Genetyczne przyczyny upośledzenia umysłowego, z którymi neurolog może spotkać się w codziennej praktyce

• Authors: Karol Jastrzębski , Magdalena Justyna Kacperska , Tadeusz Pietras , Maciej Radek

Title variants

EN

The genetic causes of mental retardation, which the neurologist may encounter in everyday practice

• Languages of publication: PL

Abstracts

PL

Upośledzenie umysłowe określane jest jako istotnie niższy od przeciętnego poziom funkcjonowania intelektualnego, występujący łącznie z upośledzeniem w zakresie przystosowania się, wiążący się ze zmianami w ośrodkowym układzie nerwowym. Zamiennie używa się takich terminów, jak: niedorozwój umysłowy, zahamowanie rozwoju umysłowego, obniżenie sprawności intelektualnych, opóźnienie rozwoju umysłowego oraz niepełnosprawność intelektualna, ostatnio zaś mówi się o zaburzeniach w uczeniu się. W latach 90. XX wieku nastąpiły ogromne zmiany w ujęciu upośledzenia umysłowego. Nastąpiło odejście od tradycyjnej, medycznej i biologicznej koncepcji, według której upośledzenie było traktowane jako stan nieodwracalny i wyznaczający niski pułap rozwojowy. Upośledzenie umysłowe jest nie tylko zaburzeniem biologicznym, ale także psychologicznym stanem, do którego dochodzi się w rezultacie nieprawidłowego procesu rozwojowego. Wpływ na ten stan mają: okres prenatalny (naświetlanie promieniami rentgenowskimi, zażywanie przez matkę leków w czasie ciąży, alkohol, dym papierosowy, narkotyki, wirusowe i bakteryjne zakażenia, czynniki immunologiczne), okres perinatalny (wstrząs dla rodzącego się dziecka, uszkodzenia funkcjonowania mózgu, przedwczesny poród, zamartwica, błędy jatrogenne w okresie okołoporodowym) oraz okres postnatalny [przebyte choroby zakaźne i powikłania (odra i krztusiec), urazy (wypadki), zatrucia (np. ołowiem) oraz zatrucia pokarmowe]. Klasyfikacja upośledzeń umysłowych może być rozmaita, zależy od wybranego kryterium. Najbardziej znana jest czterostopniowa klasyfikacja: 1) upośledzenie w stopniu lekkim, 2) umiarkowanym, 3) znacznym oraz 4) głębokim. Jak wykazano, bardzo ważną rolę w przypadku przyczyn upośledzeń umysłowych odgrywają czynniki genetyczne. Wśród czynników genetycznych powodujących upośledzenie umysłowe wyróżnia się zmiany związane z: liczbą lub strukturą chromosomów, mutacjami pojedynczego genu, poligenowym i epigenetycznym dziedziczeniem cechy. Coraz więcej badaczy koncentruje się na wnikliwej ocenie roli czynników genetycznych w przypadku tych zaburzeń. Nie wszystkie czynniki, jak dotąd, zostały odkryte i dokładnie zbadane, zatem niezbędne są dalsze badania. Nie ulega również wątpliwości, iż upośledzenie umysłowe, autyzm oraz padaczka mają ze sobą wiele wspólnego, gdyż część pacjentów spełnia kryterium rozpoznania wszystkich ww. jednostek chorobowych. Prezentowana praca przedstawia wybrane jednostki chorobowe i ich genetyczne podłoże.

