Infantile hypotonia as a presentation of rett syndrome

Abstract

Rett syndrome (RTT) is classically defined by meeting certain clinical diagnostic criteria. It affects mostly females, and one possible pathogenic mechanism was considered to involve mitochondrial function. This was based on the finding of ultrastructural alterations in the mitochondria and decreased respiratory chain enzyme activity. However, the principal etiology of RTT has since been found to be mutations in the MECP2 gene, which is located on the X chromosome. Molecular analysis has allowed the phenotype of MECP2 mutations to be broadened beyond RTT to include girls who have mild mental retardation, autism, and an Angelman syndrome phenotype, as well as males with severe encephalopathy. We present a girl with a previously described mutation in the MECP2 gene whose phenotype is of atypical RTT. She presented with hypotonia and developmental delay in infancy without a clear period of normal development. As part of her evaluation for hypotonia, a muscle biopsy and respiratory chain enzyme analysis showed a slight decrease in respiratory chain enzyme activity consistent with previous reports. This report supports broadening the phenotype of patients who should be considered for MECP2 mutation analysis to include cases of developmental delay and hypotonia without evidence of an initial period of normal development. Furthermore, it supports the hypothesis of an underlying secondary defect in energy metabolism contributing to the pathogenesis of RTT.

Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome

“…With the realization that MeCP2, a nuclear transcriptional repressor, is mutated in RTT, the mitochondrial link became less compelling. It was recently noted, however, that a patient with symptoms normally associated with mitochondrial disorders (hypotonia, small stature, developmental delay, and a slight decrease in respiratory chain enzyme activity) harbored mutations in the MECP2 gene (11). This overlap between symptoms of RTT and mitochondrial disorders recalls early reports of structural abnormalities (4,8,9,34) and defects in the electron transport chain (7,8) in mitochondria from skin and muscle biopsies of RTT patients.…”

Impaired enzymatic defensive activity, mitochondrial dysfunction and proteasome activation are involved in RTT cell oxidative damage

“…Mitochondrial dysfunction and its derived oxidative stress may contribute to RTT pathogenesis. Indeed, some RTT clinical signs such as hypotonia [49] and myocardial dysfunctions [50] correlate with mitochondrial dysfunctions and oxidative stress. In muscle and frontal lobe biopsies of RTT patients [48,51,52] and in cortex and hippocampus of MeCP2−/y mice [53], morphological alterations of mitochondria have been found.…”

Energetics, epigenetics, mitochondrial genetics

“…Rett patients have been reported to harbor mitochondrial structural aberrations and reductions in skeletal muscle OXPHOS complexes I, III, IV, though not II. Furthermore, mice in which MeCP2 is inactivated have increased complex III and core protein 1 gene ( Ugcrc1 ) expression, together with reduced OXPHOS coupling (Eeg-Olofsson et al, 1989; Heilstedt et al, 2002; Kriaucionis et al, 2006). The MeCP2 protein binds to methyl CpG nDNA domains and modulates gene expression, either activation or repression, in part by recruiting histone-modifying enzymes such as deacetylases and methyltransferases (Chen et al, 2003b; Klein et al, 2007).…”