Progetto Mitofusina

Exon

Protein change

Inheritance

Ethnicity

Onset age

Symptoms at onset

Reference

Additional remarks

Glu 288 Asp

Familial

22-29y

weakness and sensory loss
in the anterior compartments
of both legs foot drop

Bergamin et al., 2014

Ataxic steppage, gait, severe lower limb atrophy, weakness,
and Areflexia; sensory–motor axonal polyneuropathy

Thr356A la

Familial

Chinese

8-16y

Foot deformities, severe muscle atrophy,

Wang et al., 2012

2

Arg104Trp

Sporadic

German

3 y

slowly progressive motor and
sensory polyneuropathy in childhood

Brockmann et al., 2008

One patient with gait disturbance,
increased OT reflexes, optic atrophy,
saccadic interruption of horizontal eye movements,
secondary macrocephaly, impaired hand function,
abnormal MRI; one patients with gait disturbance,
optic atrophy, impaired hand function, normal MRI

9

Ser378Pro

Sporadic

German

7 y

Slowly progressive motor and
sensory polyneuropathy in childhood

Brockmann et al., 2008

Gait disturbance, increased OT reflexes, normal MRI

IVS5-1G>C

Familial

German

7 y

Slowly progressive motor and
sensory polyneuropathy in childhood

Brockmann et al., 2008

Gait disturbance, secondary macrocephaly, abnormal MRI

 Arg94Gln
(
heterozygous mutations) 

Familial

Japanese

3 y

Foot drop and gait disturbance

Kijima et al., 2005

CMT2 phenotype

Phe223Leu

Familial

Japanese

7 y

Walking difficulties and leg pain

Kijima et al., 2005

Congenital dislocation of the hip and mild mental retardation,
fatty, sleep apnea and classical CMT2 phenotype

Thr236Met

Sporadic

Japanese

7 y

Running difficulties

Kijima et al., 2005

CMT2 phenotype

Val244Met

Sporadic

Japanese

10 m

walking difficulties

Kijima et al., 2005

CMT2 phenotype with no sensory impairments

Phe284Tyr

Sporadic

Japanese

10 y

pes cavus

Kijima et al., 2005

slowly progressive muscle weakness of lower legs, atrophy

in the lower extremities, no sensory impairments
and no decreased tendon reflexes

Lys357Asn

Sporadic

Japanese

10 m

Frequent falls

Kijima et al., 2005

CMT2 phenotype with no sensory impairments

Glu424Gly

Familial

Japanese

10 y

congenital hearing loss of the right ear and
pain in the lower extremities during exercise

Kijima et al., 2005

severe leg pain at work, drop feet, CMT2 phenotype
with mildly decreased sensitivity to vibration,
normal or slightly elevated deep tendon reflexes

8

Arg259Leu

Sporadic

Caucasian

19 y

progressive leg weakness and numbness

Ajroud-Driss et al., 2009

CMT2 phenotype with brisk deep tendon reflexes except
for the ankle jerks that were depressed.
He had bilateral Hoffman
sign with normal tone and flexor plantar response.

5

Gly127Asp

Sporadic

Korean

16 y

Chung et al., 2006

Lower limbs muscles weakness,
sensory loss (pain>vibration), extensor plantar responses

6

His165Arg

Familial

Korean

10 and 50 y

Chung et al., 2006

Mild muscular weakness, pain and
vibration sensory loss, tremor, SNHL, hoarseness

6

His165Arg

Familial

Korean

14 y

Chung et al., 2006

Mild muscular weakness, pain and vibration sensory loss

11

Thr362Met

Familial

Korean

42 y

Chung et al., 2006

Mild lower extremities muscle weakness
and atrophy, transient sensory loss

11

Met376Thr

Familial

Korean

39 y

Chung et al., 2006

Mild muscular weakness, pain and vibration sensory loss

Ala164Val

Thr362Met

Familial, CH

3 y

Falls

Nicholson et al., 2008

Slightly deaf, CMT2 phenotype with
upper and lower limbs involvement

Asp214Asn

Cys390Arg

Familial, CH

3 y

Talipes

Nicholson et al., 2008

CMT2 phenotype with upper and lower limbs involvement

Arg707Trp

Familial

2 y

Clubfoot

Nicholson et al., 2008

Slightly deaf, Lipodystrophy, CMT2 phenotype
with upper and lower limbs involvement