EN

Mental retardation is defined as significantly lower than the average level of intellectual functioning in association with impairments in adapting, binding to changes in the central nervous system. Alternatively, such terms as mental stunting, reduced intellectual performance, mental retardation and intellectual disability, and more recently learning disorders, are used. In the 1990s there have been tremendous changes in terms of mental retardation by deviating from the traditional medical and biological concepts, according to which the impairment was treated as a state of irreversible and defining a low ceiling development. Mental retardation is not only biological disorder, but also the psychological state which occurs as a result of improper development process. The impact on this state are: the prenatal period (exposure to X-ray beam, the use of drugs by the mother during pregnancy, alcohol, cigarette smoke, drugs, viral and bacterial infections, immune factors), the perinatal period (shock to the newborn child, the brain damage, premature birth, asphyxia, iatrogenic mistakes) and postnatal period [a history of infectious diseases and complications of (measles and whooping cough), trauma (accidents), poisoning (e.g. lead) and food poisoning]. Classification of intellectual disability can be very different depending on the selected criteria. The most famous is a four stage classification of degrees: 1) light, 2) moderate, 3) a large and 4) deep retardation. As shown, genetic factors play a very important role in the causes of mental disability. Among the genetic factors that cause impairment are distinguished: changes in the number or structure of chromosomes, single-gene mutation, polygene and epigenetic heredity. More and more researchers focus on in-depth assessment of the role of genetic factors for these disorders. Not all of the factors has been discovered and thoroughly investigated, so further research is necessary. It is also clear that mental retardation, autism and epilepsy have a lot in common. Presented by us work presents some of the disease and their genetic causes.

Keywords

EN

Angelman syndrome; Duchenne muscular dystrophy; Prader-Willi syndrome; Rett syndrome; Smith-Lemli-Opitz syndrome; czynniki genetyczne; dystrofia mięśniowa typu Duchenne’a; genetic factors; mental retardation; mental retardation associated with fragile X chromosome; neurology; stwardnienie guzowate; tuberous sclerosis; upośledzenie umysłowe; upośledzenie umysłowe związane z łamliwościąchromosomu X; zespół Angelmana; zespół Pradera-Williego; zespół Retta; zespół Smitha-Lemliego-Opitza

Discipline

• MEDICINE: MEDICINE

• Publisher: Medical Communications
• Journal: Aktualności Neurologiczne
• Year: 2013
• Volume: 13
• Issue: 2
• Pages: 119–129

Contributors

author

Karol Jastrzębski

• Klinika Neurologii i Epileptologii, Katedra Chorób Układu Nerwowego, Uniwersytet Medyczny w Łodzi

author

Magdalena Justyna Kacperska

• Klinika Neurologii i Epileptologii, Katedra Chorób Układu Nerwowego, Uniwersytet Medyczny w Łodzi

author

Tadeusz Pietras

• Klinika Pneumonologii i Alergologii, Uniwersytet Medyczny w Łodzi

author

Maciej Radek

• Klinika Neurochirurgii i Chirurgii Nerwów Obwodowych, Uniwersytecki Szpital Kliniczny im. Wojskowej Akademii Medycznej w Łodzi – Centralny Szpital Weteranów

