Hereditary neuropathy
CMT and HMSN-P
on 5th. August, 7:30 to 8:30, Multidisciplinary Pain Group.
Masanori Nakagawa, M.D.
Professor and chairman
Department of Neurology,
Graduate School of Medical Science,
Kyoto Prefectural University of Medicine, Kyoto, JapanThe overseas scientific research for the elucidation of the mechanism of
a novel hereditary motor sensory neuropathy originated in Japan
This work is supported by a Grant-in-Aid for Scientific Research (B) from JSPS (21406026).
: JSPS KAKENHI (21406026)

Milwaukee
Seattle関西空港

Atlanta

7月31日～8月7日

Sao Paulo

Charcot-Marie-Tooth disease (CMT) is themost commonly inherited peripheral
neuropathy and is found worldwide among
all races and ethnic groups. Discovered in
1886 by three physicians, Jean-Martin
Charcot, Pierre Marie, and Howard Henry
Tooth, CMT affects an estimated 2.6
million people.

Charcot , Jean-Martin
1825-1893

Marie , Pierre
1853-1940
Tooth, Howard Henry
1856-1925

Clinical presentation of CMT
The disease onset usually occurs in the first two
decades of life and subsequently shows a slow
progression over decades. Symptoms and signs
indicative of CMT include: pes cavus (or pes
planus); hammer toes; difficulty in running; twistingof the ankle and tripping; difficulty in walking; footdrop; steppage gait; wasting, weakness, and sensory
loss of distal segments of lower and then upper
limbs; difficulties in hand manipulation; andreduced or absent deep-tendon reflexes. Other
common symptoms and signs are hand tremors,muscle cramps, cold feet, foot callosities,
acrocyanosis and pain.

The uncommon associated features such as
involvement of cranial nerves, vocal cord palsy,
pupillary abnormalities, glaucoma, optic atrophy,
pyramidal involvement, predominant upper-limb
involvement, prominent sensory abnormalities, andproximal dominant involvement.

CMT1

CMT (Intermediate forms)

CMT2

NCV in median nerve
38m/sec

Demyelinationg CMT
CMT1(AD), CMT4(AR)CMT1Axonal CMT
CMT2（AD, AR)

CMT2

CMT X
DI-CMT
RI-CMT
CMT 2
CMT1A
CMAP：almost normal
or slightly delayed
Segemental demyelination
Onion bulb formation

10

20

30
40
50
MCV m/sec60

CMAP：markedly reduced
Decreased myelinated fiber density

Intermediate CMT ：unable to classify by 38m/sce, DI-CMT、RI-CMTGenes and loci of Inherited Peripheral Neuropathies
About 50 loci and 40 genes have been identified

http://www.molgen.ua.ac.be/CMTMutations/Home/IPN.cfm

MicrotubuleMFN
2
mitochondria

Laminin
DAG1

NEFL
GAN

KIF1B

DRP2
PRX

X

X

X

X
X
X

Node of Ranvier

Basallamina

X

X

X

X
X
X

Axon

Schmidt-Lantermann
Incisure

X
X
X

compact
myelinSchwann Cell

Incisure

XX
MPZ

X

X

PRX

X

X

X

X Cx32

X
X
X

X

PMP22

MTMR2

XX

MTMR13
NDRG1
SOX10
MFN2
PRX
EGR2
MPZ
PMP22
GJB1

Saifi GM, et al. J Investigative Med 51:5:261-283, 2003

Different forms of CMT disease
and associated genes

Lancet Neurol 2009; 8: 654–67

Genetic classification of CMT
CMTIntermediate CMT

CMT2

CMT１
AD

AR

X-linkedAD

AR

X-linked

AD

AR

PMP22
MPZ
LITAF
EGR2
NEFL

GDAP1
MTMR2
MTMR13
SH3TC2
NDGR1
EGR2
PRX
HK1
FGD4
FIG4
CTDP1
PMP22
MPZ

GJB1

KIF1B
MFN2
RAB7
TRPV4
GARS
NEFL
HSPB1
HSPB8
MPZ
AARS
GDAP1

LMNA
MED25
GDAP1
NEFL
MFN2
HSPB1

PRPS1

DNM2
YARS

GJB1
NEFL
MPZ
GDAP1

J Peripheral Nervous System 16:1–14 (2011)

