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A case of McLeod syndrome with unusually severe myopathy
Journal of the Neurological Sciences 166 (1999) 36–39
A case of McLeod syndrome with unusually severe myopathy a, a a a a Tadataka Kawakami *, Yoshihisa Takiyama , Kumi Sakoe , Tomoko Ogawa , Toru Yoshioka , Masatoyo Nishizawa a , Marion E. Reid b , Osamu Kobayashi c , Ikuya Nonaka c , Imaharu Nakano a a
Department of Neurology, Jichi Medical School, Tochigi 329 -0498, Japan b New York Blood Center, New York, NY, USA c Department of Ultrastructural Research, National Center of Neurology and Psychiatry, Tokyo 187 -8502, Japan Received 8 June 1998; received in revised form 16 March 1999; accepted 30 April 1999
Abstract A 51-year-old man developed weakness and muscle atrophy in the legs at the age of 41, later followed by choreiform involuntary movements. Neurological and laboratory examinations revealed severe muscle weakness and atrophy, and areflexia in all the extremities, acanthocytosis and an elevated serum creatine kinase level. Together with these findings, the weak expression of Kell blood group antigens and the absence of the Kx antigen led to a definite diagnosis of McLeod syndrome for his condition. Brain magnetic resonance imaging revealed marked atrophy of the head of the caudate nuclei. Although immunocytochemical analysis of dystrophin in muscle specimens from our patient revealed normal staining, we found prominent fiber size variability, central nuclei, and connective tissue proliferation as well as necrotic and regenerating fibers, which are as a whole compatible with the myopathology of muscular dystrophy. Moreover, muscle computerized tomography of the lower extremities revealed the ‘selectivity pattern’ characteristically reported in muscular dystrophies including Duchenne type muscular dystrophy. The muscular symptoms and pathology in McLeod syndrome have been reported to be mild, but the present case clearly shows that the muscular features in this condition may be much more severe than previously thought. 1999 Published by Elsevier Science B.V. All rights reserved. Keywords: McLeod syndrome; Myopathy; Muscular dystrophy; Muscle biopsy; Muscle CT scan
1. Introduction Neurological disorders associated with acanthocytosis include McLeod syndrome, chorea acanthocytosis, and abetalipoproteinemia [1]. McLeod syndrome is characterized by choreiform or dystonic movements, peripheral neuropathy with areflexia, myopathy, cardiomyopathy, an elevated serum creatine kinase (CK) level, and a permanent hemolytic state [1,2], and is a unique form defined on the basis of depressed Kell blood group antigens and the absence of the Kx antigen [3,4]. The Kx antigen is regulated by the gene responsible for McLeod syndrome, *Corresponding author. Tel.: 181-285-58-7352; fax: 181-285-445118. E-mail address: [email protected] (T. Kawakami)
XK, which is located on chromosome Xp21 between the loci of Duchenne type muscular dystrophy (DMD) and chronic granulomatous disease (CGD), Xp21 [5,6]. The co-occurrence of McLeod syndrome with CGD, retinitis pigmentosa, and DMD can be explained by large deletions in Xp21, affecting XK and neighboring genes [7–10]. XK encodes a novel protein with the structural characteristics of membrane transport proteins [6]. To date, point mutations in intron 2 or exon 2 in the XK gene have been identified in addition to large deletions of the X chromosome in McLeod males [6,11]. Muscle weakness and atrophy reported in McLeod syndrome have constantly been mild, supporting the previous designation of this condition as ‘benign X-linked myopathy with acanthocytes’ [12]. We report here a McLeod patient with severe muscle weakness and atrophy,
0022-510X / 99 / $ – see front matter 1999 Published by Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00108-2
T. Kawakami et al. / Journal of the Neurological Sciences 166 (1999) 36 – 39
37
and prominent myopathologic changes indistinguishable from those of muscular dystrophy. In addition, we present the ‘selectivity pattern’ seen on leg muscle CT, which is also characteristic of muscular dystrophy.
