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MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother
Brain & Development 29 (2007) 47–50 www.elsevier.com/locate/braindev
Case report
MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother Alexandre G. Dayer a,*, Armand Bottani a, Isabelle Bouchardy a, Joel Fluss b, Stylianos E. Antonarakis a, Charles-Antoine Haenggeli b, Michael A. Morris a a
Service of Medical Genetics and Neuropediatric Unit, Geneva University Hospitals, 1 rue Michel-Servet 1211, Geneva Switzerland b Neuropediatric Unit, Geneva University Hospital, 1 rue Michel-Servet 1211, Geneva, Switzerland Received 16 February 2006; received in revised form 31 May 2006; accepted 9 June 2006
Abstract Rett syndrome is a severe neurodevelopmental disorder affecting principally females and characterized by a normal postnatal development followed by stagnation and regression of acquired skills. We report a 4-year-old boy with a Rett syndrome phenotype and his unaffected mother both carrying a 44 bp truncating deletion mutation (c.1158del44 or p.388X) in the MECP2 gene. The presence of a skewed X inactivation in the mother provides a possible explanation for the absence of penetrance. The finding of a MECP2 mutation in an unaffected female complicates genetic counseling and further confirms that it is essential to look for mutations in the mothers of all patients with MECP2 mutations. Ó 2006 Elsevier B.V. All rights reserved. Keywords: MECP2; Rett syndrome; Mental retardation; X-linked disease
1. Introduction Rett syndrome (RTT, MIM #312750) is a severe neurodevelopmental disorder affecting almost exclusively females and classically characterized by a normal postnatal development followed by stagnation and regression of acquired skills such as language and purposeful movement of the hands [1]. Mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) were first identified in female RTT patients [2]. Recently MECP2 mutations to have been found in males presenting a wide phenotypic spectrum: some died in early infancy consecutively to severe encephalopathies [3,4], others displayed developmental delay associated with seizures and neurological disorders [5–9], while others showed non-specific mental retardation [10]. *
Corresponding author. Tel.: +41 22 379 53 41; fax: +41 22 379 57
06. E-mail address: [email protected] (A.G. Dayer). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.06.001
We report a 4-year-old boy with a Rett syndrome phenotype and his unaffected mother both carrying a 44 bp truncating deletion mutation (c.1158del44 or p.388X) in the MECP2 gene. The significance of these results is discussed in the context of an emerging genetic and clinical understanding of MECP2 mutations in males.
2. Material and methods 2.1. Clinical description The patient was born at term after a pregnancy marked by diminished foetal movements. Delivery and neonatal period were unremarkable; birth weight (2700 g) and OFC (31.5 cm) were below the 10th centile, while length (47 cm) was at the 10th centile; Apgar scores were 9/10/10. The parents were 24 (mother) and 26 years old (father), healthy, and of normal intelli-
48
A.G. Dayer et al. / Brain & Development 29 (2007) 47–50
gence. The mother did not present any of the clinical symptoms observed in Rett syndrome. There was no consanguinity. At 4 months, the baby was placid and hypotonic. At 8 months convergent alternating strabismus and hypermetropia (+4.75 dioptres) were noted. Sitting was achieved at 10 months. At 15 months the boy could only stand with help and unstably. First words were said at 20 months. At this age, EEG, brain CT scan and blood karyotype did not reveal any abnormality. At 26–27 months, the patient could only walk with the help of a frame, but could turn over and crawl unaided. He could pronounce very few words (‘‘mama’’, ‘‘baba’’). Intention tremor of the upper limbs and saccadic eye movements were observed. Clinical examination revealed a mentally retarded, sociable, happily disposed boy; height and OFC were below the 3rd centile (80 and 46 cm respectively). There was marked brachycephaly, intermittent convergent strabismus, low-set anteverted ears, a prominent frontal upsweep (‘‘cow lick’’), slight axial hypotonia but no scoliosis. Language was lost by 32 months. At the age of 46 months, motor regression was evident, the child being unable to crawl or stand anymore. Seizures (up to 20 episodes/day) characterized by tonic upper limb movements, eye revulsion and loss of contact were observed. EEG showed bilateral frontal paroxysmal discharges. At that time he also developed gastro-oesophageal reflux. Clinical examination at 47 months revealed: height 90 cm, weight 12.3 kg, OFC 47 cm (all < P3), involuntary stereotypic hand movements and frequent handto-mouth movements, intention tremor, permanent head nodding, intermittent convergent strabismus, multidirectional nystagmus, bruxism, absent speech with nonverbal sounds, spasticity of the lower limbs with hyperreflexia and a bilateral Babinski sign. Brain MRI with spectroscopy was normal. At this time, the diagnosis of ‘‘male Rett syndrome’’ was considered and mutation analysis of the MECP2 gene performed.