References

• 1. Prather P., de Vries P.J.: Behavioral and cognitive aspects of tuberous sclerosis complex. J. Child Neurol. 2004; 19: 666–674.
• 2. Jozwiak S., Goodman M., Lamm S.H.: Poor mental development in patients with tuberous sclerosis complex: clinical risk factors. Arch. Neurol. 1998; 55: 379–384.
• 3. Roach E.S., Gomez M.R., Northrup H.: Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J. Child Neurol. 1998; 13: 624–628.
• 4. Lazarowski A., Lubieniecki F., Camarero S. i wsp.: Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy. Pediatr. Neurol. 2004; 30: 102–106.
• 5. Jozwiak S., Schwartz R.A., Janniger C.K. i wsp.: Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance. Int. J. Dermatol. 1998; 37: 911–917.
• 6. van Slegtenhorst M., de Hoogt R., Hermans C. i wsp.: Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277: 805–808.
• 7. Tapon N., Ito N., Dickson B.J. i wsp.: The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001; 105: 345–355.
• 8.Nellist M., Brook-Carter P.T., Connor J.M. i wsp.: Identification of markers flanking the tuberous sclerosis locus on chromosome 9 (TSC1). J. Med. Genet. 1993; 30: 224–227.
• 9. Sherr C.J.: Principles of tumor suppression. Cell 2004; 116: 235–246.
• 10. Garami A., Zwartkruis F.J., Nobukuni T. i wsp.: Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 2003; 11: 1457–1466.
• 11. Roach E.S., Sparagana S.P.: Diagnosis of tuberous sclerosis complex. J. Child Neurol. 2004; 19: 643–649.
• 12. O’Callaghan F.J.: Tuberous sclerosis. BMJ 1999; 318: 1019–1020.
• 13. Tee A.R., Manning B.D., Roux P.P. i wsp.: Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 2003; 13: 1259–1268.
• 14. Abraham R.T.: Identification of TOR signaling complexes: more TORC for the cell growth engine. Cell 2002; 111: 9–12.
• 15. Inoki K., Zhu T., Guan K.L.: TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115: 577–590.
• 16. O’Callaghan F.J., Shiell A.W., Osborne J.P., Martyn C.N.: Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet 1998; 351: 1490.
• 17. Jóźwiak S., Kotulska K.: Stwardnienie guzowate – zmiany skórne i narządowe. Neurologia – Magazyn Neurologów, NR, 2 maja 2005 r. (płyta CD).
• 18. Gold A.P.: Stwardnienie guzowate. W: Rowland L.P. (red.): Neurologia Merritta. Urban & Partner, Wrocław 2004: 596–601.
• 19. Carsillo T., Astrinidis A., Henske E.P.: Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc. Natl Acad. Sci. USA 2000; 97: 6085–6090.
• 20. Herry I., Neukirch C., Debray M.P. i wsp.: Dramatic effect of sirolimus on renal angiomyolipomas in a patient with tuberous sclerosis complex. Eur. J. Intern. Med. 2007; 18: 76–77.
• 21. Franz D.N., Leonard J., Tudor C. i wsp.: Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. 2006; 59: 490–498.
• 22. Ehninger D., Silva A.J.: Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders. Trends Mol. Med. 2010; 17: 78–87.
• 23. Rett A.: [On a unusual brain atrophy syndrome in hyperammonemia in childhood]. Wien. Med. Wochenschr. 1966; 116: 723–726.
• 24. Rett A.: Über ein eigenartiges hirnatrophisches Syndrom bei Hyperammonämie im Kindesalter. Wien. Med. Wochenschr. 1966; 116: 723–726.
• 25. Hagberg B., Aicardi J., Dias K., Ramos O.: A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann. Neurol. 1983; 14: 471–479.
• 26. Boltshauser E., Künzle C.: Prevalence of Rett syndrome in Switzerland. Helv. Paediatr. Acta 1987; 42: 407–411.
