Hypothyroidism unmasking proximal myotonic myopathy

Neuromuscular Disorders 10 (2000) 165±172 www.elsevier.com/locate/nmd

Hypothyroidism unmasking proximal myotonic myopathy V. Sansone a,*, R.C. Griggs b, R.T. Moxley III b a

b

Department of Neurology, University of Milan, San Donato Hospital, Via Morandi, 30, 20097 San Donato Milanese, Milan, Italy Department of Neurology, and the Wayne C. Gorrell Jr. Molecular Biology Laboratory, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA Received 15 March 1999; received in revised form 28 June 1999; accepted 15 September 1999

Abstract No speci®c diagnostic test is available to identify patients with proximal myotonic myopathy and to distinguish them from common disorders causing similar complaints. We describe three patients from three separate families who were initially diagnosed as having hypothyroid myopathy. Proximal weakness, stiffness and myotonia have persisted in each patient (2±10 years) despite the restoration of the euthyroid state. A familial pattern of autosomal dominant inheritance for proximal weakness, myotonia, and cataracts was clearly identi®ed in one family and was likely in the other two families. DNA testing showed normal size of CTG repeat in the gene for myotonic dystrophy. The clinical presentation of these three patients strongly suggests that hypothyroidism can unmask PROMM in asymptomatic individuals who carry the genetic abnormality. Other cases of `hypothyroid myopathy' may represent examples of unmasked PROMM. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Proximal myotonic myopathy; Hypothyroid myopathy; Myotonic dystrophy

1. Introduction The core features of proximal myotonic myopathy (PROMM) are: autosomal dominant inheritance, proximal weakness, primarily in thigh muscles, variable grip myotonia, iridescent cataracts identical to those in DM, and normal size of the (CTG)n repeat in the DM gene [1±9]. When a patient presents with the core features outlined above, the diagnosis of PROMM is straight forward. However, patients with PROMM acquire these core features over years. Several other associated ®ndings commonly occur in PROMM, such as, muscle pain, tremor, and neck ¯exor weakness [3±9], and these symptoms may lead the clinician to suspect a toxic myopathy, polymyositis, or thyrotoxic myopathy without considering the possibility of PROMM. The elevation of creatine kinase and the muscle biopsy ®ndings of non-speci®c myopathy that occur in PROMM [3±8] can reinforce the diagnosis of toxic or atypical in¯ammatory myopathy and the variable severity of myotonia, even on electromyographic study [8], may further conceal the diagnosis of PROMM. In the present report we describe the ability of hypothyroidism to amplify the symptoms of PROMM and at the * Corresponding author. Tel.: 139-025-277-4556; fax: 139-025-274717. E-mail address: [email protected] (V. Sansone)

same time to obscure the diagnosis. We discuss three patients, each from separate kindreds, who came for diagnosis and treatment of muscle weakness and stiffness accompanied by myotonia. These complaints developed with the onset of severe hypothyroidism in all three patients, and all three patients initially received a diagnosis of hypothyroid myopathy. Subsequent evaluation has demonstrated that each of these patients has PROMM, which abruptly became manifest in the presence of a marked de®ciency of thyroid hormone. 2. Materials and methods All patients and available family members (Fig. 1) had a detailed clinical history and neurological examination. Muscle strength was assessed by manual muscle testing and rated on a 1±5 MRC scale in which the highest score signi®es no muscle impairment [10]. Genetic screening for CTG repeat size was performed on blood DNA as previously described [6]. All three of our patients and affected individuals within each of their families had proximal weakness and other typical clinical features of PROMM [3±9]. None of our patients or their family members had distal wasting or weakness present in typical DM [1]. None of our patients had clinical features resembling the recently reported phenotypes of proximal

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Fig. 1. Family trees: ( ) ( ) proximal weakness; ( ) ( ) myotonia; ( ) ( ) cataracts; ( ) ( ) muscle pain; (*) examined; ( b ) index case.

myotonic dystrophy [11] or variants of distal myotonic atrophy without (CTG)n repeat expansion [12,13]. Cardinal PROMM features and additional neuromuscular and systemic characteristics of the index cases and family members are summarized in Table 1.

