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In both cases, numerical aberrations of ihe X chromosomes as a cause for the uncommon fiuorescent PCR patrerns were excluded by rhe presence of a normal 46,XX karyorype.

These rwo patients show a similar deletion with an equivalent mosaicism race in blood, bur a distinct clinicaJ presenration. X inacrivation study on probanci 1 with typical Rert syndrome showed a random partem of inactivarion in rhe periphera! blood. Although the results have co be extrapo!ated from the peripheraJ blood cells, it would suggest that in the brain the majoriry of murated X chromosomes may remain active in the gir; with dassicai Ren syndrome. Our results illusrrate cJearly once again the difficulty in esrablishing a correlation berween genotype ar.d phenotype in RTT.

Recenrly, a boy with a mosaic mutation has been describedT To our knowledge, we show for the first time that somatic mosaicism for MECP2 mutation in girls is not infreąuent (iwo somatic murations on 102 puiarive RTT cases studiea) and may cause different phenorypes. These clinical and molecular hndings suggest that multiple forms of mosaicism (X inacriva-tion mosaicism and somatic mosaicism) may be presenr in a single paiienr with RTT. Mosaicism has been documented for chromosomai abnormaliries, mitochondnaJ murations, triplet repeats,"³ and in a growing number of dominant and recessive X Jinked gene disorders, such as Duchenne muscular dystrophyy⁴ hae-mophilia B/' Conradi-Hunermann-Happle syndrome,^:e and double corte.N/Iissencephaly syndrome.*" Because a proporrion of cells carry the mutation not only in blood but also in tis-sues dermng from other celi lineages. it musi be assumed that the mutation occurred very eariy during embryogenesis.

Finally, the derection of mosaic mutation depends mainly on the method used for the identihcation of mutations within the MECP2 gene. Nowadays. the method of choice for identifying deleterious murations relies on direer DNA seąuencing. The ability of this method to derect mosaic mutations is poor, which is parricularly truć when the mosaicism rare is Iow. Our findings underline the need for ar least two complemenrary approaches, such as methods based on heterodup!ex analysis and seąuencing, for an efhcient screening of the MECP2 gene.

Vfc thank Dr Dcblay tor criucal advice, Dr rlnrencc Rousselci for her techntcał contnbution, and rAssoctation Franęaisc du Syndrome dc Ren, l’Assoriatton Franęaisc contrę Ics myopa-tbirs, and the Minisierc dc rEducation Nationale, dc la Re che r-che et dc Ja Technologie for their łinunciai support.

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MECP2 gene in a cohort of girls wiih Rc:t senJrome. 7 M<d Gam 2000;37:010-12.

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K, Horiuchi I, Kagamitsu S, Iwanaga R, Kimura A, Omon J, Endo S, Mori K, Kondo I. Mutation analysis of the methvl-CpG btnding protein 2 gene (MEC1*2) in patients with kert syndrome. JMcd Gam 2000;37:60S-10.

14    W art M, l^c SS, Zhanę X, Houwink MI, Song HR. Amir

RE, Buddęn S, N^:aidu S, Pereira Jl^ Lo IF, Żoghbi HY, Schancn NC, Franckc U. Rett syndrome and bcyond: recurrcnt spontaneous and familia! MECP2 mutations at CpG hotspots. Am J Huni Gam l^r<°9;65:l 520-°

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