4

Leu92Pro

Unknown

Belgium

1 y

Verhoeven et al., 2006

nerve biopsy revealed a similar loss of large myelinated
fibres with even low evidence of regeneration

4

Arg100Gly

Familial

Bulgaria

10 y

Verhoeven et al., 2006

5

Pro123Leu

Familial

Germany

2 y

Verhoeven et al., 2006

sural nerve biopsy with an apparent
loss of large myelinated nerve fibres

6

His165Arg

Familial

Serbia

6 y

Verhoeven et al., 2006

6

His165Tyr

Familial

Czech Republic

12 y

Verhoeven et al., 2006

8

Arg250Trp Arg400X

Unknown

Poland

4 y

Verhoeven et al., 2006

8

Arg250Gln

Unknown

Belgium

21 y

Verhoeven et al., 2006

9

His277Arg

Familial

Germany

10 y; 15 y

Verhoeven et al., 2006

parkinsonism occurred at older age

11

Met376Ile

Familial

Czech Republic

35 y

Verhoeven et al., 2006

11

Leu379_Met381del

Familial

USA

3 y

Verhoeven et al., 2006

11

Gln386Pro

De novo

Israel

1.5 y

Verhoeven et al., 2006

18

Leu710Pro

Unknown

Bulgaria

6 y

Verhoeven et al., 2006

19

Gln751X

De novo

Czech Republic

4 y

Verhoeven et al., 2006

19

Gln751

Familial

Belgium

5 y

Verhoeven et al., 2006

5

His128Arg

De novo

< 5 y

Calvo et al., 2009

Severe and asymmetrical phenotype

5

Ser156Ile

Sporadic

< 10 y

Calvo et al., 2009

Moderate phenotype

9

His277Tyr

Familial

> 10 y

Calvo et al. 2009

Moderate phenotype with pyramidal signs,
vasomotor troubles

11

Arg364Pro

Familial

< 5 y

Calvo et al. 2009

Severe phenotype

11

Arg364Pro

Familial

< 5 y

Calvo et al., 2009

Severe phenotype

17

Arg364Gln

Sporadic

> 10 y

Calvo et al., 2009

Moderate phenotype

19

Phe665Ser

Familial

< 10 y

Calvo et al., 2009

Moderate and asymmetrical phenotype

Trp740Cys

Familial

< 10 y

Calvo et al., 2009

Mild phenotype with pyramidal signs

19

Trp740Cys

Familial

< 10 y

Calvo et al., 2009

Moderate and asymmetrical phenotype
with pyramidal signs, vasomotor troubles, tremor