2. Case report A 51-year-old male was admitted to Jichi Medical School Hospital for neurological evaluation. His birth, growth, and development were normal until the age of 41 when he first experienced muscle weakness and atrophy in the lower extremities. He noted choreiform movements of the limbs at 49 years of age, and the symptom gradually worsened thereafter. Physical examination revealed no evidence of cardiac enlargement or cardiomyopathy. He showed severe proximal dominant muscular atrophy and muscle weakness without hypertrophic calf muscles, and Gowers sign was also noted. Choreic movements of the limbs were evident. There was no tongue or lip biting. He showed areflexia and no Babinski signs. Sensation was normal. His choreic movements were increased in degree by mental stress and walking. He walked with a waddling gait because of his girdle muscle weakness. Routine blood tests showed neither hemolytic anemia nor abetalipoproteinemia. About 20% of the RBCs in peripheral blood were acanthocytes, which was confirmed on scanning electron microscopy (Fig. 1). Serum creatine kinase (CK) was markedly increased (2016 IU / l; normal, ,150). Kell blood group antigen expression was weak (K2, K4, K5, K7, and K14), and the Kx antigen was absent. Brain MRI showed marked atrophy of the head of the caudate nuclei and mild atrophy of the cerebral cortex (Fig. 2). A CT scan of the lower extremities revealed diffuse low density in the quadriceps femoris, hamstring, adductor magnum, and gastrocnemius muscles, but normal density in the rectus femoris muscles (Fig. 3). This finding on muscle CT scanning indicated fatty changes of these
Fig. 1. Acanthocytes by scanning electron microscopy. About 20% of the RBCs in the peripheral blood were acanthocytes, which was confirmed by scanning electron microscopy.
Fig. 2. Brain MRI (T1-weighted, coronal section) showed marked atrophy of the head of the caudate nuclei and mild atrophy of the cerebral cortex.
muscles, with the exception in the rectus femoris muscles. The sartorius, gracilis, rectus femoris, and tibialis anterior muscles showed almost normal densities. In particular, the gracilis muscles were round and enlarged. Electromyo-
Fig. 3. The CT scan of the lower extremities showed diffuse low density in the quadriceps femoris, hamstring, adductor magnum, and gastrocnemius muscles, but normal density in the rectus femoris muscles.
38
T. Kawakami et al. / Journal of the Neurological Sciences 166 (1999) 36 – 39
Fig. 4. (a) Muscle pathologic findings. In the right biceps brachii muscle there are advanced myopathic changes with evidence of necrotic and regenerating processes (HE: 3123). Note the marked variation in fiber size and interstitial fibrosis. (b) Immunocytochemical analysis of dystrophin. Immunocytochemical analysis of dystrophin revealed normal staining (NCL-DYS2, Novocastra: 3187).
graphic examination revealed a myogenic pattern in all muscles examined. An electrophysiological study revealed slight to moderate reduction of motor and / or sensory conduction velocities in the median, ulnar, and sural nerves. A sural nerve biopsy specimen showed mild demyelination (data not shown). After informed consent had been obtained, muscle specimens were taken by means of open biopsy from the biceps brachii muscles. There was notable variation in fiber size, with scattered necrotic and regenerating fibers. Fibers with centrally placed nuclei were increased in number to about 10%. Interstitial connective tissue was markedly increased without inflammatory cell infiltration (Fig. 4a). On immunocytochemical staining, dystrophin was observed to be normally expressed along the muscle surface membrane except for that on the necrotic fibers (Fig. 4b). The 45-year-old sister of our patient had acanthocytes: 7% of the peripheral RBCs were acanthocytes. She showed the typical bimodal pattern of Kell group antigens (K2, K4, K5, K7, and K14) on flow cytometric analysis, and her Kx antigen level was normal. It is noteworthy that she showed involuntary movements mimicking a tic in her upper extremities and a mildly increased CK level (227 IU / l; normal, ,150). Electrophysiological studies revealed normal nerve conduction velocities and electromyography. Brain MRI was normal.