• 27. Skjeldal O.H., von Tetzchner S., Aspelund F. i wsp.: Rett syndrome: geographic variation in prevalence in Norway. Brain Dev. 1997; 19: 258–261.
• 28. Laurvick C.L., de Klerk N., Bower C. i wsp.: Rett syndrome in Australia: a review of the epidemiology. J. Pediatr. 2006; 148: 347–352.
• 29. Guideri F., Acampa M., Hayek G. i wsp.: Reduced heart rate variability in patients affected with Rett syndrome. A possible explanation for sudden death. Neuropediatrics 1999; 30: 146–148.
• 30. Laurvick C.L., Msall M.E., Silburn S. i wsp.: Physical and mental health of mothers caring for a child with Rett syndrome. Pediatrics 2006; 118: e1152–e1164.
• 31. Lee S.S., Wan M., Francke U.: Spectrum of MECP2 mutations in Rett syndrome. Brain Dev. 2001; 23 supl. 1: S138–S143.
• 32. Percy A.K., Neul J.L., Glaze D.G. i wsp.: Rett syndrome diagnostic criteria: lessons from the Natural History Study. Ann. Neurol. 2010; 68: 591–595.
• 33. Amir R.E., Van den Veyver I.B., Wan M. i wsp.: Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat. Genet. 1999; 23: 185–188.
• 34. Sirianni N., Naidu S., Pereira J. i wsp.: Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am. J. Hum. Genet. 1998; 63: 1552–1558.
• 35. Scala E., Ariani F., Mari F. i wsp.: CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms. J. Med. Genet. 2005; 42: 103–107.
• 36. Hanefeld F.: The clinical pattern of the Rett syndrome. Brain Dev. 1985; 7: 320–325.
• 37. Mari F., Azimonti S., Bertani I. i wsp.: CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. Hum. Mol. Genet. 2005; 14: 1935–1946.
• 38. Ariani F., Hayek G., Rondinella D. i wsp.: FOXG1 is responsible for the congenital variant of Rett syndrome. Am. J. Hum. Genet. 2008; 83: 89–93.
• 39. Papa F.T., Mencarelli M.A., Caselli R. i wsp.: A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett-like features. Am. J. Med. Genet. A 2008; 146A: 1994–1998.
• 40. Jian L., Nagarajan L., de Klerk N. i wsp.: Predictors of seizure onset in Rett syndrome. J. Pediatr. 2006; 149: 542–547.
• 41. Pintaudi M., Calevo M.G., Vignoli A. i wsp.: Epilepsy in Rett syndrome: clinical and genetic features. Epilepsy Behav. 2010; 19: 296–300.
• 42. Huppke P., Köhler K., Brockmann K. i wsp.: Treatment of epilepsy in Rett syndrome. Eur. J. Paediatr. Neurol. 2007; 11: 10–16.
• 43. Angelman H.: ‘Puppet’ children. A report on three cases. Dev. Med. Child Neurol. 1965; 7: 681–688.
• 44. Hart H.: ‘Puppet’ children. A report on three cases (1965). Dev. Med. Child Neurol. 2008; 50: 564.
• 45. http://www.angelman.org/_angelman/assets/File/facts%20 about%20as%202009%203-19-10.pdf.
• 46. Bower B.D., Jeavons P.M.: The “happy puppet” syndrome. Arch. Dis. Child. 1967; 42: 298–302.
• 47. Williams C.A., Angelman H., Clayton-Smith J. i wsp.: Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation. Am. J. Med. Genet. 1995; 56: 237–238.
• 48. American Society of Human Genetics, American College of Medical Genetics Test and Technology Transfer Committee: Diagnostic testing for Prader-Willi and Angelman syndromes: Report of the ASHG/ACMG Test and Technology Transfer Committee. Am. J. Hum. Genet. 1996; 58: 1085–1088.
• 49. Petersen M.B., Brøndum-Nielsen K., Hansen L.K., Wulff K.: Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county. Am. J. Med. Genet. 1995; 60: 261–262.
• 50. Clayton-Smith J.: On the prevalence of Angelman syndrome. Am. J. Med. Genet. 1995; 59: 403–404.
• 51. Buckley R.H., Dinno N., Weber P.: Angelman syndrome: are the estimates too low? Am. J. Med. Genet. 1998; 80: 385–390.