Leu745Pro

Familial

> 10 y

Calvo et al., 2009

Mild phenotype and vasomotor problems

19

Leu745Pro

Familail

> 10 y

Calvo et al., 2009

Mild phenotype

Met747Thr

De novo

< 10 y

Calvo et al., 2009

Moderate phenotype

Lys38del

Familial, CH

Italian

3 y

Foot drop

Polke et al., 2011

4

Val69Phe

Familial

Turkey

5-15 y

Züchner et al., 2004

4

Leu76Pro

Familial

European

7-44 y

Züchner et al., 2004

4

Leu92Arg

Sporadic

3 y

McCorquodale et al., 2011

4

Leu92Pro

Sporadic

Korean

1 y

Chung et al., 2010

Chung et al., 2006

Severe phenotype

Arg94Gly

Sporadic

1 y

Feely et al., 2011

early onset CMT

Arg94Gly

Sporadic

1 y

Feely et al., 2011

CMT neuropathy score: moderate

Arg94Gly

Sporadic

1 y

Feely et al., 2011

CMT neuropathy score: severe

4

Arg94Gln

Familial

Russia

6-17 y

Züchner et al., 2004

CMT neuropathy score: moderate

4

Arg94Gln

Familial

Japan

3-15 y

Züchner et al., 2004

Arg94Gln

Sporadic

4 y

Feely et al., 2011

Arg94Gln

Chinese

Zhang et al., 2009

CMT neuropathy score: severe

Arg94Gln

Sporadic

Germany

2 y

Neusch et al., 2007

4

Arg94Gln

Familial

Norwegian

4 y

Stumble and dorsal toes weakness

Braathen et al., 2010

early-onset CMT2 with no central
nervous system pathology

4

Arg94Gln

Familial

Spain

I decade

Severe sensory and motor neuropathy

Casasnovas et al., 2010;

Banchs et al., 2008

4

Arg94Trp

Familial

AfroAmerican

3-8 y

Axonal neuropathy with optic atrophy

Züchner et al., 2006

optic atrophy

Arg94Trp

Sporadic

1 y

Feely et al., 2011

Axonal neuropathy with optic atrophy

Arg94Trp

Sporadic

4 y

Feely et al., 2011

CMT neuropathy score: moderate

Arg94Trp

Sporadic

1 y

Feely et al., 2011

CMT neuropathy score: severe

4

Arg94Trp

Familial

Korea

8 y

Frequent fall, weakness in LE

Cho et al., 2007

CMT neuropathy score: severe

4

Arg94Trp

Familial

Norwegian

4 y

weakness in LE

Braathen et al., 2010

One pt with CMT1 phentype,
one pt with weakness in legs and pes cavus

Arg94Trp

Familial

Korean

8 y

Chung et al., 2010

Arg94Trp

Sporadic

Korean

8 y

Chung et al., 2010

early onset CMT

4

Arg94Trp

Familial

Spain

I decade

Moderate sensory/motor neuropathy

Casasnovas et al., 2010

early onset CMT

Arg94Trp

China

5 y

progressive distal limb muscle weakness and wasting

Lv et al., 2013

Gly103TrpfsX41

Familial

Spain

22 y

Classic CMT2 phenotype, moderate instability

Sivera et al., 2013

4

Arg104Trp

Familial

Italy

2 y; 4 y

Awkward walk with frequent falling

Del Bo et al., 2008

4

Arg104Trp

isolated case, de novo

3 y

Progressive weakness in his legs

Genari et al., 2011

Cognitive impairment may be another feature
of the MFN2-related phenotype.

4

Arg104Trp

isolated case, de novo

Greek

< 1 y

Developmental delay

Baets et al., 2011

Severe and early onset axonal neuropathy
plus learning problems, obesity, glucose intolerance,
leukoencephalopathy, brain atrophy,
evidence of myelin involvement and
mitochondrial structural changes on sural nerve biopsy.

4

Arg104Trp

Japanese

Childhood

Abe et al., 2011

Thr105Met

Sporadic

1 y

Feely et al., 2011

Thr105Met

Familial

USA

Lawson et al., 2005

CMT neuropathy score: mild

IV5

Thr105LeufsX2

Familial

Korea

31 y

late-onset AD mild axonal CMT

Park et al., 2012

Gly127Val

Germany

48 y

weakness in LE

Engelfried et al., 2006

double mutation in CIS with c.668T>A

Asn131Ser

Familial

Turkey

4 y

severe and typical early onset CMT1

Fischer et al., 2012

Cys132Thr

Chinese

Zhang et al., 2009

Leu146Phe

Familial

Northern European,
 Cherokee American Indian descent 

Klein et al., 2011

Thr159_Gln162del

Familial

Han Chinese

13 y

Lin et al., 2011

intron5

Sporadic

Korean

7 y

Chung et al., 2010

intron5

Thr159_Gln162del

Familial

Taiwan

13 y

Lin et al., 2011

early onset CMT

del intron 5-ex6

Val160fsX26

Familial

French

3 y

axonal degeneration, myelin modifications,
and intra-axonal mitochondria with distorted cristae