3. Discussion The characteristics of muscle changes seen in McLeod syndrome vary in different cases. Some cases were re-
ported to have a mixture of myogenic and neurogenic changes in terms of electromyography [13] and muscle histopathology [13,14]. However, the majority exhibited myopathic changes alone that comprised necrosis and regeneration of muscle fibers, internal nuclei, and the absence of inflammatory cell infiltration [15–17]. Irrespective of the pathomechanisms of the muscle lesions, the histological changes were all subtle, corresponding to the mildness, if present, of muscle weakness in McLeod syndrome [12–18]. In striking contrast to this general tendency of muscle lesions in McLeod syndrome, our case showed considerable weakness and muscle pathology; clinically he exhibited an obvious Gowers sign and a waddling gait, and a biopsied muscle specimen exhibited marked muscle fiber size variability with massive proliferation of interstitial tissue and fatty infiltration, as well as necrotic and regenerative fibers. Thus, the muscle pathology was indistinguishable from that of muscular dystrophy. Even the muscle histology in a McLeod patient with only mild muscle weakness and therefore subtle muscle pathology was reported to strikingly resemble the carrier status of DMD [17]. Of course, the normal dystrophin staining in our case ruled out the possibility of a dystrophinopathy such as DMD and Becker type muscular dystrophy as the cause of the myopathy. We found a deletion mutation (intron 2 and exon 3) within the XK gene of the present case by PCR and Southern blot analyses (Ogaura et al., manuscript in preparation). This case indicates that muscular lesions can develop in McLeod syndrome that are much more severe than believed so far, and that in the proximity of the dystrophinopathy gene is at least another gene, XK, the alteration of which can cause muscle dystrophy-like changes. In order to determine why the present case showed more severe features clinically and myopathologically than the previously reported cases, phenotype and genotype correlation studies on McLeod syndrome are required. In the present case, we demonstrated for the first time the ‘selectivity pattern’ on muscle CT scanning in McLeod syndrome. This pattern is characteristically observed in muscular dystrophy with functionally compensated lower extremities [19], giving further support to the notion that the myopathologic changes in the present case may be a sort of muscular dystrophy. The sister of the present case is thought to be a carrier of the McLeod phenotype based on the bimodal pattern of Kell group antigens observed on flow cytometry. In this condition, like others of X-linked recessive inheritance, female carriers may manifest symptoms, although they are generally milder, according to the degree of inactivation of the X chromosome carrying the abnormal gene; the so far single female patient with McLeod syndrome reported in Family L in whom the Kx antigen was absent [1,11] can be considered to be an extreme example of this phenomenon. Since the sister of the present case showed involuntary movements resembling a ‘tic’, although they were mini-
T. Kawakami et al. / Journal of the Neurological Sciences 166 (1999) 36 – 39
mal, in her upper extremities, she might be a quite mild ‘manifesting carrier’ of the McLeod phenotype, like the mother and niece of the female patient in Family L [11]. Therefore, we should carefully monitor her clinical features including the involuntary movements.
[7] [8]
[9]
Acknowledgements We would like to thank the family members for their cooperation; Dr Dong-Sheng Fan, Department of Neurology, Jichi Medical School, for examination of the dystrophin staining; Dr Yasufumi Tanaka, Department of Neurology, Jichi Medical School, for his help in the clinical examination; Prof. Akio Kanzaki, Department of Hematology, Kawasaki Medical University, for the laboratory examinations; Prof. Eiji Kajii, Department of Legal Medicine, Jichi Medical School, and Miss Junko Takahashi, Osaka Red Cross Blood Center, for the cytometric analysis of the expression of the Kell antigen on RBCs. This work was supported, in part, by a Research Grant (8A-2) for Nervous and Mental Disorders from the Ministry of Health and Welfare, Japan.
