Background: Wolfram syndrome (WFS) is a genetic disorder clinically characterized by optic atrophy (OA), diabetes mellitus, sensorineural deafness, and diabetes insipidus. It is caused by mutations in WFS1 (mono- or biallelic) or CISD2 (biallelic) genes. Neuroradiological features include cerebellar and/or brainstem atrophy with visual pathway and white matter involvement. We report two subjects with WFS in which multifocal, progressive, and contrast-enhancing white matter abnormalities (WMA) led to the consideration of multiple sclerosis (MS). Methods: We retrospectively analyzed the clinical, genetic, and radiological data from two unrelated subjects with genetically confirmed WFS and multifocal WMA. Results: Subject I: a 43-year-old woman, heterozygous for a known WFS1 variant, had a history of congenital deafness and OA. The brain MRI documented progressive multifocal WMA including pericallosal lesions. Subject II: a 28-year-old woman, compound heterozygous for two WFS1 variants, was known for OA and diabetes mellitus. The brain MRI revealed multifocal periventricular, callosal, subcortical, and juxtacortical WMA, with some enhancing after gadolinium injection. Conclusions: Our report expands the WFS spectrum of white matter involvement to include progressive, seemingly inflammatory lesions. Although we cannot exclude a dual diagnosis, the roles of WFS1 and CISD2 in myelination suggest a selective white matter vulnerability in WFS.

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the selective degeneration of motor neurons in the brain and spinal cord resulting in progressive paralysis and death. Current diagnosis of ALS is based on clinical assessment of related symptoms, which appear only late in the disease course after degeneration of a significant number of motor neurons. As a result, the identification and development of disease-modifying therapies is difficult, making ALS an incurable disease. Novel strategies for early diagnosis of ALS, to monitor disease progression and to assess response to existing and future treatments are urgently needed.

Many neurological disorders, including ALS, are accompanied by skin changes that often precede the onset of neurological symptoms. We have developed a unique ALS tissue-engineered skin model (ALS-TES), derived from the cells of ALS patients, in order to study the earliest stages of ALS-related skin pathology. For each participant, two skin biopsies were collected using a 6-mm diameter punch biopsy. Tissue-engineered skin was then generated from isolated keratinocytes and fibroblasts, and examined by routine histochemistry and immunohistochemistry, as well as by confocal microscopy. The ALS-TES model presents a number of striking features including altered epidermal differentiation, abnormal dermo-epidermal junction, delamination, keratinocyte infiltration, collagen disorganization and cytoplasmic TDP-43 inclusions, which are not seen in skin models derived from healthy subjects. The same abnormal skin model changes were detected skin models derived from the cells of pre- symptomatic C9orf72-linked ALS patients carrying the GGGGCC DNA repeat expansion. Consequently, our ALS-TES skin model could represent a renewable source of human tissue to better understand the physiopathological mechanisms underlying this disease, including cytoplasmic TDP43 accumulation, and lead to better tools for early diagnosis and disease monitoring.

Extended abstract of a paper presented at Microscopy and Microanalysis 2011 in Nashville, Tennessee, USA, August 7–August 11, 2011.

We present a study of the {100}<100> biaxially textured Ni (001) surface and oxide seed layer nucleation by in situ reflection high-energy electron diffraction and Auger electron spectroscopy. Our observations revealed the existence of a c(2×2) superstructure on the textured Ni surface due to segregation of sulfur contained in the bulk metal. The sulfur superstructure promotes the epitaxial (002) nucleation of seed layers such as Y2O3-stabilized ZrO2 (YSZ) and CeO2 on the metal and optimizes the biaxial texture necessary for high Jc superconductors on RABiTS.

The size distributions of Si and ZnTe nanoparticles produced by low energy density ArF (193 nm) pulsed laser ablation into ambient gases were measured as a function of the gas pressure, P, and target-substrate separation, Dts. For both Si and ZnTe, the largest nanoparticles were found closest to the ablation target, and the mean nanoparticle size decreased with increasing Dts. For Si ablation into He, the mean nanoparticle diameter did not increase monotonically with gas pressure but reached a maximum near P = 6 Torr. High resolution Z-contrast transmission electron microscopy and energy loss spectroscopy revealed that ZnTe nanoparticles consist of a crystalline core surrounded by an amorphous ZnO shell; growth defects and surface steps are clearly visible in the crystalline core. A pronounced narrowing of the ZnTe nanocrystal size distribution with increasing Dts also was found. The results demonstrate that the size of laser-ablated nanoparticles can be controlled by varying the molecular weight and pressure of an ambient gas and that nanometer-scale particles can be synthesized. Larger aggregates of both ZnTe and Si having a “flakelike” or “weblike” structure were formed at the higher ambient gas pressures; for ZnTe these appear to be open agglomerates of much smaller (∼10 nm) particles.

A systematic study has been made of changes in the bonding and optical properties of hydrogen-free tetrahedral amorphous carbon (ta-C) films, as a function of the kinetic energy of the incident carbon ions measured under film-deposition conditions. Ion probe measurements of the carbon ion kinetic energies produced by ArF and KrF laser ablation of graphite are compared under identical beam-focusing conditions. Much higher C+ kinetic energies are produced by ArF-laser ablation than by KrF for any given fluence and spot size. Electron energy loss spectroscopy and scanning ellipsometry measurements of the sp3 bonding fraction, plasmon energy, and optical properties reveal a well-defined optimum kinetic energy of 90 eV to deposit ta-C films having the largest sp3 fraction and the widest optical (Tauc) energy gap (equivalent to minimum near-gap optical absorption). Tapping-mode atomic force microscope measurements show that films deposited at near-optimum kinetic energy are extremely smooth, with rms roughness of only ~ 1 Å over distances of several hundred nm, and are relatively free of particulates.