Table 1 Primers for amplification of MECP2 gene fragments
2.2. Mutation analysis
PCR analysis of genomic DNA revealed an apparent deletion within exon 4 identified by sequencing as a 44 bp deletion beginning at nucleotide position 1158, coded c.1158del44 (Fig. 1). This mutation was predicted to result in a frame-shift at codon 386 and subsequent premature truncation of the MeCP2 protein just two amino acids downstream (p.388X). PCR analysis of leukocyte DNA from the mother and DNA sequencing indicated that she was a heterozygous carrier of the same deletion (Fig. 1). DNA polymorphism analysis showed that the deletion occurred on the grandpaternal allele (alleles for the markers FMR1 (Xq27.3) and F8C (Xq28) were respectively: grandfather 2 1; mother 1/2 1/2; patient 2 1) and was de novo in the mother.
Genomic DNA was prepared from blood leukocytes by standard techniques (Puregene, Gentra). The three coding exons and the flanking intronic sequences of MECP2-A isoform were separately PCR-amplified from genomic DNA in 8 fragments, using the primer pairs shown in Table 1. For mutation identification, PCR products were first verified by agarose electrophoresis and then scanned for sequence variants by non-radioactive single-stranded conformation analysis (SSCA) using the Genephor system (Amersham Biotech). PCR products were sequenced directly with Big Dye terminator version 3 on an ABI 3100 (Applied Biosystems, Rotkreuz, Switzerland).
Fragment
Sequence of primers
Exon 2
L: 5 0 -GTTATGTCTTTAGTCTTTGG-3 0 R: 5 0 -TGTGTTTATCTTCAAAATGT-3 0 L: 5 0 -CCTGCCTCTGCTCACTTGTT-3 0 R: 5 0 -GGGGTCATCATACATGGGTC-3 0 L: 5 0 -AGCCCGTGCAGCCATCAGCC-3 0 R: 5 0 -GTTCCCCCCGACCCCACCCT-3 0 L: 5 0 -GCCCAGAGGAGGCTCACTG-3 0 R: 5 0 -TTGCAATCCGCTCCGTGTA-3 0 L: 5 0 -TGGCTCCTTGGGGCAGCCGT-3 0 R: 5 0 -GGGCGCAGCAGCAGCGCCTC-3 0 L: 5 0 -TGATGGTGGTGGTGCTCCTTC-3 0 R: 5 0 -TGGTGGCAGCCGCTGCCGCCGAG-3 0 L: 5 0 -CTCCTGCACAGATCGGATAGAA-3 0 R: 5 0 -CAAAGGGAGCGGCACCAC-3 0 L: 5 0 -GCACACCCTCTGACGTGG-3 0 R: 5 0 -CCTCTAATTGTTCCTTGTGTC-3 0
Exon 3.1 Exon 3.2 Exon 4.1 Exon 4.2 Exon 4.3 Exon 4.4 Exon 4.5
2.3. Parental origin The parental origin of the mutation was determined by microsatellite analysis of markers linked to the FMR1 and F8C loci (respectively centromeric and telomeric to MECP2), using standard techniques. 2.4. X chromosome inactivation X chromosome inactivation was studied as described [11] using PCR analysis of the ZNF261 loci, which contain methylation-sensitive restriction sites (CfoI) and highly polymorphic STR (small tandem repeats) allowing differentiation of the two alleles. Inactivation bias is evaluated by comparison of relative allele intensities after PCR amplification of intact genomic DNA and genomic DNA predigested to completion with CfoI and capillary electrophoresis.