3. Case reports 3.1. Family 1 patient II-2 A 66-year-old man had a history of progressive proximal

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167

Table 1 Clinical features of the three families with PROMM. Data related to CK levels, muscle biopsy results and electrodiagnostic studies refer to the euthyroid condition. Cardinal PROMM symptoms

Family 1

Family 2

Family 3

Proximal weakness

Index case (66 years), son of index case (47 years), niece of index case (21 years)

Index case (35 years), his father (65 years) and paternal uncle (74 years)

EMG myotonia

Index case, son of index case, niece of index case Son of index case Index case, son and niece of index case

Index case (72 years), son of index case (39 years), paternal aunt (68 years) and paternal cousin (34 years) Index case, son of index case, paternal aunt and her daughter Index case Index case, son of index case

Index case, his father and paternal uncle None Index case

Index case, son of index case

Index case

Index case b Index case

None Index case

None Son of index case ( £ 2) None Index case d None

None Index case ( £ 2) None Index case e Index case f

Cataracts Normal (CTG)n expansion Supportive ®ndings for PROMM Muscle pain Cardiac involvement Preserved DTR Calf hypertrophy High CK Frontal balding Abnormal muscle biopsy Oligospermia

Index case, son and niece of index case Index case a Index case, son and niece of index case Son of index case Nobody Son of index case Index case c None

a

Myocardial infarction. Coronary heart disease. c Muscle biopsy of the right biceps showed a few necrotic ®bers, phagocytosis, regenerating ®bers, increase internal nuclei (in 30% of ®bers), and an increased variation in ®ber size. A second muscle biopsy, 6 years after the diagnosis of hypothyroid, showed similar ®ndings. d Initial muscle biopsy of the left biceps showed increased variability in ®ber size, increased central nuclei (in 40% of ®bers), pyknotic nuclear clumps and type I predominance. A repeat biopsy of the deltoid muscle 1 year later showed similar ®ndings. e Muscle biopsy of the quadriceps femoris muscle showed increased variability in ®ber size, type I ®ber atrophy, type II ®ber hypertrophy, and increased numbers of central nuclei (in 40% of ®bers) and pyknotic nuclear clumps. f Plasma testosterone level was 332 ng/dl (normal values 270±1200) and the accompanying plasma FSH was 25.4 mIU/ml (normal values 1.0±14.0). Age of patients in years is indicated in brackets. b

weakness. He complained of muscle pain, cramps, stiffness and fatigue on mild exercise. Past medical history included recurrent myocardial infarction. Examination revealed symmetric, moderate to severe shoulder and hip girdle muscle weakness (grade 3 MRC). No de®nite action or grip myotonia was observed. Electromyographic studies revealed myotonic discharges in proximal and distal muscles in the arms and legs. Low amplitude, brief duration, rapidly recruited motor unit potentials appeared with muscle contraction of the quadriceps femoris muscles. Serum T4 levels were undetectable. Creatine kinase (CK) was elevated 30-fold above normal (6870 units/l). A diagnosis of hypothyroid myopathy was made. Levothyroxine treatment was gradually increased over several months. With the gradual replacement of thyroid hormone, CK and TSH values returned to the normal range approximately 2±3 years after initiating therapy. However, thigh muscle weakness progressed. Muscle stiffness also remained. Repeat electromyograms demonstrated persistent myotonia in the quadriceps femoris and biceps muscles. Initial exploration of the family history failed to reveal any individuals with neuromuscular problems. However, 6 years after the initial diagnosis of hypothyroid myopathy in the patient, his son

(III-1) and niece (IV±1) complained of proximal lower limb weakness, cramps and stiffness. EMG showed myotonic discharges. Posterior subcapsular cataracts were identi®ed. Frontal balding was present. Myotonic dystrophy was suspected. Genetic analysis showed a normal size CTG repeat in the myotonic dystrophy gene. The diagnosis of PROMM was made. 3.2. Family 2, Patient III-1 A 72-year-old woman came for evaluation of her progressive weakness. Past medical history included coronary artery disease. At the age of 58 she developed hyperthyroidism. She was treated with Tapazole. Hypothyroidism subsequently developed, and she developed weakness. She received Synthroid (0.1 mg qd). Despite restoration of the euthyroid state, her weakness has continued to progress. Muscle pain, cramps and stiffness have appeared more recently. On neurologic examination she has moderately severe proximal shoulder girdle muscle weakness (grade 3 MRC) more severe hip girdle muscle weakness (grade 2 MRC). EMG shows myotonic discharges in all muscles tested. Cataracts were removed at the age of 55. Given the