CMT

脱髄型（CMT１）

軸索型（CMT2）中間型（DI or RI CMT）

AD

AR

X-linkedAD

AR

X-linked

AD

AR

PMP22
MPZ
LITAF
EGR2
NEFL

GDAP1
MTMR2
MTMR13
SH3TC2
NDGR1
EGR2
PRX
HK1
FGD4
FIG4
CTDP1
PMP22
MPZ

GJB1

KIF1B
MFN2
RAB7
TRPV4
GARS
NEFL
HSPB1
HSPB8
MPZ
AARS
GDAP1

LMNA
MED25
GDAP1
NEFL
MFN2
HSPB1

PRPS1

DNM2
YARS

GJB1
NEFL
MPZ
GDAP1

Incidence of CMT related genes in USA, Italy and Japan
Abe A, Hayasaka K, et al. J human Genet (in press)ｎ

Gene mutations in demyelinating CMT
PMP22
dupliPMP22
cation

MPZ

LITAF

NEFL

GJB1

GDAP1 MTMR2 MTMR13 EGR2

PRX

DNM2

YARS

Unknown

Total

Japan

53
10
20
23.3% 4.4% 8.8%08
19
0% 3.5% 8.5%

0
0%

0
0%

0
1
5
0% 0.4% 2.2%

0
0%

0
111
0% 48.9%

227

Italy

98
2
4
57.6% 1.2% 2.3%

N.D.

N.D.

12
7.1%

N.D.

N.D.

N.D.

N.D.

N.D.

N.D.

N.D.

54
31.8%

170

USA

79
5
5
54.1% 3.4% 3.4%

N.D.

N.D.

80
5.5%

0
0%

N.D.

N.D.

1
1
0.7% 0.7%

N.D.

N.D.

51
34.9%

146

PMP22 mutations include a compound heterozygote of a PMP22 deletion and a missense Arg157Gly mutation22 and acompound heterozygote of a PMP22 deletion and an exon 5 deletion mutation. N.D. not done.

Incidence of CMT related genes in USA and Japan
Abe A, Hayasaka K, et al. J human Genet (in press)

Gene mutations in axonal CMT
MFN2

RAB7

Japan

14
11.0%

0

USA
(2011)

21
21.9%

－

Commentary

NEFL

HSP2
7

1
0.8%

0

0

3
3.1%

4
4.2%

－

GARS

MPZ

HSP22

GDAP1

GJB1

DNM2

YARS Unknown Total

5
4.0%

0

1
0.8%

6
4.7%

0

0

100
78.7%

－

－

5
5.2%

－

－

－

63
65.6%

127

96

How can we ultimately identify the causative genes in the patients withunknown cause? What are the genetic and epigenetic modifying factorsthat potentially affect the phenotypic expression of the patients with
PMP22 duplication? It could be helpful to establish a high-throughput
screening method using the next-generation sequencer for identification of
the causative gene of patients with unidentified mutations and the genetic
and epigenetic modifying factors of CMT. In addition, molecularepidemiological study of CMT in Asian countries including Korea andChina, where Japanese lineage may encroach, so as to provide moreinsights into the genetic background of the low prevalence of PMP22
duplication in Japan.

DNA chip for hereditary neuropathy diagnosis
Gene Chip image （１００K array)

Known genes: 28 genes

MPZ

GJB1

PMP22

SIMPLE

Candidate genes: 11 genes

EGR2

NEFL

PRX

MTMR2

KIAA1985

SBF2 /MTMR13

DNA Chip（resequencing chip）
110.938 bp on the chip

GDAP1

SOX10

MFN2
HSPB8

RAB7
LMNA

APTX
DHH

NDRG1
GARS

HSPB１

DMN2

YARS

SETX
GAN1

TDP1
KCC3

AAAS

HARS

ANKG

CARS

KARS

CNTN1

TAG1

SARS
SCN8A

It is able to screen 28 genes and 11 candidate genes at once.

MARSGenetic diagnosis system for hereditary neuropathy diagnosis
High throughput and low cost protocol
Multiplex PCR reactionB

Pts DNA sample
no PMP22 duplication
CMT2

B

B
B

B

B
DNase I
digestionB

End-labeled fragments

PCR products
Pooled PCR (Max 548 reactions)

DNA chip for hereditary neuropathy diagnosis

Roche GS Junior
Personal genome sequencer
40million bp/8hours

Microarray analysis
Gene Chip Scanner 3000

Diagnostic system for CMT
Patients suspected of CMT
Clinical symptoms and electrophisiological evaluation
CMT2 excluded
PMP22 FISH or MLPA method

