Lower Motor and Primary Sensory Neuron

Diseases With Peroneal Muscular Atrophy

I.

Neurologic, Genetic, and Electrophysiologic Findings

in Hereditary Polyneuropathies

Peter James

Dyck, MD, and Edward H. Lambert, MD, Rochester, Minn

THIS

report gives the neurologic, genetic, those affecting anterior horn and dorsal root
electrophysiologic findings of a prospec- ganglion cell neurons (Part II), this rigid
study of kinships with different heredi- separation is not always possible because of
tary neurologic disorders having symmetric insufficient information and because both
neurogenic weakness and atrophy as an ear- may be affected. In diseases causing death
ly- and often major manifestation. The study of anterior horn and dorsal root ganglion
was undertaken to obtain more reliable incells, there will be alteration in structure
formation about the natural history of these and in function in the peripheral nerve. In
disorders, to test the usefulness of electro addition, disease of the neuron may be ex
physiologic studies in distinguishing affected pressed distally in the peripheral nerve
from nonaffected persons, to compare the re- ("dying back"). Furthermore, in severe dis
sults of nerve biopsies from representative ease of peripheral nerves, retrograde changes
affected persons with these disorders, and to and even death may occur in anterior horn
develop a more meaningful classification. In and dorsal root ganglion cells.
this, the first of two articles on the subject,
Historical Review
the results of neurologic, genetic, and electrophysiologic studies of 67 persons with hyCharcot-Marie-Tooth Syndrome.Clini
pertrophic neuropathy of the Charcot-Marie\x=req-\
Tooth type, five persons with hypertrophic cal Features.Prior to Charcot and Marie's1
neuropathy of the Dejerine-Sottas type, and and Tooth's2 papers in 1886, patients with
150 unaffected relatives are given. We also peroneal muscular atrophy had been de
wished to determine whether these syn- scribed by Virchow,3 Eulenburg,4 Friedreich/'
dromes were phenotypic variations of one and others,68 as recorded by Schultze.9 The
or several diseases or were separate enreport by Eichhorst8 in 1873, in particular,
tities on the basis of natural history, inherit- should be mentioned because he described
ance, cerebrospinal fluid (CSF) findings, affected persons in six generations.
electrophysiologic studies, and histology of
In 1886, Charcot and Marie1 described a
nerves.
specific form of progressive muscular atro
Chronic progressive symmetric peroneal phy, often familial, that started in the feet
muscular atrophy may result from disease of and
legs and later involved the hands. They
anterior horn cells, of peripheral nerves, or
stated that the illness often afflicted several
of muscle. We will discuss only the neuro
siblings and sometimes the ancestors also
logic disorders with neurogenic peroneal (suggesting dominant inheritance). Fascicumuscular atrophy (not the distal myopathie
lations and the reaction of degeneration was
diseases). Although we have divided the dis found in
atrophie muscles. Vasomotor ab
orders into those affecting the peripheral
normalities
occurred in affected extremities.
nerves predominantly (Part I) and into
Sensation was often intact although some
Submitted for publication Sept 28, 1967; accepted times affected. They thought that the basis
Jan 8, 1968.
for the disorder was either a myelopathy or
From the Mayo Clinic and Mayo Foundation:
Section of Neurology (Dr. Dyck) and Physiology a neuropathy, and they favored the former.
(Dr. Lambert).
Tooth's2 thesis, at Cambridge University,
Reprint requests to Mayo Clinic, 200 First St SW,
on the peroneal type of progressive muscuRochester, Minn 55901 (Dr. Dyck).
and
tive

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lar atrophy was also published in 1886.

Tooth concluded that the disease affected
peripheral nerves. There seems little doubt
that the disorders described by Eichhorst,8
Charcot and Marie,1 and Tooth2 were alike.
Sensory signs in association with peroneal
muscular atrophy were stressed by Hoff
mann10 in 1893 and by England and Den
ny-Brown11 in 1952. Lidge and Chandler12
suggested that the disease is self-limiting.
Bell13 reviewed the cases in the literature
and concluded that the disease could be in
herited as a dominant, recessive, or sexlinked trait and that some cases were spo
radic.
Pathologic Features.There are few recent
pathologic studies of Charcot-Marie-Tooth
disease. Pathologic alterations noted351415
include decreased numbers of anterior horn
cells, decreased numbers of myelinated fibers
in peripheral nerve, increased endoneurium,
and some posterior column degeneration.
More recently, on the basis of muscle biop
sies, Haase and Shy16 found myopathie
changes "suggesting primary disease of mus
cle" in ten of 17 cases of Charcot-MarieTooth disease. That the pathologic fea

they considered as indicative

primary disease of muscle can result from
chronic denervation is suggested by a recent
study by Drachman and associates17 in
which similar changes were found. In pa
tients with dominantly inherited Charcottures which

of

Marie-Tooth disease with low conduction

nerves, biopsy studies of the
greater auricular and sural nerves by Dyck
and co-workers1821 have clearly shown path
ologic alterations in peripheral nerve. The
transverse fascicular area (a good index of
the size of a nerve trunk) was abnormally
large, numbers of myelinated nerve fibers
per nerve and per unit area of transverse
section were decreased, and the largest
myelinated fibers were smaller than normal.
Under the electron microscope, small "on
ion-bulb formations" were seen. Segmental
demyelinization and remyelinization has
been demonstrated2122 in this disorder, and
considerable variation in the degree of on
ion-bulb formation from one affected person
to the next has been found.
Since the description by Dejerine and
Sottas2324 of hypertrophie interstitial neuri
tis, kinships have been described2539 which

velocity of

had clinical features of the cases of Eichhorst,8 Charcot and Marie,1 and Tooth2
but which, on the basis of clinical enlarge
ment or onion-bulb formations of nerves,
were placed in the category of Dejerine and
Sottas' hypertrophie interstitial neuritis.
These kinships differed from those of the sib
lings whose parents were unaffected (prob
ably recessive inheritance) as described by
Dejerine and Sottas23 in their first report, in
that they had a dominant inheritance, a
lesser neurologic impairment, and a more fa
vorable prognosis. Recently, it also has been
shown that the onion-bulb formation is not
the hallmark of a single variety of neuropa
thy.2040 The presence of onion-bulb forma
tions in nerves in both the dominantly and
the recessively inherited disorder therefore
does not mean that they are the same disor

der.

Electrophysiologic Features.Lambert41
drew attention to the low conduction veloci
ties of peripheral nerves in chronic familial
neuropathies. Similar observations were re
ported by Gilliatt and Thomas42 and oth
ers.4345 Dyck and co-workers46 did a pro
spective clinical and conduction-velocity
study on 103 persons of a kinship with dom
inantly inherited Charcot-Marie-Tooth dis
ease. They were divided into three groups:
(1) those with definite signs, (2) those with
equivocal signs, and (3) those without signs
of the disease. In all of those for whom a
definite clinical diagnosis could be made,
conduction velocities were low in all nerves
tested. In two persons, low conduction veloc
ity was the only evidence of involvement. In
five of 14 persons in the equivocal group,
low conduction velocities allowed a definite
diagnosis to be made. A similar study was
done by Amick and Lemmi47 on 28 persons
of a 62-member kinship. They also found
low conduction velocities in the group with
"well-developed signs." One of the persons
in the mild category had normal conduction
velocity values. However, on later examina
tion of this person by Amick, (written com
munication from L. Amick, June 27, 1966)
no definite evidence of the disease was
found.
Myrianthopoulos and associates48 did
neurologic examinations and conduction ve
locity measurements on persons from three
kinships with peroneal muscular atrophy.

