Characterising the refractive error in paediatric patients with congenital stationary night blindness: a multicentre study

BACKGROUND/AAIMS: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression. METHODS: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated. RESULTS: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively. CONCLUSIONS: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia

Hydrogenation of geraniol and related compounds. --.

The terpenes constitute an important group amongst the naturally occurring organic compounds. They vary greatly in nature and character and a very large number of them are still of unknown constitution. An interesting number of these compounds have been termed terpene aliphatic alcohols. They are comparatively small in number and although non-cyclic in nature, they are closely related to cyclic compounds and prone to cyclize under certain conditions. [...] Their general structure and chemical properties have been fairly thoroughly investigated but the question of their isomeric structures has not yet been definitely settled. A brief historical review of the chemistry of the primary aliphatic terpene alcohols, namely, geraniol and citronellol, will be given. The attention attached to these compounds is largely due to their importance in the perfumery trade. Geraniol is a colourless liquid of sweet odour, recalling that of rose and pelargonium. It is found in the free state and also in the form of its esters in a large number of essential oils. Most of the work done on its occurrence was carried out in the last decade of the nineteenth century. It was found to be a constituent of palmarosa, Bulgarian and Turkish rose oils, geranium oils, citronella oils, lemongrass oil, linaloe oil, nutmeg oil, sassafras oil, petigrain oil, lavender oil and in smaller quantities in a large number of other oils. [...

Anointing Chemicals and Hematophagous Arthropods: Responses by Ticks and Mosquitoes to Citrus (Rutaceae) Peel Exudates and Monoterpene Components

Some birds and mammals roll on or wipe themselves with the fruits or leaves of Citrus spp. or other Rutaceae. These anointing behaviors, as with anointing in general, are thought to function in the topical acquisition of chemicals that deter consumers, including hematophagous arthropods. We measured avoidance and other responses by nymphal lone star ticks (Amblyomma americanum) and adult female yellow fever mosquitoes (Aedes aegypti) to lemon peel exudate and to 24 volatile monoterpenes (racemates and isomers), including hydrocarbons, alcohols, aldehydes, acetates, ketones, and oxides, present in citrus fruits and leaves in order to examine their potential as arthropod deterrents. Ticks allowed to crawl up vertically suspended paper strips onto a chemically treated zone avoided the peel exudate and geraniol, citronellol, citral, carveol, geranyl acetate, α-terpineol, citronellyl acetate, and carvone. Ticks confined in chemically treated paper packets subsequently were impaired in climbing and other behaviors following exposure to the peel exudate and, of the compounds tested, most impaired to carveol. Mosquitoes confined in chambers with chemically treated feeding membranes landed and fed less, and flew more, when exposed to the peel exudate than to controls, and when exposed to aldehydes, oxides, or alcohols versus most hydrocarbons or controls. However, attraction by mosquitoes in an olfactometer was not inhibited by either lemon peel exudate or most of the compounds we tested. Our results support the notion that anointing by vertebrates with citrus-derived chemicals deters ticks. We suggest that some topically applied compounds are converted into more potent arthropod deterrents when oxidized on the integument of anointed animals

HACE1 deficiency leads to structural and functional neurodevelopmental defects

Objective We aim to characterize the causality and molecular and functional underpinnings of HACE1 deficiency in a mouse model of a recessive neurodevelopmental syndrome called spastic paraplegia and psychomotor retardation with or without seizures (SPPRS). Methods By exome sequencing, we identified 2 novel homozygous truncating mutations in HACE1 in 3 patients from 2 families, p.Q209{*} and p.R332{*}. Furthermore, we performed detailed molecular and phenotypic analyses of Hace1 knock-out (KO) mice and SPPRS patient fibroblasts. Results We show that Hace1 KO mice display many clinical features of SPPRS including enlarged ventricles, hypoplastic corpus callosum, as well as locomotion and learning deficiencies. Mechanistically, loss of HACE1 results in altered levels and activity of the small guanosine triphosphate (GTP)ase, RAC1. In addition, HACE1 deficiency results in reduction in synaptic puncta number and long-term potentiation in the hippocampus. Similarly, in SPPRS patient-derived fibroblasts, carrying a disruptive HACE1 mutation resembling loss of HACE1 in KO mice, we observed marked upregulation of the total and active, GTP-bound, form of RAC1, along with an induction of RAC1-regulated downstream pathways. Conclusions Our results provide a first animal model to dissect this complex human disease syndrome, establishing the first causal proof that a HACE1 deficiency results in decreased synapse number and structural and behavioral neuropathologic features that resemble SPPRS patients

Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development

Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations.

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development