Variant Philadelphia t(X;9;22)(q22?;q34;q11.2) can be successfully treated with second generation tyrosine kinase inhibitors: A case report and literature review.

Chronic myeloid leukemia (CML) is characterized by the reciprocal translocation between chromosomes 9 and 22: t(9;22)(q34;q11). However, 5-10% of patients with CML have complex variant translocations involving at least a third chromosome; only a few cases affect the X chromosome. Therefore, the data available regarding their features and the response to treatment is limited. In the present report, a case of a variant Philadelphia translocation t(X;9;22)(q22?;q34;q11.2) identified in a 51-year-old female with a newly diagnosed CML is described. The patient was treated with nilotinib. A major molecular response was observed after 12 months of starting treatment. Deep molecular response was obtained 20 months later and maintained after the 110-month follow-up. Additionally, a literature review was performed, with the aim of comprehending the complex clinical and biological characteristics of CML cytogenetic variants involving the X chromosome.

The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies.

Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands' close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for "rare" condition.