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subsequently appearing in the upper extrem

ities, fasciculation, decreased reactivity of
muscles to electric stimulation, areflexia,
marked sensory loss in all four extremities,
tients with Charcot-Marie-Tooth disease. In incoordination of the arms, Romberg sign,
these two kinships the conduction velocities miosis, and nystagmus. Prior to her death at
were normal or only slightly low, and the
age 45 years, Fanny Roy was unable to
authors concluded that the disorder was pri walk.
The father of these two siblings died of
marily in the spinal cord. In kinship E,
Kinships J and D, although showing domi
inheritance, had other neurologic fea
tures, such as corticospinal tract signs,
which we think distinguish them from pa
nant

conduction velocities were low in affected

persons, and in these the disorder was pri
marily in peripheral nerve.

Roussy-Lvy Syndrome.The syndrome

described by Roussy and Levy49 resembled

that of Charcot and Marie in the following
features: (1) familial nature, (2) clubfoot,
(3) weakness and minimal atrophy of the
distal extremity muscles, (4) decreased ex
citability of muscles to galvanic and faradic
stimulation, and (5) some distal sensory
loss. Their cases differed from those of
Charcot and Marie and Tooth because there
was a static tremor of the hands. Roussy
and Levy stressed the absence of character
istic cerebellar signs, speech disturbance,
Babinski sign, and nystagmus. Recently,
Yudell and associates50 described a kinship
similar to the kinships of Roussy and Levy.
The patients with the fully developed syn
drome might be said to have CharcotMarie-Tooth disease with a superimposed
tremor. Genetic review of the kinship did
not bear out the hypothesis that the
full-blown syndrome might be a combina
tion of two nonlinked dominant genes, one
for Charcot-Marie-Tooth disease and the
other for tremor. A striking feature was the
low conduction velocity of peripheral nerves
in all affected persons, with or without trem
or. Because only the older persons had the
complete syndrome and only the affected
younger persons who were direct descend
ants of these had peroneal muscular atrophy
without tremor, it seemed reasonable to as
sume that the tremor would eventually de

velop in younger persons.

Dejerine-Sottas Syndrome.In 1893 De
jerine and Sottas23 described two siblings
with a neurologic disorder, beginning in in
fancy in the case of Fanny Roy and at age
14 years in the case of Henri Roy. The
syndrome included clubfoot, kyphoscoliosis,
weakness and atrophy (most severe distally) beginning in the lower extremities and

tuberculosis at age 45 years and was said to

be free of neurologic disease. The mother
was examined at age 61 years and no abnor
mality was found. Two living siblings of the
patients also had no neurologic abnormality.
Five siblings had died during infancy or
childhood. A child of Fanny Roy was also
examined and was without abnormality. On
the basis of this information, recessive inher
itance or dominant inheritance with poor ex
pressivity in one of the parents might be
inferred.
Portmortem examination of Fanny Roy
revealed the following changes in peripheral
nerves: nerve trunks were increased in size,
the myelin sheath was unusually thin or
totally absent (leaving a denuded axis cylin
der) and a hypertrophie mterstitium of con
nective tissue with fusiform cells surrounded
nerve fibers. It was concluded that the lesion
was exclusively interstitial. These peripheral
,

changes were most severe distally;

however, similar changes were also observed
in the dorsal root and its ganglion. Posterior
column degeneration also occurred.
nerve

For substantial accounts of the clinical and

pathologic features of hypertrophie neu
ropathy, the reports of others should be
read.365051 In these reports, the criterion for
the diagnosis of hypertrophie neuropathy
was the finding of nerve enlargement on
neurologic or postmortem examination or
the presence of onion-bulb formations in his
tologie sections. In the published reports of
cases with hypertrophie neuropathy there is
a considerable diversity in the inheritance,
clinical syndrome, prognosis, and CSF data.
One group of reports24"385253 concerned
dominantly inherited cases with hypertroph
ie neuropathy. In these the clinical syn
drome was similar to that described by
Eichhorst, by Charcot and Marie, and by
Tooth, but the original descriptions of this
syndrome did not list hypertrophie nerves as
a feature. It seems reasonable to believe that

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mild nerve enlargement may have been over

looked by these early authors, notwith
standing Dejerine's statement55 that Marie
had not found nerve enlargement in his
cases.

A second group of

reports525657 described
sporadic or recessively inherited hypertrophic neuropathy in which the clinical fea
tures were similar to those described by De
jerine and Sottas.23 The disorder began in
infancy or early life, was progressive, was a
severe mixed polyneuropathy, and was asso
ciated with an increased CSF protein con

(3,7,11,15-tetramethylhexadecanoic
urine, serum, liver, kidney, skeletal
muscle, and adipose tissue.8" !'2 In a similar
patient, Kolodny and co-workers93 did not
find phytanic acid in urine, serum, liver, or
ic acid
acid) in

cornea.

tent.
A third group of

reports285869 described a
sporadic hypertrophie neuropathy of adult

life which is sometimes called the RoussyCornil type. The disorder usually began aft
er the second decade, was usually progres
sive, and was associated with an increased
CSF protein content.
A fourth group of reports3470"78 was on re
lapsing cases of hypertrophie neuropathy.
The onset was not related to age. The CSF
protein content frequently was high. The
disorder may begin with peroneal muscular
weakness and atrophy and so must be con
sidered with the peroneal muscular atro

phies.
Hypertrophie neuropathy has also been
reported by Stewart79 in acromegaly and by

Thomas and Lascelles80 in diabetes mellitus.

The case of hypertrophie neuritis described
by De Bruyn and Stern81 may have been
unrecognized familial amyloid neuropathy
because deposits of amorphous material
were found in peripheral nerve and because
the clinical course and inheritance had the
features of primary amyloidosis.

Methods of Study
Five years ago, a prospective study was
to delineate the hereditary neurologic
disorders in which symmetric neurogenic
peroneal muscular atrophy was present. The
initial patient, the proband, was referred to
the authors by other neurologic and medical
consultants in our institution. The patients
were studied by means of neurologic exami
nation, genetic history, nerve conduction ve
locity measurements, and, in representative
cases, by nerve biopsy and CSF examina
tion. In addition, all relatives accompanying
these patients were examined, including
similar conduction velocity determinations.
Field trips were made to examine kinships,
and relatives were subsequently seen at the
Mayo Clinic. Biopsy specimens of greater
auricular and sural nerves were obtained in
representative cases and studied by quanti
tative histologie methods and by light, phasecontrast, and electron microscopy.1821
Conduction velocity of motor fibers (A<*)
of the ulnar, median, and peroneal nerves
was measured on affected and unaffected
persons from the kinships by methods pre
viously described.46 Conduction velocities
greater than 47, 45, and 40 meter/sec for the
ulnar, median, and peroneal nerves (be
tween elbow and wrist or knee and ankle),
respectively, were considered normal. Con
duction in large afferent fibers of digital
nerves was often studied. The nerve action
potential was recorded, with electrodes over
lying the median and ulnar nerves at the
wrist, after stimulation of the digital nerves
at the base of the index and fifth fingers, re
spectively.94 Sural nerve conduction veloci
ties were determined in vivo in some of the
patients. The compound action potential of
excised sural nerves was recorded as pre

begun

Refsum's Syndrome.Refsum82 described

syndrome strikingly similar to that of De
jerine and Sottas; he called it "heredopathia
atctica polyneuritiformis."83 This also is a
recessive disorder, begins in childhood or
puberty, has a grave prognosis, and is often
associated with increased CSF protein con
tent. Cammermeyer84 found hypertrophie
neuropathy associated with it. Additional
features are retinitis pigmentosa, ichthyosis,
and electrocardiographic and bony changes. viously reported.10
Additional cases of the Refsum type have
During the study it became evident that
been described by others.84"87 Klenk and the affected persons within a kinship had
Kahlke89 found an inborn error of lipid similar disorders. Different syndromes were
metabolism, with large amounts of phytan- not present within a single kinship although
a

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variations in time of onset and

of
severity
signs. The entire kinship could
be
placed into one category.
always
On the basis of inheritance, course, neuro
logic signs, CSF protein level, electrophysi
ologic tests, and histologie appearance of
nerve on biopsy, a separation of cases into
distinct syndromes was apparent.
there

were

Fig 1.Moderate pes cavus in an 18-year-old boy

(case III. 12, kinship 9) with dominantly inherited
hypertrophie neuropathy of the Charcot-Marie-Tooth
type with low conduction velocities of peripheral nerves.

