Proximal myotonic myopathy and proximal myotonic dystrophy: Two different entities? The phenotypic variability of proximal myotonic syndromes

Neuromuscular Disorders 11 (2001) 485±488

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Case report

Proximal myotonic myopathy and proximal myotonic dystrophy: Two different entities? The phenotypic variability of proximal myotonic syndromes C. Schneider a,*, C. Wessig a, C.R. MuÈller b, D. Brechtelsbauer c, T. Grimm b a

Department of Neurology, University of WuÈrzburg, Josef-Schneider-Strasse 1197080,WuÈrzburg, Germany b Department of Human Genetics, University of WuÈrzburg, WuÈrzburg, Germany c Department of Neuroradiology, University of WuÈrzburg, Germany Received 27 July 2000; received in revised form 19 September 2000; accepted 10 October 2000

Abstract Multisystemic myotonic myopathies are characterised by a variable pattern of symptoms and signs and a variable degree of disease severity. Proximal myotonic dystrophy has been described as an entity distinct from proximal myotonic myopathy because of severe proximal muscle weakness and dystrophic changes on magnetic reasonace imaging and on muscle histopathology. We describe two siblings, one of them presenting with a proximal myotonic myopathy phenotype, the other with a proximal myotonic dystrophy-like phenotype. The variability of disease expression in these two siblings suggests that a proximal myotonic dystropohy-like variant may occur in proximal myotonic myopathy. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Proximal myotonic myopathy; Proximal myotonic dystrophy; Myotonic dystrophy type 1; Myotonic dystrophy type 2; Multisystemic myotonic myopathies

1. Introduction In 1994, Thornton et al. [1] and Ricker et al. [2] reported several atypical myotonic dystrophy (DM) patients without the diagnostic expansion of CTG repeats on chromosome 19q 13.3. Due to preferential involvement of proximal limb muscles this new entity was called proximal myotonic myopathy (PROMM) by Ricker et al. [2]. Like DM, PROMM follows an autosomal dominant trait. In 1997, Udd et al. [3] described a multisystemic myotonic myopathy with severe proximal muscle weakness and wasting, dystrophic changes of these muscles on MRI and on muscle histopathology, electromyographical myotonia, cataracts, deafness and hypogonadism which they named proximal myotonic dystrophy (PDM). Linkage studies in PROMM as well as in PDM families revealed linkage to chromosome 3q [4,5], a gene locus previously described in myotonic dystrophy type 2 (DM2) [6]. Thus, although phenotypically different, DM2, PROMM and PDM seem to have a common genetic background. All these multisystemic myotonic * Corresponding author. Tel.: 149-931-201-2621; fax: 149-931-2013489. E-mail address: [email protected] (C. Schneider).

syndromes are now classi®ed as myotonic dystrophies (DM 1 and DM2) according to the genetic background but regardless of the clinical phenotype [7]. 2. Case report 2.1. Patients Patient 1: The index patient, a 61-year-old woman, had experienced dif®culties in climbing stairs and getting up from a squatting position for ®ve years. She had suffered from hirsutism and progressive frontal balding since her twenties. Mild diabetes mellitus type II was diagnosed at the age of 58. In her early 50s, cataracts on both sides had been extracted. Cardiac arrythmias, which she experienced as sudden attacks of fast heart rate, had appeared at the age of 58 and were successfully treated with sotalol. Clinically, she had mild weakness of head ¯exors, deltoid, and biceps muscles Medical Research Council (MRC) grade 4±5 and of hip ¯exors MRC grade 4. There was almost no atrophy of upper arm and thigh muscles, and there was no winging of the scapula. She did not complain about myalgias. Tendon re¯exes and sensory examination were normal. Electromyography showed myotonic runs in distal and proximal arm