3. Results
A.G. Dayer et al. / Brain & Development 29 (2007) 47–50
49
A Grandfather
Mother
Patient
C
Grandfather
Mother
Patient
Father
B
IntactDNA
het norm del44
After CfoI digestion
1
3
4
5
6
Fig. 1. (A) Sequence analysis of the MECP2 deletion in the maternal grandfather (normal sequence), in the mother (heterozygous for the deletion) and the patient (deleted). Bar: the deleted sequence; arrowheads: the position of the deletion. Traces were obtained with a reverse primer and represent the reverse and complement of the coding sequence. (B) PCR analysis of the normal and mutant c.1158del44 allele. Lane 1, size markers. Lanes 3–6, PCRs of genomic (leukocyte) DNA from the patient; his parents and maternal grandfather. het, heteroduplex; norm, normal allele; del44: mutant c.1158del44 allele. (C) ZNF261 analysis reveals a skewed inactivation of the mother’s X chromosomes with a ratio of approximately 95:5. Using capillary electrophoresis, PCR amplification of intact mother DNA shows two peaks of almost equal heights (upper line peaks). After CfoI digestion (which digests only unmethylated alleles), the larger allele shows considerably lower levels of amplification compared to the smaller (lower line peaks). The figures represent the peak heights determined with Genotyper (Applied Biosystems, Foster City, California).
Skewed inactivation of the mother’s X chromosomes in leukocyte DNA was revealed by ZNF261 analysis with a ratio of approximately 95:5 (Fig. 1).
4. Discussion This patient with a truncating deletion mutation of MECP2 fulfills the revised diagnostic criteria for Rett syndrome [1] and confirms that males with MECP2 mutations can present a phenotype closely resembling classical female Rett syndrome. Review of the published male MECP2 mutations suggests that in males, severe mutations responsible for typical Rett syndrome in females cause lethal neonatal encephalopathy unless attenuated by somatic mosaicism or an XXY karyotype [5]. In contrast, milder mutations (for example certain missense mutations) are present in patients with a wide range of clinical pictures from male
Rett syndrome [8,9] to non-specific X-linked mental retardation and even early onset schizophrenia [10]. C-terminal truncation mutations such as the one described here are typically found in females with classical, sporadic Rett syndrome. It was therefore entirely unanticipated to find that the mother of our patient was heterozygous for the mutation while having a normal intellect and no evident neurological symptoms. The discovery of a skewed X-chromosome inactivation (XCI) provides a possible explanation for the lack of penetrance of the mutated allele, since asymptomatic female carriers with highly skewed XCI have been occasionally described [3]. In conclusion, the finding of a MECP2 mutation in an asymptomatic female further confirms that it is essential to look for mutations in the mothers of all patients with MECP2 mutations. In families such as the one we describe, genetic counseling would be extremely difficult were the mutation to be transmitted to a female foetus.
50
A.G. Dayer et al. / Brain & Development 29 (2007) 47–50
We suggest that the X-inactivation status be examined in asymptomatic carriers, in the aim of elucidating the absence of penetrance in a minority of heterozygotes.
[4]
[5]
Acknowledgement We thank Simon Merolle for technical assistance.
References [1] Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol 2002;6:293–7. [2] 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;23:185–8. [3] Wan M, Lee SS, Zhang X, Houwink-Manville I, Song HR, Amir RE, et al. Rett syndrome and beyond: recurrent spontaneous and
[6]
[7]
[8] [9]
[10]
[11]
familial MECP2 mutations at CpG hotspots. Am J Hum Genet 1999;65:1520–9. Villard L, Kpebe A, Cardoso C, Chelly PJ, Tardieu PM, Fontes M. Two affected boys in a Rett syndrome family: clinical and molecular findings. Neurology 2000;55:1188–93. Clayton-Smith J, Watson P, Ramsden S, Black GC. Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet 2000;356:830–2. Meloni I, Bruttini M, Longo I, Mari F, Rizzolio F, D’Adamo P, et al. A mutation in the rett syndrome gene, MECP2, causes Xlinked mental retardation and progressive spasticity in males. Am J Hum Genet 2000;67:982–5. Hoffbuhr K, Devaney JM, LaFleur B, Sirianni N, Scacheri C, Giron J, et al. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology 2001;56:1486–95. Budden SS, Dorsey HC, Steiner RD. Clinical profile of a male with Rett syndrome. Brain Dev 2005;27(Suppl 1):S69–71. Masuyama T, Matsuo M, Jing JJ, Tabara Y, Kitsuki K, Yamagata H, et al. Classic Rett syndrome in a boy with R133C mutation of MECP2. Brain Dev 2005;27:439–42. Couvert P, Bienvenu T, Aquaviva C, Poirier K, Moraine C, Gendrot C, et al. MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet 2001;10:941–6. Beever C, Lai BP, Baldry SE, Penaherrera MS, Jiang R, Robinson WP, et al. Methylation of ZNF261 as an assay for determining X chromosome inactivation patterns. Am J Med Genet A 2003;120:439–41.