Hypertrophie Neuropathy of
Charcot-Marie-Tooth Type
(Dominant Inheritance)
In this category we include kinships such
as those described by Charcot and Marie, by
Tooth, and by Roussy and Levy. The Roussy-Lvy syndrome is included in this cate

gory because the inheritance, slow course,

distribution of neurologic signs, electrophys
iologic characteristics, and histologie abnor
mality of nerves are the same as those in
Charcot-Marie-Tooth disease. Although pa
tients with the Roussy-Lvy syndrome may
have static tremor of the hands in addition
to peroneal muscular atrophy, only a few
with more advanced disease have exhibited
static tremor in some kinships. Consequent
ly, this one inconstant feature did not merit
a

separate diagnostic category.

Two hundred four persons from 21 kin

ships were evaluated; 38 male and 29 female
patients had this disorder. Two large kin
ships previously reported4650 have been in

cluded.
Clinical Features.The earliest evidence

of the disorder was usually a foot deformity

(Fig 1 and 2). Parents, anticipating the dis
ease in their children, were sometimes able
to recognize this during the first few years
of life. Many patients said they always had
high arches and curled-up toes (hammer
toes). Many with these deformities com
plained of frequent corns and calluses, and
many said that they had been unable to find
properly fitting shoes. Some affected pa
tients, however, had normal arches or even
flat feet (Fig 3). The incidence of pes cavus
noted on examination in the affected group
increased with age as shown in Table 1. As
previously reported,4" a few persons had high
arches but no neurologic or electrophysi
ologic evidence of a neurogenic disorder.
Only two of 67 affected persons gave a his
tory of an ulcer of the foot. A few affected
children in the latter part of the first decade

Fig 2.Muscle atrophy In identical twins (cases IV.

20 and 21, kinship 1) with dominantly inherited hypertrophic neuropathy of the Charcot-Marie-Tooth type
with low conduction velocities of peripheral nerves.
Note grooves between metatarsal bones resulting from
muscle atrophy and mild pes cavus. Although these
boys were unable to walk on their heels because of
weakness of the dorsiflexors of the ankles, the degree
of atrophy was not striking.
Fig 3.Left, Legs and feet of 17-year-old boy (case
III. 2, kinship 5-10) without pes cavus but with other
clinical features of hypertrophie neuropathy of the
Charcot-Marie-Tooth type with low conduction velocities
of peripheral nerves. Right, The 45-year-old mother
(case II. 3, kinship 5-10) also had flat feet. Her neuro
logic examination gave normal results but conduction
velocities of all peripheral nerves tested were unequivo
cally low.

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Table

1.Hypertrophie Neuropathy

of the Charcot-Marie-Tooth

Muscle weakness

Decade

No.
Affected
Persons

2 &3
4 & later

27
31

Pes
Cavus

(%)

Type

Tendon reflexes

Peroneal Gastrocnemius Intrinsic

Ankle

Knee

Arm

Soleus(%)

(%)

(%)

(%)

(%)

Hand(%)

22

11

22

11

67
58

59

15
26

12

~78

59

28

81

48

52
47

Enlarged

Nerves (%)
11
41
16

ity of gait or of running. This usually devel

oped during the latter part of the first dec
ade or during the second decade. It was
described as awkwardness, clumsiness, "the
family walk," or frequent tripping. Charac
teristically, the knees were raised higher
than normal (compensation for the drop
foot) and in this position the feet would as
sume a marked pes equinovarus deformity.
As the foot was brought down, it would slap

the floor. Persons with marked weakness of

the plantar flexors of the ankles, in addition
to weakness of the dorsiflexors, encountered
difficulty in standing still. Some found they
could fix their ankles by standing with the
knees bent. Others shifted their feet continu
ously to maintain balance.
Difficulty in digital manipulations, such
as picking up small objects, buttoning, or
sewing, was reported more often by the old
er affected persons.
There was a striking absence of discom
fort. Some patients described an aching,
particularly of the leg muscles, after exces
sive activity. Several women complained
that their legs ached while they were inac
tive, but this was promptly relieved by ac
tivity (similar to the restless leg syndrome).
Not infrequently, patients reported pain
from corns or calluses. Others had pain in
the region of the arch of the foot after much
walking. None reported burning, prickling,
or lancinating pains. Some used words such
as "numbness" when they meant weakness.
Coldness of the feet was a rather common

complaint.
Fig 4.Enlarged
(arrow) in
18-year-old boy (case III. 12, kinship 9) with domi
nantly inherited hypertrophie neuropathy of the CharcotMarie-Tooth type with low conduction velocities of
greater auricular

peripheral

nerve

nerves.

begun walking on the ball of the foot.

Surgical procedures for lengthening the
Achilles tendon had been performed.
Another early symptom was an abnormalhad

None of the patients had ichthyosis, retin

itis pigmentosa, miosis, nystagmus, or cere

bellar ataxia.
Muscle weakness could first be detected in
the peroneal muscles. Weakness of the small
foot muscles may have developed even ear
lier, but tests of strength in these muscles
are not reliable. Weakness of ankle dorsi
flexors was manifested by the patient's in-

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Table 2.Conduction Velocity of Motor Fibers of Peripheral Nerves and Amplitude and
Distal Latency of Muscle Action Potential Evoked by Maximal Stimulus to the Nerve
Persons

velocity
(meters/sec)

Conduction
Mean

Age
(yr)

Type

Ulnar

Hypertrophie neuropathy
Affectedf
Unaffectedf
Affected
Unaffected}

Median Peroneal

Ulnar

of the Charcot-Marie-Tooth

Median Peroneal

latency (msec)

Ulnar

Median Peroneal

type (dominant inheritance)

64

33.8

23.5

24.0

20.3

4.8

4.5

2.3

7.1

9.2

12.1

118

27.1

61.6

56.6

50.4

9.9

9.1

5.1

2.6

3.2

4.4

3.0

22.6

22.7

26.3

3.8

3.5

1.9

6.7

7.9

7.9

2.4

55.1

47.4

51.5

7.5

7.4

3.4

1.8

2.3

3.1

15

Hypertrophie neuropathy of the Charcot-Marie-Tooth type (sporadic,

expressivity, or recessive inheritance)
Affectedf
Unaffectedf

Distal

Amplitude* (mv)

dominant inheritance with poor

10

14.1

25.5

25.9

25.4

3.6

4.8

1.2

5.3

7.7

11.3

26

31.5

59.7

57.5

50.2

10.9

9.8

5.1

2.4

3.1

4.2

*Amplitude of maximal muscle action potential. Ulnar nerve, hypothenar muscles, median nerve, thenar muscles,
and peroneal nerve, extensor digitorum brevis muscle. The mean distance between stimulating cathode and record
ing electrode on the belly of the muscle in adults was 6.5, 6.5, and 8.5 cm, respectively, for the ulnar, median,
and peroneal nerves.
tPersons 5 years old and older.
Persons less than 5 years old.

QOg

d%_
I

BO

^QQ^CiiQ

JQnluloQluSoOouu
Male.normal

conduction

conduction

C.M.T. disease diagnosed from

velocity

Female, low conduction velocity

0 Neurologic examination negative but no

O
velocity measurements
^Propositus
_

neurological

examination only
Not available for s^ no evidence of CMT diseose
Not available for study, probably had CMT. disease

Fig 5.Kinship 1. Dominantly inherited peroneal muscular atrophy with low conduction velocity
peripheral nerves, previously described. Males are identified by a square and females by a circle
(From Dyck, P.J. et al45)

cf

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were diminished more frequently than were

other modalities. No sensory loss was noted
in the nine patients in the first decade

to walk on his heels. Other distal

muscles of legs and arms were affected subse
quently (Table 1). Muscle atrophy of slight
degree was seen in many patientsfor ex
ample, in the intrinsic foot muscles of iden
tical twins (Fig 2). "Stork legs," with vir
tual absence of all muscles below the knee,
was not found in this group. Fasciculations
of weak muscles were seen infrequently.
During the course of the disease, tendon
reflexes became diminished in the following

ability

(Table 1).