Vital et al., 2012

6

His165Leu

Familial

Italian

14 y

Weakness, mild distal leg sensory loss

Marchesi et al., 2011

Simultaneous heterozygous MFN2
and GDAP1 mutations

His165Arg

Sporadic

Korean

7 y

Chung et al., 2010

Co-occurence of ALS and CMT2A

His165Arg

Familial

Korean

16 y

Weakness in LE

Cho et al., 2007

early onset CMT

7

Ile203met

Familial

Spain

II decade

Moderate sensory/motor neuropathy

Casasnovas et al., 2010

7

Thr206Ile

Familial

European

3 y

Axonal neuropathy with optic atrophy

Züchner et al., 2006

tremor

Asp210Val

Familial

Tunisian

LL weakness + visual, hearing deficit

Rouzier et al., 2012

Axonal neuropathy with optic atrophy

Ile213Thr

Familial

USA

Lawson et al., 2005

mDNA instability + optic atrophy ‘plus’ phenotype

7

Phe216Ser

Familial, CH

British

12-18 m

Foot drop

Polke et al., 2011

Leu218Pro

Norwegian

Ostern et al., 2013

del ex7-8

Familial, CH

British

12-18 m

Foot drop

Polke et al., 2011

7

Phe223Tyr

familial

Korea

31 y

late-onset AD mild axonal CMT

Park et al., 2012

Leu233Val

familial

Taiwan

12 y

Lin et al., 2011

double mutation in CIS with c.474+4A>G

Leu248Val

familial

1 y

Feely et al., 2011

Leu248Val

sporadic

1 y

Feely et al., 2011

CMT neuropathy score: moderate

Leu233Val

familial

Han Chinese

12 y

Lin et al., 2011

CMT neuropathy score: severe;
profound proprioception loss

Ser249Phe

Japanese

Childhood

Abe et al., 2011

8

Arg250Gln

familial

12 y

McCorquodale et al., 2011

8

Pro251Ala

familial

Italy

8-50 y

Züchner et al., 2004

Pro251Arg

familial

1 y

Feely et al., 2011

Pro251Arg

sporadic

1 y

Feely et al., 2011

CMT neuropathy score: moderate

8

Pro251Arg

familial

2 y

McCorquodale et al., 2011

CMT neuropathy score: severe;
profound proprioception loss

Pro251Leu

sporadic

Spain

25 y

Classic CMT2 phenotype

Sivera et al., 2013

Wheelchair

8

Asn252Lys

familial

Spain

II decade

Severe sensory and motor neuropathy

Casasnovas et al., 2010

8

Ser263Pro

familial

Korea

13 y

Weakness in LE

Cho et al., 2007

Chung et al., 2006

Axonal neuropathy with optic atrophy

Val273Gly

familial

USA

Lawson et al., 2005

9

Gln276Arg

familial

European

10 y

Axonal neuropathy with optic atrophy

Züchner et al., 2006

Gln276His

familial

Chinese

9 y

Steppage gait; progressive distal muscle weakness
and atrophy in lower and upper limbs

Ching et al., 2010

Axonal neuropathy with optic atrophy

9

Gln276His

familial

Spain

III decade

Mild sensory and motor neuropathy

Casasnovas et al., 2010;

Banchs et al., 2008

Intrafamilial variability was observed

9

Arg280His

familial

European

11-35 y

Züchner et al., 2004

Arg280His

Vinci et al., 2011

Arg280His

sporadic

Korean

8 y

Chung et al., 2010

Severe lower-limbs sensory worsening
with loss of independent ambulation after epidural
anesthesia for hip osteo-synthesis,