• 52. Kyllerman M.: On the prevalence of Angelman syndrome. Am. J. Med. Genet. 1995; 59: 405; author reply 403–404.
• 53. Buiting K.: Prader-Willi syndrome and Angelman syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 2010; 154C: 365–376.
• 54. Cali F., Ragalmuto A., Chiavetta V. i wsp.: Novel deletion of the E3A ubiquitin protein ligase gene detected by multiplex liga­tion-dependent probe amplification in a patient with Angel­man syndrome. Exp. Mol. Med. 2010; 42: 842–848.
• 55. Michelson M., Eden A., Vinkler C. i wsp.: Familial partial tri­somy 15q11-13 presenting as intractable epilepsy in the child and schizophrenia in the mother. Eur. J. Paediatr. Neurol. 2011; 15: 230–233.
• 56. Dindot S.V., Antalffy B.A., Bhattacharjee M.B. i wsp.: The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal den­dritic spine morphology. Hum. Mol. Genet. 2008; 17: 111–118.
• 57. Yamasaki K., Joh K., Ohta T. i wsp.: Neurons but not glial cells show reciprocal imprinting of sense and antisense tran­scripts of Ube3a. Hum. Mol. Genet. 2003; 12: 837–847.
• 58. Weeber E.J., Jiang Y.H., Elgersma Y. i wsp.: Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J. Neurosci. 2003; 23: 2634–2644.
• 59. Moncla A., Malzac P., Voelckel M.A. i wsp.: Phenotype-geno­type correlation in 20 deletion and 20 non-deletion Angelman syndrome patients. Eur. J. Hum. Genet. 1999; 7: 131–139.
• 60. Prader A., Labhart A., Willi H.: Ein Syndrom von Adipositas, Kleinwuchs, Kryptorchismus und Oligophrenie nach Myoto­niertigem Zustand im Neugeborenenalter. Schweiz Med. Wochenschr. 1956; 6: 1260–1261.
• 61. Szczepański Z., Gruszczyński J.: Przypadek Pradera-Willego u 11-letniej dziewczynki. Wiad. Lek. 1969; 22: 1601–1604.
• 62. Whittington J.E., Holland A.J., Webb T. i wsp.: Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willi syndrome in one UK Health Region. J. Med. Genet. 2001; 38: 792–798.
• 63. Goldstone A.P., Holland A.J., Hauffa B.P. i wsp.: Recommen­dations for the diagnosis and management of Prader-Willi syndrome. J. Clin. Endocrinol. Metab. 2008; 93: 4183–4197.
• 64. Molinas C., Cazals L., Diene G. i wsp.: French database of children and adolescents with Prader-Willi syndrome. BMC Med. Genet. 2008; 9: 89.
• 65. Midro A.T., Olchowik B., Lebiedzińska A., Midro H.: Wiedzieć więcej o zespole Pradera-Williego. Diagnostyka. Psychiatr. Pol. 2009; 43: 135–149.
• 66. Einfeld S.L., Kavanagh S.J., Smith A. i wsp.: Mortality in Prad­er-Willi syndrome. Am. J. Ment. Retard. 2006; 111: 193–198.
• 67. Smith D.W., Lemli L., Opitz J.M.: A newly recognized syn­drome of multiple congenital anomalies. J. Pediatr. 1964; 64: 210–217.
• 68. Porter F.D.: Smith-Lemli-Opitz syndrome: pathogenesis, diag­nosis and management. Eur. J. Hum. Genet. 2008; 16: 535–541.
• 69. Jezela-Stanek A., Ciara E., Malunowicz E.M. i wsp.: Mild Smith-Lemli-Opitz syndrome: further delineation of 5 Polish cases and review of the literature. Eur. J. Med. Genet. 2008; 51: 124–140.
• 70. Nowaczyk M.J., Zeesman S., Waye J.S., Douketis J.D.: Incidence of Smith-Lemli-Opitz syndrome in Canada: results of three-year population surveillance. J. Pediatr. 2004; 145: 530–535.
• 71. Bzdúch V., Behúlová D., Škodová J.: Incidence of Smith- Lemli-Opitz syndrome in Slovakia. Am. J. Med. Genet. 2000; 90: 260.
• 72. Ciara E., Nowaczyk M.J., Witsch-Baumgartner M. i wsp.: DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome. Clin. Genet. 2004; 66: 517–524.