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and leg muscles. On voluntary effort we found early motor unit action potential (MUAP) recruitment in the tibialis anterior and the quadriceps muscle, but con®guration of MUAPs was normal except from some high-amplitude potentials in the tibialis anterior muscle. In the deltoid muscle mainly small and polyphasic MUAPs were observed. Audiometry revealed mild sensorineural deafness within the speech region starting at 1000 Hz. On MRI T1weighted spin echo (SE)-sequence showed no obvious fatty degeneration of the thigh muscles but the rectus femoris muscle seemed to be slightly darker than the other muscles (Fig. 1). Cranial magnetic resonance imaging (MRI) revealed moderate cerebellar atrophy but no white matter lesions. Serum creatinine kinase (CK) was 102 U/l and gGT (glutamyl transferase) was normal. Elevation of luteinizing hormone (LH) and follicle stimulating hormone (FSH) values was compatible with a postmenopausal status. There was hypertriglyceridemia (324 mg/dl) but cholesterol was only mildly elevated (232 mg/dl). Histopathological examination of a muscle biopsy of the left vastus lateralis muscle revealed an increased number of central nuclei with multiple nuclei within several (hypertrophic) ®bres (Fig. 2), an increased variation in ®bre size, some nuclear clumps and a few scattered small angular ®bres. Some degenerating muscle ®bres and mild increase of endomysial ®brous tissue were also present. There was no ®bre type predominance and no selective ®bre type atrophy. We identi®ed two ragged red ®bres in the trichrome staining, but no COX-negative ®bres in the COX staining. Patient 2: On presentation, the brother of the index patient was 62 years old and complained about dif®culties in climbing stairs, walking uphill and getting up from a sitting position for 5 years. He had noticed progressive thinning of the shoulder, humeral and thigh muscles. He had mild gyneco-

mastia. Diabetes had been diagnosed at the age of 42 years and had to be treated with insulin during the last 5 years. Also, at the age of 42 years, he had undergone a thyroid operation. Cataracts on both sides had been operated in his early 40s. Erectile dysfunction occurred in his mid-50s. Since the age of 45 he suffered from marked hyperhidrosis of hands and feet. On examination, the head ¯exors were moderately paretic (MRC grade 4), but there was marked weakness and atrophy of the pectoralis, deltoid, biceps, and quadriceps muscles (MRC grade 3). Hip ¯exor muscles were preferentially affected (MRC grade 2). The shoulders were rotated inwardly, and there was bilateral but asymmetric winging of the scapula (Fig. 3). He did not suffer from myalgias. Tendon re¯exes were diminished, and there was a distal hypaesthesia of the lower limbs. Electromyogram (EMG) of the deltoid muscle revealed a mild myopathic pattern with about 30% of polyphasic potentials, whereas the EMG of the vastus lateralis and the tibialis anterior muscle revealed a mild neurogenic recruitment pattern. Myotonic discharges were found in all three muscles. On electrocardiogram (ECG) a sinus rhythm, a ®rst degree AV-block and a right bundle branch block were found, the 24 h recording revealed intermittent atrial ®brillation, some couplets, and supraventricular and polytopic ventricular extrasystoles. Echocardiography showed moderate concentric hypertrophy. Nerve conduction studies showed a mild axonal polyneuropathy. Additional ®ndings were sensorineural deafness within the speech region on audiometry. The patient had a hearing aid on the right side. On MRI T1-weighted SE-sequence revealed fatty degeneration of the leg muscles, which was much more pronounced in the anterior thigh muscles, but spared the rectus femoris muscle within the quadriceps group (Fig. 4). The patient refused to undergo a muscle biopsy. Cranial MRI showed enlargement of the ventricles

Fig. 1. Muscle MRI (T1-weighted SE-sequence) of patient 1 showing no obvious fatty degeneration of proximal leg muscles but a slightly darker rectus femoris muscle on both sides.

