ABSTRACT
UNLABELLED: SURF1 gene mutations are the most common cause of Leigh syndrome (LS), a rare progressive neurodegenerative disorder of infancy, characterized by symmetric necrotizing lesions and hypervascularity in the brainstem and basal ganglia, leading to death before the age of 4 years. Most of the reported mutations create premature termination codons, whereas missense mutations are rare. The aim of the study was to characterize the natural history of LS patients carrying at least one missense mutation in the SURF1 gene. Nineteen such patients (8 own cases and 11 reported in the literature) were compared with a reference group of 20 own c.845_846delCT homozygous patients, and with other LS(SURF-) cases described in the literature. Disease onset in the studied group was delayed. Acute failure to thrive and hyperventilation episodes were rare, respiratory failure did not appear before the age of 4 years. Dystonia, motor regression and eye movement dissociation developed slowly. The number of patients who survived 7 years of life totaled 9 out of 15 (60%) in the 'missense group' and 1 out of 26 (4%) patients with mutations leading to truncated proteins. IN CONCLUSION: (i) The presence of a missense mutation in the SURF1 gene may correlate with a milder course and longer survival of Leigh patients, (ii) normal magnetic resonance imaging (MRI) findings, normal blood lactate value, and only mild decrease of cytochrome c oxidase (COX) activity are not sufficient reasons to forego SURF1 mutation analysis in differential diagnosis.
Subject(s)
Leigh Disease/genetics , Membrane Proteins/genetics , Mitochondrial Proteins/genetics , Mutation, Missense/genetics , Adolescent , Adult , Blotting, Western , Case-Control Studies , Cell Extracts , Child, Preschool , DNA Mutational Analysis , Female , Heterozygote , Homozygote , Humans , Infant , Leigh Disease/pathology , Magnetic Resonance Imaging , Male , Membrane Proteins/deficiency , Mitochondrial Proteins/deficiency , Muscles/pathology , Pedigree , Phenotype , Proteomics , White People/geneticsABSTRACT
There is considerable evidence that elevated bone turnover is an independent form of low bone mineral density (BMD) risk factor of osteoporotic fractures. The aim of our study was to test whether a group of postmenopausal women could be divided into subgroups of high and low bone turnover rate using different pairs of bone turnover markers (one resorption, one formation). Cluster analysis was used to obtain high and low bone turnover subgroups within the study group. A magnitude of difference in lumbar spine BMD (expressed as Z-score) between high- and low-turnover groups was used as a criterion of division success. According to this criterion, the division obtained with a urinary type I collagen crosslinked N-telopeptide/bone alkaline phosphatase pair of markers appeared to be the most significant. This method of separation of two subgroups was highly concordant with the division based on the upper thresholds of the normal values for those markers found for the premenopausal women. It seems that the observed existence of high-and low-turnover subject clusters is not an incidental phenomenon, because the effects obtained for the whole study group were further confirmed by the consistent results of cluster analysis, performed separately for two randomly selected subgroups (A and B) from the study group. The results obtained appear to support the view that bone turnover rate in postmenopausal women is distributed in the bimodal fashion. This finding seems to justify further investigations of more elaborated models, enabling clinicians to individually classify their patients as low- or high-turnover cases with higher efficiency, as in the case of cutoff values for single markers.