CMT１A/HNPP

CMT2 confirmed（Nerve biopsy if nesessary）
Screening the causative gene
Gene analysis centers in Japan

PMP22 deletion/duplication detected by FISH
One copy of PMP22

HNPP（Hereditary Neuropathy withliability to pressure palsies ）Fiber FISH

Two copies of PMP22

Three copies of PMP22

NormalCMT1A

Diagnostic system for CMT
Patients suspected of CMT
Clinical symptoms and electrophisiological evaluation
CMT2 excluded
PMP22 FISH or MLPA method

CMT１A/HNPP

CMT2 confirmed（Nerve biopsy if nesessary）
Screening the causative gene
Gene analysis centers in Japan

Kagoshima University, Prof. Takashima is organizing
cmtdiag@m3.kufm.kagoshima-u.ac.jp

Autosomal dominant hereditary motor andsensory neuropathy with proximal dominancy(HMSN-P)

Scientific background of this research -1HMSN-P is an autosomal dominant slowly progressive neuromuscular disease that
we first described in patients from Okinawa, a southern archipelago in Japan. The
clinical features of HMSN-P include proximal dominant neurogenic atrophy with
fasciculations, painful muscle cramp, sensory involvement, and areflexia. The serum
level of creatine kinase is elevated and the patients have a higher incidence ofhyperlipidemia and diabetes mellitus. The electrophysiological findings are consistent
with motor and sensory axonal neuropathy. In neuropathology, the number of anterior
horn cells and dorsal root ganglion cells markedly decreased, suggesting that thesensorimotor neuronopathy is the cardinal feature in HMSN-P (Ann Neurol 41: 771,
1997). We have mapped the gene locus to chromosome 3p14.2-3q13. The presenceof a common allele of marker D3S1591 and the geographical specificity of thedisease suggested the presence of linkage disequilibrium and a single founder of thisdisease.

Okinawa

Scientific background of this research -2HMSN-P is a slowly progressive intractable disease and somepatients eventually require a tracheotomy with artificial ventilation,
mimicking the clinical course of familial amyotrophic lateral sclerosis(FALS). It is thus no wonder that preexisting diagnoses in patients with
HMSN-P include FALS, adult-onset spinal muscular atrophy (SMA), or
Charcot-Marie-Tooth disease type 2 (CMT2). When a patient with
HMSN-P is diagnosed, the disease has often been transmitted to thenext generation because HMSN-P is essentially an adult-onset
autosomal dominant disorder. Genetic counseling is, therefore, crucial.
The gene locus of HMSN-P has been mapped to an overlapping
centromeric region on chromosome 3 in two independent linkage
analyses, one from Okinawa family and another family reported in
Shiga prefecture in mainland Honshu, Japan.

Okinawa

Shiga/Kansai

Clinical and pathological features in HMSN-P
1) Adult onset slowly progressive proximal dominant neurogenic atrophy
Mean ages of disease onset are 43.3 y.o. in men and 36.5 y.o. in women.

2) Obvious sensory involvement and areflexia
Areflexia was present in the very early stage of disease in all patients.

3) Painful muscle cramp and fasciculations
4) High incidences of elevated creatine kinase levels, diabetes mellitus
and hyperlipidemia5) Electrophysiological evidence of axonal degeneration in peripheral
nervesNeedle EMG revealed fasciculation and fibrillation potentials andneuromyotonic signs in the early stage of the disease.

6) Markedly decreased anterior horn cells and loss of myelinated fibers in
the posterior funiculus and peripheral nerves
7) Autosomal dominant inheritanceMore than 100 patients with HMSN-P, 8/105 population, are estimated in Okinawa.

More than 100 patients with HMSN-P, 8/105 population,
are estimated in Okinawa by our epidemiological study.
Only 7 of １8 families with HMSN-P are shown in this figure.

?

?
?
?

Transverse section of spinal cord (C8)Anterior horn (Th 8)

Dorsal root ganglion (L5)

Tibial nerve

Biceps brachii muscle

Autoradiogram of alleles of DNA marker D3S1591 in 20 patientswith HMSN-P and 20 unrelated normal controls. Allele 6 waspresent in all 20 patients in contrast to only 6 of 20 controls.