Enlargement and increased firmness of

peripheral nerves (Fig 4) was observed clin

17 of 67 affected persons.
Genetic Features.The disorders of the
21 kinships of this group were dominantly
inherited (Fig 5). A direct line of inherit
ance from one generation to the next was
demonstrated by personal examination of
affected persons in more than one genera
tion in nine of these kinships and from in
formation supplied by the propositus, his
family, or medical records in the 12 other

ically in

Achilles, quadriceps, and upper

extremity (Table 1). Hyperreflexia and the
Babinski sign were not seen.
Sensory impairment was later in onset
and less severe than the motor impairment.
The feet, especially the toes, were the first
sequence:

kinships.

considerable variation in ex
of the 67 persons had no
Three
pressivity.
neurologic signs but had the characteris
tic low conduction velocity of peripheral

sites at which sensory loss could be demon

strated; sensory loss was then noted in the
fingers and hands. Vibration sense, twopoint discrimination, and joint-position sense

There

was

Fig 6.Conduction velocity of motor fibers of ulnar nerve of unaffected (solid symbols) and affected
(open symbols) persons from kinships with dominantly inherited peroneal muscular atrophy with low
conduction velocities of peripheral nerves. The line represents low limit of normal.

70

60

>

,\*y,

50

40

..-....

"jL-t._

r*

rX
-

30
O

20

OD

itffe
<t

Unaffected, male

So

10

Affected,female

^Without clinical

stigmata

10

20

30

40

50

60

70

Age .years

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80

nerves.

Two of these

were

less than 5 years

old, and subsequent reexamination of one

demonstrated the signs of this syndrome.
The third (case II. 3, kinship 5-10), a 45year-old woman, was carefully examined on
several occasions and no neurologic signs

found. Conduction velocities of motor

fibers (A) of her left ulnar, median, and
peroneal nerves were 33, 35, and 34 me
were

ter/secall unequivocally low. Her 17-

son had definite symptomatic dis

and
conduction velocities for his left
ease,
ulnar, median, and peroneal nerves were 12,
14, and 6 meter/sec. This variation of ex
pressivity may explain some of the reports
in the literature of apparently sex-linked in
heritance in Charcot-Marie-Tooth disease.13
The penetrance of this gene was calculated
for completely and incompletely studied
offspring groups. In a group in which entire
families were studied by neurologic exami
nation and conduction velocity determi
nations, the percentage of affected chil
dren from affected parents was determined.
Twenty-two (42%) of 53 such children had
evidence of the disorder (83% penetrance).
In another group in which sibships were
only partially examined, 47 (37%) of 128
children had evidence of the disorder (73%

year-old

penetrance).

Conduction Velocity Studies.Low con

duction velocities of peripheral nerves were
a hallmark of this disorder. The conduction
velocities of the ulnar, median, and peroneal
nerves of the affected persons were, on the
average, less than one-half the values in un
affected persons (Table 2). The mean am
plitude of the muscle action potential was
also decreased by more than half. The distal
latencies were almost three times greater.
No affected persons had a normal conduc
tion velocity (Fig 6). In one clinically nor
mal child the first conduction velocity in the
ulnar nerve (at age IV2 years) was just be
low normal, but the distal latency was great
ly prolonged; subsequently, clinical signs
were evident at age 1/^ years when conduc
tion velocities were 32, 34, and 37 meter/sec
for the ulnar, median, and peroneal nerves
(well below normal values for that age).
Sensory nerves were also affected. A digit
al nerve action potential usually could not
be detected by procedures which are uni
formly successful in normal persons. If an

action potential was detected, it had a low

amplitude and a long latency. Study of the
compound action potential of the sural

in vitro10 has demonstrated low con

duction velocity and decreased amplitude of
the action potential of alpha and delta fibers
without comparable changes in the action
potential of C fibers.
Cerebrospinal Fluid.CSF was examined
in three affected persons of this group. The
protein levels were 16, 35, and 37 mg/100 cc
by the sulfosalicylic acid method. Electro
phoretic patterns of the proteins were nor
mal in these cases.
Nerve Biopsy Studies.The results of
nerve biopsy have been outlined in several
other communications.1822 The transverse
fascicular area of nerves was abnormally
large. The number of myelinated nerve fi
bers per unit of transverse fascicular area
and per nerve was decreased. The mean di
ameter of myelinated fibers was less than
normal. On light and phase-contrast micros
copy, distinct, large, onion-bulb formations
were seen in transverse sections of some
nerves. In other nerves these were not ap
parent under the light microscope, but they
were seen under the electron microscope. In
teased-fiber preparations, only occasional internodes of myelinated fibers had juxtanodal or complete demyelinization. There was
a great variation of lengths and diameters of
internodes of myelinated fibers, a character
istic of disorders with segmental demyelini
zation and remyelinization. In addition, a
few fibers were in various stages of wallerian
nerve

degeneration.
Hypertrophie Neuropathy of
Charcot-Marie-Tooth Type
Sporadic, Dominant Inheritance With

Poor Expressivity or Recessive Inheritance.

In eight patients there was no history of a
similar disorder in the kinship. Twenty-three
unaffected close relatives of seven of these

examined. Except for one case, both

parents of each propositus were studied. The
were

other normal relatives were siblings and

grandparents. In addition, two affected sib
lings have been included in this group; no
clinical or conduction velocity abnormality
was found in two other siblings or in either

parent.

Clinical Features.The findings in af-

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fected persons were similar to those in the

first group except that all affected persons
were symptomatic and had been brought to
the Mayo Clinic because of the disorder. All
except one of the affected persons were
young. In every case the chief complaint
was an abnormal gait recognized by parents
as clumsiness, inability to run as fast as oth
er siblings, a tendency to trip or stumble, or
awkwardness. Two children began to walk
on the ball of the foot at about 2 years of
age. The development of the disorder and
the neurologic signs were similar to those of
the first group and will not be listed in de
tail.

Conduction Velocity Studies.The

con

velocity of the motor nerves and the

amplitude of the evoked muscle action
potentials in the affected group were less
duction

than one half the normal values in the unaf

fected group (Table 2). In the two affected
persons tested, no nerve action potential
was detected over the median nerve after
stimulation of afferent fibers in the fingers.
In each of 16 unaffected persons tested, a re
sponse was obtained (mean time from stim
ulus to peak of the action potential was 2.9
msec, range 2.2 to 3.9 msec).
Cerebrospinal Fluid.CSF was normal in
two affected persons.

Hypertrophie Neuropathy

of

Dejerine-Sottas Type

Sporadic or Recessive Inheritance.In

this category we include kinships such as
those originally described by Dejerine and
Sottas.23
Five affected and 13 unaffected close rela
tives from four kinships were evaluated.
Four of the five affected persons were
brought to the Mayo Clinic because of
symptoms of a severe sensory motor polyneuropathy present since birth. An asympto
matic sibling of one of these four was found
by examination to have a mild form of the
same disorder. None of the parents had evi
dence of a peripheral neuropathy in the neu
rologic examination or in conduction veloc
ity studies.

