Clinical expression of Menkes disease in females with normal karyotype
<p>Abstract</p> <p>Background</p> <p>Menkes Disease (MD) is a rare X-linked recessive fatal neurodegenerative disorder caused by mutations in the <it>ATP7A </it>gene, and most patients are males. Female carriers are mosaics of wild-type and mutant cells due...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2012-01-01
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| Series: | Orphanet Journal of Rare Diseases |
| Online Access: | http://www.ojrd.com/content/7/1/6 |
| _version_ | 1818551670417653760 |
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| author | Møller Lisbeth Lenartowicz Malgorzata Zabot Marie-Therese Josiane Arnaud Burglen Lydie Bennett Chris Riconda Daniel Fisher Richard Janssens Sandra Mohammed Shehla Ausems Margreet Tümer Zeynep Horn Nina Jensen Thomas G |
| author_facet | Møller Lisbeth Lenartowicz Malgorzata Zabot Marie-Therese Josiane Arnaud Burglen Lydie Bennett Chris Riconda Daniel Fisher Richard Janssens Sandra Mohammed Shehla Ausems Margreet Tümer Zeynep Horn Nina Jensen Thomas G |
| author_sort | Møller Lisbeth |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Menkes Disease (MD) is a rare X-linked recessive fatal neurodegenerative disorder caused by mutations in the <it>ATP7A </it>gene, and most patients are males. Female carriers are mosaics of wild-type and mutant cells due to the random X inactivation, and they are rarely affected. In the largest cohort of MD patients reported so far which consists of 517 families we identified 9 neurologically affected carriers with normal karyotypes.</p> <p>Methods</p> <p>We investigated at-risk females for mutations in the <it>ATP7A </it>gene by sequencing or by multiplex ligation-dependent probe amplification (MLPA). We analyzed the X-inactivation pattern in affected female carriers, unaffected female carriers and non-carrier females as controls, using the human androgen-receptor gene methylation assay (<it>HUMAR</it>).</p> <p>Results</p> <p>The clinical symptoms of affected females are generally milder than those of affected boys with the same mutations. While a skewed inactivation of the X-chromosome which harbours the mutation was observed in 94% of 49 investigated unaffected carriers, a more varied pattern was observed in the affected carriers. Of 9 investigated affected females, preferential silencing of the normal X-chromosome was observed in 4, preferential X-inactivation of the mutant X chromosome in 2, an even X-inactivation pattern in 1, and an inconclusive pattern in 2. The X-inactivation pattern correlates with the degree of mental retardation in the affected females. Eighty-one percent of 32 investigated females in the control group had moderately skewed or an even X-inactivation pattern.</p> <p>Conclusion</p> <p>The X- inactivation pattern alone cannot be used to predict the phenotypic outcome in female carriers, as even those with skewed X-inactivation of the X-chromosome harbouring the mutation might have neurological symptoms.</p> |
| first_indexed | 2024-12-12T09:02:59Z |
| format | Article |
| id | doaj.art-bc15a5c9398a4fd2b6e016d76ea537a9 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-12T09:02:59Z |
| publishDate | 2012-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-bc15a5c9398a4fd2b6e016d76ea537a92022-12-22T00:29:47ZengBMCOrphanet Journal of Rare Diseases1750-11722012-01-0171610.1186/1750-1172-7-6Clinical expression of Menkes disease in females with normal karyotypeMøller LisbethLenartowicz MalgorzataZabot Marie-ThereseJosiane ArnaudBurglen LydieBennett ChrisRiconda DanielFisher RichardJanssens SandraMohammed ShehlaAusems MargreetTümer ZeynepHorn NinaJensen Thomas G<p>Abstract</p> <p>Background</p> <p>Menkes Disease (MD) is a rare X-linked recessive fatal neurodegenerative disorder caused by mutations in the <it>ATP7A </it>gene, and most patients are males. Female carriers are mosaics of wild-type and mutant cells due to the random X inactivation, and they are rarely affected. In the largest cohort of MD patients reported so far which consists of 517 families we identified 9 neurologically affected carriers with normal karyotypes.</p> <p>Methods</p> <p>We investigated at-risk females for mutations in the <it>ATP7A </it>gene by sequencing or by multiplex ligation-dependent probe amplification (MLPA). We analyzed the X-inactivation pattern in affected female carriers, unaffected female carriers and non-carrier females as controls, using the human androgen-receptor gene methylation assay (<it>HUMAR</it>).</p> <p>Results</p> <p>The clinical symptoms of affected females are generally milder than those of affected boys with the same mutations. While a skewed inactivation of the X-chromosome which harbours the mutation was observed in 94% of 49 investigated unaffected carriers, a more varied pattern was observed in the affected carriers. Of 9 investigated affected females, preferential silencing of the normal X-chromosome was observed in 4, preferential X-inactivation of the mutant X chromosome in 2, an even X-inactivation pattern in 1, and an inconclusive pattern in 2. The X-inactivation pattern correlates with the degree of mental retardation in the affected females. Eighty-one percent of 32 investigated females in the control group had moderately skewed or an even X-inactivation pattern.</p> <p>Conclusion</p> <p>The X- inactivation pattern alone cannot be used to predict the phenotypic outcome in female carriers, as even those with skewed X-inactivation of the X-chromosome harbouring the mutation might have neurological symptoms.</p>http://www.ojrd.com/content/7/1/6 |
| spellingShingle | Møller Lisbeth Lenartowicz Malgorzata Zabot Marie-Therese Josiane Arnaud Burglen Lydie Bennett Chris Riconda Daniel Fisher Richard Janssens Sandra Mohammed Shehla Ausems Margreet Tümer Zeynep Horn Nina Jensen Thomas G Clinical expression of Menkes disease in females with normal karyotype Orphanet Journal of Rare Diseases |
| title | Clinical expression of Menkes disease in females with normal karyotype |
| title_full | Clinical expression of Menkes disease in females with normal karyotype |
| title_fullStr | Clinical expression of Menkes disease in females with normal karyotype |
| title_full_unstemmed | Clinical expression of Menkes disease in females with normal karyotype |
| title_short | Clinical expression of Menkes disease in females with normal karyotype |
| title_sort | clinical expression of menkes disease in females with normal karyotype |
| url | http://www.ojrd.com/content/7/1/6 |
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