Acquired Microcephaly,Regression of Milestones,Mitochondrial Dysfunction,and Episodic Rigidity in a 46,XY Male With a De Novo MECP2 Gene Mutation

Abstract

We report a case of acquired microcephaly in a male infant. Testing for mutations in the MECP2 gene identified a de novo hemizygous c.378-3C>G mutation at a highly conserved 3^′ splice site, consistent with Rett syndrome. Other distinctive features included periodic hypertonicity, decreased mitochondrial complex III activity, and abnormal magnetic resonance imaging (MRI) T2 signal in the pons. Rett syndrome was originally described in females with a clinical phenotype of deceleration of head growth, abnormal hand movements, and developmental regression. The clinical diagnosis can now be supported by genetic testing for MECP2 mutations, and the phenotype of disorder has expanded. Cases of Rett syndrome in males are rare and a total of 17 such cases have been reported. This case extends the clinical phenotype of Rett syndrome in males and associates this mutation with mitochondrial dysfunction.

Keywords

Rett syndrome microcephaly mitochondria

Get full access to this article

View all access options for this article.

References

Woods GC Human microcephaly. Curr Opin Neurobiol. 2004 ; 14(1):112-177.

Hagberg B. , Aicardi J. , Dias K. , Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett syndrome: report of 35 cases. Ann Neurol. 1983;14(4): 471-479.

Amir RE , Van den Veyver IB , Wan M. , Tran CQ , Francke U. , Zoghbi HY Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185-188.

Bebbington B. , Anderson A. , Ravine D. , et al. Investigating genotype-phenotype relationships in Rett syndrome using an international data set. Neurology . 2008;70(11):868-875.

Schule B. , Armstrong DD , Vogel H. , Oviedo A. , Francke U. Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure. Clin Genet. 2008;74(2):116-126.

Ghosh RP , Horowitz-Scherer RA , Nikitina T. , Gierasch LM , Woodcock CL Rett syndrome-causing mutations in human MeCP2 result in diverse structural changes that impact folding and DNA interaction. J Biol Chem . 2008;283(29): 20523-20534.

Palmer A. , Qayumi J. , Ronnett G. MeCP2 mutation causes distinguishable phases of acute and chronic defects in synaptogenesis and maintenance, respectively. Mol Cell Neurosci. 2008;37(4): 794-807.

Kriaucionis S. , Paterson A. , Curtis J. , Guy J. , Macleod N. , Bird A. Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol Cell Biol. 2006; 26(13):5033-5042.

Kankirawatana P. , Leonard H. , Ellaway C. , et al. Early progressive encephalopathy in boys and MECP2 mutations. Neurology. 2006; 67(1):164-166.

10.

Neul JL , Fang P. , Barrish J. , et al. Specific mutations in MethylCpG-Binding Protein 2 confer different severity in Rett Syndrome. Neurology. 2008 ;70(16):1313-1321.

11.

Dayer AG , Bottani A. , Bouchardy I. , et al. MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain and Dev. 2007;29(1):47-50.

12.

Percy AK Genetics of Rett syndrome: properties of the newly discovered gene and pathobiology of the disorder. Curr Opin Pediatr. 2000;12(6):589-595.

13.

Ventura P. , Galluzzi R. , Bacca SM , Giorda R. , Massagli A. A novel familial MECP2 mutation in a young boy: clinical and molecular findings . Neurology. 2006;67(5):867-868.

14.

Raffaele LS , Engerstrom IW , Schanen C. Occurrence of Rett syndrome in boys. J Child Neurol. 2001;16(5):333-338.

15.

Saneto RP , Friedman SD , Shaw DW Neuroimaging of mitochondrial disease. Mitochondrion. 2008;8(5-6):396-413.

16.

Belichenko PV , Wright EE , Belichenko NP , et al. Widespread changes in dendritic and axonal morphology in Mecp2-mutant mouse models of Rett syndrome: evidence for disruption of neuronal networks. J Comp Neurol. 2009;514(3):240-258.