The clinical syndromes were alike in the

four probands. Motor development was ab
normal. Walking occurred at 15, 33, 36, and
48 months. None of the probands was ever
able to run. In retrospect, they could identi-

fy an age at which they had walked best8,

8, 12, and 15 years of age. Even at their
best, they experienced great difficulty in
walking short distances. One, a 43-year-old
woman, has been in

wheelchair since age

19-year-old girl, al
though able to take an occasional step,
needs to use a wheelchair to get about. The
other two, ages 11 and 12 years, do not use
a wheelchair but have a severe disturbance
of gait.
On the basis of the four persons with the
well-developed syndrome, the neurologic
disorder is best characterized as a severe
mixed polyneuropathy. None had miosis or
nystagmus. The 43-year-old woman had
shuddering eye movements and sensorineural hearing loss. Enlargement, increased
firmness, and insensitivity of greater auricu
lar, cervical, ulnar, median, and peroneal
nerves was seen in all cases. Weakness and
atrophy were greater in the distal muscles,
especially of the lower limbs, but were pres
ent also in proximal muscles of the limbs.
All were areflexic. Sensory loss was most
marked distally in the limbs in all four pa
tients. All modalities of sensation were af
fected, but light touch, joint movement, and
vibration perception were most abnormal.
Locomotor ataxia was apparent in both up
per and lower extremities. All patients ex
hibited some mild truncal instability on sit
ting. Some had choreiform-like movements
of the fingers of the outstretched hands. The
mildly affected 12-year-old brother of one of
the four probands (case III. 17, kinship 9-16)
was asymptomatic but had enlargement of
peripheral nerves and diminished tendon re
flexes in the lower extremities without weak
ness or sensory loss.
All five affected persons had increased
CSF protein content (76, 96, 126, 129, and
180 mg/100 cc). The boy with the incom
pletely developed syndrome had the lowest
value.
All five had low conduction velocities of
all nerves tested. Three of the five had ex
tremely low conduction velocities (in the ul
nar nerves, 3, 4 and 5 meter/sec). In the two
others the values were 22 and 42 meter/sec,
within the range of values seen in cases of
the Charcot-Marie-Tooth type of neuropa
thy. The highest value was obtained in the

31 years;

another,

asymptomatic sibling.

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Sural nerve biopsies were performed on

the four persons with the well-developed
syndrome. The findings of these studies
have been reported previously.18202295 En
largement of the nerve was noted at the
time of biopsy in all four cases. In one case,
in which the entire nerve trunk was re
moved for a short distance, the transverse
fascicular area was approximately three
times that of healthy nerves. In every case
there was a decrease in the number of mye
linated nerve fibers per unit of transverse
fascicular area. Largest myelinated fibers
had a much smaller diameter than seen in

healthy nerves. Segmental demyelinization

frequently seen in teased fibers and in
longitudinal sections examined under phasecontrast and electron microscopes. In the
was

studied under the electron microscope,

myelin sheaths were abnormally thin and
distinctly different from those of nerves in
the Charcot-Marie-Tooth type of neuropa

nerves

thy.

Report of Cases
Case III. 18, kinship 9-16.This 11-year-old
boy, with the diagnosis of hypertrophie neurop
athy of Dejerine and Stottas, was referred to
the Mayo Clinic for these studies by Dr. Garth
G. Myers, neurologist, of Salt Lake City, Utah.
(The quantitative histologie and teased-fiber
measurements on a biopsy specimen of sural
nerve from this patient are reported else
where.22) His place in the kinship (Fig 7) is
indicated by an arrow. His brother, although
asymptomatic, was found to have a similar dis
order. A younger brother of the maternal
grandfather became ill at age 8 years with fre
quent convulsions and inability to walk. He
died at age 16 years of an unknown disease.

Neither parent of the proband had any evi

dence of disease in neurologic and conduction
velocity studies.
The patient was born 6 weeks prematurely
after an uneventful pregnancy. In infancy, no
problems were encountered, although the
mother noted that he did not cry like other
babies when hypodermic injections were given.
He did not walk until 2% years of age. He was
always clumsy in walking, reaching his best
performance at age 8 or 9 years. His parents
thought that his performance deteriorated aft
er age 9 years; he could ride a bicycle then but
cannot

now.

His presenting symptoms were poor coordi

nation in walking and writing and weakness in
getting in and out of chairs. He denied having
visual or auditory symptoms. On neurologic ex
amination, no abnormality of cranial nerves
was observed. He did not have miosis or nys
tagmus. When sitting on the bedside with his
arms outstretched before him, there was some
swaying of the trunk and some irregular choreiform movements of his fingers. He had a
Romberg sign. He had mild weakness of
shoulder and hip girdle muscles and moderate
to severe weakness of distal muscles. The
greatest weakness occurred in the dorsiflexor
muscles of the ankle. Tendon reflexes were ab
sent. Perception of sensory stimuli was de
creased, especially distally in the lower extremi
ties. Recognition of touch, joint position, and
the vibrations of a tuning fork was especially
decreased distally in the feet. There was also a
slight decrease in the recognition of painful
stimuli in the feet. The greater auricular and
cervical nerves were visible beneath the skin
and, on palpation, were abnormally hard. The
median, ulnar, and peroneal nerves were also en
larged and unusually firm and insensitive. The
conduction velocities of motor fibers of the left
ulnar and median nerves were 5 and 6 me-

Fig 7.Kinship with the hypertrophie neuropathy of Dejerine

and Sottas,

showing

recessive

inheritance.

Kinship

9-16

QS>.

OP,

^ri

n-^

1~s

ye

7 ^9 ^

in
1-5

9-12

13-16

^^. ^9
fi
17yr

18

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9-22

23-25

ter/sec, respectively. No response was obtained

from the extensor digitorum brevis muscle aft
er stimulation of the peroneal nerve at the
knee and ankle. No action potential could be

detected over median and ulnar nerves at the

wrist after stimulation of digital nerves. The
CSF contained 3 lymphocytes per cu mm and
96 nig of protein per 100 ml.
Case III. 17, kinship 9-16.The 12-year-old
brother of the preceding patient was asympto
matic. On examination, however, the greater
auricular nerve was enlarged and firmer than
normal. Tendon reflexes in the lower extremi
ties were moderately reduced. Muscle strength
was normal (he could walk on toes and heels
and could rise from a squat). No sensory ab
normality was found. Conduction velocities of
the motor fibers of the left ulnar, median, and
peroneal nerves were 42, 44, and 29 meter/sec,
respectively. The initial pressure of the CSF
on lumbar puncture was 20 cm. With jugular
vein compression, it increased to 33 cm and
with release of compression, it decreased
promptly to 17 cm. The CSF protein content
was 76 mg/100 cc.
Case III. 2, kinship 5-13.The clinical,
genetic, and electrophysiologic data and results
of histologie examination of the nerve biopsy
of the proband of this kinship have previously
been presented.1920
Case IV. 7, kinship 9-15.The clinical, ge
netic, and histologie data regarding the proband of this kinship are being published else
where.95
Case II. 5, kinship 8-13.This 43-year-old
woman had been born at full term after a nor
mal pregnancy. At age 9 months, delayed mo
tor development was recognized. She sat at 9
months, crawled at 12 to 14 months, and
walked at 3 years. Mental development, how
ever, was normal. Her best motor skills oc
curred in high school, when she could walk ap
proximately iy2 blocks. She was never able to
run or jump. Walking gradually deteriorated
until, at age 31 years, she could not even walk
with support. She has been in a wheelchair
since that time. She fell frequently and had
several fractures.
There was a shuddering movement of the
eyes. Hearing was decreased bilaterally. There
was moderate weakness of all muscles of the
arms; in the legs there was considerable weak
ness affecting especially muscles below the
knee. She was totally areflexic. There was
marked locomotor ataxia. In addition, there
was severe sensory loss, greatest distally in all
extremities but including the trunk and possi
bly the face. Joint-position sense was absent in
the toes and ankles and at the wrists and el-

Pinprick and temperature sensation were

only minimally impaired over the face and
bows.

trunk. Conduction velocities of motor fibers of

the left ulnar and median nerves were 22 and
12 meter/sec, respectively. Conduction velocity
of the left peroneal nerve to the anterior tibial
muscle was 20 meter/sec. A blood smear was
made for acanthocytes, but none was seen. The
CSF contained 1 lymphocyte per cu mm and a
protein content of 129 mg/100 cc. Results of
electrophoresis of the CSF protein were pre-

albumin, 1%; albumin, 52%; j-globulin, 7%;

2-globulin, 9%; -globulin, 20%; -globulin,
11%. No enlargement of nerves was detected
by palpation, but this was not surprising be
cause of the large amount of subcutaneous tis
Fascicular biopsy of the left sural nerve
showed hypertrophie neuritis and segmental
sue.

demyelinization.

