Novel compound heterozygous pathogenic variants in nucleotide-binding protein like protein (NUBPL) cause leukoencephalopathy with multi-systemic involvement.

NUBPL (Nucleotide-binding protein like) protein encodes a member of the Mrp/NBP35 ATP-binding proteins family, deemed to be involved in mammalian complex I (CI) assembly process. Exome sequencing of a patient presenting with infantile-onset hepatopathy, renal tubular acidosis, developmental delay, short stature, leukoencephalopathy with minimal cerebellar involvement and multiple OXPHOS deficiencies revealed the presence of two novel pathogenic compound heterozygous variants in NUBPL (p.Phe242Leu/p.

'Amish Nemaline Myopathy' in 2 Italian siblings harbouring a novel homozygous mutation in Troponin-I gene.

Amish Nemaline Myopathy is a severe form of nemaline myopathy associated to mutation in TNNT1 gene, firstly reported among the Old Order Amish. Here we report two Italian siblings who manifested, by the age of 7 months, progressive and severe muscle weakness and wasting, respiratory insufficiency, pectus carinatum deformity and failure to thrive. Muscle biopsy was consistent with nemaline myopathy and novel homozygous missense mutation in TNNT1 was found.

Novel homozygous TSFM pathogenic variant associated with encephalocardiomyopathy with sensorineural hearing loss and peculiar neuroradiologic findings.

TSFM is a nuclear gene encoding the elongation factor Ts (EFTs), an essential component of mitochondrial translational machinery. Impaired mitochondrial translation is responsible for neurodegenerative disorders characterized by multiple respiratory chain complex defects, multisystemic involvement, and neuroradiological features of Leigh-like syndrome. With the use of a next-generation sequencing (NGS)-based multigene panel for mitochondrial disorders, we identified the novel TSFM homozygous variant c.

The role of the P2X7 receptor in myeloid-derived suppressor cells and immunosuppression.

Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells expanded and recruited from the bone marrow to the periphery or to a specific site of inflammation/infection. MDSC have been described in different pathological conditions including cancer, infections, autoimmunity and obesity. The main function of MDSC is immunosuppression occurring through different mechanisms such as induction of immunosuppressive cells, impairment of lymphocyte homing, free radical production, depletion of amino acids critical for T cell functions, upregulation of ectoenzymes involved in adenosine production and activation of immune regulatory molecules responsible of T cell anergy.

Clinical and neuroimaging features of the m.10197G>A mtDNA mutation: New case reports and expansion of the phenotype variability.

Complex I (CI) is the largest component of the mitochondrial respiratory chain (MRC) and it is made up of 7 mitochondrial DNA (mtDNA)-encoded and at least 38 nuclear DNA-encoded subunits. Isolated CI deficiency is the most common single enzyme deficiency in the heterogeneous group of MRC disorders and it is a relatively common etiology of Leigh-like syndrome (LS). With a few exceptions, descriptions of the clinical spectrum of specific mutations in CI are scarce.

The Danger Signal Extracellular ATP Is Involved in the Immunomediated Damage of α-Sarcoglycan-Deficient Muscular Dystrophy.

In muscular dystrophies, muscle membrane fragility results in a tissue-specific increase of danger-associated molecular pattern molecules (DAMPs) and infiltration of inflammatory cells. The DAMP extracellular ATP (eATP) released by dying myofibers steadily activates muscle and immune purinergic receptors exerting dual negative effects: a direct damage linked to altered intracellular calcium homeostasis in muscle cells and an indirect toxicity through the triggering of the immune response and inhibition of regulatory T cells. Accordingly, pharmacologic and genetic inhibition of eATP signaling improves the phenotype in models of chronic inflammatory diseases.

Unusual white matter involvement in EAST syndrome associated with novel KCNJ10 mutations.

Background: Epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) is a rare channelopathy due to KCNJ10 mutations. So far, only mild cerebellar hypoplasia and/or dentate nuclei abnormalities have been reported as major neuroimaging findings in these patients.

Methods: We analyzed the clinical and brain MRI features of two unrelated patients (aged 27 and 23 years) with EAST syndrome carrying novel homozygous frameshift mutations (p.