20/20

6/20

Family 1
I

II

1

3

2

4

5

6

7

III

1

3

2

4

IV
D3S3652
D3S3632
D3S1591
D3S1291
A281WA5
D3S1563
D3S3654
D3S1281
D3S3638

151
142
250
184
252
223
160
129
160

151
144
240
188
242
223
158
115
152

159
140
242
188
252
223
160
119
152

153
140
246
186
252
223
160
119
160

159
140
242
188
252
223
160
119
152

153
140
246
186
252
223
160
119
160

151
142
250
184
252
223
160
129
160

153
140
246
186
252
223
160
119
160

159
140
242
188
252
223
160
119
152

151
142
240
188
252
223
158
115
152

159
140
242
188
252
223
160
119
152

155
140
242
186
252
223
160
137
164

151
142
238
188
252
223
160
137
156

151
144
240
188
252
223
158
115
152

159
140
242
188
252
223
160
119
152

153
140
238
188
244
215
162
115
164

159
140
242
188
252
223
160
119
152

151
142
240
188
252
223
158
115
152

HMSN-P gene mapped to 3cM region at 3q13.1
by genetic linkage and linkage disequilibrium analysis*604484
NEUROPATHY, HEREDITARY MOTOR AND SENSORY, OKINAWA TYPE: HMSNO
HEREDITARY MOTOR AND SENSORY NEUROPATHY, PROXIMAL TYPE: HMSNP

0.8
1.3
0.1

D3S3652

Gene Map Locus: 3q13.1

D3S3632

TEXT
Takashima et al. (1997) reported ……………locus almost certainly lies on 3q13.1.
CREATION DATE Victor A. McKusick : 1/31/2000

D3S1591
D3S1291

2.8

HMSNP gene
A281WA5
0.1
D3S1563
D3S3654

0.1
0.1

D3S1281
D3S3638

0.0

cM
Map distance

Chromosome 3

Takashima H, Nakagawa M, et al.
Neuromuscul Disord 9: 368-371, 1999
Nakagawa M, Takashima H, et al.
Ann NY Acad Sci 883: 449-452, 1999

Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy
With proximal dominancy (HMSN-P) and genetic heterogeneity
Maeda K, Kaji R et al. J Hum Genet 2007;52:907–14.

Comparison between Okinawa and Kansai families
Okinawa

KansaiMode of inheritanceAD
Onset age (year)
39.2±9.0
Unable to walk (year)
56.9±6.2
Symptoms
slowly progressive＋
proximal dominant atrophy＋
painful muscle cramp＋
fasciculations＋
areflexia＋
sensory involvement＋
Electrophysiological findings
motor and sensory axonal neuropathy ＋
Loboratory findings
highCKnemia＋
hyperlipidemia, and diabetes mellitus ＋
Pathological findings
loss of myelinated fibers＋
decreased numbers of anterior hornand dorsal ganglion cells＋
Gene locus
3q12-13AD37.5±8.0
＋
＋
＋
＋
＋
＋
＋
＋
＋
＋
＋
3q13.1

Scientific background of this research -3Maeda et al. has recently reported a new case of HMSN-P
in a Brazilian family with Japanese ancestry. It is interesting
to note that Brazil has held huge immigrants from Japan
since 1908, reaching eighteen million at present. In addition,
more than one third of the initial Brazilian immigration camefrom Okinawa islands. The people from Okinawa prefecture
have immigrated to American continents, including Brazil(approximately 130,000), United States (80,000), Peru
(40,000), Argentina (30,000), Bolivia (10,000), Canada(1,500), and Mexico (650), and other countries (7,250). We
can thus assume that HMSN-P is not only limited in Japan,
but might have spread worldwide, especially in the countries
which holds with many Okinawan immigrants.

【Case 1】 A 42-year-old man
He was a second-generation descendent of immigrants of Okinawan origin whose
residence was Brazil. His parents, born in Okinawa, had immigrated to Brazil in 1958.
His father had walking difficulty since 40 years of age, had become bedridden, anddied of respiratory disease at the age of 50. Our patient, born in Brazil, had noticed
weakness of his shoulders at the age of 33. He also experienced difficulty in climbing
stairs. Occasionally, he had painful muscle cramping in his abdominal muscles.
At age 38, he had been diagnosed as having spinal muscular atrophy based onneurogenic changes detected on electromyography and increased level of CK. Smallgrouped atrophy and fiber type grouping were found in biopsied muscle. However,nerve conduction study showed decreased amplitude of SNAP in the median, ulnar,and sural nerves.
Cranial nerves were normal, and the tongue was not atrophic. Weakness was
pronounced in the proximal limbs. His deltoid muscles were atrophic. The MRC scalevalues were 3/3 (right/left) for the deltoid, 4/4 for the biceps and triceps, 5/5 for thewrist extensor and flexor, 4/4 for the iliopsoas, and 5/5 for the hip extensor, quadriceps
femoris, hamstrings, anterior tibial, and gastrocnemius muscles. Fasciculation was
found in the anterior chest muscles. Deep tendon reflexes were decreased. Vibratory
sensations were slightly decreased in the digits of the hands and great toes.
Superficial sensations were normal.

