A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation.

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Primary CNS lymphoma and HLA class I and II alleles in a German cohort of immunocompetent patients

Human leukocyte antigens (HLA) are involved in the regulation of immune response to infection and in malignant transformation. Several HLA alleles are associated with immunological or malignant diseases. The aim of the present study was to evaluate a potential association of HLA class I and II alleles with primary central nervous system lymphoma (PCNSL) in immunocompetent patients. We therefore analyzed particular HLA-A, HLA-B and HLA-DRB1 alleles in 82 PCNSL patients and compared the data to those in 327 population controls. No significant difference between these two groups was found using Pearson's chi(2) test. These data do not support the hypothesis that HLA alleles play a major role in the pathogenesis of PCNSL

Genetic variants of folate and methionine metabolism and PCNSL incidence in a German patient population

Functional genetic polymorphisms involved in folate and methionine metabolism play an important role in both DNA synthesis and methylation, and affect the risk of various malignancies including lymphoproliferative disorders such as systemic non-Hodgkin's lymphoma. In a retrospective analysis of 185 immunocompetent patients with primary central nervous system lymphoma (PCNSL) and 212 population controls we therefore investigated eight genetic polymorphisms affecting methionine metabolism for potential association with the development of PCNSL. We observed underrepresentation of the G-allele of the methyltetrahydrofolate homocysteine S-methyltransferase (MTR) c.2756A > G (D919G) missense polymorphism among PCNSL patients (P = 0.045; odds ratio (OR) = 0.65; 0.43-0.99). Furthermore, for the methylenetetrahydrofolate reductase (MTHFR) c.1298A > C (E429A) polymorphism the mutated C-allele was found more frequently among PCNSL patients than among population controls (P = 0.026; OR = 1.57; 1.05-2.34). There were no associations of the other polymorphisms investigated (MTHFR c.677C > T, transcobalamin 2 (Tc2) c.776C > G, cystathionin beta-synthase (CBS) c.844_855ins68, reduced folate carrier-1 (RFC-1) c.80G > A, thymidylate synthase (TYMS) 28-bp repeat, and dihydrofolate reductase (DHFR) c.594 + 59del19 bp) and the presence of PCNSL. This analysis is the largest to date to evaluate associations between genetic variants of folate and methionine metabolism and PCNSL. Our results suggest the hypothesis that folate and methionine metabolism is relevant to susceptibility to PCNSL

Primary CNS lymphoma in the elderly: temozolomide therapy and MGMT status

This retrospective series explores temozolomide monotherapy in elderly patients with primary CNS lymphoma (PCNSL) and severe comorbidities. In 17 patients (62-90 years old), the complete response rate was 47%, median progression-free survival was 5 months, and median overall survival was 21 months. Five of 17 patients (29.4%) had prolonged responses for at least 12 months and survived for more than 24 months. Three of these patients had a methylated O(6)-methylguanine-DNA methyltransferase (MGMT) promoter, while the MGMT status was not assessable in the remaining two patients. Temozolomide monotherapy appears to be effective in a subgroup of elderly PCNSL patients and deserves further evaluation

Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

International audiencePatients with SPG7 had a mean age of 35.5 ± 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (>20 years, n = 62) showed more cerebellar dysarthria (p < 0.05), deep sensory loss (p < 0.01), muscle wasting (p < 0.01), ophthalmoplegia (p < 0.05), and sphincter dysfunction (p < 0.05) than those with a shorter duration (<10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 ± 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs (p < 0.05), diminished visual acuity due to optic atrophy (p < 0.0001), and deep sensory loss (p < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 ± 13.7 vs 32.8 ± 14.6 years, p < 0.05) and showed ataxia at onset (p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons

Coarelli et al., Table 4

Table 4. New SPG7 variants found in the analyzed cohort

Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in similar to 3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909 + 22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909 + 22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909 + 22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 x 10(-4)). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome