Christian Wertenbaker

BASICS

DESCRIPTION

• Myotonic dystrophy is an inherited disorder of the muscles and other body systems.

• Type 1: DM1 (Steinert’s disease)

– Represents 98% of all cases

– Severe congenital form with marked developmental disability

• Type 2: DM2 (Proximal myotonic myopathy)

– Milder version of DM1 with more restricted manifestations

EPIDEMIOLOGY

• Most common muscular dystrophy affecting adults

• DM1: Age of onset is childhood to 40 years

• DM2: Age of onset is 20–60 years

• Men and women equally affected

Prevalence

• ∼1 case per 8,000 population

• Varies widely in different geographic areas

RISK FACTORS

Genetics

• Myotonic dystrophy is inherited in an autosomal dominant pattern

• Exhibits anticipation, getting progressively worse with each generation

– More severe when the disorder is passed on from the mother

• One of several known nucleotide repeat disorders

– DM1: DPMK gene-expanded repeat of CTG on chromosome 19

– DM2: ZNF9 gene-expanded quadruplet repeat of CCTG on chromosome 3

GENERAL PREVENTION

• Genetic counseling

• Prenatal and preimplantation diagnosis possible

PATHOPHYSIOLOGY

• CUG or CCUG repeats in the mutant RNA interact with RNA binding proteins and disrupt RNA splicing, affecting many genes

– Skeletal muscle chloride channel: Responsible for myotonia

– Insulin receptor

– Cardiac troponin T

DIAGNOSIS

Ophthalmic features of myotonic dystrophy include varying degrees of:

• Cataract: Most common ocular abnormality

– “Christmas tree cataract”: Multicolored iridescent crystalline lens opacities

– Later, stellate posterior cortical cataract

• Orbicularis weakness

• Delayed opening of eyes after forceful closure (myotonia of orbicularis)

• Ptosis: Involvement of levator muscle

• Slow saccades

• Progressive external ophthalmoplegia (diplopia rare)

• Low intraocular pressure

• Pigmentary retinopathy similar to that of Kearns Sayre syndrome

HISTORY

• Myotonia: Slow relaxation of muscles after contraction, often the first detectable finding

• Dysphagia

• Muscle weakness (and pain in DM2)

• Hypoventilation, disturbed sleep, and excessive daytime sleepiness

• Gastrointestinal symptoms: Dysphagia, constipation, abdominal pain

• Incontinence

• Infertility

• Cardiac history: Palpitations, blackouts, syncope

• Cognitive impairment/personality disturbance

• Complications of pregnancy and delivery

PHYSICAL EXAM

• Myotonia (handshake sign)

• Frontal balding

• Hollowing of the masseter and temporalis muscles

• Facial weakness

• Slackened mouth

• “Long face”

• Frontal bossing

• “Hatchet face”

• Wasting of neck and limb muscles

• Monotonous nasal voice

• Cardiac abnormalities: Bradyarrhythmias, tachyarrhythmias

• Endocrine disturbance: Insulin resistance, testicular atrophy

• Gastrointestinal disorders

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Blood work may show insulin resistance and mild to moderate elevations in serum creatine kinase

• Serum immunoglobulin studies may show IgG and IgM hypogammaglobulinemia

Imaging

• Brain MRI

– Scattered or diffuse bilateral symmetrical white matter hyperintense lesions, with variable frontal or temporal-insular predominance

Diagnostic Procedures/Other

• Molecular analysis for the nucleotide expansions in the DMPK and ZNF9 gene is the gold standard

• Electromyography (EMG) may detect presence of myotonia

• Slit-lamp examination may show typical cataract formation

• Electrocardiography (ECG) may show atrioventricular and intraventricular conduction disturbances with prolongation of the PR interval and QRS complex

• Muscle biopsy (see path)

• Forced vital capacity (FVC) measurements to detect weakness of respiratory muscles

• Swallowing assessment to assess for dysphagia

Pathological Findings

• Centrally-located nuclei run down the centers of muscle fibers

• The myofilaments and sarcoplasmic reticulum are disrupted, and accumulations of impaired mitochondria may be found

DIFFERENTIAL DIAGNOSIS

• Other muscular dystrophies

• Other myotonic syndromes

• Mild tetanus

• Polymyositis

• Stiff person syndrome

TREATMENT

ADDITIONAL TREATMENT

General Measures

• Symptomatic support

• Muscle weakness: Exercise training

• Ankle-foot-orthotics for foot drop

• Excessive daytime sleepiness: Modafinil, BiPAP

• Conduction abnormalities: Pacemaker placement

• Myotonia rarely requires treatment

SURGERY/OTHER PROCEDURES

• Cataract extraction for cataracts

• Ptosis repair for sight limiting ptosis: Caution not to precipitate exposure keratopathy

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Ophthalmologist

• Neurologist

• Cardiologist

• Pulmonologist

• Physical therapist

• Endocrinologist

• Rheumatologist

• Genetic counseling

PATIENT EDUCATION

• The myotonic dystrophy foundation (www.myotonic.org)

• MDA USA homepage (http://www.mda.org)

• International Myotonic Dystrophy Organization (http://www.myotonicdystrophy.com)

PROGNOSIS

• DM1: Life expectancy appears to be reduced

• DM2: Life expectancy appears to be normal

COMPLICATIONS

• High risk of cardiovascular and respiratory complications during general anesthesia

ADDITIONAL READING

• Arsenault ME, Prévost C, Lescault A, Laberge C, et al. Clinical characteristics of myotonic dystrophy type 1 patients with small CTG expansions. Neurology 2006;66(8):1248–1250.

• Cho DH, Tapscott SJ. Myotonic dystrophy: Emerging mechanisms for DM1 and DM2. Biochim Biophys Acta 2007;1772(2):195–204.

• Day JW, Ricker K, Jacobsen FJ, et al. Myotonic dystrophy type 2: Molecular, diagnostic and clinical spectrum. Neurology 2003;60(4):657–664.

• Machuca-Tzili L, Brook D, Hilton-Jones D. Clinical and molecular aspects of the myotonic dystrophies: A review. Muscle Nerve 2005;32:1–18.

CODES

ICD9

• 359.21 Myotonic muscular dystrophy

• 366.9 Unspecified cataract

• 374.30 Ptosis of eyelid, unspecified

CLINICAL PEARLS

• Myotonic dystrophy is the most common inherited neuromuscular disease in adults.

• It is a multisystem disorder characterized by skeletal muscle weakness and myotonia, cardiac conduction abnormalities, cataracts, testicular failure, hypogammaglobulinemia, and insulin resistance.

• Due to its wide range and variability of presentations, the diagnosis can often be initially missed, but it can usually be confirmed by careful attention to all the clinical features and/or by detailed family history.

• Treatment is symptomatic and there is no disease-modifying therapy available.

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