Myotonic Dystrophy




Keywords

Myotonic dystrophy, congenital myotonic dystrophy, childhood myotonic dystrophy, myotonic dystrophy type 1, myotonic dystrophy type 2, spliceopathy, antisense oligonucleotides

 




Clinical Presentation and Phenotypes


Brief Overview of History and Epidemiology


In 1909, Hans Steinert (Leipzig, Germany) described the typical pattern of muscle weakness and myotonia in adult-onset myotonic dystrophy type 1 (DM1). Over subsequent years, clinical studies demonstrated dominant inheritance and a wide spectrum of variable multisystem manifestations (skeletal and smooth muscle, heart, brain, eyes, respiratory, gastrointestinal, immune, and endocrine systems). In 1992, researchers discovered that DM1 results from an unstable trinucleotide repeat expansion (CTG) in the dystrophia myotonica-protein kinase ( DMPK ) gene located on chromosome 19q13.3. This discovery stimulated widespread DNA testing of clinically diagnosed patients felt to have Steinert’s disease. Interestingly, in 1994, clinical researchers in the United States and Germany identified kindreds of patients with dominantly inherited myotonia, cataracts, and proximal weakness without an abnormal expansion of the CTG repeat in the DMPK gene and without linkage to hereditary myotonic disorders caused by mutations of the skeletal muscle chloride or sodium channels. They proposed two names for this newly identified disorder: myotonic dystrophy type 2 (DM2) and proximal myotonic myopathy (PROMM). In 1998, genetic mapping linked both disorders to chromosome 3q21, and in 2001, researchers discovered that DM2/PROMM resulted from an unstable CCTG repeat expansion in intron 1 of the CNBP/ZNF9 gene at locus 3q21.3.


The relatively recent discoveries of the assays to identify the mutations responsible for DM1 and DM2 create a challenge to determining the exact prevalence of DM1 and DM2. DNA confirmation of DM1 has only become widely available since the mid 1990s, and for DM2 since 2003. Prior estimates of the prevalence of myotonic dystrophy relied solely upon clinical diagnosis. Study populations primarily involved symptomatic adults and probably included a mixture of patients with DM1 and DM2. Patients with minimal or no symptoms are unlikely to have participated. Within these limitations, prior studies report a range of prevalence for myotonic dystrophy of 5 to 20 per 100,000. There are clusters of higher prevalence in the Basque region of Spain, northern Sweden, Istria region of Croatia, and the Saguenay-Lac St. Jean region of Quebec, Canada (158–189 per 100,000). Few studies of the prevalence of congenital myotonic dystrophy type 1 (CDM) and childhood DM1 are available. However, a recent nationwide study of CDM in Canada calculated the prevalence to be approximately 2.1/100,000. This estimate is lower than estimates in previous non-population-based studies in Sweden, Spain, and Britain, and probably reflects a stricter definition of CDM. The definition used for CDM in the Canadian study was: symptoms of DM1<30 days after birth (hypotonia, feeding and/or respiratory difficulty, required hospitalization>72 hours) and positive DNA testing. Other reports classifying children with positive DNA testing for DM1 have defined CDM as an infant<1 year of age with symptoms consistent with DM1; childhood DM1 (ChDM) as a child between 1–10 years of age with symptoms; and older teens and adults as the adult group. More epidemiological studies are necessary in DM1 to establish the rate of appearance and progression of disease manifestations, especially in children.


Until recently no estimates of prevalence for DM2 were available. In 2011, clinical researchers in Finland published findings indicating a higher prevalence of DM2 in Europeans than most clinicians suspected. In a large study of over 5000 anonymous blood donors, they observed a higher prevalence for DM2 than DM1. The higher prevalence of DM2 identified in this Finnish population emphasizes the wide spectrum of phenotypes and points out the diagnostic challenge that exists due to the variation in different symptoms that occur in DM2. For example, clinical findings such as myotonia on physical examination or even on electromyographic testing may be absent, limiting the ability of myotonia screening alone as a means to identify individuals with DM2. Whole blood DNA testing in individuals at known risk for DM1 or DM2 or in individuals presenting with one of the common manifestations ( Tables 37.1 and 37.2 ) is needed to determine more exactly the actual prevalence of individuals with abnormal repeat expansions of DMPK and CNBP/ZNF9 genes.



