Additional Investigation After Muscle Biopsy Diagnosis

Based on the patient’s clinical presentation , clinical and EMG myotonia, and muscle biopsy findings, the DM2 gene test was ordered. It showed a repeat expansion mutation of DM2 with the expanded repeat size of 13,170 base pairs (normal: <176 base pairs), diagnostic for DM2. CBC, comprehensive metabolic panel, HbA1C, thyroid function test, ANA, and Vitamin D level were all normal.

Final Diagnosis

Myotonic dystrophy type 2

Patient Follow-up

The diagnosis, management, and prognosis of DM2 were discussed with the patient . He received physical therapy for the proximal limb weakness with benefit. His clinical myotonia was mild, and he did not want to take a medication for it. He underwent cardiology evaluation with no significant abnormalities found. His glycemic control was optimal. He was followed annually by neurology, cardiology, endocrinology, and ophthalmology.

Discussion

Myotonic dystrophy is the most common form of muscular dystrophies seen in adults . It is a unique muscular dystrophy characterized by multisystem involvement, clinical and EMG myotonia, RNA toxicity being the disease-causing mechanism, and lack of dystrophic changes on muscle biopsy.

Myotonic dystrophy is an autosomal dominant disease. It has two types: myotonic dystrophy type 1 (DM1) and DM2. While both types manifest muscle atrophy, weakness, myotonia, early-onset cataract (before age 50 years), diabetes mellitus, gastrointestinal dysfunction, hypogonadism, and cardiac abnormalities including arrhythmia, conduction defects, and cardiomyopathy, there are several differences between the two types [1, 2]. DM1 has an early symptom onset with the presence of a congenital form, while the onset of DM2 is late, most often in the fourth and fifth decades of life with no congenital form [1]. DM1 mainly affects distal limb muscles such as finger flexors, wrist flexors, and ankle dorsiflexors, while DM2 predominantly involves proximal and axial muscles including neck flexors, arm abductors, hip flexors, and hip extensors. Frontal balding is common in both types, but facial weakness is mainly seen in DM1. Cardiac dysfunction and central nervous system involvement are less common in DM2 than in DM1 [3–6].

DM2 is also known as proximal myotonic myopathy (PROMM) [7–11]. It is less common than DM1. The prevalence of DM2 is uncertain, and it likely varies by population. DM2 is probably underdiagnosed as the disease manifestation is variable and can be very mild and non-specific [12]. Some patients may only have muscle pain, fatigue, or mild weakness. Clinical myotonia is usually mild and can be absent. Percussion of forearm extensors and thenar muscles is the most sensitive clinical test for myotonia. When clinical myotonia is prominent in a patient with DM2, a superimposed chloride or sodium channel gene mutation should be considered [13, 14]. CK is usually mildly elevated or normal. Needle EMG in resting muscles may show myotonia which can be evoked by percussion; the myotonic discharges tend to be waning in DM2 as opposed to waxing-waning in DM1 [15]. EMG myotonia can be minimal or absent in DM2.

Muscle biopsy is not necessary in myotonic dystrophy as gene testing is commercially available for making the definitive diagnosis. However, due to the heterogeneity of the clinical presentation in DM2, muscle biopsy may still be useful in patients with mild and non-specific symptoms and findings. Muscle biopsy in myotonic dystrophy usually does not show dystrophic changes which consist of prominent myofiber degeneration, regeneration, and necrosis, and endomysial inflammation and fibrosis [16–18]. It typically shows markedly increased internal nuclei and increased fiber size variation with angulated or rounded atrophic fibers and some hypertrophic fibers [16–18]. In DM1, it may also show sarcoplasmic mass and prominent type 1 fiber hypotrophy [19, 20]. In DM2, it usually shows prominent pyknotic nuclei clumps and type 2 fiber atrophy and/or hypertrophy but not type 1 fiber hypotrophy [16–18]. Ring fibers is an infrequent finding [16, 18], and it is caused by disorientation of peripheral myofibrils running at right angles to the main body of the fibre [21]. It is best viewed by NADH stain or electron microscopy (EM). Muscle biopsies in individual DM2 cases may not show all the pathological features; while some show ring fibers (Fig. 12.1), the others do not (Fig. 12.2). In general, the pathological changes are more prominent in type 2 fibers in DM2 but more involving type 1 fibers in DM1 [17]. The pathological changes in DM2 do not correlate with individual clinical symptoms [16].

The pathogenic mechanism underlying myotonic dystrophy involves RNA toxicities. DM1 is caused by expanded CTG repeats in the 3′ untranslated region of the myotonic dystrophy protein kinase gene (DMPK) on chromosome 19q13 [22, 23]. DM2 is caused by expanded CCTG repeats in intron 1 of the zinger finger protein 9 gene (ZNF9) on chromosome 3q [24, 25]. These expanded repeats in the noncoding regions are transcribed into RNAs which exert a toxic gain-of-function to deregulate several RNA binding proteins including muscleblind-like proteins, resulting in aberrant RNA slicing, polyadenylation, or expression of hundreds of genes. The expanded RNA repeats may also affect cell signaling and are sometimes translated into neurotoxic peptides [26]. The multilevel toxicities and the large number of genes affected by the expanded RNA repeats account for the complex phenotype of myotonic dystrophy. The phenotype of DM2 is milder than that of DM1, which is most likely contributed by modifiers [27]. Currently, there is active therapy development to target and reduce the RNA toxicities by antisense oligonucleotides and others [26].

There is no cure for myotonic dystrophy at this point. Genetic counseling should be provided to every patient. Given the multisystem involvement, the symptomatic management of DM2 requires multiple clinical specialties, including neurology, cardiology, endocrinology, ophthalmology, gastroenterology, and rehabilitation. Myotonia, pain, and hypersomnolence are managed by neurologist. Grip myotonia is usually mild, and mexiletine may be used if bothersome [28]. A thorough cardiac evaluation is needed to identify and control the risks for major cardiac arrhythmia and cardiomyopathy [3]. Diabetes mellitus is more frequently seen in DM2 than in DM1, and it should be monitor and treated by endocrinologist. Periodic slit-lamp exam should be performed by ophthalmologist to detect cataract and treat accordingly. Rehabilitation is important for DM2 patients to manage their proximal limb weakness.

Pearls