708 Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy affecting adults with an estimated incidence of 1 in 8000 among Caucasians.
GENETICS/BASIC DEFECTS
1. Inheritance: autosomal dominant 2. Molecular genetic perspective
a. Considerable variability of phenotype between affect- ed individuals even within the same family
b. An association of myotonic dystrophy with specific haplotypes in the population, indicating that most cases have resulted from a small number of genetic events c. Multi-systemic nature of the phenotype
d. An apparent increase in severity of symptoms and reduction in age at onset that is observed during trans- mission of the gene within families
3. Genetic defect: caused by an expanded CTG (cytosine- thymine-guanine)-repeat in the dystrophia myotonica phosphokinase (DMPK) gene
a. Encodes for a serine-threonine protein kinase b. Mapped on chromosome 19q13.3
4. CTG triplet repeat
a. Transcribed and located in the 3’ untranslated region of an mRNA that is expressed in tissues affected by myotonic dystrophy
b. Repeat size
i. Highly variable in the normal population (5–36 triplets)
ii. Undergoing expansion in myotonic dystrophy patients (50-several thousand copies)
a) Expansion of at least 50 repeats in patients who are minimally affected
b) Expansion of up to several kilobase pairs in more severely affected patients
c. Intergenerational instability (unstable CTG expansion at mitotic and meiotic levels with a bias towards length increase in the successive generations)
i. Accounting for anticipation (the CTG-repeat size increases in successive generations in paral- lel with increasing severity of the disease) ii. Accounting for somatic instability and
mosaicism (the CTG-repeat size varies consider- ably among different tissues and organs with coexistence in the same subject of cell lines with different CTG-repeats)
d. Genotype–phenotype correlations
i. Size of the CTG trinucleotide repeats generally correlated with the age of onset and clinical severity of the disease
ii. Longer CTG repeat expansions correlate, in gen- eral, with an earlier age of onset and more severe disease
iii. Relation of cardiac abnormalities and CTG- repeat size in myotonic dystrophy
a) Increased cardiac involvement with increas- ing CTG-repeat size in patients age 21–50 b) The number of CTG-repeats needed to
develop a reasonable cardiac involvement is higher in young patients than in older patients
CLINICAL FEATURES
1. Highly variable phenotypic expression and age of onset a. The mildest form
i. Seen in middle or old age
ii. Characterized by cataracts and baldness with lit- tle or no muscle involvement
iii. Occasionally difficult to diagnose: the pleomor- phic manifestations, due to a dynamic mutation in the length of CTG repeat, lead to difficulty in clinical identification of asymptomatic or mildly affected patients
b. The classic (juvenile or adult) form i. The more common form
ii. Usually becoming evident between the ages of 15 and 35 years
iii. Phenotypically variable iv. Characteristic clinical features
a) Myotonia b) Muscle weakness c) Cardiac arrhythmias d) Male balding e) Hypogonadism
f) Psychocognitive dysfunction g) Glucose intolerance
c. The most severe (congenital) form
i. Recognized at birth or in the neonatal period ii. Pregnancy
a) Maternal polyhydramnios b) Reduced fetal movement c) Breech presentation d) Prematurity
iii. Associated with generalized muscular hypotonia iv. Respiratory distress
a) Aspiration pneumonia b) Recurrent bronchitis c) Hypoventilation d) Sleep apnea e) Bronchiectasis v. Feeding difficulties vi. Dysphagia
vii. Nasal regurgitation
viii. Facial diplegia with a “tented-shaped” mouth ix. Delayed motor development
x. Joint deformities xi. Mental retardation xii. High neonatal mortality
xiii. Those survived invariably exhibiting the classical form of the disease in late childhood or adolescence xiv. Almost all congenital cases are exclusively
maternally transmitted