Table 37.1

Summary of Genetics and Core Clinical Features of Myotonic Dystrophy (DM1 and DM2) in Mild to Moderately Affected Adult Patients (mother of congenital DM1 patient or late teenage onset DM1 patient as well as the father or mother of childhood onset DM1 patient may have these features)
























































Adult Onset Myotonic Dystrophy Type 1 (DM1) Adult Onset Myotonic Dystrophy Type 2 (DM2)
Genetics
Inheritance Autosomal dominant Autosomal dominant
Anticipation Pronounced Exceptionally rare
Congenital form Yes No
Chromosome 19q13.3 3q21.3
Locus DMPK CNBP
Expansion mutation (CTG) n (CCTG) n
Location of the expansion 3′ untranslated region Intron 1
Core features: Mild to moderately affected patients
Clinical myotonia

  • •

    Usually occurs in the distal limb (grip and intrinsic hand muscles);


  • •

    Can manifest in the tongue, jaw, eye, and smooth muscles;


  • •

    Percussion myotonia in thenar and forearm muscles often present;


  • •

    Myotonia may be absent in some patients.



  • •

    Not as prominent as in DM1;


  • •

    Often first appears intermittently with hand grip;


  • •

    May be limited mainly to percussion of wrist extensor muscles;


  • •

    May be absent in some patients.

Muscle weakness

  • •

    Forearm finger flexors; foot dorsi- and plantar flexors; and facial muscles;


  • •

    Ptosis;


  • •

    Laryngeal (dysarthria);


  • •

    Occasional extraocular weakness;


  • •

    Weakness of shoulder girdle and proximal upper limb, neck (flexors>extensors), and knee flexors and extensors more prominent in later stages as disease progresses.



  • •

    Involvement of distal and facial muscles is usually absent;


  • •

    Initial weakness is in proximal hip girdle and neck (flexors>extensors) muscles;


  • •

    Occasional mild ptosis less common than in DM1;


  • •

    Calf muscle hypertrophy is common.

Muscle wasting

  • •

    Significant atrophy is typically apparent in patients affected moderately;


  • •

    Anterior neck;


  • •

    Masseter and temporalis;


  • •

    Distal forearm;


  • •

    Intrinsic hand;


  • •

    Distal lower extremity.



  • •

    Significant muscle atrophy is typically mild and involves anterior neck and hip and shoulder girdle.

Cataracts

  • •

    Iridescent, posterior capsular opacities, typically before age 50 years.



  • •

    Similar in appearance to DM1 but less commonly seen on initial exam.



Table 37.2

Summary of Multisystem Manifestations of Myotonic Dystrophy (DM1 and DM2) in Mild to Moderately Affected Adult Patients






























































Adult Onset Myotonic Dystrophy Type 1 (DM1) Adult Onset Myotonic Dystrophy Type 2 (DM2)
Multisystem manifestations: Mild to moderately affected patients
Brain

  • •

    Visual spatial deficits;


  • •

    Reduced executive function (trouble organizing & staying on task, reduced goal directed action);


  • •

    Apathy.



  • •

    Similar visual-spatial and executive function deficits to those present in DM1.

Heart

  • •

    Conduction defects, particularly heart block and arrhythmias.



  • •

    Significant disturbances in conduction much less common than in DM1.

Respiratory

  • •

    Reduced forced vital capacity;


  • •

    Obstructive and central sleep apnea;


  • •

    Weak cough;


  • •

    Microatelectasis;


  • •

    Frequent respiratory infections.