• 73. Irons M., Elias E.R., Salen G. i wsp.: Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet 1993; 341: 1414.
• 74. Moebius F.F., Fitzky B.U., Lee J.N. i wsp.: Molecular clon­ing and expression of the human delta7-sterol reductase. Proc. Natl Acad. Sci. USA 1998; 95: 1899–1902.
• 75. Fitzky B.U., Witsch-Baumgartner M., Erdel M. i wsp.: Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc. Natl Acad. Sci. USA 1998; 95: 8181–8186.
• 76. Koide T., Hayata T., Cho K.W.: Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehy­drocholesterol reductase. Development 2006; 133: 2395– –2405.
• 77. Witsch-Baumgartner M., Fitzky B.U., Ogorelkova M. i wsp.: Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am. J. Hum. Genet. 2000; 66: 402–412.
• 78. Irons M., Elias E.R., Abuelo D. i wsp.: Treatment of Smith- Lemli-Opitz syndrome: results of a multicenter trial. Am. J. Med. Genet. 1997; 68: 311–314.
• 79. Elias E.R., Irons M.B., Hurley A.D. i wsp.: Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS). Am. J. Med. Genet. 1997; 68: 305–310.
• 80. Sikora D.M., Ruggiero M., Petit-Kekel K. i wsp.: Cholester­ol supplementation does not improve developmental prog­ress in Smith-Lemli-Opitz syndrome. J. Pediatr. 2004; 144: 783–791.
• 81. Jira P.E., Wevers R.A., de Jong J. i wsp.: Simvastatin. A new therapeutic approach for Smith-Lemli-Opitz syndrome. J. Lipid Res. 2000; 41: 1339–1346.
• 82. Correa-Cerro L.S., Wassif C.A., Kratz L. i wsp.: Develop­ment and characterization of a hypomorphic Smith-Lemli- Opitz syndrome mouse model and efficacy of simvastatin therapy. Hum. Mol. Genet. 2006; 15: 839–851.
• 83. Chan Y.M., Merkens L.S., Connor W.E. i wsp.: Effects of dietary cholesterol and simvastatin on cholesterol synthesis in Smith-Lemli-Opitz syndrome. Pediatr. Res. 2009; 65: 681–685.
• 84. Haas D., Garbade S.F., Vohwinkel C. i wsp.: Effects of cho­lesterol and simvastatin treatment in patients with Smith- Lemli-Opitz syndrome (SLOS). J. Inherit. Metab. Dis. 2007; 30: 375–387.
• 85. Szabó G.P., Oláh A.V., Kozak L. i wsp.: A patient with Smith-Lemli-Opitz syndrome: novel mutation of the DHCR7 gene and effects of therapy with simvastatin and cholesterol supplement. Eur. J. Pediatr. 2010; 169: 121–123.
• 86. Martin J.P., Bell J.: A pedigree of mental defect showing sex-linkage. J. Neurol. Psychiatry 1943; 6: 145–157.
• 87. Richards B.W., Sylvester P.E., Brooker C.: Fragile X-linked mental retardation: the Martin-Bell syndrome. J. Ment. Defic. Res. 1981; 25: 253–256.
• 88. Lubs H.A.: A marker X chromosome. Am. J. Hum. Genet. 1969; 21: 231–244.
• 89. Lubs H.A., Watson M., Breg R. i wsp.: Restudy of the origi­nal marker X family. Am. J. Med. Genet. 1984; 17: 133–144.
• 90. Proops R., Webb T.: The ‘fragile’ X chromosome in the Mar­tin-Bell-Renpenning syndrome and in males with other forms of familial mental retardation. J. Med. Genet. 1981; 18: 366–373.
• 91. de Vries B.B., Halley D.J., Oostra B.A. i wsp.: The fragile X syndrome. J. Med. Genet. 1998; 35: 579–589.
• 92. Lachiewicz A.M., Dawson D.V., Spiridigliozzi G.A.: Physi­cal characteristics of young boys with fragile X syndrome: reasons for difficulties in making a diagnosis in young males. Am. J. Med. Genet. 2000; 92: 229–236.
• 93. Lachiewicz A.M., Dawson D.V.: Do young boys with fragile X syndrome have macroorchidism? Pediatrics 1994; 93: 992–995.
