Anticipation in Myotonic Dystrophy: Fact or Fiction?

Abstract

In 1918 Fleischer reported that after transmission from one generation to the next, myotonic dystrophy has an earlier onset and is more severe. The hypothesis put forward by Penrose in 1948 that 'anticipation' is caused by bias of index case selection was based on theoretical arguments only and has not been supported by clinical observations. This hypothesis was tested in a clinical and genetic study of 14 families with myotonic dystrophy. Excluding index patients, an earlier onset in the child was found in 98% of 61 parent-child pairs. A greater mean difference in age of onset was found with transmission via the father than via the mother. The comparison of the severity of the disease between parents and children was difficult because of the variation in symptoms but, in general, the disease was more severe in the child than in the parent. The penetrance of the abnormal gene was nearly complete in the 14 families combined, leaving little room for the observation of 'complementary' parent-child pairs in the future. Also in retrospect no complementary parent-child pairs were found in the first generations. Fertility was severely reduced only in the very early onset patient group and this selective infertility cannot be responsible for the total amount of anticipation observed. It is therefore concluded that anticipation may be inherent in the transmission of myotonic dystrophy. This has important consequences for genetic counselling.

Reproductive fitness in familial schizophrenia

“…This phenomenon has been observed in myotonic dystrophy (Howeler et al, 1989), Huntington disease (Mastromauro et al, 1989) and fragile X syndrome (Fryns, 1986;Loesch and Hay, 1988). As in these other conditions, increased fitness in women with schizophrenia spectrum features may be due to possible hormonal disturbances involving ovarian function or the hypothalamic-pituitary-adrenal axis, vulnerability to prolific mates, poor judgment or decreased intellect (Fryns, 1986;Loesch and Hay, 1988).…”

“…The lower fitness of affected men compared with women, is similar to sex differences seen in other genetic disorders. Interestingly, these include several neuropsychiatric diseases caused by dynamic mutations: myotonic dystrophy (Howeler et al, 1989;de Die-Smulders et al, 1994), fragile X syndrome (Fryns, 1986;Loesch and Hay, 1988), Huntington disease in some studies (Mastromauro et al, 1989) and spinocerebellar ataxia type 1 (Jodice et al, 1994). The common mechanism for reduced fitness in these disorders appears to be low marital rates.…”

“…Differential expression depending on parental origin of disease genes, or imprinting, may be important in psychiatric illnesses (Flint, 1992). Imprinting has not been established to date in familial schizophrenia (Sharma et al, 1993;Asherson et al, 1994;Bassett and Honer, 1994), however sex differences in fitness may obscure the observation of imprinting effects (Howeler et al, 1989;de Die-Smulders et al, 1994). …”

Anticipation in familial chronic lymphocytic leukaemia

“…Other possible mechanistic bases for anticipation have been proposed. 26 The mutation might be made more severe between generations by a persistent shared environmental factor (rather than intrinsic instability). An epigenetic effect -perhaps involving DNA methylation or gene conversion -which, instead of being eliminated, is fixed in the genome during subsequent meiosis might lead to an accumulation of defects during following generations.…”

Anticipation in Japanese families with schizophrenia

“…However, since the late 1980s, new evidence of epidemiological anticipation in several neuromuscular and neurological diseases has been reported, even after ascertainment biases were excluded (Ridley et al 1988;Höweler et al 1989), and these lines of evidence were soon followed by evidence of biological anticipation that showed a correlation between decrease in AO and increase in severity with the presence of TRE. These findings provide not only a new understanding of the molecular-genetic basis of anticipation in those diseases but also suggest a reconsideration of the involvement of anticipation in psychiatric disorders.…”