xv. The phenomenon of anticipation often most strikingly manifested in a family producing a congenitally affected child
2. Neurologic manifestations
a. Myotonia (delayed relaxation of muscles after an ini- tial contraction) (100%)
b. Muscle weakness and atrophy
i. Muscles most prominently affected a) Superficial facial muscles b) Levator palpebrae superioris c) Temporalis
d) Sternocleidomastoids e) Distal muscles of forearm
f) Dorsiflexors of foot
ii. Other muscles commonly affected a) Quadriceps
b) Diaphragm and intercostals c) Intrinsic muscles of hand and feet d) Palate and pharyngeal muscles e) Tongue
f) External ocular muscles
c. Percussion myotonia and voluntary myotonia aggra- vated by cold
d. Dysarthria
e. Slow nasal indistinct speech f. Foot drop
g. Step page gait
h. Contractures of the Achilles tendon i. Diminished deep tendon reflexes j. Cognitive and behavioral abnormalities 3. Craniofacial appearance
a. Long thin face
b. Flat, sagging, sad, and expressionless face c. Frontal bossing
d. Hollow temple secondary to atrophy of temporalis e. Bilateral facial weakness (facial diplegia)
f. Tented mouth g. Micrognathia
h. Swan neck appearance (sternocleidomastoid muscle wasting)
4. Ocular findings a. Cataracts (>85%) b. Ptosis
c. Extraocular weakness d. Peripheral retinal changes e. Coloboma of retina/choroid
f. Optic atrophy g. Blepharospasms
h. Decreased ocular pressure 5. Cardiac involvement (76%)
a. An integral part of myotonic dystrophy targeting:
i. Almost selectively the conduction system ii. Less specifically the myocardium
b. Electrocardiographic conduction abnormalities i. Manifesting with or without ventricular tachy-
arrhythmias or brady-arrhythmias
ii. The first-degree atrioventricular (AV) block (most common)
iii. Intraventricular conduction abnormalities (pre- mature ventricular complexes like couplets and triplets)
iv. Atrial arrhythmias (atrial fibrillation and flutter) c. A high incidence of sudden death
d. Possible cardiomyopathy e. Congestive heart failure (6%) 6. Gastrointestinal findings
a. Achalasia b. Gastroparesis c. Constipation d. Megacolon e. Gallstones 7. Genitourinary findings
a. Dysuria
b. Urinary retention c. Polycystic kidneys d. Testicular atrophy 8. Endocrine findings
a. Hypogonadism
b. Male infertility secondary to testicular atrophy c. Hypothyroidism
d. Goiter/hyperparathyroidism
e. Multiple endocrine neoplasia type 2A (pheochromo- cytoma and amyloid-producing medullary thyroid carcinoma)
f. Dysmenorrhea
g. Postprandial hyperinsulinemia 9. Joint deformities
a. Arthrogryposis b. Talipes 10. Female patients
a. Decreased total reproductive rate b. Higher rate of spontaneous abortions
11. Occasional accompanying benign or malignant neoplasms a. Pilomatrixoma
b. Parathyroid adenoma c. Small bowel carcinoma d. Neurofibromatosis e. Thymoma
f. Pleomorphic adenoma of the parotid gland g. Pituitary adenoma
h. Ovarian cancer i. Ovarian cyst j. Laryngeal cancer 12. Natural history
a. Usually progressive
b. Usually leading to severe disability within 15–20 years c. Greatly reduced life expectancy, particularly in the case of an early disease onset and proximal muscle involvement
d. The high mortality rate reflecting an increase in deaths due to:
i. Respiratory diseases ii. Cardiovascular diseases
iii. Neoplasms
iv. Sudden deaths induced by cardiac arrhythmias 13. Differential diagnosis
a. Myotonic dystrophy type 2 (DM2)
i. Reported by Day et al. (1999): a five-generation family from Minnesota with an unusual form of myotonic dystrophy
ii. Clinical characteristics similar to those of DM1 a) Myotonic
b) Distal weakness c) Frontal balding
d) Polychromatic cataracts e) Infertility
f) Cardiac arrhythmias iii. Molecular genetic analysis
a) No CTG expansion associated with DM1 b) No linkage of the disease locus to the DM1
region on chromosome 19
c) Exclusion of a disease locus from the chro- mosomal regions containing the gene of muscle sodium and chloride channels, both of which are involved in other myotonic disorders