Neurologic examinations and conduction

ve

locity studies of both parents revealed no ab

normalities. The maternal great grandparents
were

first cousins.

Comment
There is a growing body of evidence2037409897 that hypertrophie neuropa
thy (clinical enlargement of peripheral
nerves, increase in transverse fascicular area,
and onion-bulb formations with increase in
the endoneurium) is not a hallmark of one
disease but rather is a histologie reaction
common to several disorders. In this pro
spective study of kinships with neurogenic
peroneal muscle atrophy, we have encoun
tered two types of inherited hypertrophie
neuropathy which we believe to be different
disorders. A third type of inherited hypertrophic neuropathy, an example of which we
did not see during this study, is that first de
scribed by Refsum8283 and Cammermeyer.84
We saw several kinships with dominantly
inherited primary amyloidosis during the
course of the study but, because symmetric
peroneal muscle weakness and atrophy was
not a distinguishing feature of the disease,
this disorder will not be discussed.
The first type of inherited neuropathy in
this report has the natural history, inherit
ance, and clinical features of the kinships
described by Eichhorst, Charcot and Marie,
Tooth, and Roussy and Levy. We agree
with Symonds and Shaw98 that there is no
convincing evidence that kinships, as origi
nally described by Roussy and Levy, should
be set into a separate category. In this type

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of inherited

neuropathy there is peripheral tas types, extremely low values were seen
enlargement and onion-bulb forma only in the latter. In three cases of the Detion. It seems reasonable to designate this jerine-Sottas type, the conduction velocity
group of cases as "hypertrophie neuropathy of the ulnar nerve was 3, 4, and 5 meter/sec.
of the Charcot-Marie-Tooth type."
Such low values were not seen in the Char
In the majority of cases in our study, this cot-Marie-Tooth type. There was a differ
disorder was inherited as a dominant trait. ence in the histologie features of nerve.
We did not find any cases of sex-linked in Enlargement of nerve trunks, onion-bulb for
heritance, as did others.13 Sex-linked inherit mations, increased endoneurium, and evi
ance was suspected in some of our kinships
dence of segmental demyelinization were
on the basis of information supplied by the
seen in both disorders but were more
propositus, but subsequent examination of marked in the Dejerine-Sottas type. As a re
the kinship did not confirm it. There were sult of the increased severity of the seg
cases in which dominant inheritance could
mentai demyelinization, many internodes of
not be established, even with examination myelinated fibers were denuded of myelin
and conduction velocity determinations of and most internodes had an unusually thin
parents and siblings, although these were myelin sheath (these were considered to be
considerably fewer than the dominantly in incompletely remyelinated internodes).
herited cases. In these cases, the following
In addition to these inherited forms, we
possibilities must be considered: (1) the have seen sporadic cases starting in later life
condition was unrelated to the dominantly (similar to the cases described by Roussy
inherited variety but had a similar pheno- and Cornil)80 and sporadic relapsing cases
type; (2) the condition was dominantly in with onset at any age. Because of their dif
herited but the true parent with the disorder ferent natural history, such sporadic cases
is unidentified; (3) the condition was domi have not been included with the inherited
nantly inherited but, because of poor expres types.
sivity, was unrecognized in the parent; and
Summary
(4) the condition was recessively inherited.
nerve

We were unable to obtain evidence to reach

a conclusion regarding these possibilities.
The second type of hereditary hypertroph
ie neuropathy (the hypertrophie neuropa
thy of the Dejerine-Sottas type) is probably
much rarer than the first and is probably in
herited as a recessive trait. This kind of case
occurred only sporadically or in siblings,
and the parents were sometimes consanguine
ous but always unaffected (favoring reces
sive inheritance). In addition, these cases
had a more severe mixed motor and sensory
neuropathy, so that normal motor develop
ment was usually not reached. The patients
had a worse prognosis than did the affected
persons with hypertrophie neuropathy of
the Charcot-Marie-Tooth type. Also, in all
affected persons, the CSF protein content
was increased whereas it was not increased
in any case of the Charcot-Marie-Tooth
type. Increased protein content was seen in
a young boy whose disorder was asympto
matic and who had no blockage of the CSF.
Although diffusely low conduction velocities
of peripheral nerves were seen in both the
Charcot-Marie-Tooth and the Dejerine-Sot-

In a prospective study of neurologic dis

orders with symmetric peroneal muscular
weakness or atrophy, 67 persons with hypertrophic neuropathy of the Charcot-MarieTooth type, five persons with hypertrophie
neuropathy of the Dejerine-Sottas type, and
150 unaffected relatives have been evaluated
by neurologic, genetic, and electrophysiolog
ic studies. The hypertrophie neuropathy of
the Charcot-Marie-Tooth type usually has
the following characteristics: dominant in
heritance, onset with foot or gait symptoms
in the first or second decade, pes cavus, a
variable amount of clinically apparent nerve
enlargement, weakness and mild atrophy
only in distal muscles of the limbs beginning
in the peroneal muscle group, areflexia or
hyporeflexia beginning with the Achilles re
flex, mild sensory loss distally in the limbs,
normal CSF protein content, low conduction
velocity of peripheral nerves, and increase
in transverse fascicular area and a variable
degree of onion-bulb formation. The progno
sis is favorable, and confinement to wheel
chair is uncommon. We have not found suf
ficient reasons to designate as a separate

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disorder those kinships with the additional

feature of static tremor of the hands (like
the kinship described by Roussy and Levy).
In the hypertrophie neuropathy of the
Dejerine-Sottas type, the usual characteris
tics are probably recessive inheritance, onset
in infancy, delayed motor development, se
vere gait disturbances, severe mixed poly-

neuropathy affecting the limbs, ataxia,

marked enlargement of nerves, increased
CSF protein content, often extremely low
conduction velocity of nerves, and very

marked

degrees of segmental demyeliniza

tion, onion-bulb formation, and thin myelin
sheaths. Such patients often become con

fined to wheelchairs in the third and later

decades.
Patients with the inherited hypertrophie
neuropathy of the Refsum type were not
seen in this study.
This investigation was supported in part by re
search grant NB-5811 from the National Institutes
of Health, Public Health Service.
J. Isabell Dyck and Dr. R. E. Espinosa helped in
translation of articles from the French literature.