  • •

    Obstructive sleep apnea.

Anesthesia

  • •

    Increased frequency of respiratory insufficiency/failure following general anesthesia;


  • •

    Paradoxical reaction to depolarizing muscle relaxant medications;


  • •

    Hypersensitivity to opioids and sedative medications;


  • •

    Neuroleptic malignant syndrome;


  • •

    Failed respiratory wean;


  • •

    Arrhythmias.



  • •

    Limited information is available to determine if there is a significant and increased risk of general anesthesia;


  • •

    Recommend careful monitoring in postoperative period until more information is published.

Hypersomnia and fatigue

  • •

    Excessive daytime sleepiness;


  • •

    Obstructive and central sleep apnea;


  • •

    CNS and muscle-related fatigue.



  • •

    Excessive daytime sleepiness is not as prominent as in DM1;


  • •

    Obstructive sleep apnea;


  • •

    CNS and muscle related fatigue.

Endocrine

  • •

    Gonadal insufficiency;


  • •

    Low testosterone;


  • •

    Erectile dysfunction;


  • •

    Insulin resistance;


  • •

    Hyperlipidemia;


  • •

    Hypothyroidism;


  • •

    Decreased growth hormone release.



  • •

    Gonadal insufficiency;


  • •

    Low testosterone;


  • •

    Erectile dysfunction;


  • •

    Insulin resistance;


  • •

    Hyperlipidemia;


  • •

    Hypothyroidism.

Gastrointestinal

  • •

    Dysphagia;


  • •

    Gastroesophageal reflux;


  • •

    Gastroparesis;


  • •

    Small intestinal dysmotility (diarrhea, abdominal cramps, bloating, pain);


  • •

    Colonic dysmotility (pain, “spastic colon,” constipation);


  • •

    Pseudo-obstruction;


  • •

    Anorectal dysfunction (anal incontinence, constipation, fecal impaction).



  • •

    Limited information is available;


  • •

    Manifestations often less severe than DM1 and can include:


  • •

    Dysphagia;


  • •

    Gastroesophageal reflux;


  • •

    Abdominal pain;


  • •

    Constipation.

Muscle pain

  • •

    Posterior neck, trapezius, anterior lateral chest wall, and upper and lower back;


  • •

    Can worsen with exercise and cold temperature.



  • •

    Often a major symptom, especially the arms and upper and lower back;


  • •

    Fluctuates in duration, location, and intensity;


  • •

    Can worsen with exercise and cold temperature;


  • •

    Aches and stiffness;


  • •

    Pain on muscle palpitation.

Pregnancy

  • •

    Vital capacity declines and shortness of breath occurs often in the 3rd trimester;


  • •

    Frequent miscarriage;


  • •

    Failed maintenance of pregnancy;


  • •

    Polyhydramnios;


  • •

    Prolonged 1st stage of labor;


  • •

    Placenta previa;


  • •

    Postpartum hemorrhage;



  • •

    Limited information is available to determine if there is significant risk of complications during pregnancy and delivery;


  • •

    Weakness and stiffness may worsen during pregnancy and improve following delivery.

Liver

  • •

    Elevated liver enzymes, especially gamma glutamyl transferase;


  • •

    Decreased to low normal albumin;


  • •

    Gallstones and diffuse fatty liver.



  • •

    Similar to DM1.

Immune System

  • •

    Decreased immunoglobulins, primarily IgG and IgM.



  • •

    Similar to DM1.

Eye

  • •

    Cataract;


  • •

    Ptosis;


  • •

    Exposure keratitis;


  • •

    Retinal pigmentary abnormalities;


  • •

    Decreased intraocular pressure;


  • •

    Abnormal dark adaptation;


  • •

    Epiretinal membrane;


  • •

    Oculomotor abnormalities.



  • •

    Cataract.

Pilomatricoma

  • •

    Asymptomatic, slow growing, firm, superficial mass (0.15–4.0 cm) usually in the head/neck region.



