Muscle weakness



There have been several reports of individuals with MED presenting with symptoms of tiredness and muscle weakness (i.e. mild myopathy).

The following terms have all be used to describe these clinical features:-

  • Fatigue during walking
  • Mild muscle weakness
  • Difficulty standing (rising) from a sitting position
  • Problems walking up stairs
  • Gower’s sign

Although these secondary observations were initially thought to be restricted to COMP missense mutations in the carboxyl terminal domain of COMP, in particular the p.Arg718Trp mutation, it has now become clear that these features are more widespread than initially believed.

In this context, genotypes reported to result in MED with mild myopathy include:-

COMP: Asp326Tyr, Glu457del, Asp605Asn and Arg718Trp.

MATN3: Asp176_Val176del*.

COL9A2: exon 3 skip; see here COL9A2 myopathy and AJMA_33240_sm_SupplFig1.

COL9A3: exon 3 skip; see here COL9A3 myopathy.

*The clinical presentation in this family includes normal height, an abnormal (waddling) gait, fatigue and pain after long walks and periods of walking with a ‘stretched leg’.

For a full review see here Muscle Review.

Interestingly, we have recently demonstrated that mild myopathy appears to be specifically associated with COMP but not MATN3 mutations in our mouse models of genetic skeletal diseases.

Preliminary conclusion:

It is clear from clinical presentation and mouse model studies that myopathy is more commonly associated with MED than has previously been appreciated, but the precise genetic causes in the context of COMP and/or COL9A2-3 and/or MATN3 mutations has yet to be fully resolved.

Furthermore, the underlying pathological cause(s) of this ‘mild myopathy’ deserves further investigation through both human and genetic model studies.

Our initial studies of COMP and MATN3 mutations in targeted mouse models have provided some insight:-

Pirog 2010

Pirog 2013

Genetically engineered mice are an ideal model system to study musculoskeletal pathobiology in an entire tissue system and are only happy to prove how strong they are.

Mouse workout

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