[10]
[11]
[12]
[13]
[14]
References [15] [1] Hardie RJ, Pullon HWH, Harding AE, Owen JS, Pires M, Daniels GL, Imai Y, Misra VP, King RHM, Jacobs JM, Tippet P, Duchen LW, Thomas PK, Marsden CD. Neuroacanthocytosis: a clinical, haematological and pathological study of 19 cases. Brain 1991;114:13–49. [2] Hardie RJ. Acanthocytosis and neurological impairment: a review. Q J Med 1989;71:291–306. [3] Allen Jr. FH, Krabbe SMR, Corcoran PA. A new phenotype (McLeod) in the Kell blood group system. Vox Sang 1961;6:555–60. [4] Marsh WL, Redman CM. Recent developments in the Kell blood group system. Transfus Med Rev 1987;1:4–20. [5] Bertelson CJ, Pogo AO, Chadhuri A, Redman CM, Banerjee D, Symman WA, Simon T, Kunkel LM. Localization of the McLeod locus (XK) within Xp21 by deletion analysis. Am J Hum Genet 1988;423:703–11. [6] Ho M, Chelly J, Carter N, Danek A, Crocker P, Monaco AP.
[16]
[17]
[18]
[19]
39
Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Cell 1994;77:869–80. Marsh WL. Chronic granulomatous disease, the McLeod syndrome, and the Kell blood group. Birth Defects 1978;14:9–25. Fikring SM, Phillipp JCD, Smithwick EM, Øyen R, Marsh WL. Chronic granulomatous disease and McLeod syndrome in a black child. Pediatrics 1980;66:403–4. Francke U, Ochs HD, De Martinville B, Giacalone J, Lindgren V, ` Disteche C, Pagon RA, Hofker MH, Van Ommen GJB, Pearson PL, Wedgwood RJ. Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome. Am J Hum Genet 1985;37:250–67. ¨ Frey D, Machler M, Seger R, Schmid W, Orkin SH. Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the XK gene locus. Blood 1988;71:252– 5. Ho MF, Chalmers RM, Davis MB, Harding AE, Monaco AP. A novel point mutation in the McLeod syndrome gene in neuroacanthocytosis. Ann Neurol 1996;39:672–5. Swash M, Schwartz MS, Carter ND, Heath R, Leak M, Rogers KL. Benign X-Iinked myopathy with acanthocytes (McLeod syndrome). Brain 1983;106:717–33. Takashima H, Sakai T, Iwashita H, Matsuda Y, Tanaka K, Oda K, Okubo Y, Reid ME. A family of McLeod syndrome, masquerading as chorea-acanthocytosis. J Neurol Sci 1994;124:56–60. Malandrini A, Fabrizi GI, Truschi F, Di Pietro G, Moschini F, Bartalucci P, Berti G, Salvadori C, Bucalossi A, Guazzi G. Atypical McLeod syndrome manifested as X-linked chorea-acanthocytosis, neuromyopathy and dilated cardiomyopathy: report of a family. J Neurol Sci 1994;124:89–94. Marsh WL, Marsh NJ, Moore A, Symmans WA, Johnson CL, Redman CM. Elevated serum creatine phosphokinase in subjects with McLeod syndrome. Vox Sang 1981;40:403–11. Zyskowski LP, Bunch TW, Hoagland HC, Taswell HF, Fairbanks VF. McLeod syndrome (hemolysis, acanthocytosis, and increased serum creatine kinase): potential confusion with polymyositis. Arthritis Rheum 1983;26:806–8. Witt TN, Danek A, Reiter M, Heim MU, Dirschunger J, Olsen EGJ. McLeod syndrome: a distinct form of neuroacanthocytosis. J Neurol 1992;239:302–6. Engel AG, Yamamoto M, Fischbeck KH. An Xp21 myopathy without dystrophinopathy. In: Engel AG, Franzini-Armstrong C, editors, Myology, Vol. 2, New York: McGraw-Hill, 1994, p. 1146. Kawai M, Nakano I. Computed tomography of the skeletal muscles: a new imaging technique for the diagnosis of neuromuscular disease. Prog Comput Tomogr 1985;7:485–97, in Japanese with English abstract.
