CMT 2: Molecular diagnosis of axonal forms of Charcot-Marie-Tooth disease

[Guest guest]

Rev Neurol (Paris). 2009 Nov 24

Molecular diagnosis of axonal forms of Charcot-Marie-Tooth disease.]

Latour P, Vial C.

Centre de référence maladies neuromusculaires rares Rhône-Alpes, 69677 Bron,

France; Service de biochimie-neurobiologie, centre de biologie Est, hospices

civils de Lyon, 69677 Bron, France.

Charcot-Marie-Tooth (CMT) disease is the most common cause of inherited

peripheral neuropathies with a frequency estimated at 1/2500.

Electroneuromyographic examination distinguishes a myelinic form (CMT1) and an

axonal form of the disease (CMT2). Significant genetic heterogeneity is found in

CMT, with 15 genes or loci for CMT2.

To date, a molecular diagnosis has not been established for most CMT2 patients

and the distribution of identified mutations is wide spreading over nearly all

genes. Simple guidelines for daily practice are difficult to establish from

compilation of mutation reports or consultation of databases; little

simplification can be expected from future findings.

We present our results of molecular diagnosis for 251 CMT2 index cases

characterized by their mode of inheritance (217 dominant and 34 recessive

cases), and a motor conduction velocity in median nerve equal to or above to

38m/s. For each case, at least one of the genes known to date for CMT2 (MFN2,

RAB7, GARS, NF-L, HSPB1, GDAP1, MPZ, HSPB8, GJB1, DNM2, YARS, LMNA, and MED25)

was studied.

Around 22% of diagnoses were established and efficiency was comparable for

dominant or recessive cases. For dominant cases, the first objective was to

search for mutations of proteins connexin32, mitofusin2 and P0. For recessive

cases, GDAP1 provided the key to molecular diagnosis; lamin A/C mutations were

only found for patients with an ethnic background from North Africa.

Heat shock proteins HSPB1 and HSPB8 were implicated in a significant proportion

of " spinal " (or pure motor) CMT2. NF-L or RAB7 mutations were rare. We did not

identify any deleterious mutations in GARS, DNM2, YARS orMED2. We propose a

simple decision tree for molecular diagnosis of CMT2.