Myopathy, X-linked, with excessive autophagy (MEAX)
ミオパチー, X連鎖性, 過剰な自己貪食を伴う
責任遺伝子: 300913 VMA21, S. erevisiae, homolog of (VMA21)
Flexion contracture (屈曲拘縮) [HP:0001371] 
Limited extraocular movements (外眼筋制限) [HP:0007941] 
Motor delay (運動遅滞) [HP:0001270] 
Neonatal hypotonia (新生児筋緊張低下) [HP:0001319] 
Respiratory insufficiency (呼吸不全) [HP:0002093] 
Scoliosis (側弯) [HP:0002650] 
Difficulty climbing stairs (昇段困難) [HP:0003551] 
Difficulty running (走行困難) [HP:0009046] 
Elevated serum creatine kinase (血清クレアチニンキナーゼ上昇) [HP:0003236] 
Gowers sign (Gowers サイン) [Hp:0003391] 
Incomplete penetrance (不完全浸透) [HP:0003829]
Myopathy (ミオパチー) [HP:0003198] 
Myotonia (筋緊張症, ミオトニア) [HP:0002486] 
Proximal muscle weakness in lower limbs (下肢の近位筋筋力低下) [HP:0008994] 
Skeletal muscle atrophy (骨格筋萎縮) [HP:0003202] 
Slow progression (緩徐進行性) [HP:0003677]
X-linked recessive inheritance (X連鎖劣性遺伝) [HP:0001419]
Delayed motor development (in some patients)
生検は筋線維の膜攻撃複合体の C5b-9 沈着を示す
alpha-glucosidase または acid maltase 活性 (GAA, 606800) は正常
心肥大, 軽度 (一部の患者で)
【検査】血清 CK 増加
Increased urinary beta-2-microglobulin (1 family)
Upper limb involvement and distal muscle involvement may occur later in disease course (often by second decade)
By fourth decade, many patients need help with ambulation
Danon 病（ダノン病）と過剰自己貪食を伴うＸ連鎖性ミオパチー（XMEA）では, 原因遺伝子が発見されたが, その他の臨床病型は原因不明である。
Danon 病 → Lysosome-associated membrane protein 2 (LAMP2)
過剰自己貪食を伴うＸ連鎖性ミオパチー (XMEA) → VMA21, S. erevisiae, homolog of (VMA21)
また病気の発症のメカニズムは依然未解明である。特徴的な自己貪食空胞が共通して出現することから, 筋変性過程に自己貪食（オートファジー）が関与することが疑われ, 何らかの共通の分子病態との関連が推測される。
（2）心筋障害による進行性の心筋症（肥大型, 拡張型）, 不整脈
但し, 臨床病型によっては, （2）, （3）を伴わないことがある。
発症年齢は様々で, 生下時から 50 歳代まで報告がある。 男女ともに発症するが, 男性の方が早い場合が多い。
治療法は確立していない。心筋障害は予後決定因子で致死性であり, 心臓移植のみが根治療法である。 他の症状や合併症については, 対症療法が主体である。
男女ともに発症年齢を問わず, 心臓移植を行わない場合, 心不全症状の出現から平均２年で急速に死 に至る（Sugie et al. Neurology 2002）。けいれんなどの中枢神経障害や肝障害, 腎障害, 肺水腫, 網膜症など多臓器障害を来すことがある。また, 自閉症や脳血管障害, 末梢神経障害を有する症例の報告もある。筋障害が進行すると, 呼吸困難や嚥下困難, 筋緊張低下をきたす。生下時より発症した場合は, 運動発育 遅延を呈する。
（MIM# 310440, X-linked Myopathy with excessive autophagy: XMEA）
A. 臨床的特徴（a は必須, b-f は参考所見）
e. 血清 CK 値は, 正常から中等度高値（1,500IU/L 以下）
f. 針筋電図で筋原性変化（fibrillation potential や高振幅 MUP）が認められることがある
B. 筋生検所見 （a,b は必須, c-f は参考所見）
b. 空胞膜上でのアセチルコリンエステラーゼ活性の上昇 （骨格筋での組織化学染色）
c. 空胞膜上での筋鞘膜蛋白（ジストロフィン, サルコグリカン, ラミニンα2, カベオリン-3 など）発現（骨格筋での免疫組織化学染色）
d. 筋鞘膜への補体 C5b-9 の沈着 （骨格筋での免疫組織化学染色）
e. 筋線維の基底膜の重層化 （電子顕微鏡）
f. 自己貪食空胞膜上の基底膜 （電子顕微鏡）
a. VMA21 遺伝子変異
(Responsible gene) *300913 VMA21, S. erevisiae, homolog of (VMA21)
.0001 Myopathy, X-linked, with excessive autophagy (310440) [VMA21, IVS1, A-C, -27] (rs878854352) (RCV000190826) (Ramachandran et al. 2013)
.0002 Myopathy, X-linked, with excessive autophagy [VMA21, IVS1, A-T, -27] (rs878854352) (RCV000190827) (Ramachandran et al. 2013)
.0003 Myopathy, X-linked, with excessive autophagy [VMA21, IVS2, A-G, +4] (rs797044909) (RCV000190737...) (Ramachandran et al. 2013)
.0004 Myopathy, X-linked, with excessive autophagy [VMA21, IVS2, T-G, -7] (rs878854353) (RCV000190829) (Ramachandran et al. 2013; Kurashige et al. 2013; Crockett et al. 2014)
.0005 Myopathy, X-linked, with excessive autophagy [VMA21, 272G-C] (rs878854354) (RCV000190830) (Ramachandran et al. 2013)
.0006 Myopathy, X-linked, with excessive autophagy [VMA21, TER+6, A-G] (rs878854355) (gnomAD:rs878854355) (RCV000190831) (Ramachandran et al. 2013)
.0007 Myopathy, X-linked, with excessive autophagy [VMA21, IVS2, T-G, -6] (rs878854356) (RCV000190832) (Munteanu et al. 2015)
.0008 Myopathy, X-linked, with excessive autophagy [VMA21, 92-BP DEL, NT13] (rs1556035617) (RCV000190833) (Ruggieri et al. 2015)
.0009 Myopathy, X-linked, with excessive autophagy [VMA21, 9-BP DEL, NT54] (rs878854357) (RCV000190834) (Ruggieri et al. 2015)