A case of McLeod syndrome with unusually severe myopathy a, a a a a Tadataka Kawakami *, Yoshihisa Takiyama , Kumi Sakoe , Tomoko Ogawa , Toru Yoshioka , Masatoyo Nishizawa a , Marion E. Reid b , Osamu Kobayashi c , Ikuya Nonaka c , Imaharu Nakano a a
Department of Neurology, Jichi Medical School, Tochigi 329 -0498, Japan b New York Blood Center, New York, NY, USA c Department of Ultrastructural Research, National Center of Neurology and Psychiatry, Tokyo 187 -8502, Japan Received 8 June 1998; received in revised form 16 March 1999; accepted 30 April 1999
Abstract A 51-year-old man developed weakness and muscle atrophy in the legs at the age of 41, later followed by choreiform involuntary movements. Neurological and laboratory examinations revealed severe muscle weakness and atrophy, and areflexia in all the extremities, acanthocytosis and an elevated serum creatine kinase level. Together with these findings, the weak expression of Kell blood group antigens and the absence of the Kx antigen led to a definite diagnosis of McLeod syndrome for his condition. Brain magnetic resonance imaging revealed marked atrophy of the head of the caudate nuclei. Although immunocytochemical analysis of dystrophin in muscle specimens from our patient revealed normal staining, we found prominent fiber size variability, central nuclei, and connective tissue proliferation as well as necrotic and regenerating fibers, which are as a whole compatible with the myopathology of muscular dystrophy. Moreover, muscle computerized tomography of the lower extremities revealed the ‘selectivity pattern’ characteristically reported in muscular dystrophies including Duchenne type muscular dystrophy. The muscular symptoms and pathology in McLeod syndrome have been reported to be mild, but the present case clearly shows that the muscular features in this condition may be much more severe than previously thought. 1999 Published by Elsevier Science B.V. All rights reserved. Keywords: McLeod syndrome; Myopathy; Muscular dystrophy; Muscle biopsy; Muscle CT scan
1. Introduction Neurological disorders associated with acanthocytosis include McLeod syndrome, chorea acanthocytosis, and abetalipoproteinemia [1]. McLeod syndrome is characterized by choreiform or dystonic movements, peripheral neuropathy with areflexia, myopathy, cardiomyopathy, an elevated serum creatine kinase (CK) level, and a permanent hemolytic state [1,2], and is a unique form defined on the basis of depressed Kell blood group antigens and the absence of the Kx antigen [3,4]. The Kx antigen is regulated by the gene responsible for McLeod syndrome, *Corresponding author. Tel.: 181-285-58-7352; fax: 181-285-445118. E-mail address: [email protected] (T. Kawakami)
XK, which is located on chromosome Xp21 between the loci of Duchenne type muscular dystrophy (DMD) and chronic granulomatous disease (CGD), Xp21 [5,6]. The co-occurrence of McLeod syndrome with CGD, retinitis pigmentosa, and DMD can be explained by large deletions in Xp21, affecting XK and neighboring genes [7–10]. XK encodes a novel protein with the structural characteristics of membrane transport proteins [6]. To date, point mutations in intron 2 or exon 2 in the XK gene have been identified in addition to large deletions of the X chromosome in McLeod males [6,11]. Muscle weakness and atrophy reported in McLeod syndrome have constantly been mild, supporting the previous designation of this condition as ‘benign X-linked myopathy with acanthocytes’ [12]. We report here a McLeod patient with severe muscle weakness and atrophy,
0022-510X / 99 / $ – see front matter 1999 Published by Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00108-2
T. Kawakami et al. / Journal of the Neurological Sciences 166 (1999) 36 – 39
37
and prominent myopathologic changes indistinguishable from those of muscular dystrophy. In addition, we present the ‘selectivity pattern’ seen on leg muscle CT, which is also characteristic of muscular dystrophy.
2. Case report A 51-year-old male was admitted to Jichi Medical School Hospital for neurological evaluation. His birth, growth, and development were normal until the age of 41 when he first experienced muscle weakness and atrophy in the lower extremities. He noted choreiform movements of the limbs at 49 years of age, and the symptom gradually worsened thereafter. Physical examination revealed no evidence of cardiac enlargement or cardiomyopathy. He showed severe proximal dominant muscular atrophy and muscle weakness without hypertrophic calf muscles, and Gowers sign was also noted. Choreic movements of the limbs were evident. There was no tongue or lip biting. He showed areflexia and no Babinski signs. Sensation was normal. His choreic movements were increased in degree by mental stress and walking. He walked with a waddling gait because of his girdle muscle weakness. Routine blood tests showed neither hemolytic anemia nor abetalipoproteinemia. About 20% of the RBCs in peripheral blood were acanthocytes, which was confirmed on scanning electron microscopy (Fig. 1). Serum creatine kinase (CK) was markedly increased (2016 IU / l; normal, ,150). Kell blood group antigen expression was weak (K2, K4, K5, K7, and K14), and the Kx antigen was absent. Brain MRI showed marked atrophy of the head of the caudate nuclei and mild atrophy of the cerebral cortex (Fig. 2). A CT scan of the lower extremities revealed diffuse low density in the quadriceps femoris, hamstring, adductor magnum, and gastrocnemius muscles, but normal density in the rectus femoris muscles (Fig. 3). This finding on muscle CT scanning indicated fatty changes of these
Fig. 1. Acanthocytes by scanning electron microscopy. About 20% of the RBCs in the peripheral blood were acanthocytes, which was confirmed by scanning electron microscopy.
Fig. 2. Brain MRI (T1-weighted, coronal section) showed marked atrophy of the head of the caudate nuclei and mild atrophy of the cerebral cortex.
muscles, with the exception in the rectus femoris muscles. The sartorius, gracilis, rectus femoris, and tibialis anterior muscles showed almost normal densities. In particular, the gracilis muscles were round and enlarged. Electromyo-
Fig. 3. The CT scan of the lower extremities showed diffuse low density in the quadriceps femoris, hamstring, adductor magnum, and gastrocnemius muscles, but normal density in the rectus femoris muscles.
38
T. Kawakami et al. / Journal of the Neurological Sciences 166 (1999) 36 – 39
Fig. 4. (a) Muscle pathologic findings. In the right biceps brachii muscle there are advanced myopathic changes with evidence of necrotic and regenerating processes (HE: 3123). Note the marked variation in fiber size and interstitial fibrosis. (b) Immunocytochemical analysis of dystrophin. Immunocytochemical analysis of dystrophin revealed normal staining (NCL-DYS2, Novocastra: 3187).
graphic examination revealed a myogenic pattern in all muscles examined. An electrophysiological study revealed slight to moderate reduction of motor and / or sensory conduction velocities in the median, ulnar, and sural nerves. A sural nerve biopsy specimen showed mild demyelination (data not shown). After informed consent had been obtained, muscle specimens were taken by means of open biopsy from the biceps brachii muscles. There was notable variation in fiber size, with scattered necrotic and regenerating fibers. Fibers with centrally placed nuclei were increased in number to about 10%. Interstitial connective tissue was markedly increased without inflammatory cell infiltration (Fig. 4a). On immunocytochemical staining, dystrophin was observed to be normally expressed along the muscle surface membrane except for that on the necrotic fibers (Fig. 4b). The 45-year-old sister of our patient had acanthocytes: 7% of the peripheral RBCs were acanthocytes. She showed the typical bimodal pattern of Kell group antigens (K2, K4, K5, K7, and K14) on flow cytometric analysis, and her Kx antigen level was normal. It is noteworthy that she showed involuntary movements mimicking a tic in her upper extremities and a mildly increased CK level (227 IU / l; normal, ,150). Electrophysiological studies revealed normal nerve conduction velocities and electromyography. Brain MRI was normal.