9

Gly298Arg

familial

Spain

II decade

Moderate sensory/motor neuropathy

Casasnovas et al., 2010

early onset CMT

9

Glu308X

Familial, CH

British

14 months

Difficulty walking

Polke et al., 2011

Gl u347Val

Germany

childhood

Engelfried et al., 2006

Nonsense-mediated decay
in MFN2 transcripts sequencing

Ser350Pro

sporadic

Korean

3 y

Chung et al., 2010

Ser350Pro

familial

Korea

3 y

Gait abnormality

Cho et al., 2007

early onset CMT

Thr356Ala

familial

China

8 y

Hollow foot, claw hand deformity,
and severe muscle atrophy of the lower
and upper distal extremities

Wang et al., 2012

11

His361Tyr

familial

European

1 y

Axonal neuropathy with optic atrophy

Züchner et al., 2006

His361Tyr

sporadic

1 y

Feely et al., 2011

Axonal neuropathy with optic atrophy

Thr362Met

Familial, CH

Italian

3 y

Foot drop

Polke et al., 2011

CMT neuropathy score: severe

11

Arg364Trp

familial

European

1 y

Axonal neuropathy with optic atrophy

Züchner et al., 2006

11

Arg364Trp

sporadic

1 y

Feely et al., 2011

Axonal neuropathy with optic atrophy

11

Arg364Trp

sporadic

1 y

Feely et al., 2011

CMT neuropathy score: severe

11

Arg364Trp

sporadic

1 y

Feely et al., 2011

CMT neuropathy score: severe;
profound proprioception loss

11

Arg364Trp

familial

2 y

Feely et al., 2011

CMT neuropathy score: severe

11

Arg364Trp

familial

2 y

Feely et al., 2011

CMT neuropathy score: severe

11

Arg364Trp

familial

Korean

8 y

Chung et al., 2010

CMT neuropathy score: severe

11

Arg364Trp

sporadic

Korean

3 y

Chung et al., 2010

early onset CMT

11

Arg364Trp

familial

Korean

5 y

Chung et al., 2010

early onset CMT

11

Arg364Trp

familial

Korean

4 y

Chung et al., 2010

early onset CMT

11

Arg364Trp

familial

Korean

8 y

Chung et al., 2010

early onset CMT

11

Arg364Trp

sporadic

Korean

3 y

Chung et al., 2010

early onset CMT

11

Arg364Trp

sporadic

Taiwan

2 y

Lin et al., 2011

early onset CMT

11

Arg364Trp

sporadic

Taiwan

2 y

Lin et al., 2011

Arg364Trp

sporadic

Han Chinese

2 y

Lin et al., 2011

Arg364Trp

sporadic

Han Chinese

2 y

Lin et al., 2011

Arg364Trp

China

6 y

progressive distal limb muscle
weakness and wasting

Lv et al., 2013

11

Arg364Gln

familial

Spain

III decade

Moderate sensory/motor neuropathy

Casasnovas et al., 2010

Banchs et., 2008

11

Arg364Pro

sporadic

22 y

slowly progressive muscle atrophy and weakness of distal extremities and steppage gait