79

44%

180

100%

15%

27

Initial stiffness Recovered: 38 Improved: 19 Unchanged: 2 Recovered: 21% Improved: 10%

Abnormal: 64 b Normal: 107 Abnormal: 35%

Muscle exam after therapy

Muscle exam before therapy

Abnormal: 52%

Abnormal: 62 c Normal: 7

Electrodiagnostic studies before therapy

Abnormal: 50%

Abnormal: 2 Normal: 2

Electrodiagnostic studies after therapy

Abnormal: 98%

Abnormal: 54 d Normal: 1

Muscle biopsy abnormalities before therapy

Reversal: 48% Improved: 52%

Reversal: 10 Improved: 11

Muscle biopsy abnormalities after therapy

None

None

Cataracts

A total of 180 patients are reported in references [22±56] and all had an initial muscle examination with 44% describing subjective weakness and 15% noting muscle stiffness. Smaller numbers of patients had electrodiagnostic studies on initial evaluation (total of 69 patients) and muscle biopsy (total of 55 patients). An even smaller fraction of the initial 180 patients had a muscle examination after therapy (total of 59 patients), follow-up electrodiagnostic testing (total of four patients) and follow-up of muscle biopsy (total of 21 patients). These small numbers of follow-up assessments relative to the initial population of 180 patients need to be considered when referring to the 100% of `total' in this table. b Abnormal muscle exam: seven patients described as having myotonia and 57 patients described as having muscle weakness. c Abnormal electrodiagnostic studies: 28 patients described as having myopathic EMG; 24 patients described as having neuropathic EMG; ®ve patients described as having myasthenia-like decrement; ®ve patients described as having true myotonic discharges. d Abnormal muscle biopsy ®ndings: 35 muscle biopsy specimens showing increase in central nuclei; 22 showing type II atrophy; 13 showing glycogen accumulation; 11 showing type I predominance; eight showing type II predominance; six showing core-like structures.

a

Initial subjective weakness

Patients

Table 2 Clinical overview of hypothyroidism and associated muscle symptoms, electrodiagnostic ®ndings and muscle biopsy abnormalities before and after thyroxine replacement therapy: summary of literature [22±56] a

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progression of weakness, myotonic discharges and earlyonset cataracts, myotonic dystrophy was suspected. Genetic analysis showed a normal size CTG repeat in the myotonic dystrophy gene. Further inquiry into the patient's family history reveals that other family members complained of lower limb weakness, stiffness and muscle pain, suggestive of PROMM (Table 1). 3.3. Family 3, Patient III-1 A 35-year-old man had thyroid cancer at the age of 13 and was maintained on daily Synthroid 0.3±0.25 mg. Inadvertently he received a ten-fold lower dose. Subsequently he developed symptoms of muscle pain, cramping, chest pain and fatigue. T4 was undetectable, TSH was .50 mIU/ml and CK were increased by 60-fold (.10 000 units/l). His dosage of Synthroid was returned to proper amount and most of his symptoms improved. However, despite long-term restoration of the euthyroid state he still complains of cramps in his legs, muscle aches and fatigue. He also has dif®culty with ®ne motor control and releasing objects. Neurologic evaluation revealed grip and percussion myotonia in addition to slight (grade 41 MRC) proximal muscle weakness. EMG reveals myotonic discharges in proximal and distal muscles. This latter ®nding and the persistence of muscle weakness suggested the diagnosis of myotonic dystrophy. Genetic analysis shows a normal size of CTG repeats for the DM gene. Further inquiry into the family history revealed his 65 year-old father (II-4) and 74 yearold paternal uncle (II-5) have complained of lower limb muscle weakness, stiffness and dif®culty releasing objects since the age of 40 (Table 1). 4. Discussion Determining the cause of variable fatigue, slowly progressive muscle weakness, varying muscle stiffness, and intermittent muscle pain in a patient can sometimes pose a challenge for diagnosis. These symptoms can occur in common disorders such as arthritis and certain collagen vascular diseases, and are very frequent in hypothyroid myopathy and in the recently delineated disorder, PROMM. This report describes three patients in whom we believe hypothyroidism ampli®ed the manifestations of PROMM. Hypothyroidism is a relatively common medical problem and it is conceivable that the association between the development of worsening signs of PROMM and hypothyroidism that we have reported in these three patients is coincidental. However, none of the patients had symptoms of muscle disease until they developed hypothyroidism. Prior to the diagnosis of hypothyroid myopathy all three patients were asymptomatic and had no functional limitations. It seems much more likely that all three patients had subclinical PROMM that emerged