References
1. Charcot, J.M., and Marie, P.: Sur une forme
particuli\l=e`\red'atrophie musculaire progressive souvent familial d\l=e'\butantpar les pieds et les jambes
et atteignant plus tard les mains, Rev Med (Paris)
6:97-138 (Feb) 1886.
2. Tooth, H.H.: The Peroneal Type of Progressive Muscular Atrophy, thesis, London: H. K. Lewis & Co., Ltd., 1886.
3. Virchow, R.: Ein Fall von progressiver Muskelatrophie, Virchow Arch Path Anat 8:537, 1855.
4. Eulenburg, M.: Ueber progressive Muskelatrophie, Deutsch Klin (Berlin) 8:129-131, 1856.
5. Friedreich, N.: Ueber progressive Muskelatrophie, \l=u"\berwahre und falsche Muskelhypertrophie,
Berlin: A. Hirschwald, 1873.
6. Bamberger: cited by Schultze, F.9
7. Hemptenmacher: cited by Schultze, F.9
8. Eichhorst, H.: Ueber Heredit\l=a"\tder progressiven Muskelatrophie, Berlin Klin Wschr 10:497-499
(Oct 20); 511-514 (Oct 27) 1873.
9. Schultze, F.: \l=U"\berdie vererbbare neurale oder
neurospinale Muskelatrophie, Deutsch Z Nervenheilk 112:1-19 (Jan) 1930.
10. Hoffmann, J.: Ueber chronische spinale
Muskelatrophie im Kindesalter, auf famili\l=a"\rerBasis, Deutsch Z Nervenheilk 3:427-470 (May) 1893.
11. England, A.C., and Denny-Brown, D.: Severe
Sensory Changes, and Trophic Disorder, in Peroneal Muscular Atrophy
(Charcot-Marie-Tooth
Type), Arch Neurol 67:1-17 (Jan) 1952.
12. Lidge, R.T., and Chandler, F.A.: Charcot\x=req-\
Marie-Tooth Disease, J Pediat 43:152-163 (Aug)
1953.
13. Bell, J.: "On the Peroneal Type of Progressive Muscular Atrophy," in Fisher, R.A. (ed.): Treasury of Human Inheritance: Nervous Diseases and
Muscular Dystrophies, London: Cambridge University Press, 1935, vol 4, pp 69-139.
14. Marinesco, M.: Contribution \l=a`\ l'\l=e'\tudede
l'amyotrophie Charcot-Marie, Arch Med Exp
6:921-965, 1894.
15. Biemond, A.: Neurotische Muskelatrophie
und Friedreichsche Tabes in derselben Familie,
Deutsch Z Nervenheilk 104:113-145 (June) 1928.
16. Haase, G.R., and Shy, G.M.: Pathological
Changes in Muscle Biopsies From Patients With
Peroneal Muscular Atrophy, Brain 83:631-637 (Dec)
1960.

17. Drachman, D.B., et al: "Myopathic" Changes

in Chronically Denervated Muscle, Arch Neurol
19:14-24 (Jan) 1967.
18. Dyck, P.J.; Beahrs, O.H.; and Miller, R.H.:
Peripheral Nerves in Hereditary Neural Atrophies:
Number and Diameters of Myelinated Fibers. Communications from the Sixth International Congress
of Electroencephalography and Clinical Neurophysiology, Vienna, Sept 5-10, 1965, pp 673-677.
19. Dyck, P.J., and Lambert, E.H.: Numbers and
Diameters of Nerve Fibers and Compound Action
Potential of Sural Nerve: Controls and Hereditary
Neuromuscular Disorders, Trans Amer Neurol Assoc
91:214-217, 1966.
20. Dyck, P.J.: Histologic Measurements and
Fine Structure of Biopsied Sural Nerve: Normal,
and in Peroneal Muscular Atrophy, Hypertrophic

Neuropathy, and Congenital Sensory Neuropathy,

Mayo Clin Proc 41:742-774 (Nov) 1966.

21. Gutrecht, J.A., and Dyck, P.J.: Segmental
Demyelinization in Peroneal Muscular Atrophy:
Nerve Fibers Teased From Sural Nerve Biopsy
Specimens, Mayo Clin Proc 41:775-777 (Nov) 1966.
22. Dyck, P.J., et al: Histologic and Teased\x=req-\

Fiber Measurements of Sural Nerve in Disorders of

Lower Motor and Primary Sensory Neurons, Mayo
Clin Proc 43:81-123 (Feb) 1968.
23. Dejerine, J., and Sottas, J.: Sur la n\l=e'\vriteinterstitielle, hypertrophique et progressive de l'enfance, C R Soc Biol 45:63-96, 1893.
24. Dejerine, J.: N\l=e'\vriteinterstitielle hypertrophique et progressive de l'enfance, Rev Med 16:881\x=req925 (Nov) 1896.
25. Boveri, P.: De la nevrite hypertrophique familiale (type Pierre Marie), Sem Med (Paris)

30:145-150, 1910.
26. Hoffman,

phische Neuritis,

J.: \l=U"\ber progressive hypertroDeutsch Z Nervenheilk 44:65-94,

1912.
27. Yokomori, K.: \l=U"\berNeuritis interstitialis hypertrophica et progressiva (D\l=e'\j\l=e'\rineand Sottas)
mit einem Sektionsbefund, Mitt Med Fakult Univ
Tokyo 15:1-48, 1915-1916.
28. Cornil, L.; Chalnot, R.; and Thomas: N\l=e'\vrite
hypertrophique progressive non familiale (\l=e'\tude
anatomoclinique), Rev Neurol 1:1187-1192 (June)
1930.
29. Sears, W.G.: Progressive Hypertrophic Poly-

Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/12/2015

neuritis, J Neurol Psychopath

12:137-147 (Oct)
1931.
30. Russell, W.R., and Garland, H.G.: Progressive Hypertrophic Polyneuritis With Case Reports,
Brain 53:376-384 (Oct) 1930.
31. Villaret, M.; Haguenau, J.; and Klotz, P.H.:
N\l=e'\vrite hypertrophique familiale, Rev Neurol
63:211-218 (Feb) 1935.
32. Cooper, E.L.: Progressive Familial Hypertrophic Neuritis (Dejerine-Sottas), Brit Med J
1:793-794 (April 18) 1936.
33. Andr\l=e'\-vanLeeuwen, M., and Moreau, M.: De
la valeur des troubles pupillaires en dehors de la
syphilis, comme manifestation d'une affection h\l=e'\r\l=e'\do-d\l=e'\g\l=e'\nerative:IV. Une souche d'amyotrophie
neurale (type n\l=e'\vritehypertrophique) avec troubles
pupillaires: Rapports avec la pupillotonie (Adie) et
la dystasie ar\l=e'\flexique(Roussy-L\l=e'\vy),Mschr Psychiat Neurol 112:121-168, 1946.
34. Bruns, G.: Zur Kenntnis der hypertrophischen
Neuritis (Roussy-Cornil), Beitr Path Anat
111:407-418 (June) 1951.
35. Luban, B.: 2. Neurale Muskelatrophie und
hypertrophische Neuritis: Klinischer und genealogischer Beitrag anhand einer bernischen Sippe,
Schweiz Arch Neurol Psychiat 68:34-63, 1952.
36. Creutzfeldt, H.G.; Curtius, F.; and Kr\l=u"\ger,
K.H.: Zur Klinik, Histologie und Genealogie der
D\l=e'\jerine-SottasschenKrankheit, Arch Psychiat
Nervenkr 186:341-360, 1951.
37. Austin, J.H.: Observations on the Syndrome
of Hypertrophic Neuritis (The Hypertrophic Interstitial Radiculoneuropathies), Medicine (Balt)
35:187-237 (Sept) 1956.
38. Bedford, P.D., and James, F.E.: A Family
With the Progressive Hypertrophic Polyneuritis of
Dejerine and Sottas, J Neurol Neurosurg Psychiat
19:46-51 (Feb) 1956.
39. Isaacs, H.: Familial Chronic Hypertrophic
Polyneuropathy With Paralysis of the Extremities
in Cold Weather, S Afr Med J 34:758-761 (Sept 3)
1960.
40. Webster, H.deF., et al: The Role of Schwann
Cells in the Formation of "Onion Bulbs" Found in
Chronic Neuropathies, J Neuropath Exp Neurol
26:276-299 (April) 1967.
41. Lambert, E.H.: Clinical Examinations in
Neurology, Philadelphia: W. B. Saunders Company, 1956, pp 287-317.
42. Gilliatt, R.W., and Thomas, P.K.: Extreme
Slowing of Nerve Conduction in Peroneal Muscular
Atrophy, Ann Phys Med 4:104-106 (Aug) 1957.
43. Lambert, E.H.; Bastron, J.A.; and Mulder,
D.W.: Conduction Velocity of Motor Fibers of Peripheral Nerves in Peroneal Muscular Atrophy
(C.M.T. Disease), read before the annual meeting
of the American Academy of Neurology, Philadelphia, April 19, 1958.
44. Christie, B.G.: Electrodiagnostic Features of
Charcot-Marie-Tooth Disease, Proc Roy Soc Med
54:321-324 (April) 1961.
45. Blom, S.; Hagbarth, K.E.; and Lundberg,
P.O.: Motor Conduction Velocities in Amyotrophic
Lateral Sclerosis, Polyradiculoneuritis and Charcot-Marie-Toooth's Disease, Acta Neurol Scand
40:6-12, 1964.

