Myopathy, X-Linked, With Excessive Autophagy

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.

Description

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 multilayered 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.

Clinical 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.

Clinical Variability

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.

Inheritance

The transmission pattern of XMEA in the families reported by Ramachandran et al. (2013) was consistent with X-linked recessive inheritance.

Mapping

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.

Molecular Genetics

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 previously been 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.

Pathogenesis

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.