169

abruptly during the onset of severe hypothyroidism. Of interest, is a recent report [14] suggesting an important hormonal in¯uence over symptoms of muscle weakness and painful myotonia in PROMM. One may question whether our three patients actually have PROMM as opposed to having extreme neuromuscular symptoms from a de®ciency of thyroid hormone. Patient 1, clearly has PROMM based on the clinical criteria for this illness [8]. His son and his son's daughter have dif®culty climbing stairs, and have fatigue and stiffness which improve with exercise. Myotonia was consistently present on serial electromyography studies. There are early-onset cataracts in two generations of this family. Muscle biopsy in the patient's son shows ®ndings typical for PROMM. The diagnosis of PROMM in patients 2 and 3 in this report is also likely. However, their evaluations do not meet all the core criteria for PROMM [8]. Patient 2 has all the typical clinical ®ndings of PROMM. Her progressive weakness, the persistence of clinical and electrical myotonia, and the abnormalities present on her muscle biopsy before and after therapy, in the presence of the euthyroid state for over 10 years, strongly support the diagnosis of PROMM. Additional features in favor of PROMM in this patient are her mild facial weakness, muscle pain and progressive bilateral sensorineural hearing loss [3±9,11]. Patient 3 also has clinical ®ndings typical for PROMM. However, he has punctate opacities on slit-lamp examination.rather than the typical iridescent, spoke-like cataracts seen in both PROMM and DM [1±9]. The natural history of the development of cataracts in PROMM is unknown [7]. There was a clear temporal relationship between the onset of muscle weakness, clinical myotonia, and the development of hypothyroidism. He developed mild proximal weakness of the neck and girdle muscles, grip and percussion myotonia, and he has recently developed shoulder pain. These problems have persisted despite maintenance of the euthyroid state for the past 2 years. Another concern that one may have is that the three patients in the present report may have hypothyroidism in association with some other myotonic neuromuscular disease than PROMM. The myotonia might have resulted from another myotonic disease, such as, those involving the skeletal muscle chloride [15±17] and sodium [18±21] channels. Our patients and symptomatic family members did not have muscle stiffness in childhood. This observation argues against the diagnosis of chloride channel myotonia which typically becomes symptomatic in childhood [15±17]. The presence of cataracts and progressive weakness in our patients are not typical for either chloride or sodium channel myotonias. The lack of any history of episodes of muscle weakness or muscle stiffness with exercise following exposure to cold in our three patients as well as in family members, argues against paramyotonia congenita [19,20], a disease of the skeletal muscle sodium channel. The lack of spontaneous attacks of weakness, the presence of cataracts and slowly progressive muscle weakness, and the relatively

