Search Results (4)

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype. Full article

Dominant Optic Atrophy (DOA) is one of the most common inherited mitochondrial diseases, leading to blindness. It is caused by the chronic degeneration of the retinal ganglion cells (RGCs) and their axons forming the optic nerve. Until now, DOA has been mainly associated with genes encoding proteins involved in mitochondrial network dynamics. Using next-generation and exome sequencing, we identified for the first time heterozygous PMPCA variants having a causative role in the pathology of late-onset primary DOA in five patients. PMPCA encodes an α subunit of the mitochondrial peptidase (MPP), responsible for the cleavage and maturation of the mitochondrial precursor proteins imported from the cytoplasm into mitochondria. Recently, PMPCA has been identified as the gene responsible for Autosomal Recessive Cerebellar Ataxia type 2 (SCAR2) and another severe recessive mitochondrial disease. In this study, four PMPCA variants were identified, two are frameshifts (c.309delA and c.820delG) classified as pathogenic and two are missenses (c.1363G>A and c.1547G>A) classified with uncertain pathological significance. Functional assays on patients’ fibroblasts show a hyperconnection of the mitochondrial network and revealed that frameshift variants reduced α-MPP levels, while not significantly affecting the respiratory machinery. These results suggest that alterations in mitochondrial peptidase function can affect the fusion-fission balance, a key element in maintaining the physiology of retinal ganglion cells, and consequently lead to their progressive degeneration. Full article

Accumulating evidence suggests a relationship between type 2 diabetes mellitus and sleep problems. A comprehensive study is needed to decipher whether shared polygenic risk variants exist between diabetic traits and sleep traits. Methods: We integrated summary statistics from different genome-wide association studies and investigated overlap in single-nucleotide polymorphisms (SNPs) associated with diabetes-related traits (type 2 diabetes, fasting glucose, fasting insulin, and glycated hemoglobin) and sleep traits (insomnia symptoms, sleep duration, and chronotype) using a conditional/conjunctional false discovery rate approach. Pleiotropic genes were further evaluated for differential expression analysis, and we assessed their expression pattern effects on type 2 diabetes by Mendelian randomization (MR) analysis. Results: We observed extensive polygenic pleiotropy between diabetic traits and sleep traits. Fifty-eight independent genetic loci jointly influenced the risk of type 2 diabetes and the sleep traits of insomnia, sleep duration, and chronotype. The strongest shared locus between type 2 diabetes and sleep straits was FTO (lead SNP rs8047587). Type 2 diabetes (z score, 16.19; P = 6.29 × 10⁻⁵⁹) and two sleep traits, sleep duration (z score, −6.66; P = 2.66 × 10⁻¹¹) and chronotype (z score, 7.42; P = 1.19 × 10⁻¹³), were shared. Two of the pleiotropic genes, ENSA and PMPCA, were validated to be differentially expressed in type 2 diabetes, and PMPCA showed a slight protective effect on type 2 diabetes in MR analysis. Conclusions: Our study provided evidence for the polygenic overlap between diabetic traits and sleep traits, of which the expression of PMPCA may play a crucial role and provide support of the hazardous effect of being an “evening” person on diabetes risk. Full article

Background: Peptidase mitochondrial processing alpha (PMPCA) biallelic mutations cause a spectrum of disorders ranging from severe progressive multisystemic mitochondrial encephalopathy to a milder non-progressive cerebellar ataxia with or without intellectual disability. Recently, we and others described an intermediate phenotype in two unrelated patients. Methods: We report a second Italian patient carrying novel PMPCA variants (p.Trp278Leu; p.Arg362Gly). Molecular modeling, dynamics simulation, RT-qPCR, and Western blotting were performed to predict the pathogenic impact of variants in the two Italian patients and attempt genotype-phenotype correlates. Results: In line with the two patients with intermediate phenotypes, our case presented global psychomotor delay with regression, intellectual disability, spastic-ataxic gait, and hyperkinetic movements, with cerebellar atrophy and bilateral striatal hyperintensities. However, blood lactate, muscle biopsy, and MRI spectroscopy were normal. PMPCA protein levels were significantly higher than controls despite normal cDNA levels. Dynamics simulation of several PMPCA missense variants showed a variable impact on the flexibility of the glycine rich loop and, for some cases, on the overall protein stability, without clear genotype-phenotype correlates. Conclusion: We confirm the expansion of PMPCA phenotypic spectrum including an intermediate phenotype of progressive encephalopathy without systemic involvement. The association of cerebellar atrophy with “Leigh-like” striatal hyperintensities may represent a “red flag” for this condition. Full article