MCV, motor conduction velocity; CMAP, compound muscle action potential; SCV, sensory conduction velocity; SNAP, sensory nerve action potential;

CK, creatine kinase; ND, not done. Abnormal values are expressed in bold letters. Values in parentheses are normal values.

Family tree
He had walking difficulty since 40 years ofage, had become bedridden, and died of
respiratory disease at the age of 50.

ＣＶＤ
②

③

①

Living in Brazil

HMSN-P patients in the world?
It is interesting to note that Brazil has held huge
immigrants from Japan since 1908, reaching eighteen
million at present. In addition, more than one third of theinitial Brazilian immigration came from Okinawa islands.
The people from Okinawa prefecture have immigrated toAmerican continents, including Brazil (approximately
130,000), United States (80,000), Peru (40,000), Argentina(30,000), Bolivia (10,000), Canada (1,500), and Mexico(650), and other countries (7,250). We can thus assume
that HMSN-P is not only limited in Japan, but might havespread worldwide, especially in the countries which holdswith many Okinawan immigrants.

The overseas scientific research for the elucidation of the mechanism of
a novel hereditary motor sensory neuropathy originated in Japana Grant-in-Aid for Scientific Research (B) from JSPS (21406026).
: JSPS KAKENHI (21406026)

Peru

Japan
BrazilPeru
Argentina

It is speculated that there arepatients diagnosed as having“Familial ALS or SMA” in theworld including South andNorth America.

HMSN-P gene mapped to

3p11.2-3q13.1
D3S3652
0.8
1.3
0.1

D3S3632
D3S1591

Kansai type

D3S1291
2.8

MIM*604484

HMSNP gene

Okinawa(Shiga)

A281WA5
0.1

0.1
0.1
0.0

D3S1563

type

D3S3654
D3S1281
D3S3638cM
Map distance
Chromosome 3

Takashima H, Nakagawa M et al. Ann Neurol 41: 771-780, 1997
Takashima H, Nakagawa M, et al. Neuromuscular Disorders 9: 368-371,
1999
Nakagawa M, Takashima H, et al. Ann NY Acad Sci 883: 449-452, 1999
Maeda K, Kaji R, et al.

J Hum Genet 52:907–914, 2007

Whole genome analysis for HMSN-P gene locus using SNP array
Chromosome No.

Lod score

High lod score at centromere region of ch. 3

Several SNPs with LOD>5 are located in 43.8 Mb region at Ch.3.

Construction of BAC clone contig derived from HMSN-P patients
500Kb

0Kb
Cen

3qter

Two Mb candidate region at 3q12-13

BAC clones

Full sequencing using the next generation autosequencer

Collaboration with Dr. Kaname in Ryukyu University

Analysis of HMSN-P gene by the next generation autosequencer

One billion base sequence in 75hrs

Scope of this research
The gene locus has been mapped on the chromosome 3; however,the causative gene has yet to be identified. Genetic analyses of
HMSN-P pedigrees living in Brazil and other countries will definitely
accelerate the gene cloning because entry of other ethnic
chromosomes and genetic crossover are expected in heterogeneous
populations. In addition to the genetic study, molecular biological andpathological studies including oxidative stress in nervous system areimportant to clarify the pathomechanism of HMSN-P using humanmaterials obtained from Japan and other countries.
The purpose of this research is to clarify the global epidemiology,
pathomechanism and therapeutic strategy for HMSN-P incollaboration with south American neurologists and neuropathologists, especially with Prof. Marchiori, Dr. Teresa and Dr.
Angelina Lino in Sao Paulo University.

Tasks of this overseas scientific research are:
• To clarify the epidemiology of HMSN-P in Brazil and othercountries in South America, especially the countries withnumerous immigrants from Okinawa，and compare the clinical,
electrophysiological and neuropathological findings of patientswith HMSN-P in Japan and those in south American countries.
• To conduct seminars to develop the knowledge for HMSN-P insouth American neurologists and neuropathologists.
• To clarify the pathological findings of HMSN-P in Brazil and othercountries.
• To identify the responsible gene for HMSN-P using DNA obtained
from south American and Japanese patients by the next
generation sequencer.
• To develop an animal model for HMSN-P after the gene is
identified, and develop the therapeutic strategy.