3. Discussion The characteristics of muscle changes seen in McLeod syndrome vary in different cases. Some cases were re-
ported to have a mixture of myogenic and neurogenic changes in terms of electromyography [13] and muscle histopathology [13,14]. However, the majority exhibited myopathic changes alone that comprised necrosis and regeneration of muscle fibers, internal nuclei, and the absence of inflammatory cell infiltration [15–17]. Irrespective of the pathomechanisms of the muscle lesions, the histological changes were all subtle, corresponding to the mildness, if present, of muscle weakness in McLeod syndrome [12–18]. In striking contrast to this general tendency of muscle lesions in McLeod syndrome, our case showed considerable weakness and muscle pathology; clinically he exhibited an obvious Gowers sign and a waddling gait, and a biopsied muscle specimen exhibited marked muscle fiber size variability with massive proliferation of interstitial tissue and fatty infiltration, as well as necrotic and regenerative fibers. Thus, the muscle pathology was indistinguishable from that of muscular dystrophy. Even the muscle histology in a McLeod patient with only mild muscle weakness and therefore subtle muscle pathology was reported to strikingly resemble the carrier status of DMD [17]. Of course, the normal dystrophin staining in our case ruled out the possibility of a dystrophinopathy such as DMD and Becker type muscular dystrophy as the cause of the myopathy. We found a deletion mutation (intron 2 and exon 3) within the XK gene of the present case by PCR and Southern blot analyses (Ogaura et al., manuscript in preparation). This case indicates that muscular lesions can develop in McLeod syndrome that are much more severe than believed so far, and that in the proximity of the dystrophinopathy gene is at least another gene, XK, the alteration of which can cause muscle dystrophy-like changes. In order to determine why the present case showed more severe features clinically and myopathologically than the previously reported cases, phenotype and genotype correlation studies on McLeod syndrome are required. In the present case, we demonstrated for the first time the ‘selectivity pattern’ on muscle CT scanning in McLeod syndrome. This pattern is characteristically observed in muscular dystrophy with functionally compensated lower extremities [19], giving further support to the notion that the myopathologic changes in the present case may be a sort of muscular dystrophy. The sister of the present case is thought to be a carrier of the McLeod phenotype based on the bimodal pattern of Kell group antigens observed on flow cytometry. In this condition, like others of X-linked recessive inheritance, female carriers may manifest symptoms, although they are generally milder, according to the degree of inactivation of the X chromosome carrying the abnormal gene; the so far single female patient with McLeod syndrome reported in Family L in whom the Kx antigen was absent [1,11] can be considered to be an extreme example of this phenomenon. Since the sister of the present case showed involuntary movements resembling a ‘tic’, although they were mini-
T. Kawakami et al. / Journal of the Neurological Sciences 166 (1999) 36 – 39
mal, in her upper extremities, she might be a quite mild ‘manifesting carrier’ of the McLeod phenotype, like the mother and niece of the female patient in Family L [11]. Therefore, we should carefully monitor her clinical features including the involuntary movements.
[7] [8]
[9]
Acknowledgements We would like to thank the family members for their cooperation; Dr Dong-Sheng Fan, Department of Neurology, Jichi Medical School, for examination of the dystrophin staining; Dr Yasufumi Tanaka, Department of Neurology, Jichi Medical School, for his help in the clinical examination; Prof. Akio Kanzaki, Department of Hematology, Kawasaki Medical University, for the laboratory examinations; Prof. Eiji Kajii, Department of Legal Medicine, Jichi Medical School, and Miss Junko Takahashi, Osaka Red Cross Blood Center, for the cytometric analysis of the expression of the Kell antigen on RBCs. This work was supported, in part, by a Research Grant (8A-2) for Nervous and Mental Disorders from the Ministry of Health and Welfare, Japan.