d) The disease locus in this family mapped to a 10-centimorgan region of chromosome 3q iv. Sharing many clinical features of previously
reported proximal myotonic myopathy (PROMM) but distinguished by the presence of significant early distal weakness and severe car- diac arrhythmias
b. Proximal myotonic myopathy i. Autosomal dominant disorder ii. Clinical features
a) Proximal muscle weakness b) Myotonia
c) Cataracts
d) Symptoms usually appearing between 30 and 40 years of age
e) No infantile form comparable to severe con- genital DM1 observed
iii. Molecular genetic analysis: a normal size of the [GTG]n repeat in the DM1 gene
c. Proximal myotonic dystrophy (PDM)
i. Reported by Udd et al. in 1977: a 4-generation family from Finland’s Vasa region
ii. An autosomal dominant disorder iii. Clinical features
a) Late-onset proximal muscular dystrophy b) Electrophysiological myotonia
c) Cataracts
d) Late-onset deafness e) Male hypogonadism
iv. Differential diagnosis from PROMM
a) Similarities: prominent proximal weakness, inconstant clinical and electrical myotonia, and cataracts
b) Differences: more severe muscle involve- ment (atrophy of the affected muscles and dystrophic changes on muscle biopsy and computed tomography scan) and hearing loss
v. Molecular genetic testing
a) No expansion of the unstable [CTG]n trinu- cleotide repeat on chromosome 19q13.3 b) Exclusion of the linkage with three known
myotonia loci: DMPK, CLCN1, and SCN4
DIAGNOSTIC INVESTIGATIONS
1. Clinical examination to search muscle and nonmuscle manifestations
2. Lab: mildly elevated serum creatine kinase 3. Electromyography to identify subclinical myotonia 4. Slit-lamp examination to detect characteristic cataracts 5. Muscle biopsy
a. Diagnostic but not indicated or useful for routine clin- ical evaluation
b. Atrophic small type I fibers c. An increase in central nuclei d. Ringed fibers
6. Radiography
a. Kyphosis of cervical spine
b. Thin ribs observed in neonates suffering from myotonic dystrophy
7. Electrocardiogram abnormalities (60–70%) a. ST abnormalities
b. AV block I
c. Increased QTc-interval d. Tall R and/or S-waves e. Left anterior hemi-block
f. Supraventricular ectopic beats g. T-wave abnormalities
h. Pace-maker
i. Missing R-progression j. Abnormal U-wave k. Left bundle branch block 8. Echocardiography
a. Septal thickness >11 mm b. Posterior wall thickness >11 mm c. Fractional shortening <30%
d. E/A ratio >1
e. Left ventricular end-diastolic diameter >57 mm f. Valve abnormalities
9. DNA testing for CTG repeat size
a. Gold standard for the diagnosis of DM1 b. CTG repeat size in various phenotype
i. Normal: 5–37 ii. Premutation: 38–49 iii. Mild: 50–150
iv. Classical: 100–1500 v. Congenital: 1000 ≥ 2000 10. Presymptomatic carrier testing
a. Leukocyte DNA analysis: provides an earlier oppor- tunity to diagnose DM1 in family members at risk who are clinically asymptomatic
b. Providing more aggressive monitoring program to detect:
i. Early cardiac conduction disturbance ii. Cataract formation
iii. Respiratory difficulties
iv. At risk of developing anesthetic complications, especially delayed-onset apnea
GENETIC COUNSELING
1. Recurrence risk
a. General principle for genetic counseling
i. A normal molecular analysis excludes the risk of developing or transmitting myotonic dystrophy in essentially all situations
ii. For women who have had a child with congeni- tal myotonic dystrophy, almost all subsequently affected pregnancies are likely to be severely affected
iii. Clinically affected women, in general, have around a 30 percent chance that an affected child would have congenital or severe childhood myotonic dystrophy. The risk of a congenitally affected child is related to maternal repeat size iv. The risk for the healthy sib of a congenitally
affected patient developing the disorder after childhood is low