  • •

    Not reported.



Mode of Inheritance and Prevalence


DM1 and DM2 are autosomal dominant. Anticipation (earlier onset of more severe symptoms in successive generations) occurs primarily in DM1 (see Figure 37.1 ). Congenital myotonic dystrophy (CDM) occurs almost exclusively through maternal transmission (see Figures 37.2 and 37.3 ). In contrast, both mothers and fathers with DM1 can have children with childhood onset of DM1. However, only 5–10% of DM1 patients have onset before their mid-teens. DM2 occurs neither in infancy nor childhood, although teenage onset of myotonic symptoms can occur in some DM2 patients carrying concomitant mutations in the gene for the skeletal muscle chloride channel.




Figure 37.1


The uppermost panel of this three panel figure shows photographs of a father and son both afflicted with myotonic dystrophy type 1 (DM1). The left photo is of the father (age 77 years) and the right is of the son (age 41 years). Both patients have had cataract surgery, right eye lens implant for the father and left eye for the son. Ptosis, bifacial weakness, wasting of the sternocleidomastoid, temporalis, and masseter muscles as well as frontal balding is apparent in the son and difficult to detect in the father. The middle panel shows the forearms of both father and son. There is greater severity of forearm muscle wasting (forearm flexor compartment being more wasted than forearm extensors) in the son (lower forearm photo) compared to the father (upper forearm photo). The bottom panel shows the lower extremities of the father (left) and son (right). The son shows more wasting of the leg musculature. The shaved areas on the anterior lateral regions of both thighs in the son represent the sites for needle muscle biopsies that were obtained in association with a research study in which the patient participated.

Reprinted from Moxley (1992) with permission from Elsevier.



Figure 37.2


Mother and her son are the same individuals described in Case Example 37.1 in the text (left panel). At the time of this photograph, she was 27 years old and he was 8 months of age. The information in Case Example 37.1 also includes discussions of video clips of myotonia in the mother and floppiness in the infant. The right panel shows a 4 year old with congenital DM1 riding his tricycle. This child is described in Case Example 37.2 in the text.



Figure 37.3


Mother, who has mild to moderate myotonic dystrophy type 1, with her two daughters, both of whom have congenital DM1. At the time of the photograph, the mother was 34 years old and the daughters were 9 and 5 years old. The mother is now 49 years old, performs all activities of daily living well, cares for the daughters, has mild facial and distal limb weakness, and has left bundle branch block on her electrocardiogram. The older daughter is 24 years old, ambulatory, goes horseback riding each week, has no difficulty with feeding, lives with her parents, performs activities of daily living, and participates in housekeeping activities. Her electrocardiogram is normal. The younger, more severely affected daughter with severe CDM is 20 years old, still has a tracheostomy, and receives G-tube feeding and night-time ventilation. She is ambulatory, using ankle-foot orthoses during the day, and is off ventilator support. She climbs stairs and rides a bike. She attends a day program and receives weekly physical therapy, occupational therapy, and speech therapy. The younger daughter has regular follow-up care with pulmonary, cardiology, and otolaryngology consultants. Both daughters along with their mother have regular neuromuscular physician evaluations.

Reproduced from Moxley and Meola (2000), with permission from S. Karger AG.


Clinical Presentation and Phenotypes


Tables 37.1 and 37.2 summarize the genetics, core clinical features, and multisystem manifestations typically observed in the initial evaluation of adults with either mild or moderate signs and symptoms of DM1 and DM2. Figure 37.4 outlines the workup and Table 37.3 presents general guidelines for patient care. Childhood and infant onset symptoms occur only in DM1. Figures 37.5 and 37.6 outline the evaluation and workup of DM1 patients who present in infancy and childhood. Table 37.4 summarizes the clinical problems they often have as well as their management.


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Jun 25, 2019 | Posted by in NEUROLOGY | Comments Off on Myotonic Dystrophy

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