• 94. Rousseau F., Rouillard P., Morel M.L. i wsp.: Prevalence of carriers of premutation-size alleles of the FMRI gene – and implications for the population genetics of the fragile X syn­drome. Am. J. Hum. Genet. 1995; 57: 1006–1018.
• 95. Turner G., Webb T., Wake S. i wsp.: Prevalence of fragile X syndrome. Am. J. Med. Genet. 1996; 64: 196–197.
• 96. Crawford D.C., Acuña J.M., Sherman S.L.: FMR1 and the fragile X syndrome: human genome epidemiology review. Genet. Med. 2001; 3: 359–371.
• 97. Willemsen R., Olmer R., De Diego Otero Y., Oostra B.A.: Twin sisters, monozygotic with the fragile X mutation, but with a dif­ferent phenotype. J. Med. Genet. 2000; 37: 603–604.
• 98. Mazurczak T., Bocian E., Milewski M. i wsp.: Frequency of Fra X syndrome among institutionalized mentally retarded males in Poland. Am. J. Med. Genet. 1996; 64: 184–186.
• 99. Puusepp H., Kahre T., Sibul H. i wsp.: Prevalence of the fragile X syndrome among Estonian mentally retarded and the entire children’s population. J. Child Neurol. 2008; 23: 1400–1405.
• 100. Rajkiewicz M., Sułek-Piatkowska A., Krysa W. i wsp.: Screen­ing for premutation in the FMR1 gene in male patients suspect­ed of spinocerebellar ataxia. Neurol. Neurochir. Pol. 2008; 42: 497–504.
• 101. Sutherland G.R.: Heritable fragile sites on human chromo­somes I. Factors affecting expression in lymphocyte culture. Am. J. Hum. Genet. 1979; 31: 125–135.
• 102. Yu S., Pritchard M., Kremer E. i wsp.: Fragile X genotype char­acterized by an unstable region of DNA. Science 1991; 252: 1179–8111.
• 103. Oberle I., Rousseau F., Heitz D. i wsp.: Instability of a 550- base pair DNA segment and abnormal methylation in fragile X syndrome. Science 1991; 252: 1097–1102.
• 104. Verkerk A.J., Pieretti M., Sutcliffe J.S. i wsp.: Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in frag­ile X syndrome. Cell 1991; 65: 905–914.
• 105. Fu Y.H., Kuhl D.P., Pizzuti A. i wsp.: Variation of the CGG repeat at the fragile X site results in genetic instability: resolu­tion of the Sherman paradox. Cell 1991; 67: 1047–1058.
• 106. Eichler E.E., Richards S., Gibbs R.A., Nelson D.L.: Fine struc­ture of the human FMR1 gene. Hum. Mol. Genet. 1993; 2: 1147–1153.
• 107. Devys D., Lutz Y., Rouyer N. i wsp.: The FMR-1 protein is cyto­plasmic, most abundant in neurons and appears normal in car­riers of a fragile X premutation. Nat. Genet. 1993; 4: 335–340.
• 108. Jacquemont S., Hagerman R.J., Leehey M. i wsp.: Fragile X pre­mutation tremor/ataxia syndrome: molecular, clinical, and neu­roimaging correlates. Am. J. Hum. Genet. 2003; 72: 869–878.
• 109. Jacquemont S., Hagerman R.J., Leehey M.A. i wsp.: Pene­trance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004; 291: 460–469.
• 110. Pacey L.K., Doering L.C.: Developmental expression of FMRP in the astrocyte lineage: implications for fragile X syndrome. Glia 2007; 55: 1601–1609.
• 111. Bassell G.J., Warren S.T.: Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 2008; 60: 201–214.
• 112. Eberhart D.E., Malter H.E., Feng Y., Warren S.T.: The frag­ile X mental retardation protein is a ribonucleoprotein con­taining both nuclear localization and nuclear export signals. Hum. Mol. Genet. 1996; 5: 1083–1091.
• 113. Sittler A., Devys D., Weber C., Mandel J.L.: Alternative splic­ing of exon 14 determines nuclear or cytoplasmic localisation of fmr1 protein isoforms. Hum. Mol. Genet. 1996; 5: 95–102.
• 114. Bakker C.E., de Diego Otero Y., Bontekoe C. i wsp.: Immu­nocytochemical and biochemical characterization of FMRP, FXR1P, and FXR2P in the mouse. Exp. Cell Res. 2000; 258: 162–170.
