Myotonic Dystrophy Information - Correlation of Phenotype and CTG Repeat Length

Correlation of Phenotype and CTG Repeat Length

Posted by Jerry Milliken

Saturday, 04 November 2006

Correlation of Phenotype and CTG Repeat Length in Myotonic Dystrophy Type 1

Phenotype	Clinical Signs	CTG Repeat Size ¹	Age of Onset (Years)	Average Age of Death (Years)
Premutation	None	35 to 49	NA ²	NA ²
Mild	Cataracts Mild myotonia	50 to ~150	20 to 70 yrs	60 yrs to normal life span
Classic	Weakness Myotonia Cataracts Balding Cardiac arrhythmia Others	~100 to ~1000	10 to 30 yrs	48 to 55 yrs
Congenital	Infantile hypotonia Respiratory deficits Mental retardation	>2000 ³	Birth to 10 yrs	45 yrs ⁴

1. CTG repeat sizes are known to overlap between phenotypes.
2. NA = not applicable
3. Redman et al 1993 reported a few individuals with congenital DM1 with repeats between 730 and 1000.
4. Does not include neonatal deaths

Mild DM1. Individuals with mild DM1 may have only cataract, mild myotonia, or diabetes mellitus. They may have fully active lives and a normal or minimally shortened life span.

Classic DM1. Within this range of CTG repeat size, only a rough correlation with severity of symptoms exists. Individuals with CTG repeat sizes in the 100-to-1000 range usually develop classic DM1 with muscle weakness and wasting, myotonia, cataracts, and, often, cardiac conduction abnormalities. The age of onset for classic myotonic dystrophy is typically in the twenties and thirties, and less commonly after age 40 years. However, classic DM1 may be evident in childhood, when subtle signs such as myotonic facies and myotonia are observed. In classic DM1, the predominant symptom is distal muscle weakness, leading to foot drop/gait disturbance and difficulty with performing tasks requiring fine dexterity of the hands. The typical facies is mainly caused by weakness of the facial and levator palpebrae muscles. Some affected individuals have ophthalmoplegia and others may have dysarthria with nasal speech. Myotonia may interfere with daily activities such as using tools, household equipment, or doorknobs. Smooth muscle involvement may produce dysphagia, constipation, or diarrhea.

Cataracts can eventually be observed by slit lamp examination in nearly all affected individuals.

Cardiac conduction defects of varying degrees of severity are common. In one series, 90% of indviduals had conduction defects. These defects are a significant cause of early mortality in individuals with DM1. Less commonly, cardiomyopathy may occur.

Minor intellectual deficits are present in some individuals, but in others intelligence may be incorrectly assumed to be reduced because of the dull facial expression. Avoidant, obsessive-compulsive, and passive-aggressive personality features have been reported.

Gallstones occur as a result of increased tone of the gall bladder sphincter. Hypersomnia and sleep apnea are other well recognized, though later, manifestations of the disease. Endocrinopathies including hyperinsulinism, testicular atrophy, and possible abnormalities in growth hormone secretion can be observed, although they are rarely clinically significant. Pilomatricomas and epitheliomas can occur.

Rarely, after several decades of disease, DM1 progresses to the point of wheelchair confinement. Weakness/myotonia of the diaphragm and a susceptibility to aspiration increase the risk for respiratory compromise, usually in individuals with advanced disease. Several studies have evaluated life span and mortality in DM1. The most frequent causes of death are pneumonia/respiratory failure, cardiovascular, sudden death/arrhythmia, and neoplasms. In the study of Die-Smulders et al (1998) 50% of individuals were either partially or totally wheelchair bound shortly before death.

Women with DM1 are at risk for complications during pregnancy including increased spontaneous abortion rate, prolonged labor, retained placenta, and postpartum hemorrhage [Webb et al 1978]. Complications related to the presence of congenital DM1 in the fetus include reduced fetal movement and polyhydramnios.

Congenital DM1. Congenital DM1 often presents before birth as polyhydramnios and reduced fetal movement. After delivery, the main features are severe generalized weakness, hypotonia, and respiratory compromise. Typically, affected infants have a characteristic inverted "V" shape of the upper lip (also referred to as tented or "fish"-shaped mouth), which is characteristic of significant facial diplegia (weakness). Mortality from respiratory failure is high; surviving infants experience gradual improvement in motor function. Affected children are usually able to walk; however, a progressive myopathy occurs eventually, as in the classic form [Hageman et al 1993 , Joseph et al 1997]. Mental retardation is present in 50-60% of affected individuals. The cause of the mental retardation is unclear, but cerebral atrophy and ventricular dilation are often evident at birth. Mental retardation may result from a combination of early respiratory failure and a direct effect of the DM1 mutation on the brain.

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Last Updated ( Friday, 17 August 2007 )