Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.

Heterozygous mutations in REEP1 (MIM #609139) encoding the receptor expression-enhancing protein 1 (REEP1) are a well-recognized and relatively frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), SPG31.1 REEP1 localizes in the mitochondria and endoplasmic reticulum (ER) and facilitates ER-mitochondria interactions.2 In addition to the HSP phenotype, REEP1 has been associated with an autosomal dominant spinal type of Charcot-Marie-Tooth disease in 2 families.3 More recently, a patient with homozygous REEP1 mutation with a much more severe phenotype akin to spinal muscular atrophy with respiratory distress type 1 (SMARD1) was reported.4 In this report, we present a patient with a homozygous mutation in REEP1 manifesting a severe congenital distal spinal muscular atrophy (SMA) with diaphragmatic paralysis, expanding the phenotype from mild autosomal dominant HSP through to severe recessive distal SMA pattern

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome: genetic and clinical insights

Purpose of review: This review aims to summarise the present cerebellar ataxia, neuropathy, vestibular ataxia syndrome (CANVAS) literature, providing both clinical and genetic insights that might facilitate the timely clinical and genetic diagnosis of this disease. // Recent findings: Recent advancements in the range of the clinical features of CANVAS have aided the development of a broader, more well-defined clinical diagnostic criteria. Additionally, the identification of a biallelic repeat expansion in RFC1 as the cause of CANVAS and a common cause of late-onset ataxia has opened the door to the potential discovery of a pathogenic mechanism, which in turn, may lead to therapeutic advancements and improved patient care. // Summary: The developments in the clinical and genetic understanding of CANVAS will aid the correct and timely diagnosis of CANVAS, which continues to prove challenging within the clinic. The insights detailed within this review will raise the awareness of the phenotypic spectrum and currently known genetics. We also speculate on the future directions of research into CANVAS

A new quantitative 3D approach to imaging of structural joint disease.

Imaging of joints with 2D radiography has not been able to detect therapeutic success in research trials while 3D imaging, used regularly in the clinic, has not been approved for this purpose. We present a new 3D approach to this challenge called joint space mapping (JSM) that measures joint space width in 3D from standard clinical computed tomography (CT) data, demonstrating its analysis steps, technical validation, and reproducibility. Using high resolution peripheral quantitative CT as gold standard, we show a marginal over-estimation in accuracy of +0.13 mm and precision of ±0.32 mm. Inter-operator reproducibility bias was near-zero at -0.03 mm with limits of agreement ±0.29 mm and a root mean square coefficient of variation 7.5%. In a technical advance, we present results from across the hip joint in 3D with optimum validation and reproducibility metrics shown at inner joint regions. We also show JSM versatility using different imaging data sets and discuss potential applications. This 3D mapping approach provides information with greater sensitivity than reported for current radiographic methods that could result in improved patient stratification and treatment monitoring

Using human induced pluripotent stem cells to model cerebellar disease: Hope and hype

The cerebellum forms a highly ordered and indispensible component of motor function within the adult neuraxis, consisting of several distinct cellular subtypes. Cerebellar disease, through a variety of genetic and acquired causes, results in the loss of function of defined subclasses of neurons, and remains a significant and untreatable health care burden. The scarcity of therapies in this arena can partially be explained by unresolved disease mechanisms due to inaccessibility of human cerebellar neurons in a relevant experimental context where initiating disease mechanisms could be functionally elucidated, or drug screens conducted. In this review we discuss the potential promise of human induced pluripotent stem cells (hiPSCs) for regenerative neurology, with a particular emphasis on in vitro modelling of cerebellar degeneration. We discuss progress made thus far using hiPSC-based models of neurodegeneration, noting the relatively slower pace of discovery made in modelling cerebellar dysfunction. We conclude by speculating how strategies attempting cerebellar differentiation from hiPSCs can be refined to allow the generation of accurate disease models. This in turn will permit a greater understanding of cerebellar pathophysiology to inform mechanistically rationalised therapies, which are desperately needed in this field

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): genetic and clinical aspects

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) typically presents in middle life with a combination of neuropathy, ataxia and vestibular disease, with patients reporting progressive imbalance, oscillopsia, sensory disturbance and a dry cough. Examination identifies a sensory neuropathy or neuronopathy and bilaterally impaired vestibulo-ocular reflex. The underlying genetic basis is of biallelic AAGGG expansions in the second intron of replication factor complex subunit 1 (RFC1). The frequency and phenotype spectrum of RFC1 disease is expanding, ranging from typical CANVAS to site-restricted variants affecting the sensory nerves, cerebellum and/or the vestibular system. Given the wide phenotype spectrum of RFC1, the differential diagnosis is broad. RFC1 disease due to biallelic AAGGG expansions is probably the most common cause of recessive ataxia. The key to suspecting the disease (and prompt genetic testing) is a thorough clinical examination assessing the three affected systems and noting the presence of chronic cough

DYT6 Dystonia: A Neuropathological Study

BACKGROUND: Mutations in the thanatos-associated protein domain containing apoptosis-associated protein 1 gene (THAP1) are responsible for adult-onset isolated dystonia (DYT6). However, no neuropathological studies of genetically proven DYT6 cases have been previously reported. OBJECTIVE: We report the first detailed neuropathological investigation carried out on two DYT6 brains. METHODS: Genetic screening for THAP1 gene mutations using standard Sanger polymerase chain reaction sequencing identified 2 cases, 1 with a known pathogenic mutation and the other with a novel mutation. A detailed neuropathological assessment of the cases was performed. RESULTS: Both DYT6 cases showed no significant neurodegeneration and no specific disease-related pathology. CONCLUSIONS: No neuropathological features that could be defined as hallmark features of DYT6 dystonia were identified. Our study supports the notion that in isolated dystonia, there is no significant neurodegeneration or morphological lesions that can be identified using routine methods

Space Launch System Booster Separation Supersonic Powered Testing with Surface and Off-Body Measurements

A wind tunnel test was run in the NASA Langley Unitary Plan Wind Tunnel simulating the separation of the two solid rocket boosters (SRB) from the core stage of the NASA Space Launch System (SLS). The test was run on a 0.9% scale model of the SLS Block 1B Cargo (27005) configuration and the SLS Block 1B Crew (28005) configuration at a Mach of 4.0. High pressure air was used to simulate plumes from the booster separation motors located at the nose and aft skirt of the two boosters. Force and moment data were taken on both SRBs and on the core stage. Schlieren still photos and video were recorded throughout testing. A set of points were acquired using Cross-correlation Doppler Global Velocimetry (CCDGV) readings to get 3 component velocity measurements between the core and the left-hand SRB. The CCDGV laser was utilized to record flow visualization in the same location, between the core and the left-hand SRB. Pressure Sensitive Paint data were taken on a separate set of runs. Computational Fluid Dynamics (CFD) runs were computed on a subset of the wind tunnel data points for comparison. A combination of the force/moment, CCDGV and Pressure Sensitive Paint (PSP) data (as well as schlieren images) at the CFD-specified test conditions will be used te the CFD simulations that will be used to build an SLS booster separation database flight conditions

Investigating RFC1 expansions in sporadic amyotrophic lateral sclerosis

A homozygous AAGGG repeat expansion within the RFC1 gene was recently described as a common cause of CANVAS syndrome. We examined 1069 sporadic ALS patients for the presence of this repeat expansion. We did not discover any carriers of the homozygous AAGGG expansion in our ALS cohort, indicating that this form of RFC1 repeat expansions is not a common cause of sporadic ALS. However, our study did identify a novel repeat conformation and further expanded on the highly polymorphic nature of the RFC1 locus