C. Schneider et al. / Neuromuscular Disorders 11 (2001) 485±488

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Fig. 2. Micrograph of the muscle biopsy of the left vastus lateralis muscle of patient 1 showing several ®bres with central nuclei, an increased variability in ®bre size, some hypertrophic ®bres and nuclear clumps (H & E staining, £200), bar, 50 mm.

and cortical atrophy, but no white matter lesions. CK was 143 U/l. Liver function tests, basal cortisol and LH were normal. A testosteron serum value of 2.6 ng/ml and a FSH value of 35.5 ng/l indicated mild primary hypogonadism. Hypercholesterolemia was only mild (247 mg/dl). 2.2. Genetics and other family members DNA analysis could rule out a trinucleotide repeat expan-

sion on chromosome 19q 13.3 in both patients. Both siblings were involuntarily childless. The third sibling, a 58-year-old sister, did not have weakness or other symptoms or signs compatible with the PROMM or the PDM phenotype. The father of the siblings had died aged 55 due to a sudden cardiac incident, and he had had walking dif®culties during the last 5 years of his life and diabetes. His two brothers had also died before the age of 60 because of cardiac problems, they had also suffered from diabetes and leg weakness. The

Fig. 3. Atrophy of proximal arm and shoulder muscles and bilateral winging of the scapula in patient 2.

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Fig. 4. Fatty degenerative changes of proximal leg muscles with relative sparing of the rectus femoris muscle on T1-weighted SE-sequence on MRI in patient 2.

father's sister had died of a malignoma at the age of 50, she did not have any muscle weakness. Reportedly there were no cataracts in other family members. Linkage analysis was not possible in this small family.

analysis a common genetic background in these two patients is very probable.

3. Discussion

[1] Thornton CA, Griggs RC, Moxley RT. Myotonic dystrophy with no trinucleotide repeat expansion. Ann Neurol 1994;35:269±272. [2] Ricker K, Koch M, Lehmann-Horn F, et al. Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weaknees, and cataracts. Neurology 1994;44:1448±1452. [3] Udd B, Krahe R, Wallgren-Pettersson C, Falck B, Kalimo H. Proximal myotonic dystrophy-a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes? Neuromusc Disord 1997;7:217± 228. [4] Ricker K, Grimm T, Koch MC, et al. Linkage to chromosome 3q in proximal myotonic myopathy (PROMM). Neurology 1999;52:170± 171. [5] Meola G, Udd B, Sansone V, Ptacek L, Lee D, Krahe R. Dominant multisystem proximal myotonic myopathic syndromes: clinical and genetic heterogeneity in three families. Neurology 1999;51(Suppl 2):A95. [6] Ranum LPW, Rasmussen PF, Benzow KA, et al. Genetic mapping for a second myotonic dystrophy locus. Nat Genet 1998;19:196±198. [7] The International Myotonic Dystrophy Consortium (IDMC). New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). Neurology 2000;54:1218±1221. [8] Moxley III RT, Ricker K, Udd B. 54th ENMC International Workshop: PROMM (Proximal Myotonic Myopathy) and other Proximal Myotonic Syndromes. Neuromusc Disord 1998;8:508±518. [9] Phillips MF, Rogers MT, Barnetson R, et al. PROMM: the expanding phenotype. A family with proximal myopathy, myotonia and deafness. Neuromusc Disord 1998;38:439±446. [10] Harper PS. Myotonic dystrophy. 2nd ed. London: W.B. Saunders, 1989.

Our two siblings, one of them presenting with a PROMM phenotype and the other with a PDM-like phenotype, illustrate the variability of disease expression within a family. Since the ®rst description of atypical myotonic dystrophy patients several proximal myotonic syndromes have been encountered [8,9]. The degree of muscle weakness and wasting, but also the spectrum and the severity of extramuscular manifestations may be variable [3]: PDM is characterised by marked wasting and weakness of proximal muscles, dystrophic changes of proximal muscles on MRI, hearing loss, cataracts and hypogonadism [4]. Deafness seems to occur facultatively in PROMM [9], but also in DM1 [10]. The pattern of weakness may be variable in PROMM [8], DM2 [6] and DM1 [10]. Several members of the DM2 family suffered from hyperhidrosis [6] which was also present in our male patient, but not in his sister. The clinical picture of our two patients is similar in some aspects but is not identical, and shows overlapping features with those of other multisystemic myotonic myopathies. Thus, these two patients may represent another link between previously described multisystemic myotonic syndromes and may illustrate the usefulness of the new classi®cation of myotonic dystrophies [7] since despite the lack of linkage

References