Centronuclear myopathy in Labradors

Clinical Symptoms and Histological Signs

Excerpt and modified from Article by Drs. Tiret and Blot
Published in Retriever Field Trial News and Retrievers On Line ; winter 2005

At birth, affected puppies are indistinguishable from their control littermates but as from two weeks of age, a progressive significant weight loss is observed. At one month of age, the absence of tendon reflexes is noticed and used as an early and reliable diagnosis. The age of onset of the disabling phenotype varies between 2 to 5 months, with an awkward gait and a decreased exercise tolerance, associated with a generalized muscle weakness. The pup will never recover from this disabling disease.

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The age of onset of the disabling phenotype varies between 2 to 5 months with an awkward gait and a decreased exercise tolerance, associated with a generalized muscle weakness worsened with cold (see figure 1).

Figure 1.
A 5-month-old female affected by CNM.

Clinical signs are progressively accentuated and generally stabilized at one year of age. In adults, the most striking macroscopic feature of the disease progression is the atrophy of temporal, cervical and leg muscles, leading to a ventroflexion of the neck, abnormal postures and movements. As of today, the oldest affected dog is 8.5 years old and no significant premature death in the colony could be observed. Nevertheless, dogs require medical care, essentially because they suffer from respiratory complications due to megaœsophagus.

A hallmark of muscles from Labradors affected by muscular myopathy is a centralization of nuclei in muscular cells (Figures 2 and 3). This can be observed on an histological section of a biopsied muscle.
In a normal muscle, some rare nuclei can be observed at the center of cells (<1%). But most of nuclei are difficult to see because they are pushed away (under the membrane) by intracellular contractile proteins. In affected muscles, 10 to 70% of fibers have centralized nuclei (arrow heads on the right picture of Figure 2 and Blue staining on Figure 3).

Figure 2.
Transverse sections of the biceps femoris muscle taken from a normal (left) or an affected (right) dog.
Sections are stained with hemalun-eosin.

The muscular myopathy has thus been called "centronuclear myopathy", abbreviated CNM (Blot et al. 2002; Tiret et al., 2003; Blot et al. unpublished results). The main reason for deciding to change the name is that this Labrador myopathy is the only known mammalian model for a similar human myopathy, called centronuclear myopathy of man. It is also much more precise than "muscular myopathy" that, strictly speaking, should involve several distinct myopathies.

Figure 3.
Transverse sections of the biceps femoris muscle taken from an affected dog.
Position of nuclei is revealed by a nuclear staining (blue). A muscular enzyme is stained using a green fluorescence.

A metabolic remodeling of myofibers is also observed on histological sections (Figure 4). Fast contracting fibers (type II; strong staining on sections depicted Figure 4) are replaced by slow contracting fibers (type I; weak staining on sections depicted Figure 4).

During the time course of the disease, fat and fibrous tissue replaces some fibers that seem to have disappeared.

Figure 4.
Remodeling of myofibers in affected dogs (right) compared to normal dogs (left). A metabolic switch is observed, as well as replacement of fibers by fat (asterisks).

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