Severe early onset CMT2 associated with novel compound heterozygous MFN2 mntatio

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(Oral Presentation at Antwerp Conference July 2009)

Severe early onset CMT2 associated with novel compound heterozygous MFN2

mntations: Deletion ofMFN2 exons 7-8 and c.647T>C; p.Phe216Ser.

T.M. Polke\ V.S. Gibbons\ C. Devile2 , M.G. Sweeney\ M.M. ReiHl and M.B. l

INeurogenetics Laboratory, National Hospital for Neurology and Neurosurgery,

Queen Square, London, UK; 'Department of Neurology, Great Ormond Street

Hospital, London, UK; 3MRC Centre for Neuromuscular Disease and Department of

Molecular Neurosciences, National Hospital for Neurology and Neurosurgery and

Institute of Neurology, Queen Square, London, UK

Mutations in Mitofusin 2 (MFN2) are the most common cause of axonal CMT (CMT2)

Over 50 mutations have been reported, mainly causing autosomal dominant disease,

though 3 families with apparently recessive inheritance have been described. We

report results of

genetic analysis on two siblings with severe progressive early onset CMT2 and

optic atrophy.

A 10 year-old boy and a 15 year-old girl, with reportedly unaffected parents..

Multiplex ligation dependent probe amplification (MLPA) and DNA sequencing

identified a deletion of MFN2 exons 7 and 8 and an MFN2 missense mutation

(c.647T>C; pPhe216Ser) in both

children. Exons 7 and 8 code for amino acids 200-272, including pmt of the MFN2

GTPase domain.

This is the first report of a deletion in MFN2. We confirmed the deletion to be

approximately L4kb by PCR A fluther 63 CMT2 patients with no sequence mutations

in MFN2 were analysed by MLPA but no other rearangements were detected. The

missense mutation has also not been previously reported; it occurs within a

highly conserved region of

the MFN2 GTPase domain.. Analysis of parental DNA showed that the deletion is

paternally derived, while the mother carries the missense mutation.

Although the deletion and the missense mutation are predicted to be pathogenic,

the reported unaffected status of the

parents raises the possibility that these are true autosomal recessive compound

heterozygotes. Neither parent has been seen by us personally yet and further

detailed phenotype studies are

planned in both parents. Both rearangements in MFN2 and autosomal recessive

inheritance are not likely to be common but should be considered in cases of

CMT2.

Neither pm·ent has been seen by us personally yet and further detailed phenotype

studies me

planned in both pm·ents.. Both remrangements in MFN2 and autosomal recessive

inheritance

me not likely to be common but should be considered in cases of CMT2