• 115. Weiler I.J., Irwin S.A., Klintsova A.Y. i wsp.: Fragile X men­tal retardation protein is translated near synapses in response to neurotransmitter activation. Proc. Natl Acad. Sci. USA 1997; 94: 5395–5400.
• 116. Feng Y., Gutekunst C.A., Eberhart D.E. i wsp.: Fragile X men­tal retardation protein: nucleocytoplasmic shuttling and asso­ciation with somatodendritic ribosomes. J. Neurosci. 1997; 17: 1539–1547.
• 117. Ceman S., Brown V., Warren S.T.: Isolation of an FMRP-associated messenger ribonucleoprotein particle and identifi­cation of nucleolin and the fragile X-related proteins as com­ponents of the complex. Mol. Cell. Biol. 1999; 19: 7925–7932.
• 118. Feng Y., Absher D., Eberhart D.E. i wsp.: FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association. Mol. Cell 1997; 1: 109–118.
• 119. Willemsen R., Bontekoe C., Tamanini F. i wsp.: Association of FMRP with ribosomal precursor particles in the nucleolus. Biochem. Biophys. Res. Commun. 1996; 225: 27–33.
• 120. Wang H., Dictenberg J.B., Ku L. i wsp.: Dynamic association of the fragile X mental retardation protein as a messenger ribonucleoprotein between microtubules and polyribosomes. Mol. Biol. Cell 2008; 19: 105–114.
• 121. Antar L.N., Dictenberg J.B., Plociniak M. i wsp.: Localiza­tion of FMRP-associated mRNA granules and requirement of microtubules for activity-dependent trafficking in hippocam­pal neurons. Genes Brain Behav. 2005; 4: 350–359.
• 122. Gantois I., Vandesompele J., Speleman F. i wsp.: Expression profiling suggests underexpression of the GABAA receptor subunit δ in the fragile X knockout mouse model. Neurobiol. Dis. 2006; 21: 346–357.
• 123. D’Hulst C., De Geest N., Reeve S.P. i wsp.: Decreased expres­sion of the GABAA receptor in fragile X syndrome. Brain Res. 2006; 1121: 238–245.
• 124. Bassell G.J., Gross C.: Reducing glutamate signaling pays off in fragile X. Nat. Med. 2008; 14: 249–250.
• 125. Jacquemont S., Curie A., des Portes V. i wsp.: Epigenetic modification of the FMR1 gene in fragile X syndrome is asso­ciated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl. Med. 2011; 3: 64ra1.
• 126. Narayanan U., Nalavadi V., Nakamoto M. i wsp.: S6K1 phos­phorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mam­malian target of rapamycin (mTOR) signaling cascade. J. Biol. Chem. 2008; 283: 18478–18482.
• 127. Hausmanowa-Petrusewicz I.: Dystrofinopatie. W: Hausma­nowa-Petrusewicz I. (red.): Choroby nerowowo-mięśniowe. Czelej, Lublin 2005: 35–54.
• 128. Nigro G., Comi L.I., Limongelli F.M. i wsp.: Prospective study of X-linked progressive muscular dystrophy in Campania. Muscle Nerve 1983; 6: 253–262.
• 129. Kunkel L.M., Hejtmancik J.F., Caskey C.T. i wsp.: Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy. Nature 1986; 322: 73–77.
• 130. Hoffman E.P., Brown R.H. Jr, Kunkel L.M.: Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987; 51: 919–928.
• 131. Daoud F., Angeard N., Demerre B. i wsp.: Analysis of Dp71 contribution in the severity of mental retardation through com­parison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression. Hum. Mol. Genet. 2009; 18: 3779–3794.
• 132. Daoud F., Candelario-Martínez A., Billard J.M. i wsp.: Role of mental retardation-associated dystrophin-gene product Dp71 in excitatory synapse organization, synaptic plasticity and behavioral functions. PLoS One 2008; 4: e6574.

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