MOLECULAR DIAGNOSIS OF FRAGILE X SYNDROME: A COMPILATION OF DATA OF 4,238 PATIENTS AND RELATIVES FROM 849 FAMILIES IN SPAIN

M.Isabel Tejada (1); Josep Artigas (5); Antonio Bellón (2); Isabel Fernández-Carvajal (8); Yolanda De-Diego (9); Guillermo Glover (7); Miriam Guitart (5); Francisco Martinez (4); Monserrat Milá (3); Feliciano Ramos (6).(1) Cruces Hospital (Barakaldo-Basque Country); (2) GIRMOGEN; (3) Clinic Hospital (Barcelona-Catalonia); (4) La Fe Hospital (Valencia); (5) Parc-Taulí Hospital (Sabadell-Catalonia); (6) Medicine Faculty ( Zaragoza-Aragón). (7) Virgen de la Arrixaca Hospital (Murcia); (8) IBGM (Valladolid-Castilla); (9) Carlos Haya Hospital (Málaga-Andalucía); SPAIN.

INTRODUCTION

Fragile X syndrome (FXS) is caused by a full mutation (FM) in the FMR1 gene and is the most common form of inherited intellectual disability. The prevalence of the FM has been estimated to be in Spain around 1 in 6000 males, but the real number of individuals with FM or Premutation (PM) is still unknown in the majority of countries, not only in Spain. It is a family of disorders which affects both males and females being females more mildly affected, and, in the case of males, there is a broad range of features which includes a spectrum from a very mild phenotype to fully affected, but the exact frequencies of the clinical involvement remain unknown in most of the populations studied. Both males and females can be "carriers" of the Fragile X gene and pass it on to their children. Furthermore, carriers of the FMR1 gene can develop: female carriers ovarian insufficiency, infertility and early menopause (FXPOI) and male (and less frequently female) carriers an adult onset neurological condition called FXTAS.

OBJECTIVES AND METHODS

To know the number of FXS cases and families in Spain, and to obtain clinical data of FM patients and PM carriers, we (the GIRMOGEN group) created a registry in collaboration with the Spanish Federation of FXS Families and with the “Real Patronato de la Discapacidad”, a Royal trust for disabilities presided over by the Spanish Queen. With the aim of adding some new data about FXS families in the world, we will present in the Conference the data collected in our database from 1991 until the end of 2008.

GIRMOGEN

SPAIN

Grupos 1 y 2

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 TOTAL

Probands 20 32 25 57 59 45 30 30 44 44 54 45 35 62 61 46 41 41 771

Total cases studied 165 209 169 198 218 188 164 147 185 189 192 209 143 194 232 155 169 202 3328

RESULTS

Nowadays our registry contains 4,238 postnatal and prenatal cases belonging to 849 families. A total of 1,363 FM and mosaic patients (864 males and 499 females have been recorded. All FXS males have mental retardation and 65% of FXS females have mental impairments. Tables below summarizes the statistical, molecular and clinical findings of the cases, studied molecularly between 1991 and 2008. Median age at diagnosis of the proband was 16,6 years, because in the last years, probands with FXTAS and with FXPOI have increased this median. In relation to these individuals with PM, 96 women have FXPOI and, interestingly, 2 mosaic women and one FM women as well. With regard to FXTAS, a total of 38 cases have been recorded, 17 of them women. The median age of onset was 65,2 years for men and 70,7 years for women.

Individuals studied each year

0

50

100

150

200

250

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

Years

Probands

Total cases studiedTable 1 and Figure 1: Distribution of individuals studied by year.

FM Mosaics PM (55-199) Others Intermediate (45-54) Normal (<45) TOTAL

Males 779 85 275 1 25 636 1801

Females 455 44 1169 1 47 701 2417

TOTAL 1234 129 1444 2 72 1337 4218

0

200

400

600

800

1000

1200

Ca

se

s

Males Females

Sex

Individuals studied

FM

Mosaics

PM (55-199)

Others

Intermediate (45-54)

Normal (<45)

Table 2 and Figure 2: Distribution of individuals studied by sex and molecular diagnosis.

Hyperactivity

Attention deficit

Tactile defensiveness

Hand flapping

Hand biting

Poor eye contact

Repetitive Language

Males

Females0,0%

10,0%20,0%30,0%40,0%50,0%60,0%70,0%80,0%90,0%

100,0%

Behavioral Phenotypes

Flexible joints

Large ears

Protruding ears

Large testicles

Timidity

Social phobia

Abnormal behavior

Males

Females0,0%

10,0%20,0%30,0%40,0%50,0%60,0%70,0%80,0%90,0%

Physical and other Behavioral Features

Figures 2 and 3: Clinical characteristics of FXS patients distributed by sex

Table 3: Percent expansion to FM with transmission of maternal PM allele

Maternal repeat size Offspring with PM Offspring with FM % of expansion

DISCUSSION

According to the total population in Spain and to the previously estimated prevalence of FXS in Spain (Millán et al., 1999), we have recorded 1/4 of the FSX cases in our country. This large amount of cases gives a high statistical power to analyze in depth all of these data and so we will do this analysis in the next months.