Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877

Progressive choreodystonia in X-linked hyper-IgM immunodeficiency: A rare but recurrent presentation.

An association between movement disorders and immune-system dysfunction has been described in the context of rare genetic diseases such as ataxia telangiectasia as well as infectious encephalopathies. We encountered a male patient who presented immunodeficiency of unknown etiology since childhood. A medication-refractory, progressive choreodystonic movement disorder emerged at the age of 42 years and prompted an exome-wide molecular testing approach. This revealed a pathogenic hemizygous variant in CD40LG, the gene implicated in X-linked hyper-IgM syndrome. Only two prior reports have specifically suggested a causal relationship between CD40LG mutations and involuntary hyperkinetic movements. Our findings thus confirm the existence of a particular CD40LG-related condition, combining features of compromised immunity with neurodegenerative movement abnormalities. Establishing the diagnosis is crucial because of potential life-threatening immunological complications

Structure and Magnetic Properties of Iron/Iron-Oxide Nanoparticles Prepared by Precipitation from Solid State Solution

The influence of precipitation temperature on structural and magnetic properties of iron/iron-oxide nanoparticles is investigated. Nanoparticles were prepared by precipitation of$\gamma$-Fe precipitates in Cu–Fe solid solution and subsequently isolated by matrix dissolution. Precipitation annealing temperatures were 773, 873, and 973 K. Nano- particles core-shell structure and morphology were characterized by X-ray diffraction, high-resolution transmission electron microscopy, and selected area electron diffraction. These measurements showed that average diameter of nanoparticles increases with precipitation temperature from 8.5 nm to 20.5 nm. The measurements of magnetization as a function of temperature and applied field have been performed by SQUID magnetometer in temperature range from 5 K to 200 K

Magnetoimpedance Effect in Field Annealed (FeNi)78Nb7B15(FeNi)_{78}Nb_{7}B_{15} Amorphous and Nanocrystalline Bilayer Ribbons

The influence of the magnetic field annealing on the magnetoimpedance effect has been investigated in rapidly quenched $(Fe_{0.5}Ni_{0.5})_{78}Nb_{7}B_{15}$ monolayer and bilayer thin ribbons. The highest impedance ratio value $(ΔZ//Z)_{max}$=72% and the maximum field sensitivity $η_{max}$=12 %/Oe was obtained in the bilayer ribbon, annealed under longitudinal magnetic field at 773 K that exhibited nanocrystalline structure. The higher values of $(ΔZ//Z)_{max}$ in bilayer ribbons, as compared to their monolayer counterparts, are attributed to the increased ratio of their thickness to the penetration depth

Ataxia telangiectasia gene mutation in isolated segmental dystonia without ataxia and telangiectasia.

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312564-sup-v001_1.htm

Effect of Temperature on Magnetization Processes in Amorphous Rapidly Solidified FeSiB/CoSiB Bilayer Ribbons

Amorphous bilayers consisting of Fe-Si-B and Co-Si-B layers have been prepared by planar flow casting from a single crucible using a double-nozzle technique. Temperature dependencies of magnetization and hysteresis loops have been investigated in a wide temperature range. At room temperature, the effects of interlayer stresses, induced in material due to different thermal expansion coefficients of two mechanically interconnected soft magnetic layers, resulted in rounded hysteresis loops with flattened central part, indicating a dominant role of magnetization rotational processes. With an increase of measurement temperature, the interlayer stresses are relieved and the hysteresis loops became more squared

Mechanochemically Synthesized CuFeSe₂ Nanoparticles and Their Properties

The mechanochemical synthesis of nanocrystalline CuFeSe₂ particles prepared by high-energy milling in a planetary mill in an argon atmosphere from copper, iron, and selenium for 60 min is reported for the first time. The CuFeSe₂ nanoparticles crystallize in tetragonal structure with mean crystallite size of about 32±1 nm. High resolution transmission electron microscopy measurements confirmed the presence of agglomerates which are formed by small nanocrystalline domains (5-40 nm). The magnetic data revealed that paramagnetic CuFeSe₂ nanoparticles coexist with a small amount of ferromagnetic impurities at room temperature. The magnetic transition towards a weak ferromagnetic or ferrimagnetic behavior occurs in CuFeSe₂ at approximately 79 K. The band gap of the CuFeSe₂ particles is 0.95 eV which is wider than the band gap in bulk materials (0.16 eV), which could be in many aspects of application more beneficial