[10]
[11]
[12]
[13]
[14]
References [15] [1] Hardie RJ, Pullon HWH, Harding AE, Owen JS, Pires M, Daniels GL, Imai Y, Misra VP, King RHM, Jacobs JM, Tippet P, Duchen LW, Thomas PK, Marsden CD. Neuroacanthocytosis: a clinical, haematological and pathological study of 19 cases. Brain 1991;114:13–49. [2] Hardie RJ. Acanthocytosis and neurological impairment: a review. Q J Med 1989;71:291–306. [3] Allen Jr. FH, Krabbe SMR, Corcoran PA. A new phenotype (McLeod) in the Kell blood group system. Vox Sang 1961;6:555–60. [4] Marsh WL, Redman CM. Recent developments in the Kell blood group system. Transfus Med Rev 1987;1:4–20. [5] Bertelson CJ, Pogo AO, Chadhuri A, Redman CM, Banerjee D, Symman WA, Simon T, Kunkel LM. Localization of the McLeod locus (XK) within Xp21 by deletion analysis. Am J Hum Genet 1988;423:703–11. [6] Ho M, Chelly J, Carter N, Danek A, Crocker P, Monaco AP.
[16]
[17]
[18]
[19]
39
Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Cell 1994;77:869–80. Marsh WL. Chronic granulomatous disease, the McLeod syndrome, and the Kell blood group. Birth Defects 1978;14:9–25. Fikring SM, Phillipp JCD, Smithwick EM, Øyen R, Marsh WL. Chronic granulomatous disease and McLeod syndrome in a black child. Pediatrics 1980;66:403–4. Francke U, Ochs HD, De Martinville B, Giacalone J, Lindgren V, ` Disteche C, Pagon RA, Hofker MH, Van Ommen GJB, Pearson PL, Wedgwood RJ. Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome. Am J Hum Genet 1985;37:250–67. ¨ Frey D, Machler M, Seger R, Schmid W, Orkin SH. Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the XK gene locus. Blood 1988;71:252– 5. Ho MF, Chalmers RM, Davis MB, Harding AE, Monaco AP. A novel point mutation in the McLeod syndrome gene in neuroacanthocytosis. Ann Neurol 1996;39:672–5. Swash M, Schwartz MS, Carter ND, Heath R, Leak M, Rogers KL. Benign X-Iinked myopathy with acanthocytes (McLeod syndrome). Brain 1983;106:717–33. Takashima H, Sakai T, Iwashita H, Matsuda Y, Tanaka K, Oda K, Okubo Y, Reid ME. A family of McLeod syndrome, masquerading as chorea-acanthocytosis. J Neurol Sci 1994;124:56–60. Malandrini A, Fabrizi GI, Truschi F, Di Pietro G, Moschini F, Bartalucci P, Berti G, Salvadori C, Bucalossi A, Guazzi G. Atypical McLeod syndrome manifested as X-linked chorea-acanthocytosis, neuromyopathy and dilated cardiomyopathy: report of a family. J Neurol Sci 1994;124:89–94. Marsh WL, Marsh NJ, Moore A, Symmans WA, Johnson CL, Redman CM. Elevated serum creatine phosphokinase in subjects with McLeod syndrome. Vox Sang 1981;40:403–11. Zyskowski LP, Bunch TW, Hoagland HC, Taswell HF, Fairbanks VF. McLeod syndrome (hemolysis, acanthocytosis, and increased serum creatine kinase): potential confusion with polymyositis. Arthritis Rheum 1983;26:806–8. Witt TN, Danek A, Reiter M, Heim MU, Dirschunger J, Olsen EGJ. McLeod syndrome: a distinct form of neuroacanthocytosis. J Neurol 1992;239:302–6. Engel AG, Yamamoto M, Fischbeck KH. An Xp21 myopathy without dystrophinopathy. In: Engel AG, Franzini-Armstrong C, editors, Myology, Vol. 2, New York: McGraw-Hill, 1994, p. 1146. Kawai M, Nakano I. Computed tomography of the skeletal muscles: a new imaging technique for the diagnosis of neuromuscular disease. Prog Comput Tomogr 1985;7:485–97, in Japanese with English abstract.