v. For the adult healthy sib of an adult onset case, the risk of carrying the mutation is also low (around 10%), with about half of this developing clinically significant disease
b. Patient’s sib: recurrence risk depending on the genet- ic status of the parents
i. Not increased if both parents are normal ii. 50% risk if the mother is affected
iii. Minimal risk (<1%) if the father is affected c. Patient’s offspring
i. Offspring of an individual with an expanded allele (>37 CTG repeats) have a 50% chance of inheriting the mutant allele
ii. Disease-causing alleles may expand in length dur- ing gametogenesis, resulting in the transmission of longer CTG trinucleotide repeat alleles that may be associated with earlier onset and more severe disease than that observed in the parent 2. Prenatal diagnosis
a. Prenatal ultrasonography in congenital myotonic dys- trophy
i. Polyhydramnios ii. Talipes
iii. Decreased fetal movements reflecting the neuro- muscular failure of swallowing and movement b. Prenatal diagnosis possible by using mutation analy-
sis and detection of the CTG repeat expansion with the DMPK gene in amniocytes or chorionic villi c. More challenging by using the CTG repeat test to
determine whether the fetus is at risk for the severe form of myotonic dystrophy
i. Generally, in amniocytes, congenital myotonic dystrophy is association with CTG repeat expan- sion larger than that of the affected mother ii. CTG repeat size may change over time in CVS
or amniocentesis, providing different CTG repeat size at different gestational ages
d. Counseling of pregnant patients affected with myotonic dystrophy
i. An explanation of the risk associated with antic- ipation, which is the tendency toward large inter-
generational expansion of the CTG repeat during maternal transmission resulting in offspring with congenital myotonic dystrophy
ii. CTG repeat number provides only an approxi- mate guide to prognosis or to pregnancy out- come. Most cases with over 2000 repeats will have congenital or severe childhood onset dis- ease; most individuals with 50 to 100 repeats will not have significant neuromuscular disease iii. An intergenerational contraction of the CTG
fragment observed in approximately 7% of cases. Clinical anticipation was seen despite the reduced CTG repeat size, resulting in congenital myotonic dystrophy in the offspring
3. Management
a. No specific treatment available for the progressive weakness that is responsible for most of the disability in patients with myotonic dystrophy
b. To alleviate myotonia by drugs
i. Quinine, quinidine, dilantin, carbamazepine, pro- cainamide, diamox to alleviate myopia not univer- sally successful
ii. Encouraging results with mexiletine and tocainide c. Avoid cold which may induce myotonia
d. Prescription for orthoses, wheelchairs, or other assisted devices
e. Treat cataracts, diabetes mellitus, hypothyroidism, and sleep apnea
f. Avoid surgery and anesthesia (sensitive to narcotics and sedatives)
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Fig. 1. An adult (A) with myotonic dystrophy showing hard to release after shaking hand (B) and thenar myotonia after tapping (C).
Fig. 2. An adult with myotonia dystrophy showing long thin face with frontal bossing and thenar myotonia after tapping.
Fig. 3. A 23-year-old mother and her 21-month-old daughter with myotonia congenita type 1. The mother has myotonia (hard to relax after shaking hand), thenar myotonia after tapping, and absent tendon reflexes. The pregnancy was complicated by polyhydramnios, feeble fetal movement, and breech presentation. After scheduled cesarean section, the baby breathed only once and needed intubation for 5 days.
She was very floppy and just started to walk about 2 month prior to the clinic visit. She chokes easily and does not chew and talk. On physical examination, in addition to hypotonia, there is a long and sagging face with marked tented-mouth. Molecular genetic testing of the daughter showed CTG repeats of 1050.
