Patients with primary cataract as a genetic pool of DMPK protomutation

Abstract

Myotonic dystrophy 1 (DM1) is known to diminish reproductive fitness in its severe form. Since no de novo mutations are known for this disease, it has the tendency to becomeextinct from a population. To explain the preservation of DM1 in a population, a hypothesis that a pool of subjects for the mutated gene exists in the apparently healthy (non-DM1) population was tested. In order to determine the (CTG) repeat number, PCR was performed in 274 patients found to have primary cataract of adult onset who showed no DM1 symptoms, and were not related to DM1 patients. In four cataract patients (1.46%; 95% CI 0.5-3.7), a protomutation in the myotonin protein kinase gene was found which might lead to a complete mutation after transmission through the next generations. The number of (CTG) repeats in the remaining 270 cataract patients did not differ significantly from the control subjects in terms of the distribution of larger [(CTG)n ‡ 19] versus smaller [(CTG)n < 19] alleles. We consider the primary cataract patients to be the pool of DMPK protomutation from which DM1 mutation is maintained in the population.

Early onset posterior subscapular cataract in a series of myotonic dystrophy type 2 patients

“…Early onset posterior subscapular cataract is common among DM1 patients and is considered a key finding for early diagnosis of the disease. 6,7 Screening for DM1 is recommended for patients under 55 years of age, with bilateral cataracts and no other precipitating factors. 17 To our knowledge, similar studies about the prevalence of DM2 mutation in cataract patients have not been performed to date, but given the high occurrence of cataract as an early symptom of the disease reported by us and others, 3,4 it would be useful to do so, in order to establish appropriate guidelines about timely genetic testing.…”

“…4 Early onset posterior subscapular cataract (o50 years of age) is considered a characteristic feature of both myotonic dystrophy type 1 (DM1) and 2 (DM2), and at least for DM1 is known to be a key feature for timely diagnosis. [5][6][7] In DM2 patients, early onset cataract can also be a presenting feature of the disease, preceding all other symptoms, 8 making thus the ophthalmologist, sometimes, the first doctor a patient would visit. In these cases and especially in the absence of other secondary causes of cataract, 9 awareness by the treating physician that early onset cataract can be a presenting manifestation of a multisystemic disease is essential for appropriate referral of patients, avoidance of unnecessary examinations and timely diagnosis.…”

Epigenetic principles and mechanisms underlying nervous system functions in health and disease

“…While trinucleotide repeat disorders comprise the largest disease category, there are also examples of larger repeat expansions including tetranucleotides (myotonic dystrophy, type 2), pentanucleotides (spinocerebellar ataxia 10), minisatellites (progressive myoclonic epilepsy 1) and megasatellites (fascioscapulohumeral muscular dystrophy, type 1A) (Legendre et al, 2007; Mirkin, 2007; Sposito et al, 2005). These repeat expansion disorders also display complex maternal and paternal forms of transmission and minimal and alternate neurological symptoms/signs and disease manifestations due to the progressive effects of repeat length expansions on disease threshold through the expression of pre-mutations and proto-mutations, respectively (Kovtun and McMurray, 2008; Medica et al, 2007; Mirkin, 2007; Pearson et al, 2005). RNA-mediated dysfunction may also be prominent in different forms of ataxia with oculomotor apraxia (AOA), early-onset forms of autosomal recessive spinocerebellar ataxias due to mutations in aprataxin, a HIT superfamily DNA/RNA binding and nucleotide hydrolase (AOA1) and senataxin, a DNA/RNA helicase (AOA2) that is also associated with familial juvenile ALS (Chen et al, 2006b; Gueven et al, 2007; Kijas et al, 2006; Schols et al, 2008).…”

Myotonic dystrophy type 1: frequency of ophthalmologic findings

“…There are several hypotheses to explain how cataracts develop in patients with DM1: haploinsufficiency of SIX5 gene expression 13,14 , toxicity of DMPK gene products 15 , instability of DMPK gene with repercussion in the expression profile of the epithelial cell of lens 12 . It is important to realize that even patients with small CTG expansions may present cataracts, and this may be the unique clinical sign in these subjects 16 . In this study, we were not able to correlate the frequency of cataracts with the genotypes because we employed a qualitative method (TP-PCR) for most patients and also because some patients were not tested directly.…”