Case report
MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother Alexandre G. Dayer a,*, Armand Bottani a, Isabelle Bouchardy a, Joel Fluss b, Stylianos E. Antonarakis a, Charles-Antoine Haenggeli b, Michael A. Morris a a
Service of Medical Genetics and Neuropediatric Unit, Geneva University Hospitals, 1 rue Michel-Servet 1211, Geneva Switzerland b Neuropediatric Unit, Geneva University Hospital, 1 rue Michel-Servet 1211, Geneva, Switzerland Received 16 February 2006; received in revised form 31 May 2006; accepted 9 June 2006
Abstract Rett syndrome is a severe neurodevelopmental disorder affecting principally females and characterized by a normal postnatal development followed by stagnation and regression of acquired skills. We report a 4-year-old boy with a Rett syndrome phenotype and his unaffected mother both carrying a 44 bp truncating deletion mutation (c.1158del44 or p.388X) in the MECP2 gene. The presence of a skewed X inactivation in the mother provides a possible explanation for the absence of penetrance. The finding of a MECP2 mutation in an unaffected female complicates genetic counseling and further confirms that it is essential to look for mutations in the mothers of all patients with MECP2 mutations. Ó 2006 Elsevier B.V. All rights reserved. Keywords: MECP2; Rett syndrome; Mental retardation; X-linked disease
1. Introduction Rett syndrome (RTT, MIM #312750) is a severe neurodevelopmental disorder affecting almost exclusively females and classically characterized by a normal postnatal development followed by stagnation and regression of acquired skills such as language and purposeful movement of the hands [1]. Mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) were first identified in female RTT patients [2]. Recently MECP2 mutations to have been found in males presenting a wide phenotypic spectrum: some died in early infancy consecutively to severe encephalopathies [3,4], others displayed developmental delay associated with seizures and neurological disorders [5–9], while others showed non-specific mental retardation [10]. *
Corresponding author. Tel.: +41 22 379 53 41; fax: +41 22 379 57
06. E-mail address: [email protected] (A.G. Dayer). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.06.001
We report a 4-year-old boy with a Rett syndrome phenotype and his unaffected mother both carrying a 44 bp truncating deletion mutation (c.1158del44 or p.388X) in the MECP2 gene. The significance of these results is discussed in the context of an emerging genetic and clinical understanding of MECP2 mutations in males.
2. Material and methods 2.1. Clinical description The patient was born at term after a pregnancy marked by diminished foetal movements. Delivery and neonatal period were unremarkable; birth weight (2700 g) and OFC (31.5 cm) were below the 10th centile, while length (47 cm) was at the 10th centile; Apgar scores were 9/10/10. The parents were 24 (mother) and 26 years old (father), healthy, and of normal intelli-
48
A.G. Dayer et al. / Brain & Development 29 (2007) 47–50
gence. The mother did not present any of the clinical symptoms observed in Rett syndrome. There was no consanguinity. At 4 months, the baby was placid and hypotonic. At 8 months convergent alternating strabismus and hypermetropia (+4.75 dioptres) were noted. Sitting was achieved at 10 months. At 15 months the boy could only stand with help and unstably. First words were said at 20 months. At this age, EEG, brain CT scan and blood karyotype did not reveal any abnormality. At 26–27 months, the patient could only walk with the help of a frame, but could turn over and crawl unaided. He could pronounce very few words (‘‘mama’’, ‘‘baba’’). Intention tremor of the upper limbs and saccadic eye movements were observed. Clinical examination revealed a mentally retarded, sociable, happily disposed boy; height and OFC were below the 3rd centile (80 and 46 cm respectively). There was marked brachycephaly, intermittent convergent strabismus, low-set anteverted ears, a prominent frontal upsweep (‘‘cow lick’’), slight axial hypotonia but no scoliosis. Language was lost by 32 months. At the age of 46 months, motor regression was evident, the child being unable to crawl or stand anymore. Seizures (up to 20 episodes/day) characterized by tonic upper limb movements, eye revulsion and loss of contact were observed. EEG showed bilateral frontal paroxysmal discharges. At that time he also developed gastro-oesophageal reflux. Clinical examination at 47 months revealed: height 90 cm, weight 12.3 kg, OFC 47 cm (all < P3), involuntary stereotypic hand movements and frequent handto-mouth movements, intention tremor, permanent head nodding, intermittent convergent strabismus, multidirectional nystagmus, bruxism, absent speech with nonverbal sounds, spasticity of the lower limbs with hyperreflexia and a bilateral Babinski sign. Brain MRI with spectroscopy was normal. At this time, the diagnosis of ‘‘male Rett syndrome’’ was considered and mutation analysis of the MECP2 gene performed.