A number sign (#) is used with this entry because of evidence that X-linked myopathy with excessive autophagy (MEAX) is caused by mutation in the VMA21 gene (300913) on chromosome Xq28.
X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive skeletal muscle disorder characterized by childhood onset of progressive muscle weakness and atrophy primarily affecting the proximal muscles. While onset is usually in childhood, it can range from infancy to adulthood. Many patients lose ambulation and become wheelchair-bound. Other organ systems, including the heart, are clinically unaffected. Muscle biopsy shows intracytoplasmic autophagic vacuoles with sarcolemmal features and a multilayed basal membrane (summary by Ramachandran et al., 2013; Kurashige et al., 2013, and Ruggieri et al., 2015).
Danon disease (300257), caused by mutation in the LAMP2 gene (309060) on chromosome Xq24, is a distinct disorder with similar pathologic features.
Saviranta et al. (1988) and Kalimo et al. (1988) reported an unusual hereditary myopathy in 5 members of a Finnish family in a pedigree pattern consistent with X-linked recessive inheritance. The clinical course was mild; the patients suffered from slowly progressive muscle weakness mainly in the legs, but did not lose their ability to walk. There was no evidence of cardiac or neural involvement. Serum creatine kinase was elevated. By electron microscopy, an excessive number of autophagic vacuoles with staining properties of lysosomes were observed. The granular and membranous material contained in these vacuoles was actively exocytosed. The authors suggested that this disorder differed from the muscular dystrophy of Duchenne (310200) and Becker (300376) and of Emery-Dreifuss (310300) as well as from X-linked myotubular myopathy (310400).
Villanova et al. (1995) reported a family in which 4 males and their maternal grandfather were affected with a juvenile-onset, slowly progressive proximal vacuolar myopathy. Inheritance was consistent with X-linked recessive.
Minassian et al. (2002) reported 7 families with XMEA. Most had childhood onset of proximal lower limb muscle weakness characterized by difficulty climbing stairs and running. After the second decade, upper limb proximal muscle weakness and distal limb muscle weakness was often observed. The disorder was slowly progressive and some patients were wheelchair-dependent by the sixth decade.
Yan et al. (2005) reported a Chinese American family in which 2 male sibs had a severe congenital form of XMEA. The proband was a 7-year-old boy with congenital hypotonia, neonatal hypoventilation requiring mechanical ventilation, and poor suckling requiring nasogastric feeding until 2.5 years of age. He had delayed motor milestones, progressive generalized muscle weakness involving facial and neck muscles, increased serum creatine kinase, and a high-arched palate. Mentation was normal. In addition, he had incomplete cardiac right bundle branch block and left ventricular hypertrophy. His older brother had a similar phenotype but without cardiac involvement. Family history showed that 3 maternal uncles and 2 maternal granduncles died in infancy with a similar phenotype. No female relatives had clinical signs of myopathy. Skeletal muscle biopsy from the proband showed endomysial fibrosis and intracytoplasmic vacuoles with acid phosphatase activity and sarcolemmal deposition of the complement membrane attack complex and calcium, consistent with autophagic lysosomes. Electron microscopic analysis showed accumulation of electron dense granules within the vacuoles, suggesting abnormal protein degradation.
