Absence of correlation between skewed X inactivation in blood and serum creatine-kinase levels in Duchenne/Becker female carriers

Abstract

The pattern of X inactivation in lymphocyte DNA was investigated in 107 Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) carriers (102 asymptomatic and 5 manifesting carriers) and 117 normal female controls of different ages, with the aim: a) to analyze the pattern of X inactivation in blood DNA of a large number of DMD/BMD carriers as compared to normal female controls; b) to determine if there is a decrease in serum creatine kinase (CK) levels with age in obligate DMD/BMD carriers; c) to determine if there is a correlation between X-chromosome inactivation and serum CK among asymptomatic DMD/BMD carriers of different ages or with different clinical manifestations in symptomatic carriers. A high proportion of females showed extremely skewed X inactivation (>90% of one X preferentially inactivated), which was almost the same among carriers and normal controls (19 and 24%, respectively). The mean serum CK was significantly greater among young (<20 years old) than adult (>20 years old) DMD/BMD carriers and it decreased significantly until age 20 with an apparent stabilization afterwards. No statistically significant correlation was found between the proportion of active X(DMD) in blood and serum CK activity in DMD/BMD carriers although it was higher among those less than 20 years old. Our observations suggest that highly skewed X-chromosome pattern in blood (with preferential inactivation of the X(N) chromosome) is not enough to predict that a young DMD carrier will develop muscular weakness.

Comparison of X‐chromosome inactivation in Duchenne muscle/myocardium‐manifesting carriers, non‐manifesting carriers and related daughters

“…Skewed XCI, with preferential inactivation of the wild allele, is a possible mechanism to explain symptoms in DMD-manifesting carriers. The non-perfect correlation between skewed inactivation in blood lymphocytes and the corresponding phenotype -previously reported -should have several explanations: investigation of a non-homogeneous group of carriers (DMD vs BMD, only manifesting or non-manifesting carriers) (13,18,22), only young carriers (12), lack of discrimination between mutant and normal alleles (4,13,19,21), presence of autosomal alleles able to modify the phenotype, as the osteopontin promoter (SPP1) polymorfism (23,25), biochemical normalization in muscles of DMD carriers (26).…”

“…Clinical manifestations in DMD carriers is believed to depend on the amount of dystrophin expressed, that in turn depends on the pattern of X-chromosome inactivation (XCI); however, previous studies on the XCI patterns in manifesting carriers did not find a perfect correlation with the clinical manifestations (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) (Table 1).…”

Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

“…However, results concerning the use of XCI as a prognostic marker are controversial. While some studies found that the great majority of symptomatic cases exhibited skewed profiles [20-22] others found that XCI is not a reliable measure to predict whether carrier female will develop symptoms [6,10,24]. Most women in the normal population present a random XCI pattern in peripheral blood.…”

“…However, the most frequently reported mechanism to provoke symptoms in DMD carriers is skewed X-inactivation, favouring the expression of the X chromosome with the DMD mutated allele [8,20-22]. Although some studies suggest the use of X-inactivation analysis for prognostic purposes, the results of different reports are controversial [21,23,24]. …”

X chromosome inactivation in clinical practice

“…XCI in muscle was random in all manifesting carriers investigated. Furthermore, no correlation was found between XCI and phenotype measured as serum creatine kinase levels (Sumita et al 1998).…”