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A letter to the editor discussing the occurrence of the same chromosome abnormalities in Ph+ and Ph− cells in chronic myeloid leukaemia is presented.

Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this. [ABSTRACT FROM AUTHOR]

Cell reprogramming promises to make characterization of the impact of human genetic variation on health and disease experimentally tractable by enabling the bridging of genotypes to phenotypes in developmentally relevant human cell lineages. Here we apply this paradigm to two disorders caused by symmetrical copy number variations of 7q11.23, which display a striking combination of shared and symmetrically opposite phenotypes-Williams-Beuren syndrome and 7q-microduplication syndrome. Through analysis of transgene-free patient-derived induced pluripotent stem cells and their differentiated derivatives, we find that 7q11.23 dosage imbalance disrupts transcriptional circuits in disease-relevant pathways beginning in the pluripotent state. These alterations are then selectively amplified upon differentiation of the pluripotent cells into disease-relevant lineages. A considerable proportion of this transcriptional dysregulation is specifically caused by dosage imbalances in GTF2I, which encodes a key transcription factor at 7q11.23 that is associated with the LSD1 repressive chromatin complex and silences its dosage-sensitive targets. [ABSTRACT FROM AUTHOR]

The duplication of the Williams-Beuren syndrome (WBS) region (7q11.23) is a copy number variant associated with autism spectrum disorder (ASD). One of the most intriguing aspects is that the reciprocal microdeletion causes WBS, characterized by hypersociability, marked empathy, and a relative capacity in verbal short-term memory and language. Herein, we studied, by using functional morphological and volumetric magnetic resonance, a 17-year-old male patient who displays a de novo 7q11.23 duplication and ASD. The limbic system of the patient appeared hypo-functional, while the total brain volume was increased, thus contrasting, in an opposite and intriguing manner, with the global brain volume reduction reported in WBS. Even if these findings come from the analysis of a single patient and, therefore, have to be considered preliminary results, they encourage carrying on further functional and volumetric studies in patients with 7q11.23 duplication, to fully elucidate the role of this gene-dosage alteration on brain development and limbic system function. [ABSTRACT FROM AUTHOR]

Background: Familial hemiplegic migraine (FHM) is a rare autosomal dominant migraine subtype, characterized by fullyreversible motor weakness as a specific symptom of aura. Mutations in the ion transportation coding genes CACNA1A,ATP1A2 and SCN1A are responsible for the FHM phenotype. Moreover, some mutations in ATP1A2 or SCN1A also maylead to epilepsy.Case: Here we report on a three-generation family with five patients having a novel ATP1A2 mutation on exon 19, causingguanine-to-adenine substitution (c.2620G>A, p.Gly874Ser) that co-segregated in the five living relatives with migraine,four of whom had hemiplegic migraine. Moreover, three patients presented with epilepsy, one of whom had generalizedepilepsy with febrile seizures plus (GEFS+).Conclusions: The present study provides further evidence on the involvement of ATP1A2 mutations in both migraine andepilepsy, underlying the relevance of genetic analysis in families with a comorbidity of both disorders. [ABSTRACT FROM AUTHOR]

Abstract: Little is known regarding the activity of tyrosine kinase inhibitors (TKis) on chronic myeloid leukemia (CML) clonal evolution (CE). We treated 10 CE CML patients in either hematologic chronic (8 cases) or accelerated (2 cases) phase with imatinib or second generation TKi. Additional chromosomal abnormalities appeared during the course of disease in seven cases, being present at diagnosis in three. A total of 6/10 (60%) patients achieved complete cytogenetic remission (CCyR) with imatinib in 3–14 months. Major or complete molecular remission (CMR) was obtained in four CCyR patients after 21, 25, 22, and 12 months, as well as in a fifth patient who started nilotinib because of suboptimal response after 75 months of imatinib treatment. One patient received nilotinib due to imatinib intolerance after 56 months of therapy while on CMR, and maintained such status. After a median follow-up of 82 months (range, 3–116), six patients are alive, five of which are in continuous CCyR while one patient is in his third CCyR on dasatinib after relapsing on imatinib and nilotinib. Five patients are in complete (four) or major (one) molecular remission, ongoing at 3, 48, 61, 95, and 96 months, on imatinib (three) or nilotinib (two). Although a small number of patients was studied, our results suggest that long-term cytogenetic and molecular remission can be achieved in CML CE patients with TKis treatment. [Copyright &y& Elsevier]

Abstract: Additional chromosome abnormalities (ACAs) occur in less than 10% of cases at diagnosis of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). In some cases, on the basis of the persistence of the ACAs in Ph-negative cells after response to imatinib, a secondary origin of the Ph chromosome has been demonstrated. In this study, the possible prognostic value of this phenomenon was evaluated. Thirty-six Ph-positive CML patients were included in the study. In six patients, ACAs persisted after the disappearance of the Ph. A complete cytogenetic response (CCR) was obtained in five of these six patients, and five of six also had a high Sokal score. In all the other cases, ACAs disappeared together (in cases of response to therapy with imatinib) or persisted with the Ph (in cases of no response to imatinib). In the former cases, the primary origin of the Ph was demonstrated. CCR was obtained in 22 cases (17 with low to intermediate Sokal scores), while no response was observed in 8 patients (5 with a high Sokal score). Sokal score seems to maintain its prognostic value for patients in whom the Ph occurs as a primary event, but not in those in whom it occurs as a secondary one. [Copyright &y& Elsevier]

(J Card Surg 2010;25:674-676) [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a case study of a 73-year-old woman with suspected primary progressive multiple sclerosis who was diagnosed with heterozygous X-linked adrenoleukodystrophy (X-ALD)-associated progressive myelopathy.