Table 1 Primers for amplification of MECP2 gene fragments
2.2. Mutation analysis
PCR analysis of genomic DNA revealed an apparent deletion within exon 4 identified by sequencing as a 44 bp deletion beginning at nucleotide position 1158, coded c.1158del44 (Fig. 1). This mutation was predicted to result in a frame-shift at codon 386 and subsequent premature truncation of the MeCP2 protein just two amino acids downstream (p.388X). PCR analysis of leukocyte DNA from the mother and DNA sequencing indicated that she was a heterozygous carrier of the same deletion (Fig. 1). DNA polymorphism analysis showed that the deletion occurred on the grandpaternal allele (alleles for the markers FMR1 (Xq27.3) and F8C (Xq28) were respectively: grandfather 2 1; mother 1/2 1/2; patient 2 1) and was de novo in the mother.
Genomic DNA was prepared from blood leukocytes by standard techniques (Puregene, Gentra). The three coding exons and the flanking intronic sequences of MECP2-A isoform were separately PCR-amplified from genomic DNA in 8 fragments, using the primer pairs shown in Table 1. For mutation identification, PCR products were first verified by agarose electrophoresis and then scanned for sequence variants by non-radioactive single-stranded conformation analysis (SSCA) using the Genephor system (Amersham Biotech). PCR products were sequenced directly with Big Dye terminator version 3 on an ABI 3100 (Applied Biosystems, Rotkreuz, Switzerland).
Fragment
Sequence of primers
Exon 2
L: 5 0 -GTTATGTCTTTAGTCTTTGG-3 0 R: 5 0 -TGTGTTTATCTTCAAAATGT-3 0 L: 5 0 -CCTGCCTCTGCTCACTTGTT-3 0 R: 5 0 -GGGGTCATCATACATGGGTC-3 0 L: 5 0 -AGCCCGTGCAGCCATCAGCC-3 0 R: 5 0 -GTTCCCCCCGACCCCACCCT-3 0 L: 5 0 -GCCCAGAGGAGGCTCACTG-3 0 R: 5 0 -TTGCAATCCGCTCCGTGTA-3 0 L: 5 0 -TGGCTCCTTGGGGCAGCCGT-3 0 R: 5 0 -GGGCGCAGCAGCAGCGCCTC-3 0 L: 5 0 -TGATGGTGGTGGTGCTCCTTC-3 0 R: 5 0 -TGGTGGCAGCCGCTGCCGCCGAG-3 0 L: 5 0 -CTCCTGCACAGATCGGATAGAA-3 0 R: 5 0 -CAAAGGGAGCGGCACCAC-3 0 L: 5 0 -GCACACCCTCTGACGTGG-3 0 R: 5 0 -CCTCTAATTGTTCCTTGTGTC-3 0
Exon 3.1 Exon 3.2 Exon 4.1 Exon 4.2 Exon 4.3 Exon 4.4 Exon 4.5
2.3. Parental origin The parental origin of the mutation was determined by microsatellite analysis of markers linked to the FMR1 and F8C loci (respectively centromeric and telomeric to MECP2), using standard techniques. 2.4. X chromosome inactivation X chromosome inactivation was studied as described [11] using PCR analysis of the ZNF261 loci, which contain methylation-sensitive restriction sites (CfoI) and highly polymorphic STR (small tandem repeats) allowing differentiation of the two alleles. Inactivation bias is evaluated by comparison of relative allele intensities after PCR amplification of intact genomic DNA and genomic DNA predigested to completion with CfoI and capillary electrophoresis.
