Abstract:
:Non-mosaic males with a 46,XY karyotype and a MECP2 null mutation display a phenotype of severe neonatal-onset encephalopathy that is distinctly different from Rett syndrome (RTT). To increase awareness of this rare disorder, we are reporting novel findings in a sporadic case, compare them to 16 previously reported cases and establish salient criteria for clinical diagnosis. The proband suffered from general hypotonia and hypoxia caused by hypoventilation and irregular breathing. He developed abnormal movements, seizures and electroencephalogram abnormalities. He failed to thrive and to reach any motor milestones and died at 15 months from central respiratory failure without a diagnosis. In a muscle biopsy, type II fibers were reduced in diameter, indicating central hypoxia. At autopsy, the brain was small with disproportionate reduction of the frontal and temporal lobes. Synaptophysin staining of synaptic vesicles was greatly reduced in cerebellar and spinal cord sections. Analysis of Golgi-stained pyramidal neurons from cortical layers III and V of the frontal and temporal lobes revealed drastically diminished dendritic trees. Post-mortem MECP2 mutation analysis on DNA and RNA from fibroblasts revealed a novel de novo 9-nucleotide deletion including the intron 3/exon 4 splice junction. The two nucleotides flanking the deletion form a new splice site, and the aberrantly spliced transcript lacks seven nucleotides (r.378_384delTCCCCAG), causing a frameshift and premature termination codon (p.I126fsX11). Males with congenital encephalopathy, not females with RTT, represent the true human counterpart for the commonly studied Mecp2-/y mouse model and provide unique insight into the mechanisms of MeCP2 deficiency.
journal_name
Clin Genetjournal_title
Clinical geneticsauthors
Schüle B,Armstrong DD,Vogel H,Oviedo A,Francke Udoi
10.1111/j.1399-0004.2008.01005.xsubject
Has Abstractpub_date
2008-08-01 00:00:00pages
116-26issue
2eissn
0009-9163issn
1399-0004pii
CGE1005journal_volume
74pub_type
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