Ramachandran et al. (2013) reported 45 individuals with XMEA from 14 families. All patients were males with childhood-onset progressive weakness and wasting of skeletal muscle. Proximal muscles of the lower extremities were always initially and later predominantly affected. No other organ system was affected clinically. At least 1 patient from each family underwent a biopsy, and all biopsies showed the pathognomonic features of XMEA, including no inflammation, necrosis, or apoptosis. These patients had been previously reported in a paper retracted from the journal Cell in 2009.
Kurashige et al. (2013) reported a 52-year-old Japanese man with XMEA. After normal early development, he presented with difficulty running at age 6 years. The muscle weakness was progressive over his life, but he remained ambulatory and had normal cardiac and respiratory function. Laboratory studies showed increased serum creatine kinase and increased urinary beta-2-microglobulin (B2M; 109700) with normal serum B2M. Two deceased maternal uncles with a similar disorder also had increased urinary B2M, which was not found in nonaffected family members. Kurashige et al. (2013) postulated that the increased urinary B2M in these patients could be due to less urinary acidification in the distal convoluted tubules caused by decreased V-ATPase, and may be a useful preliminary marker for the disorder.
Ruggieri et al. (2015) reported 2 unrelated patients with early-onset XMEA. Both presented at birth with hypotonia, lethargy, and poor feeding, and showed delayed motor development in early childhood. Laboratory studies showed increased serum creatine kinase; 1 patient also had elevated liver enzymes. At age 14 years, 1 patient was able to walk, but had Gowers sign and severe proximal lower and upper limb weakness and muscle hypotrophy. At age 21 years, the second patient was wheelchair-bound with severe muscle atrophy and kyphoscoliosis. Both patients also showed limited extraocular movements.
Mercier et al. (2015) reported 4 patients from 2 unrelated families with XMEA confirmed by genetic analysis. In addition to early-onset progressive limb-girdle muscle weakness and atrophy and characteristic autophagic vacuoles on muscle biopsy, 3 adult patients had proximal and distal joint contractures of the upper and lower limbs. None had cardiac involvement. Whole-body muscle MRI showed that pelvic girdle and proximal thighs were the most and earliest affected regions, with sparing of rectus femoris muscles. Muscle changes essentially consisted of degenerative fatty replacement.
Crockett et al. (2014) reported a patient with XMEA confirmed by genetic analysis (300913.0004) who reported slowly progressive proximal muscle weakness of the lower limbs beginning at approximately age 55 years. He remained physically active throughout mid-adulthood and was ambulatory with assistance at age 71. He had no contractures, cardiac involvement, or myalgia. Muscle biopsy showed a vacuolar pathology, endomysial fibrosis, fatty infiltration, and atrophic fibers. Crockett et al. (2014) emphasized the late onset and relatively mild phenotype in this patient, which expanded the clinical variability associated with the disorder.
The transmission pattern in the families with XMEA reported by Ramachandran et al. (2013) was consistent with X-linked recessive inheritance.
Saviranta et al. (1988) presented linkage information excluding the mutation in their family with myopathy from the Duchenne-Becker muscular dystrophy locus (see 300377). Several other loci on the short and long arms of the X chromosome likewise showed negative lod scores, whereas a probe defining locus DXS15, located on Xq28, showed no recombinants and a lod score of 0.903 at theta = 0.0.
Using 32 polymorphic markers spanning the entire X chromosome, Villard et al. (2000) excluded linkage to most of the chromosome except the Xq28 region in a large XMEA family. Using 3 additional families for linkage analysis, they obtained a 2-point lod score with marker DXS1183 on Xq28; maximum lod = 2.69 at theta = 0.0. Multipoint linkage analysis confirmed the assignment of the disease locus with a maximum lod score of 2.74 obtained at recombination fraction zero. Villard et al. (2000) excluded allelism with Emery-Dreifuss muscular dystrophy by direct sequencing of the emerin gene (300384) in 3 of the families.
