Summary: This is a rare form of X-linked recessive myopathy and cases are identified mostly, if not exclusively, in Finland, France and Canada. The clinical course is characterized by childhood onset slow progression of muscle weakness without loss of ambulation with no evidence of cardiac, respiratory, or central nervous system involvement. Patients have normal life expectancy. Female carriers are usually asymtomatic or only very mildly affected. Muscle fibers are not necrotic and show excessive autophagic activity and exocytosis of the phagocytosed material. These vacuoles are strongly reactive for dystrophin. Membrane bound vacuoles and balls of dense material under the basal lamina are present. Deposition of C5b-9 complement attack complex, subsarcolemmal deposition of calcium, and expression of MHC1 complex are also features of this disease. The gene is probably on chromosome Xq28.

CK levels: The serum CK level may be elevated during the first years of life by 2.5 to 3 times normal and may, during adolescence, rise to 10 to 15 times normal.

Clinical features:

· Onset: Usually around 18-20 years old but cases with early onset at 5 years old have also been reported.

· Live expectancy: Normal.

· Muscular symptoms: It is usually a very slowly progressive muscle weakness that is mainly proximal and affects the legs more than the arms. Atrophy of the thigh may be apparent.

· The heart, central nervous system, and other organs are not affected.

Genetics: The candidate gene may be located in chromosome Xq28. The gene appears to be close to the Emery-Dreifuss gene.

Pathogenesis:

· Myofiber injury based theory: The vacuoles are autophagosomes clearing up sarcoplasmic debris after a sublethal injury to the myofiber.

· Membrane attack complex based theory: The injury is induced by deposition of membrane attack complex of complement on myofibers with secondary invagination and/or endocytosis.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Morphology: The cardinal feature is sarcoplasmic vacuoles that is bound by a dystrophin positive membrane.

· Marked variation in fiber size: Fibers have increased variation in size and are predominantly composed of round small and hypertrophic fibers. Necrotic fibers are uncommon. Some fibers may be partially split.

· Vacuoles: The vacuoles may have granular content that is blue with HE stain (rimmed vacuoles) or may be optically clear. These vacuoles are PAS(-) and do not contain lipid. Acid phosphatase reactivity is present in some fibers. Calcium deposition can also be seen in the vacuoles. The vacuoles have immunoreactive for dystrophin, laminin and MHC I.

· Subsarcolemmal calcium: They often occur as irregular deposition along the surface and can be well demonstrated by alizarin red. Although some fibers may appear normal with HE stain, calcium deposition can also be demonstrated in these fibers.

Immunohistochemistry:

· Dystrophin: Strongly positive at the rim of the vacuoles.

· Complement membrane attack complex: They can be demonstrated on the membrane in all fibers including those that appear normal. The membrane attack complex is also present in the walls of capillaries and perimysial vessels.

· MHC I: Immunoreactivity for MHC I can be seen in the surface of the fibers and in some vacuoles.

· LAMP-2: This is a protein that is found in the vacuoles. This protein is normally found in lysosomal membranes and is considered to be important in autophagy.

Electron microscopy:

· Balls of dense material: This is the most characteristic finding. These balls of dense material are outside the basement membrane but under the basal lamina which often appear mulilaminated. A lot of calcium is present in these sites.

· Membrane bound vacuoles: These vacuoles may contain remains of mitochondria, membrane whorls, and calcium apatite crystals.

DIFFERENTIAL DIAGNOSIS: Head

Danon’s disease: X-linked (the gene is on Xq24) vacuolar myopathy and cardiomyopathy7 with mental retardation. Danon’s disease and vacuolar myopathy and excessive autophagy are two different conditions. [Nishino I et al., 2000; Danon MJ et al., 1981; Hart ZH et al., 1987; Valeros et al., 1997].

REFERENCES: Head

Louboutin JP, Villanova M, Lucas-Heron B, Fardeau M. X-linked vacuolated myopathy: membrane attack complex deposition on muscle fiber membranes with calcium accumulation on sarcolemma. Ann Neurol. 1997 Jan;41(1):117-20.

Auranen M, Villanova M, Muntoni F, Fardeau M, Scherer SW, Kalino H, Minassian BA. X-linked vacuolar myopathies: two separate loci and refined genetic mapping. Ann Neurol. 2000 May;47(5):666-9.

Chabrol B, Figarella-Branger D, Coquet M, Mancini J, Fontan D, Pedespan JM, Francannet C, Pouget J, Beaufrere AM, Pellissier JF. X-linked myopathy with excessive autophagy: a clinicopathological study of five new families. Neuromuscul Disord. 2001 May;11(4):376-88.

Yamamoto A, Morisawa Y, Verloes A, Murakami N, Hirano M, Nonaka I, Nishino I. Infantile autophagic vacuolar myopathy is distinct from Danon disease. Neurology. 2001 Sep 11;57(5):903-5.

Hart ZH, Servidei S, Peterson PL, Chang CH, DiMauro S. Cardiomyopathy, mental retardation, and autophagic vacuolar myopathy. Neurology. 1987 Jun;37(6):1065-8.

Kalimo H, Savontaus ML, Lang H, Paljarvi L, Sonninen V, Dean PB, Katevuo K, Salminen A. X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol. 1988 Mar;23(3):258-65.

Nishino I, Fu J, Tanji K et al., Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 2000 Aug 24;406(6798):906-10.

Danon MJ, Oh SJ, DiMauro S, Manaligod JR, Eastwood A, Naidu S, Schliselfeld LH. Lysosomal glycogen storage disease with normal acid maltase. Neurology. 1981 Jan;31(1):51-7.