Myotonic dystrophy

Type 1

Congenital

There are several different phenotypes of DM1 including congenital, childhood, classic adult and mild or minimal variants. Congenital DM1 is a distinct clinical entity, is associated with a large number of trinucleotide repeats (usually > 1000) and manifests clinically at birth. Most of these cases are inherited through the maternal line. Babies with this condition have hypotonia (as opposed to myotonia), poor feeding and respiratory difficulty. About half of these infants will require mechanical ventilation and the mortality rate is at least 15%-20% and often higher. If the child survives the neonatal period the muscle weakness gradually improves, but other problems will manifest including learning impairment, intellectual disabilities, and autism spectrum disorder. Later in life these individuals develop many of the symptoms of classic DM1.[1][2][3][4][5][6][8] Overall survival is limited and the mean life expectancy for congenital DM1 is age 45.[2][6]

Childhood

Childhood DM1 has an onset between the ages 1 and 10 and has CTG repeats numbering > 500. It most often presents with cognitive and behavioral difficulties. About half of the children will have intellectual impairment. Cardiac conduction abnormalities may occur in a minority of those affected.[2][3][4][5] Over time these children will develop muscular symptoms similar to that seen with the classic adult variety and have a mean life expectancy of approximately 60 years.[5]

Classic adult

The classic version is the most common variant and occurs in about 75% of those with DM1.[1][2] This phenotype most often presents between ages 10 and 40. The relative risk for comorbid conditions is markedly increased for this variant. Thus, a number of clinical features characterise the classic or adult version of DM1. These findings include:

• Muscle weakness is common, especially of the facial muscles, sternocleidomastoid muscles, distal muscles of the extremities and intrinsic muscles of the hands. Over time the weakness can progress gradually to other areas as well. Muscle atrophy frequently occurs. This combination of weakness and atrophy leads to a characteristic appearance with a long narrow face, high arched palate, and mild ptosis (eyelid drooping). In addition, premature frontal balding is common and occurs in both men and women with the disease.[1][2][3][4][5]
• Myotonia or slowed relaxation after muscle contraction is an early, characteristic sign of the disease. It is often a presenting symptom but tends to diminish over time as weakness progresses.[1][2][3][4][5]
• Cardiac abnormalities are common and include conduction blocks, especially AV block, and arrhythmias, including sinus node dysfunction, atrial and ventricular fibrillation, and tachycardia as well as atrial flutter. Diastolic dysfunction may also occur but is usually asymptomatic. Heart failure may occur in a minority of individuals but is much less common than what is seen with other muscular dystrophies. The cardiac anomalies are a common cause of premature sudden death.[1][2][3][5][9][10]
• Respiratory complications may occur due to weakness in the pharynx and esophagus as well as myotonia in the respiratory musculature. A reduced vital capacity with hypoventilation is common. In addition, there is a risk of postoperative respiratory compromise with DM1. Pulmonary issues, especially pneumonia are the most common cause of death in those with myotonic dystrophy.[1][2][3][5]
• Sleep disturbances are common with DM1 and result in hypersomnia and excessive daytime sleepiness. This is most likely due to a central disorder of sleep regulation. Individuals with DM1 are also more likely to have both obstructive and central sleep apnea.[1][2][3][4][5][9]
• A variety of neurologic abnormalities may occur with DM1. These include anxiety, impairment of executive function, memory difficulties and problems with visuospatial processing. MRI studies of the brain show atrophy of the frontal lobes and the frontal portions of the temporal lobes. Positron emission tomography (PET) scanning shows reduced function in those same areas of the brain.[1][2][4][5][9]
• Gastrointestinal symptoms such as abdominal pain, constipation and diarrhea are common. These are due to dysmotility secondary to the effects of the disease on the smooth muscle of the GI tract.[1][2][3][4][5]
• Endocrine abnormalities include primary hypogonadism, testicular atrophy, thyroid disturbances and hyperinsulinism due to insulin resistance.[1][2][3][4][5]
• Abnormal lab findings are common and include, elevated liver function tests, hyperlipidemia (both cholesterol and triglycerides), reduced gamma globulins (IgG and IgM) and an elevated creatine kinase (CK).[1][2][4]
• Cataracts occur in virtually all patients, usually before age 50, and is a characteristic finding associated with the disease.[1][2][3][4][5][9]
• Multiple studies have indicated that individuals with DM1 are at increased risk for the development of cancer, especially of the endometrium, ovary, testes, colon, thyroid and skin (melanoma).[1][2][3][4][5][11][12]

As a result of the multiple complications noted above, the life expectancy with classic adult onset DM1 is significantly reduced with the majority of studies reporting an age at death in the range of 53 to 60 years.[13][14][15][16][17] The major causes of death are respiratory failure/pneumonia, sudden cardiac arrest and malignancies.[9][10][12][13]

Mild or minimal variant

The mild or minimal variant of DM1 is characterised by a smaller number of CTG repeats, 50 to 150. These individuals tend to develop the disease after age 50 and present with mild weakness, myotonia and cataracts but not the severe complications noted above. Thus, the life expectancy with mild DM1 is normal or near normal.[1][2][4][14][15][18]