By linkage and haplotype analysis of 9 affected families, Minassian et al. (2002) localized the MEAX locus telomeric to DXS10053. Because the pseudoautosomal region (PAR) could be excluded, the MEAX region was refined to a 4.37-Mb area between DXS10053 and DXS1108. Minassian et al. (2002) failed to identify mutations in several candidate genes from the region.
By linkage and haplotype analysis, Yan et al. (2005) obtained evidence suggestive of linkage to Xq28 (multipoint lod score of 0.46 between markers DXS8069 and DXS1073), although the results were not significant due to the small family size.
Munteanu et al. (2008) recruited additional members of the large American family with XMEA previously reported by Minassian et al. (2002). Fine-mapping and haplotype analysis of the large American family and 2 French families, which were distantly related to each other and were previously reported by Villanova et al. (1995) and Minassian et al. (2002), refined the disease locus to a 0.58-Mb region between rs1149374 and BV106355.
In 45 male patients from 14 families with XMEA, Ramachandran et al. (2013) identified 6 different hemizygous single-nucleotide substitutions in the VMA21 gene (300913.0001-300913.0006). Four of these were intronic; 1 occurred in coding sequence but abolished a predicted splice enhancer site; and 1 occurred after the termination codon in the 3-prime UTR. Ramachandran et al. (2013) found that cells from patients with XMEA had elevated lysosomal pH and a resultant partial block in the common final degradative stage of autophagy. Quantitative RT-PCR from patient fibroblasts and lymphoblasts revealed 32 to 58% reduction in VMA21 mRNA, including in patients with the 3-prime UTR mutation. Western blot analysis and immunohistochemistry showed that VMA21 protein was also reduced, and V-ATPase activity was reduced to 10 to 30% of normal values. Transfection experiments with mutant and wildtype minigenes showed greater than 40% decrease in mRNA from the variant minigenes compared to wildtype. Patient cells also showed a compensatory increase in macroautophagy, partially through inhibition of the mTOR pathway (see 601231) via reduced levels of cellular free amino acids. Restoration of VMA21 levels in cells with silenced VMA21 restored the normal morphology. The patients had been previously reported in a paper retracted from Cell in 2009 (Ramachandran et al., 2009).
In a 52-year-old Japanese man with XMEA, Kurashige et al. (2013) identified a hemizygous intronic mutation in the VMA21 gene (300913.0004).
In 2 brothers with XMEA originally reported by Yan et al. (2005), Munteanu et al. (2015) identified a hemizygous intronic mutation in the VMA21 gene (300913.0007). Patient cells showed decreased VMA21 mRNA (22 to 25% of normal controls) and significantly decreased V-ATPase activity (13% of controls).
In 2 unrelated patients with XMEA, Ruggieri et al. (2015) identified 2 different intragenic deletions in the VMA21 gene occurring in the 3-prime untranslated region and in intron 1, respectively (300913.0008 and 300913.0009). Ruggieri et al. (2015) noted that the molecular diagnosis of XMEA would be missed in the majority of patients if genetic testing were limited to cDNA sequencing, and stressed the importance of including noncoding regions of the VMA21 gene in genetic testing panels of muscular dystrophies and myopathies.
Ramachandran et al. (2013) noted that XMEA presents an unusual mechanism of disease, in which a major housekeeping complex (the V-ATPase) essential to numerous functions of all cells is impaired, but only to the extent of clinically affecting the function with the highest V-ATPase dependence (autophagy), in a tissue with high reliance on this function (skeletal muscle). Whereas pathologic analysis of skeletal muscle shows no inflammation, necrosis, or apoptosis, myofiber demise occurs through a novel form of autophagic cell death characterized by giant autophagic vacuoles 2 to 10 microns in size encircling sections of cytoplasm, including organelles. These vacuoles contain lysosomal hydrolases, yet are unable to complete digestion of their contents. Instead, they migrate to the myofiber surface, fuse with the sarcolemma, and extrude their contents extracellularly, forming a field of cell debris around the fiber.
(1) Kalimo, H., Savontaus, M.-L., Lang, H., Paljarvi, L., Sonninen, V., Dean, P. B., Katevuo, K., Salminen, A. X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann. Neurol. 23: 258-265, 1988
(2) Saviranta, P., Lindlof, M., Lehesjoki, A.-E., Kalimo, H., Lang, H., Sonninen, V., Savontaus, M.-L., de la Chapelle, A. Linkage studies in a new X-linked myopathy, suggesting exclusion of DMD locus and tentative assignment to distal Xq. Am. J. Hum. Genet. 42: 84-88, 1988
(3) Villanova, M.; Louboutin, J. P.; Chateau, D.; Eymard, B.; Sagniez, M.; Tome, F. M.; Fardeau, M. : X-linked vacuolated myopathy: complement membrane attack complex on surface membrane of injured muscle fibers. Ann. Neurol. 37: 637-645, 1995
(4) Villard, L., des Portes, V., Levy, N., Louboutin, J.-P., Recan, D., Coquet, M., Chabrol, B., Figarella-Branger, D., Chelly, J., Pellissier, J.-F., Fontes, M. Linkage of X-linked myopathy with excessive autophagy (XMEA) to Xq28. Europ. J. Hum. Genet. 8: 125-129, 2000
(5) Minassian, B. A.; Aiyar, R.; Alic, S.; Banwell, B.; Villanova, M.; Fardeau, M.; Mandell, J. W.; Juel, V. C.; Rafii, M.; Auranen, M.; Kalimo, H. : Narrowing in on the causative defect of an intriguing X-linked myopathy with excessive autophagy. Neurology 59: 596-601, 2002
(6) Sugie, K.; Noguchi, S.; Kozuka, Y.; Arikawa-Hirasawa, E.; Tanaka, M.; Yan, C.; Saftig, P.; von Figura, K.; Hirano, M.; Ueno, S.; Nonaka, I.; Nishino, I. : Autophagic vacuoles with sarcolemmal features delineate Danon disease and related myopathies. J. Neuropath. Exp. Neurol. 64: 513-522, 2005
(7) Yan, C.; Tanaka, M.; Sugie, K.; Nobutoki, T.; Woo, M.; Murase, N.; Higuchi, Y.; Noguchi, S.; Nonaka, I.; Hayashi, Y. K.; Nishino, I. : A new congenital form of X-linked autophagic vacuolar myopathy. Neurology 65: 1132-1134, 2005
(8) Munteanu, I.; Ramachandran, N.; Mnatzakanian, G. N.; Villanova, M.; Fardeau, M.; Levy, N.; Kissel, J. T.; Minassian, B. A. : Fine-mapping the gene for X-linked myopathy with excessive autophagy. Neurology 71: 951-953, 2008
(9) Ramachandran, N., Munteanu, I., Wang, P., Aubourg, P., Rilstone, J. J., Israelian, N., Naranian, T., Paroutis, P., Guo, R., Ren, Z.-P., Nishino, I., Chabrol, B., and 12 others. VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification. Cell 137: 235-246, 2009. Note: Retraction: Cell 142: 984 only, 2010
(10) Kurashige, T., Takahashi, T., Yamazaki, Y., Nagano, Y., Kondo, K., Nakamura, T., Yamawaki, T., Tsuburaya, R., Hayashi, Y. K., Nonaka, I., Nishino, I., Matsumoto, M. Elevated urinary beta-2 microglobulin in the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy. Neuromusc. Disord. 23: 911-916, 2013
11) Ramachandran, N., Munteanu, I., Wang, P., Ruggieri, A., Rilstone, J. J., Israelian, N., Naranian, T., Paroutis, P., Guo, R., Ren, Z.-P., Nishino, I., Chabrol, B., and 12 others. VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy. Acta Neuropath. 125: 439-457, 2013
(12) Crockett, C. D., Ruggieri, A., Gujrati, M., Zallek, C. M., Ramachandran, N., Minassian, B. A., Moore, S. A. Late adult-onset of X-linked myopathy with excessive autophagy. Muscle Nerve 50: 138-144, 2014
(13) Mercier, S., Magot, A., Caillon, F., Isidor, B., David, A., Ferrer, X., Vital, A., Coquet, M., Penttila, S., Udd, B., Mussini, J.-M., Pereon, Y. Muscle magnetic resonance imaging abnormalities in X-linked myopathy with excessive autophagy. Muscle Nerve 19Mar, 2015
(14) Munteanu, I., Ramachandran, N., Ruggieri, A., Awaya, T., Nishino, I., Minassian, B. A. Congenital autophagic vacuolar myopathy is allelic to X-linked myopathy with excessive autophagy. Neurology 84: 1714-1716, 2015
(15) Ruggieri, A., Ramachandran, N., Wang, P., Haan, E., Kneebone, C., Manavis, J., Morandi, L., Moroni, I., Blumbergs, P., Mora, M., Minassian, B. A. Non-coding VMA21 deletions cause X-linked myopathy with excessive autophagy. Neuromusc. Disord. 25: 207-211, 2015
2015/09/11 責任遺伝子 ノート/文献追加