2O. A second opinion was obtained for consideration of optic nerve sheath fenestration. Subnormal visual acuities of 20/50 OD and 20/40 OS with best correction of +14.00sphere OD and +13.25+0.50x090 OS were noted. Goldmann perimetry showed constricted fields OU with an enlarged blind spot OD and a superonasal defect OS (Figure 2). Examination showed normal anterior segments, 2+ vitreous cells, and nerve fiber layer thickening with blurred optic disc margins and blunted foveal reflexes OU (Figure 3). Scattered, faint tessellated pigmentary changes were noted throughout the mid-peripheral retinae. The patient was discontinued from acetazolamide under consideration of an alternative diagnosis. Fluorescein angiography subsequently showed no leakage from the optic nerve heads but window defects in the inferonasal mid-periphery. A confirmatory diagnostic test was obtained

OR33-07 ARNT2: a potential novel candidate gene for monogenic obesity in humans

Introduction: Aryl hydrocarbon nuclear translocator 2 (ARNT2) is a basic helix-loop-helix (bHLH)-PAS (Per/Arnt/Sim) transcription factor shown to be critical to the development of paraventricular nucleus of the hypothalamus (PVN), key region for energy homeostasis and feeding response. In vivo and in vitro studies have shown that ARNT2 is an obligate heterodimer for SIM1, known cause of monogenic obesity. Null mutations in Arnt2 in animals are not viable, but hypomorphic mutation results in hyperphagic obesity and its associated consequences (1). Due to the critical role of ARNT2 in the development of PVN, we hypothesize that hypomorphic mutations may result in early onset obesity in humans.Methods: The Genetics of Early Childhood Obesity (GECO) study recruits children with severe obesity (BMI > 120% of 95th percentile) of early onset (< 6 years). Whole exome sequencing (WES) was performed in a subset of proband-parent trios. The functional validation of the mutation(s) in ARNT2 is ongoing with co-transfection of tagged Arnt2 and Sim1 in HEK293 cells, with the induction of a luciferase reporter gene under the control of 6 repeats of bHLH-PAS core binding element by the Arnt2-Sim1 complex.Results: Two adolescents from unrelated families were found to have genetic variants in ARNT2. Subject 1 has a novel de novo heterozygous coding variant in ARNT2, c.388 C>G (p.P130A, CADD 25), predicted to be deleterious by 8/12 in silico algorithms. She is a 14-year old Caucasian girl with severe early onset obesity, BMI 28.1 kg/m2 (BMIz +4.72) at 2.5 years of age that has increased to 53.54 kg/m2 (BMIz + 3.25) at 14-years, and height > 95th %tile. She is non-dysmorphic, has developmental delay, absence seizures, behavior abnormalities & glucose intolerance/dyslipidemia secondary to obesity. Using genematcher, we identified another proband with the phenotype of obesity: an African American girl (BMIz +1.9) with biallelic inherited heterozygous variants in ARNT2, c.1228T>A (p.W410R, CADD 29) and c.916G>A (p.G306S, CADD 22). An only child conceived by IVF, she is non-dysmorphic and on treatment for bilateral focal epilepsy. All 3 variants are rare, with mean allele frequency < 0.005 in population-based databases such as gNOMAD. Both the patients have early onset obesity and a significant neurological phenotype. ARNT2 is a highly constrained gene of 717 amino acids with a significant depletion of missense variants in the N-terminus (1-244 aa) and overall fewer loss of function variants in ~282,644 alleles sequenced in gNOMAD.CConclusions: We propose that hypomorphic mutations in ARNT2 could be a potential novel cause of monogenic obesity in humans. Future studies will investigate the molecular mechanisms causing weight dysregulation in patient specific disease relevant hypothalamic neurons.Reference: (1) Turer et al., Dis Model Mech. 2018; 11(12

Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities

Polyamines serve a number of vital functions in humans, including regulation of cellular proliferation, intracellular signaling, and modulation of ion channels. Ornithine decarboxylase 1 (ODC1) is the rate-limiting enzyme in endogenous polyamine synthesis. In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene. This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms. Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum. Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels. Therapies aimed at reducing putrescine levels, including ODC1 inhibitors, dietary interventions, and antibiotics to reduce polyamine production by gastrointestinal flora could be considered as disease-modifying therapies. As the ODC1 gene has been implicated in neoplasia, cancer surveillance may be important in this disorder

Genetic Study in a Cohort of Children With ROHHAD Syndrome

Abstract Introduction: Rapid-onset obesity, hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) is a rare syndrome beginning at 3-6 years of age with approximately 150 cases described. Additional features include eye abnormalities, neurobehavioral dysfunction and paraneoplastic tumors. The etiology of the complex phenotype remains unknown. Methods: This study aims to investigate the genetic landscape of this complex phenotype by whole exome sequencing (WES) and copy number variation (CNV) analysis. We recruited 33 families (27 trios, 1 duo and 5 singletons) with a proband with ROHHAD syndrome (Ize-Ludlow 2007, Pediatrics). WES of 89 individuals was performed at the Center for Mendelian Genomics, Broad Institute. The Illumina platform with a mean coverage of ~100X (&gt; 90% targets 20x) and Infinium Global Screening Array BeadChip 24v1.0 were used. Results: This report includes 28 probands (female = 18, 64%) with rapid onset obesity (100%), hypoventilation (88%), hypothalamic dysfunction (69%), eye disorders (62%) and neurobehavioral abnormalities (76%). Neuroendocrine tumor, ganglioneuroblastoma, was present in 38% (n=13). No unifying causative single gene or CNV was identified, but a number of sequence variants are prioritized. ARNT2, which encodes for a helix-loop-helix transcription factor, plays a role in the development of the hypothalamic-pituitary axis, postnatal brain growth, and visual and renal function. The de novo monoallelic missense variant was found in a 14-year old white girl (BMIz +3.25) with extreme obesity and a neurobehavioral phenotype. OCRL1, a multi-domain protein involved in cytoskeleton-plasma membrane adhesion, endosomal trafficking and in primary cilium assembly. Mutations in this gene have also been known to cause Lowe syndrome. A hemizygous X-linked frameshift variant in a 5-year old white boy with extreme obesity (BMIz +5.48), central hypoventilation neurobehavioral dysfunction and ganglioneuroblastoma. A monoallelic missense variant in NSD1, a transcriptional intermediary factor acting as a histone methyltransferase, was identified in a 8-year old Hispanic girl with severe obesity (BMIz +2.91), neurobehavioral disorder, pituitary and eye dysfunction and ganglioneuroblastoma. NSD1 is known to cause Sotos and Beckwith-Wiedemann. Compound heterozygous variants in KIF7, a key component of the Hedgehog signaling pathway, were identified in a 14-year old white girl with severe obesity (BMIz +3.00), autistic behavior, pituitary dysfunction and central hypoventilation. This gene is known to cause autosomal recessive hydrolethalis and acroscallosal syndromes with mutations also noted in Bardet-Biedl, Meckel and Joubert syndromes. Conclusion: While no unifying genetic cause has been identified in ROHHAD syndrome, it is possible that the phenotype represents a collection of complex genetic syndromes.</jats:p

Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders.

BACKGROUND We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. METHODS Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. RESULTS We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. CONCLUSIONS Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories

Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome

Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05). Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation