L.M. Lien, C.C. Yang, W.H. Chen, et al

BRIEF COMMUNICATIONS

BETHLEM IN A TAIWANESE FAMILY

Li-Ming Lien, Chih-Chao Yang,1 Wei-Hung Chen, and Hou-Chang Chiu

Abstract: We report three cases of Bethlem myopathy from three consecutive gen- (J Formos Med Assoc erations of a Taiwanese family, including one woman aged 70, one man aged 40, 2001;100:416–9) and a boy aged 8. The clinical features of the patients included autosomal dominant inheritance, childhood or adolescent onset, mainly proximal and extensor Key words: involvement, early diffuse joint , and absence of cardiac involvement. Bethlem myopathy These features fulfilled the diagnostic criteria for Bethlem myopathy. Though the joint clinical course of the disease was once thought to be benign, our female patient became -bound at the age of 53. This suggests that the disease process in Bethlem myopathy is slow but ongoing.

Bethlem myopathy is a rare autosomal dominant myopathy. ing the family history, he stated that his mother and his elder It was first reported in 1976 by Bethlem and van Wijngaarden son had similar clinical features. His mother had two brothers in three unrelated Dutch families [1]. The clinical features and six sisters and he had one sister and one brother, none of include childhood onset limb-girdle weakness, slow whom were affected. He had two sons, the elder, aged 8, also progression, widespread joint contractures, and absence of suffered from gait difficulty and contractures of the distal cardiac involvement [2]. Mohire et al described a large limbs, while the younger, aged 2, was normal in developmen- French-Canadian family and proposed the name Bethlem tal milestones and free of neuromuscular symptoms. The myopathy [3]. Subsequently, patients in other parts of the authors examined the index case, his mother, and his two world have been described [4–7]. The features of autosomal sons. Other family members refused examination. The de- dominant inheritance, juvenile onset, limb-girdle muscular tailed history of these three patients is described below. dystrophy with diffuse joint contractures, and non-specific findings of muscle histopathology separate Bethlem myopa- Case 1 thy from other , such as Emery-Dreifuss muscular This 40-year-old male, a native Taiwanese, was the index dystrophy [8–12], rigid spine syndrome [13, 14], and con- case. He was not floppy at birth and had normal early genital myopathy [1, 2], and constitute a new disease entity. developmental milestones. He began to stumble easily at the Recently, it has been shown that Bethlem myopathy is due to age of 4 and had poor athletic performance throughout the a type VI disorder with mutations of the alpha 1 to school years. He gradually developed pes equinovarus and 3 subunits [15, 16]. This rare type of hereditary myopathy has toe walking at the age of 10. Rapid progression of joint not been previously reported in Taiwan; we describe three contractures, including interphalangeal joints, knees and cases of Bethlem myopathy from three generations of a elbows, were noted during the adolescent period. His Achil- Taiwanese family. les tendon was lengthened due to a tight heel cord at the age of 18 and no further shortening was noted thereafter. Diabetes mellitus was diagnosed when he was 30 years old. Physical examination at the age of 40 showed flexion contractures at ase Reports the ankles, elbows, wrists, and all interphalangeal joints. C Other abnormalities found on physical examnination in- cluded pes equinovarus, tightness of both heel cords, and A 40-year-old male patient presented with muscle wasting dark brown patches on the skin of the lower limbs (Fig. 1A). and contractures in the wrists and ankles. On inquiry regard- He had muscle wasting of all four limbs. There was no

Departments of Neurology, Shin Kong Wu Ho-Su Memorial Hospital and 1National Taiwan University Hospital, Taipei. Received: 30 June 2000. Revised: 24 July 2000. Accepted: 17 October 2000. Reprint requests and correspondence to: Dr. Hou-Chang Chiu, Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen-Chang Road, Shih Lin, Taipei, Taiwan.

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A B

Fig. 1. Contractures of elbows and fingers are evident in (A) Case 1 and (B) Case 3. Dark brown patches on the skin of both cases over the lower limbs are postinflammatory pigmentations secondary to herb drug application. Case 3 also presented with contractures of the knees and ankles.

evidence of facial weakness, scapular winging, muscle proximal weakness with extensors more seriously involved hypertrophy, or percussion . Manual muscle power than flexors. Tendon reflexes were normal. Flexion testing using Medical Research Council (MRC) grading showed contractures were seen at the elbows, interphalangeal joints, grade 4 proximally and 5 distally, with extensors weaker than knees, and ankles. A waddling gait and toe walking were flexors (except in the hip joint). Neck flexors also exhibited observed. He had normal intelligence. The CK concentration mild weakness. Tendon reflexes showed a generalized was 588 U/L. Concentric needle EMG demonstrated normal decrease. The (CK) concentration was 133 U/ motor units with early recruitment. Motor and sensory L (normal, 37–289 U/L). Concentric needle electromyogra- phy (EMG) demonstrated abundant short and small amplitude polyphasic potentials with an early recruitment pattern. Some large polyphasic potentials were also seen. No spontaneous discharges were recorded. Motor and sensory nerve conduc- tion velocities were normal. Echocardiogram and electrocar- diogram were both normal. Fasting glucose concentration was 20.7 mmol/L (376 mg/dL). HbA1C was 9.3% (normal, 4.1–6.2%). Urine analysis showed glucosuria (3+). Muscle biopsy from the left quadriceps showed increased variation in fiber size and fiber splitting, and markedly increased central nuclei. No cellular infiltrates were found. There was no evidence of muscle type grouping or angulated fibers (Fig. 2).

Case 2 This boy was the elder son of Case 1; he was 8 years old at first examination. He had frequent falling at 2 years of age, and toe walking was noted at the age of 4. He used Gower’s maneuver Fig. 2. Muscle biopsy from Case 1 shows marked variation in fiber size, to stand up at the age of 5. Gait difficulty and joint contractures an increased number of central nuclei, and round and atrophic deteriorated rapidly thereafter. Examination revealed normal muscle fibers of both type I and type II (ATPase pH 9.4, original cranial musculature, mild distal weakness and moderate magnification x 200).

J Formos Med Assoc 2001 • Vol 100 • No 6 417 L.M. Lien, C.C. Yang, W.H. Chen, et al conduction velocities were within normal limits. Electrocar- found in our patients. The muscle histopathology in the diogram was normal. He underwent Achilles tendon length- present three cases revealed a morphologically non-specific ening surgery at the age of 9, however, contractures of ankle myopathy, which indicates an absence of congenital myopa- joints developed 1 year later. thy [1, 2]. Incomplete expression of the dominant gene of must be differentiated from Bethlem Case 3 myopathy [3]; however, neither facial weakness nor myoto- This 70-year-old female was the mother of Case 1. She also nia was found in our patients. had normal early developmental milestones. Toe-walking Contracture of the joints in Bethlem myopathy is actually was evident at age 12. Elbow and heel cord contractures due to contracture of the flexor muscle rather than the joint developed gradually. She became a tailor and was married at itself. The angle of finger flexion is more prominent when the the age of 26. Disease progression was slow enough that she wrist is extended than when it is flexed. The number of joints could handle most of her daily activities without difficulty with contracture increased with age in our patients. The son through most of her adult life. It was not until the age of 53 of the index case in this report developed recontracture of the that, after casting for left tibial fracture, she could not walk ankle joint quickly 1 year after Achilles tendon lengthening because of contracture of the left knee. Weakness of the upper surgery at the age of 9 years. Corrective surgery for contrac- limbs was severe enough to prevent her from using crutches, ture in childhood should be delayed as early recontracture and she became wheelchair-bound thereafter. Diabetes mel- might occur and also because of the dynamic nature of litus was diagnosed at the age of 63. Examination at the age contracture in childhood [17]. Prolonged casting should be of 63 also revealed atrophy in the shoulder girdle and lower avoided in patients with Bethlem myopathy because of the limbs. Facial musculature was spared. Muscle power testing possibility of inducing irreversible joint contracture. The revealed MRC grade 3 proximally and 4 distally. Flexion natural course of Bethlem myopathy in adults is not always as contractures were observed at the interphalangeal joints, benign as was originally reported [1]. The oldest of our three knees, elbows, and ankles, and there were dark brown patients was confined to a wheelchair from the age of 53. patches on the skin over the lower limbs (Fig. 1B). General- Jobsis et al found that more than two-thirds of patients over 50 ized hyporeflexia was also noted. The CK concentration was years of age used a wheelchair for some ambulation and 20 U/L. Concentric needle EMG demonstrated abundant suggested that the disease process was slow but ongoing [17]. polyphasic potentials with mixed short and long duration, small to large in amplitude with an early recruitment pattern. Electrocardiogram was normal. References

1. Bethlem J, van Wijngaarden GK: Benign myopathy with autoso- Discussion mal dominant inheritance: a report on three pedigrees. Brain 1976;99:91–100. 2. Arts WF, Bethlem J, Volkers WS: Futher investigations on benign Our three patients had the following clinical features: early onset myopathy with autosomal dominant inheritance. J Neurol 1978; (childhood or adolescence); general weakness, more severe at 217:201–6. the proximal muscles and extensors; early joint contractures, 3. Mohire MD, Tandan R, Fries TJ, et al: Early-onset benign autoso- especially at the elbows and ankles but not in the spine; very mal dominant limb-girdle myopathy with contractures (Bethlem slowly progressive course; absence of cardiac involvement; myopathy). Neurology 1988;38:573–80. autosomal dominant inheritance, involving both sexes in three 4. Tachi N, Tachi M, Sasaki K, et al: Early-onset benign autosomal- consecutive generations; normal to mildly elevated CK dominant limb-girdle myopathy with contractures (Bethlem concentrations; normal mentality; and myopathic changes on myopathy). Pediatr Neurol 1989;5:232–6. muscle biopsy. The early-onset autosomal-dominant myopathy 5. Sasabe F, Takase Y, Fukusako T, et al: Early-onset benign autosomal with contractures in our patients were identical to the previously dominant limb-girdle myopathy with contractures (Bethlem myopathy) in a Japanese family. Rinsho Shinkeigaku (Clinical reported features of Bethlem myopathy. Our literature review Neurology, Tokyo) 1992;32:138–42. [In Japanese; English abstract]. found 10 pedigrees of such myopathy. Most patients were 6. Nielsen JF, Jakobsen J: A Danish family with limb-girdle muscu- European and two were from Japan [1–7, 15–17]. lar dystrophy with autosomal dominant inheritance. Neuromusc There are several other types of myopathy with early joint Disord 1994;4:139–42. contractures including Emery-Dreifuss , 7. Merlini L, Morandi L, Granata C, et al: Bethlem myopathy: early- rigid spine syndrome, and . Emery- onset benign autosomal dominant myopathy with contractures. Dreifuss muscular dystrophy is characterized by early con- Description of two new families. Neuromusc Disord 1994;4:503–11. tracture of the Achilles tendons, elbows, and posterior cervical 8. Rowland LP, Fetell M, Olarte M, et al: Emery-Dreifuss muscular muscles and cardiac conduction defects, and is usually dystrophy. Ann Neurol 1979;5:111–7. inherited as an X-linked recessive trait [8–12]. Our patients 9. Hopkins LC, Jackson JA, Elasa LJ, et al: Emery-Dreifuss humeroperoneal muscular dystrophy: an X-linked myopathy did not have cardiac abnormality and the inheritance pattern with unusual contractures and bradycardia. Ann Neurol 1981; was autosomal dominant, thus the presence of Emery-Dreifuss 10:230–7. muscular dystrophy was unlikely. Rigid spine syndrome 10. Merlini L, Granata C, Domicine P, et al: Emery-Dreifuss occurs sporadically and mostly in males and is characterized humeroperoneal muscular dystrophy: report of five cases in a by severe contractures of the spine [13, 14], which was not family and a review of literature. Muscle Nerve 1986;9:481–5.

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