3. Results
A.G. Dayer et al. / Brain & Development 29 (2007) 47–50
49
A Grandfather
Mother
Patient
C
Grandfather
Mother
Patient
Father
B
IntactDNA
het norm del44
After CfoI digestion
1
3
4
5
6
Fig. 1. (A) Sequence analysis of the MECP2 deletion in the maternal grandfather (normal sequence), in the mother (heterozygous for the deletion) and the patient (deleted). Bar: the deleted sequence; arrowheads: the position of the deletion. Traces were obtained with a reverse primer and represent the reverse and complement of the coding sequence. (B) PCR analysis of the normal and mutant c.1158del44 allele. Lane 1, size markers. Lanes 3–6, PCRs of genomic (leukocyte) DNA from the patient; his parents and maternal grandfather. het, heteroduplex; norm, normal allele; del44: mutant c.1158del44 allele. (C) ZNF261 analysis reveals a skewed inactivation of the mother’s X chromosomes with a ratio of approximately 95:5. Using capillary electrophoresis, PCR amplification of intact mother DNA shows two peaks of almost equal heights (upper line peaks). After CfoI digestion (which digests only unmethylated alleles), the larger allele shows considerably lower levels of amplification compared to the smaller (lower line peaks). The figures represent the peak heights determined with Genotyper (Applied Biosystems, Foster City, California).
Skewed inactivation of the mother’s X chromosomes in leukocyte DNA was revealed by ZNF261 analysis with a ratio of approximately 95:5 (Fig. 1).
4. Discussion This patient with a truncating deletion mutation of MECP2 fulfills the revised diagnostic criteria for Rett syndrome [1] and confirms that males with MECP2 mutations can present a phenotype closely resembling classical female Rett syndrome. Review of the published male MECP2 mutations suggests that in males, severe mutations responsible for typical Rett syndrome in females cause lethal neonatal encephalopathy unless attenuated by somatic mosaicism or an XXY karyotype [5]. In contrast, milder mutations (for example certain missense mutations) are present in patients with a wide range of clinical pictures from male
Rett syndrome [8,9] to non-specific X-linked mental retardation and even early onset schizophrenia [10]. C-terminal truncation mutations such as the one described here are typically found in females with classical, sporadic Rett syndrome. It was therefore entirely unanticipated to find that the mother of our patient was heterozygous for the mutation while having a normal intellect and no evident neurological symptoms. The discovery of a skewed X-chromosome inactivation (XCI) provides a possible explanation for the lack of penetrance of the mutated allele, since asymptomatic female carriers with highly skewed XCI have been occasionally described [3]. In conclusion, the finding of a MECP2 mutation in an asymptomatic female further confirms that it is essential to look for mutations in the mothers of all patients with MECP2 mutations. In families such as the one we describe, genetic counseling would be extremely difficult were the mutation to be transmitted to a female foetus.
50
A.G. Dayer et al. / Brain & Development 29 (2007) 47–50
We suggest that the X-inactivation status be examined in asymptomatic carriers, in the aim of elucidating the absence of penetrance in a minority of heterozygotes.
[4]
[5]
Acknowledgement We thank Simon Merolle for technical assistance.
References [1] Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001. Eur J Paediatr Neurol 2002;6:293–7. [2] 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;23:185–8. [3] Wan M, Lee SS, Zhang X, Houwink-Manville I, Song HR, Amir RE, et al. Rett syndrome and beyond: recurrent spontaneous and
[6]
[7]
[8] [9]
[10]
[11]
familial MECP2 mutations at CpG hotspots. Am J Hum Genet 1999;65:1520–9. Villard L, Kpebe A, Cardoso C, Chelly PJ, Tardieu PM, Fontes M. Two affected boys in a Rett syndrome family: clinical and molecular findings. Neurology 2000;55:1188–93. Clayton-Smith J, Watson P, Ramsden S, Black GC. Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet 2000;356:830–2. Meloni I, Bruttini M, Longo I, Mari F, Rizzolio F, D’Adamo P, et al. A mutation in the rett syndrome gene, MECP2, causes Xlinked mental retardation and progressive spasticity in males. Am J Hum Genet 2000;67:982–5. Hoffbuhr K, Devaney JM, LaFleur B, Sirianni N, Scacheri C, Giron J, et al. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology 2001;56:1486–95. Budden SS, Dorsey HC, Steiner RD. Clinical profile of a male with Rett syndrome. Brain Dev 2005;27(Suppl 1):S69–71. Masuyama T, Matsuo M, Jing JJ, Tabara Y, Kitsuki K, Yamagata H, et al. Classic Rett syndrome in a boy with R133C mutation of MECP2. Brain Dev 2005;27:439–42. Couvert P, Bienvenu T, Aquaviva C, Poirier K, Moraine C, Gendrot C, et al. MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet 2001;10:941–6. Beever C, Lai BP, Baldry SE, Penaherrera MS, Jiang R, Robinson WP, et al. Methylation of ZNF261 as an assay for determining X chromosome inactivation patterns. Am J Med Genet A 2003;120:439–41.