Takahashi et al., 2012

Arg364Pro

sporadic

2 y

Feely et al., 2011

patient with axonal neuropathy and optic atrophy

11

Met376Leu

familial

26 y

McCorquodale et al., 2011

CMT neuropathy score: severe;
profound proprioception loss

Met376Ile

Germany

22 y

Muscle cramps in LE

Engelfried et al., 2006

11

Met376Val

familial

Spain

III decade

Severe sensory and motor neuropathy

Casasnovas et al., 2010

Cys390Phe

sporadic

1 yr

Feely et l., 2011

Arg400Pro

isolated case

Italian/Irish

< 1 y

delayed motor milestones

Baets et al., 2011

CMT neuropathy score: severe

12

Arg418X

familial

European

1 y

Axonal neuropathy with optic atrophy

Züchner et al., 2006

Parental mosaicism in asymptomatic mother

Arg418X

sporadic

Korean

1 y

Chung et al., 2010

Axonal neuropathy with optic atrophy

Arg468His

Familial,
 associated to GDAP1 mutation 

Spanish

3 y

severe distal muscle weakness

Cassereau et al., 2011

early onset CMT

14

Arg468His

familial

Childhood

McCorquodale et al., 2011

14

Arg468His

familial

Spain

III decade

Moderate sensory/motor neuropathy

Casasnovas et al., 2010

This variant may represent rare benign polymorphism

14

Arg468His

familial

Spain

III decade

Mild sensory and motor neuropathy

Casasnovas et al., 2010

14

Arg468His

sporadic

Spain

V decade

Moderate sensory/motor neuropathy

Casasnovas et al., 2010

14

Arg468His

familial

Spain

V decade

Mild sensory and motor neuropathy

Casasnovas et al., 2010

14

Arg468His

sporadic

Spain

V decade

Mild sensory and motor neuropathy

Casasnovas et al., 2010

14

Arg468His

familial

Spain

V decade

Mild sensory and motor neuropathy

Casasnovas et al., 2010

Arg468His

Germany

26 y

paraeshesia in LE

Engelfried et al., 2006

14

Arg468His

familial

Norwegian

2 y

Foot deformity and stumbled

Braathen et al., 2010

CMT1 phenotype

15

Arg519Pro

Familial, CH

British

14 m

Difficulty walking

Polke et al., 2011

15

Asn570Ser

familial

Norwegian

63 y

Right foot weakness+walking difficulties

Braathen et al., 2010

dHMN phenotype

18

Val705Ile

familial

12 y

McCorquodale et al., 2011

dHMN phenotype

Val705Ile

Germany

6 y

foot deformities

Engelfried et al., 2006

18

Val705Ile

familial

Norwegian

10 y

Weakness in legs and pes cavus

Braathen et al., 2010

18

Val705Ile

familial

Norwegian

47 y

Paresthesia in feet

Braathen et al., 2010

18

Arg707Trp

familial

Norwegian

44 y

Muscular pain during exercise in left leg

Braathen et al., 2010

18

Arg707_Asn709del

sporadic

5 y

McCorquodale et al., 2011

Intermediate CMT

Ala716Thr

familial

2 y

Feely et al., 2011

18

Ala716Thr

familial

Norwegian

23 and 50 y

Recurrent ankle sprains,
weakness and reduced balance

Braathen et al., 2010

One with intermediate CMT with severe
CMT neuropathy score, one with paresthesia in foot

Leu724Pro

Japanese

childhood

Luigetti et al., 2011

Ala738Val

isolated case

35 y

Difficulty walking

Luigetti et al., 2011

19

Ala738Val

sporadic

Italy

35 y

walking difficulties

Luigetti et al., 2011

Non consanguineous healthy parents

19

Trp740Ser

familial

European

5-52 y

Züchner et al., 2004

Trp740Ser

familial

16 y

Feely et al., 2011

Trp740Ser

familial

33 y

Feely et al., 2011

CMT neuropathy score: moderate

Trp740Ser

familial

5 y

Feely et al., 2011

CMT neuropathy score: mild

Trp740Ser

familial

15 y

Feely et al., 2011

CMT neuropathy score: moderate

Trp740Arg

China

Lv et al., 2013

CMT neuropathy score: mild

Glu744Met

familial

Han Chinese

8 y

Lin et al., 2011

His750Pro

familial

6 y

Feely et al., 2011

Tyr752X

sporadic

14 y

Feely et al., 2011

CMT neuropathy score: severe

Leu753 fs

Germany

62 y

gait ataxia

Engelfried et al., 2006

CMT neuropathy score: severe;
profound proprioception loss



AD: autosomic dominant  |  CH: compound heterozygous  |  LL: lower limbs