Summary: This is a family of disease with diverse clinical presentation and genetic features but share the common histologic feature of centrally located nulcei in muscle fibers. As a general trend, those that have later onset are not as severe as those with infantile onset.

Clinical subtypes:

Infantile (neonatal) onset:

· Genetics: There is an X-linked recessive form and autosomal dominant form [De Angelis MS et al., 1991] and the X-linked form has most severe symptoms. The mutated gene (MTM1) in X-linked form is on Xq28 and encodes the protein myotubulin, believed to be a tyrosine phosphorylase [Laporte J et al, 1996].

· Clinical features: The presence of polyhydraminios and decreased fetal movement may suggest fetal onset. There is severe muscular weakness in all muscles except facial and extraocular muscles on birth. There is respiratory paralysis and dysphagia. Clinical symptoms are highly suggestive of Werdnig-Hoffmann disease and infantile myotonic dystrophy. Usually fatal during early infancy.

Infancy or childhood onset: Autosomal dominant or uncertain pattern of inheritance. There is moderate delay in motor development with craniobulbar weakness. Eyelid ptosis and external ophthalmoplegia are frequent. Usually not crippling and is compatible with prolonged survival.

Adolescent or adult onset: Autosomal dominant. Onset is insidious and may remain unnoticed during the first two decades of life. There is mild to severe weakness that progresses in a limb-girdle pattern. Craniobulbar muscles are usually spared.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Infantile X-linked type Childhood non-X-linked type Adolescent type

Infantile X-linked type:

Histology:

· Cardinal features: The overall picture looks like fetal muscle with very small fiber diameter and many centrally located nuclei.

· Fiber diameter: Fibers are much smaller than normal although a few fibers of normal size may be present. The intrafusal fibers may even be of larger caliber than extrafuzal fibers.

· Centrally located nuclei: Centrall located nuclei is the characteristic features and they may occur as chains in longitudinal sections. The proportion of fibers with centrally located nuclei varies from 5% to 50%. These fibers appear as thin rims of sarcoplasm around large nuclei.

· Vacuoles: Perinuclear accumulation of mitochondria and glycogen along the long axis of centrally located nuclei lead to the formation of vacuoles in longitudinal HE or semithin sections. These vacuoles appear as centrally located vacuoles on cross sections. They may be more numerous than centrally located nuclei. The glycogen in these vacuoles may be PAS positive.

· Semithin sections: In addition to centrally located nuclei and vacuoles, disturbed myofibrillary organization can be seen in almost all cases.

Histochemistry and immunohistochemistry:

· Oxidative enzymes: Perinuclear accumulation of mitochondria leads to enhanced oxidative enzyme activity at the center (corresponding to the vacuoles on HE sections).

· Fiber typing: Intermyofibrillary oxidative activity is lacking fiber type differentiation could not be established by NADH reaction. Typing by ATPase may be normal or type 1 fiber predominance or there may be a single histochemical type reacting as type 2C fibers. The centrally located nuclei appear as vacuoles in ATPase reaction.

· Immunohistochemistry: Many or sometimes all fibers are reactive for embryonic myosin heavy chain. There is strong central desmin staining and some fibers are positive for vimentin. Vimentin and desmin give a regular pattern of cross striation on longitudinal sections.

Childhood non-X-linked cases: Some of these cases may also be known as myotubular myopathy with type 1 fiber hypotrophy. Two population of fiber of different size tends to occur in childhood and adult onset cases.

· Histology and histochemistry: Type 1 fibers are small (hypotrophic) and numerically predominant. Centronucleation is also present. NADH reaction shows increased activity in the center of the fibers with a radial spike-like pattern.

· Immunohistochemistry: Increased immunoreactivity for desmin and some fiber are positive for vimentin. Embryonic myosin heavy chain may be present but is not seen in all cases.

Adolescent or adult onset:

· Fibers affected: Two population of fiber of different size tends to occur in childhood and adult onset cases. Type 1 fibers are rounded and show reduced caliber accompanied by some type 2 fiber hypertrophy.

· Centrally located clusters of nuclei on cross sections and chains of centrally located nuclei on longitudinal sections may be present.

· Immunohistochemistry: Increased immunoreactivity for desmin, often in stellate shape, is present in some fibers; vimentin may or may not be expressed. Embryonic myosin heavy chain and embryonic N-CAM may be present in small fibers with central nuclei.

· Accumulations and vacuoles: Substantial accumulatin of lipofuscin and glycogen adjacent to central nucle may be demonstrated. Such accumulation may lead to formation of centrally located cytoplasmic vacuoles.