Browsing by Author "Melo-Pires, Manuel"
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- Clinical, biochemical, molecular, and histological features of 65 Portuguese patients with mitochondrial disorders: authors’ reply to the Drs. Finsterer and Zarrouk-Mahjoub commentsPublication . Cruz, Simão; Taipa, Ricardo; Nogueira, Célia; Melo-Pires, Manuel; Vilarinho, LauraAuthors’ reply to the Drs. Finsterer and Zarrouk-Mahjoub comments for the study “Clinical, biochemical, molecular, and histological features of 65 Portuguese patients with mitochondrial disorders” This study confirms the high relative frequency of single large-scale deletions among mitochondrial disorders as well as its particular association with CPEO. Muscle histology seems to be particularly useful in older patients and those with mtDNA deletions, whereas RCEA might be more helpful in young children or individuals with mtDNA depletion. (Full article reference: Cruz S, Taipa R, Nogueira C, Pereira C, Almeida LS, Neiva R, Geraldes T, Guimarães A, Melo-Pires M, Vilarinho L. Clinical, biochemical, molecular and histological features of 65 Portuguese patients with mitochondrial disorders. Muscle Nerve. 2017 Nov;56(5):868-872. doi: 10.1002/mus.25593. Epub 2017 Apr 4).
- Expanding the mutation spectrum of the MTM1 gene: the first multi-exonic duplication and establishment of the MTM1 locus-specific databasePublication . Oliveira, Jorge; Oliveira, Márcia E.; Brekelmans, Roel; Melo-Pires, Manuel; Guimarães, António; den Dunnen, Johan; Santos, Manuela; Santos, RosárioCentronuclear myopathies (CNM) are a group of diseases with variable onset and severity sharing as a distinctive histological feature, a high frequency of muscle fibers with centralized nuclei. Myotubular myopathy (MIM#310400) the X-linked form of CNM is characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin, a protein involved in myofiber differentiation and muscle cell architecture. In this work, eight patients were subjected to MTM1 MLPA analysis, selected according to the following criteria: (i) muscle biopsy compatible with CNM and (ii) exclusion of MTM1 point mutations by sequencing. We identified the first gross duplication spanning exons 1–5 (c.-76-?_342+?dup) in a 7 year old boy with progressive tetraparesis, ophtalmoparesis, facial diparesis and independent ambulation, the clinical course being milder than the classical myotubular myopathies. Analysis at the mRNA level revealed both normal transcripts and a mutated isoform lacking exon 6 (r.343_444del), suggesting somatic mosaicism. As suspected, this duplication was not detected in the patient’s mother. Considering the phenotypic expression in the patient, this mutational event most likely occurred de novo during early embryogenesis. We also describe the implementation of a locus-specific database (LSDB) for this gene using the Leiden Open Variation database (LOVD) software. The MTM1-LOVD (http://www.lovd.nl/MTM1) contains 372 mutation entries identified in 370 patients (last accessed March 2011). A total of 223 unique MTM1 mutations are listed in this LSDB, including: 207 point mutations, 15 single or multi-exonic deletions and the large duplication described in the present work. Despite the significant advances in this field during the last decade about one third of the CNM cases remain genetically unresolved. Here we show that gross MTM1 gene duplications may account for a fraction of these cases.
- Reply Cruz et al 2017 Muscle & NervePublication . Cruz, Simão; Taipa, Ricardo; Nogueira, Célia; Melo-Pires, Manuel; Vilarinho, LauraWe appreciate the interest shown by Drs Finsterer and Zarrouk-Mahjoub in our study.1 Although we agree with the comments made on the mode of transmission of several mtDNA-associated disorders, the analysis of the families and the patterns of inheritance were beyond the scope of our study. As we stated in the Discussion, we do admit the possibility of a selection bias towards mitochondrial disorders with skeletal muscle involvement. However, we did not base our inclusion criteria on the existence of suggestive histological features. Instead, we selected all the patients with a molecularly confirmed diagnosis who also had a muscle biopsy performed and analyzed at the neuropathology unit that participated in this study, regardless of the results of the histology. Moreover, as per the supplementary tables, this study included several patients with predominant central nervous system or multisystem features who probably had a muscle biopsy only because it was more straightforward than obtaining other tissue for analysis.(...)