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late onset of symptoms, also argue against other forms of sodium channelopathy [21] as the cause for the muscle symptoms in these patients. If, as we believe, all three patients in this report have PROMM that became ampli®ed by thyroid de®ciency, what symptoms have occurred mainly from hypothyroidism and not from PROMM? Are most of the symptoms due to hypothyroid myopathy? The term `hypothyroid myopathy' has appeared in a number of reviews describing the neuromuscular manifestations of a de®ciency of thyroid hormone [22±50]. Although most clinicians will probably agree that the proximal weakness, the elevation of CK, and the slowed movements and re¯exes are common clinical features of hypothyroid myopathy, the clinical presentation actually described in previous reports varies. As summarized in Table 2 there are a number of reports (total n ˆ 180 patients) which describe cases of hypothyroid patients with muscle symptoms [22±50]. Relatively few patients have had serial clinical evaluations, electrodiagnostic studies or muscle biopsies following replacement therapy with thyroid hormone. The natural history and long-term response to thyroid treatment of the muscle symptoms remains uncertain. There are no consistent patterns for serum CK levels, muscle histopathologic ®ndings or the results of electrodiagnostic studies. The increase in CK levels in hypothyroidism varies and may be related to increased leakage from skeletal muscle cells or diminished clearance from the circulation [51]. Muscle biopsy may be normal [28] or it may show a variety of non-speci®c abnormalities. Electromyographic ®ndings may be normal [27,31,36,45] or may show a myopathic [28,29,36,41,44] or a neurogenic pattern [29,30,39,40,44]. Our review of the literature and our synthesis of the results agrees with the review of neuromuscular symptoms in hypothyroidism by Ramsay [50]. True myotonia is rarely ever present in hypothyroidism. One previous report of two patients [26] distinguishes between the electrically silent delayed relaxation following muscle contraction, which occurs in hypothyroidism, from the electrical response that occurs in true myotonia. From our review of the literature we have identi®ed ®ve cases in which there is true myotonia coexisting with hypothyroidism [52±56]. However, electromyograms were not performed in all of these patients either before or after replacement therapy. An underlying myotonic disorder was postulated by the authors in two of these cases and was not ruled out in the remaining patients. The three patients in the present report all have true myotonia. Their myotonia worsened with the development of severe hypothyroidism. It improved, but did not disappear, with replacement treatment and restoration of the euthyroid state. The response of our patients differs from that in patients with hypothyroidism alone. Muscle stiffness and fatigue typically resolve completely in patients with hypothyroidism. Creatine kinase levels usually return to normal with the gradual development of euthyroidism.

Persistence of high creatine kinase levels in the setting of euthyroidism in two of the three patients supports the idea of a pre-existing muscle disorder. The abrupt development of the myotonia in the three patients following severe thyroid de®ciency and its partial improvement with thyroid replacement therapy is similar to the response in the cases just described above of individuals having true myotonia. It seems likely that the ®ve patients described in the literature so far [52±56] as well as the three patients in this report are examples of a clinical presentation in which an underlying myotonic disorder, perhaps PROMM, has been unmasked by hypothyroidism. If the myotonic disorder and hypothyroidism were indeed independent of one another, one may have to consider that the incidence of the autosomal myotonic myopathies in the general population could be higher than expected. The mechanism by which hypothyroidism has worsened myotonia in PROMM or in other myotonic disorders requires further study. It may relate to altered mitochondrial function and altered energy metabolism [57±61]. Magnetic resonance spectroscopy of skeletal muscle has previously suggested the existence of a hormone-dependent reversible mitochondrial impairment in patients with exercise intolerance, fatigue and hypothyroidism [61]. Mitochondrial swelling has been described in muscle biopsies from hypothyroid patients with musculoskeletal symptoms [30,38]. There was no evidence of mitochondrial disease in our three patients. There were no ragged red ®bers or tubular aggregates. It may be that a de®ciency of thyroid hormone unmasks and worsens the muscle stiffness, myotonia, fatigue and weakness in patients with PROMM through a combination of actions that both in¯uence the stability of the muscle membrane and alter the metabolic events that regulate relaxation of the muscle ®bers. Previous investigators have demonstrated that a de®ciency of thyroid hormone reduces acid maltase activity [62], compromises the mobilization of sarcoplasmic stores of glycogen [63], decreases the stores of intracellular Na/K pumps [64±65], and, as a result, decreases the ability of insulin to recruit the Na/K ATPase [65]. Hypothyroidism also impairs insulinmediated carbohydrate metabolism, decreasing its actions on target tissues [63]. This decrease in whole-body insulin action, exerts an additive deleterious effect in patients with PROMM, who already have a high likelihood of developing insulin resistance due solely to this disorder [66]. The metabolic alterations outlined above may account for the abrupt development of muscle symptoms as a consequence of severe hypothyroidism in our three previously asymptomatic individuals with PROMM. Further studies are necessary to determine if the pathophysiological process responsible for the symptoms in PROMM has a close relationship to one or more of the cellular actions of thyroid hormone. It may be that a signi®cant number of patients previously diagnosed as having `hypothyroid myopathy' represent examples of unmasked PROMM.

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Acknowledgements The authors are grateful to Professor Giovanni Meola for support and advice. This work was supported by grants from New York, the National Institutes of Health (NIH grants R01NS22099 and 08R1AR44069A-01A1; GCRC grant M01-RR0044); the Muscular Dystrophy Association and from the University of Milan, Italy (MURST 60%).

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