Significance and expected results of this research
Our research team has been so far unique in studying this disease. This
research collaboration with Brazilian neurologists will result in expansion ofsignificant information to clarify the molecular and pathological basis of
HMSN-P and eventually to develop a possible therapeutic approach. Because
the disease develops usually in the fourth decade of life, mutant genes have ahigher chance to be transmitted to the next generation. It is urgently needed
to clarify the disease mechanism as early as possible.
The electrophysiological and neuropathological studies have suggested that
HMSN-P is essentially a neuronopathy in which motor and sensory neurons
in anterior horn or dorsal root ganglions, respectively, are induced to cell
death. To clarify the pathomechanism of HMSN-P may contribute to theclarification of other neurological diseases, such as ALS and SMA.
Lastly this unique collaboration study will definitely contribute to thecentennial partnership between Japanese and Brazilian neurologists.

Different subtypes of FALS and their genetic determinantsArchives Italiennes de Biologie, 149: 65-82, 2011.

Are the clinico-pathologic features of HMSN-P rather
similar to those of MND with sensory neuropathy?
Journal of Neurology, Neurosurgery & Psychiatry (in press)
Brainstem and spinal cord motor neuron involvement with optineurin
inclusions in proximal-dominant hereditary motor and sensory
neuropathy .
Fujita K1, Sobue G, Kaji R1 et al.
1Department of Clinical Neuroscience,
The University of Tokushima Graduate School
Commentary to the paper M. Nakagawa (in preparation)
A new classification of proximal-dominant hereditary motor and sensory neuropathy (HMSN-P) as familial
motor neuron disease with sensory neuronopathy.

(B, C) The hypoglossal nucleus shows mild
neuron loss (B) compared to the control(C).
(D) Severe myelin pallor of the posterior
and lateral columns and atrophy of theanterior horn of the cervical cord.
(E) Severe neuronal loss, atrophy of theremaining neurons (arrows), and gliosis in
the anterior horn of the cervical cord. (F)Neuronal loss and gliosis of Clarke’s
nucleus of the thoracic cord.
(G) Mild neuronal loss of Betz cell (arrowahead) and cluster of macrophages (arrow)in the precentral gyrus.
(H) Severe neurogenic atrophy of iliopsoas
muscles against a background of fatty
tissue.
(I) Both large and small myelinated fibers
are markedly decreased without onion-bulb
formation in the sural nerve.
(J) Ubiquitin-positive inclusions of motor
neurons in the facial nucleus.
(K) OPTN-positive inclusion of motor
neurons in the hypoglossal nucleus..
(L-N) Double-immunofluorescence staining for ubiquitin (L, red) and OPTN (M, green) in residual neurons in theabducens nucleus shows that ubiquitin inclusions are largely co-localized with OPTN inclusions (N)Is HMSN-P FALS or Nuerpathy?
A number of issues remain to be elucidated in HMSN-P, andamong others, the questions include: How is the motor pathology
related to the sensory counterpart ? What is the causative gene forthe disease? How are large HMSN-P families in Okinawa andKansai related? The global epidemiology, pathomechanism andtherapeutic strategy for HMSN-P remained so far. Because thedisease develops usually in the fourth decade of life, mutant genes
have a higher chance to be transmitted to the next generation,
underscoring the urgency of seeking the pathomechanism.
The quest for the search of the exact pathomechanism of HMSNP may contribute to the clarification of other neurological diseases,
such as FALS and SMA.

Collaborators
Dr. Kensuke Shiga.
Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of
Medicine, Kyoto, Japan
Prof. Ryuji Kaji.
Department of Neurology and Neuroscience, Tokushima University Graduate School of Medicine,
Tokushima, Japan
Prof. Shuji Izumo
Division of Molecular Pathology, Center for Chronic Viral Diseases, Graduate School of Medical and
Dental Sciences, Kagoshima University, Kagoshima, Japan,
Asst. Prof. Hiroshi Takashima.
Department of Neurology, Graduate School of Medical and Dental Sciences, Kagoshima University,
Kagoshima, Japan,
Dr. Kengo Maeda.
Division of Neurology, National Shiga Hospital, Shiga, Japan
Prof. Paulo Euripedes Marchiori
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil..
Dr. Maria Teresa Alves Hirata
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil..