Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.     

Idiopathic intracranial hypertension is not benign: a long-term outcome study

Idiopathic intracranial hypertension (IIH) primarily affects young obese females, and potentially causes visual loss and severe headache. The aim of this experiment is to examine relapse rate and long-term outcome in IIH patients. The methods involved in this experiment include a prospective controlled study of 18 newly diagnosed IIH patients followed for a mean observation period of 21.1 (±8.0) months. Treatment regime included diuretics, dietary recommendations and check-up visits at a dietician. Baseline and follow-up included neurological examination, detailed headache history and comprehensive neuro-ophthalmological examination, including fundus photography, Humphrey visual fields, and measurement of the retinal thickness (RT) and retinal nerve fiber layers (RNFL) by optical coherence tomography (OCT). Relapse was defined as recurrence of either: (1) papilledema or (2) symptoms and demonstrated raised ICP. The result of this experiment is that relapse was found in 28%. Visual function improved from baseline to follow-up and was generally favorable. In patients without relapse of papilledema RT and RNFL were significantly thinner than in healthy controls (p = 0.003 and 0.02), although atrophy was clinically detectable in only one patient. Headache was still present in 67% of the patients at follow-up. Headache was heterogenic and unrelated to relapse. After an initial reduction, weight increased again in the relapse group compared to reduced weight in the non-relapse group (p = 0.013). Thus, the conclusions drawn are that headache was persistent, difficult to classify, and equally represented in relapse and non-relapse patients. Headache was thus a poor marker of active disease. Relapse rate was high and clinically undetectable optic disc atrophy was discovered in apparently well treated IIH patients.     

Neural organization of afferent pathways from the stomatopod compound eye

Crustaceans and insects share many similarities of brain organization suggesting that their common ancestor possessed some components of those shared features. Stomatopods (mantis shrimps) are basal eumalacostracan crustaceans famous for their elaborate visual system, the most complex of which possesses 12 types of color photoreceptors and the ability to detect both linearly and circularly polarized light. Here, using a palette of histological methods we describe neurons and their neuropils most immediately associated with the stomatopod retina. We first provide a general overview of the major neuropil structures in the eyestalks lateral protocerebrum, with respect to the optical pathways originating from the six rows of specialized ommatidia in the stomatopod's eye, termed the midband. We then focus on the structure and neuronal types of the lamina, the first optic neuropil in the stomatopod visual system. Using Golgi impregnations to resolve single neurons we identify cells in different parts of the lamina corresponding to the three different regions of the stomatopod eye (midband and the upper and lower eye halves). While the optic cartridges relating to the spectral and polarization sensitive midband ommatidia show some specializations not found in the lamina serving the upper and lower eye halves, the general morphology of the midband lamina reflects cell types elsewhere in the lamina and cell types described for other species of Eumalacostraca.     

Late subsequent ocular morbidity in retinopathy of prematurity patients,with emphasis on visual loss caused by insidious ‘involutive’ pathology: an observational series

Purpose: This paper discusses late complications in eyes of surviving premature infants typically occurring years into the steady state attained after the initial ophthalmic events associated with preterm birth. The study focuses on insidious visual loss, as well as eventual vitreoretinal and anterior segment disorders. Methods: We carried out a retrospective uncontrolled study of a case series (n = 31) of late complications to early ocular changes associated with very preterm delivery. The birth years of our subjects extended back to 1941, but only 15 more recent cases fulfilled contemporary criteria for a diagnosis of retinopathy of prematurity (ROP). Results: Fourteen cases involved vitreoretinal pathology (median observation time 14 years, range 6–46 years) with late detachment and/or vitreous haemorrhage. Twelve cases primarily involved anterior segment pathology (median observation time 37 years, range 7–58 years). Eyes in the latter category often showed features of early arrested growth and anterior traction, which, in four eyes, eventually led to enucleation or exenteration as a result of a blind and painful terminal state. The last five cases (observation periods 22–38 years) were labelled ‘miscellaneous’. Among the 31 patients, we identified a subgroup in which insidious visual loss was a common feature (n = 20). Initially, some of these cases showed evidence of cicatricial ROP and low vision from early in life. Others retained useful vision and did not present obvious ocular incidents related to the actual visual acuity decline. Conclusions: Based on a variety of clinical ophthalmic preterm appearances, we propose the hypothesis that, in addition to increased structural vulnerability, a reduced functional reserve may pave the way for further abiotrophy or involution over time. This may manifest as reduced resistance to later ophthalmic events, such as disease or trauma, or simply the impact of age.