46. Dyck, P.J.; Lambert, E.H.; and Mulder,

D.W.: Charcot-Marie-Tooth Disease: Nerve Conduction and Clinical Studies of a Large Kinship,
Neurology (Minneap) 13:1-11 (Jan) 1963.
47. Amick, L.D., and Lemmi, H.: Electromyographic Studies in Peroneal Muscular Atrophy:
Charcot-Marie-Tooth Disease, Arch Neurol 9:273\x=req-\
384 (Sept) 1963.
48. Myrianthopoulos, N.C., et al: Nerve Conduction and Other Studies in Families With Charcot\x=req-\
Marie-Tooth Disease, Brain 87(pt 4):589-608, 1964.
49. Roussy, G., and Levy, G.: Sept cas d'une
maladie familiale particuliere: Trouble de la
marche, pieds bots et ar\l=e'\fle\l=e'\xietendineuse g\l=e'\n\l=e'\ralis\l=e'\e,avec accessoirement, l\l=e'\g\l=e`\remaladresse des
mains, Rev Neurol 1:427-450 (April) 1926.
50. Yudell, A.; Dyck, P.J.; and Lambert, E.H.: A
Kinship With the Roussy-Levy Syndrome, Arch
Neurol 13:432-440 (Oct) 1965.
51. Slauck: \l=U"\ber progressive hypertrophische
Neuritis (Hoffmannsche Krankheit), Z Neurol Psychiat 92:34-77, 1924.
52. Wolf, A.; Rubinowitz, A.H.; and Burchell;
S.C.: Interstitial Hypertrophic Neuritis of D\l=e'\j\l=e'\rine
and Sottas: A Report of Three Cases, Bull Neurol
Inst New York 2:373-428 (Nov) 1932.
53. Thomas, A., and Chausseblanche, L.: Un cas
de n\l=e'\vritehypertrophique et progressive de l'enfance
(maladie de D\l=e'\j\l=e'\rineet Sottas), Encephale 28:504\x=req-\
530 (July-Aug) 1933.
54. Massion-Verniory, L., and Radermecker, J.:
N\l=e'\vritehypertrophique interstitielle, Mschr Psychiat Neurol 113-114:246-257, 1947.
55. Marie, P.: Forme sp\l=e'\cialede n\l=e'\vriteintersitielle hypertrophique progressive de l'enfance, Rev
Neurol 14:557-560 (June) 1906.
56. Gombault, A., and Mallet: Un cas de tab\l=e`\s
ayant d\l=e'\but\l=e'\dans l'enfance\p=m-\autopsie,Arch Med
Exp Anat Path (Paris) 1:385-415, 1889.
57. St\l=o"\rring,E.: \l=U"\berPupillenst\l=o"\rungenbei neuralen Muskelatrophein: Zugleich ein Beitrag zur
Kenntnis der hypertrophischen Neuritis D\l=e'\j\l=e'\rine\x=req-\
Sottas, Z Neurol Psychiat 171:95-116 (Feb) 1941.
58. Long, E.: Atrophie musculaire progressive
des membres sup\l=e'\rieurs,type Aran-Duchenne par
n\l=e'\vriteinterstitielle hypertrophique (contribution a
l'\l=e'\tudedes maladies d'evolution), Nouv Iconog Salpetriere 20:46-65, 1907.
59. Long, E.: Atrophie musculaire progressive
type Aran-Duchenne de nature n\l=e'\vritique(second
cas suivi
d'autopsie), Nouv Iconog Salpetriere

25:281-308, 1912.
60. Roussy, G., and Cornil, L.: N\l=e'\vritehypertrophique progressive non-familial de l'adulte, Ann
Med (Paris) 6:296-305, 1919.
61. Achard, C.H., and Thiers, J.: Polyn\l=e'\vrite
chronique hypertrophique de l'adulte, Rev Neurol
39:146-150, 1924.
62. Schaller, W.F., and Newmann, H.W.: N\l=e'\vrite
interstitielle hypertrophique: Relation d'un cas avec
suggestion de traitement, Rev Neurol 1:529-539
(April) 1935.
63 Tarassi\l=e'\witch,I.J., and Mich\l=e'\jew,W.: Nevrite hypertrophique et progressive (neuromegalia
peripherica progressiva), Rev Neurol 2:18-40
(July) 1935.

Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/12/2015

64. Sloane, P.: Progressive Interstitial Hypertrophic Neuritis, J Nerv Ment Dis 90:429-438 (Oct)
1939.
65. Garcin, R., et al: Sur deux cas sporadiques
de n\l=e'\vritehypertrophique progressive de DejerineSottas avec contr\l=o^\lebiopsique, Rev Neurol 82:204\x=req-\
210 (March) 1950.
66. Roger, H., et al: Polyn\l=e'\vritehypertrophique
de l'adulte (non-familiale) avec parapar\l=e'\siespasmodique, Rev Neurol 86:695-698 (July) 1952.
67. Juliao, O.F.: Etude sur la n\l=e'\vritehypertrophique progressive de D\l=e'\jerine-Sottas,Arq Neuropsiguiat 10:221-246, 1952.
68. Ritz, O.: Zur Kenntnis der hypertrophischen
Neuritis, Confin Neurol 21:257-271, 1961.
69. Andermann, F., et al: Observations on Hypertrophic Neuropathy of D\l=e'\jerineand Sottas,
Neurology (Minneap) 12:712-724 (Oct) 1962.
70. Rossolimo, G.: Sur une forme r\l=e'\currentede
la polyn\l=e'\vriteinterstitielle hypertrophique progressive de l'enfance (Dejerine) avec participation du
nerf oculo-moteur externe, Rev Neurol 7:558-564,
1899.
71. Schaller, W.F.: Progressive Interstitial Hypertrophic Neuritis of Childhood of Dejerine and
Sottas: Report of a Case, Arch Intern Med
10:399-404 (Oct) 1912.
72. Hoestermann, E.: \l=U"\berrekurrierende Polyneuritis, Deutsch Z Nervenheilk 51:116-123 (May)
1914.
73. Nattrass, F.J.: Recurrent Hypertrophic Neuritis, J Neurol Psychopath 2:159-165 (Aug) 1921.
74. Harris, W., and Newcomb, W.D.: A Case of
Relapsing Interstitial Hypertrophic Polyneuritis,
Brain 52:108-116 (April) 1929.
75. Diddle, A.W., and Stephens, R.L.: Hypertrophic Interstitial Neuritis With Papilledema, Arch
Neurol 40:151-157 (July) 1938.
76. Reisner, H., and Spiel, W.: Zur Frage der
Polyneuritis hypertrophicans, Wein Z Nervenheilk
5:388-403, 1952.
77. Symonds, C.P., and Blackwood, W.: Spinal
Cord Compression in Hypertrophic Neuritis, Brain
85:251-260 (June) 1962.
78. Green, L.; Herzog, I.; and Aberfeld, D.: A
Case of Hypertrophic Interstitial Neuritis Coexisting With Dementia and Cerebellar Degeneration, J
Neuropath Exp Neurol 24:682-689 (Oct) 1965.
79. Stewart, B.M.: The Hypertrophic Neuropathy
of Acromegaly: A Rare Neuropathy Associated
With Acromegaly, Arch Neurol 14:107-110 (Jan)
1966.
80. Thomas, P.K., and Lascelles, R.G.: The Pathology of Diabetic Neuropathy, Quart J Med
35:489-509 (Oct) 1966.
81. De Bruyn, R.S., and Stern, R.O.: A Case of
the Progressive Hypertrophic Polyneuritis of Dejerine and Sottas, With Pathological Examination,
Brain 52:84-107 (April) 1929.
82. Refsum, S.: Heredoataxia hemeralopica polyneuritiformis\p=m-\ettidligere ikke beskrevet familiaert
syndrom? Nord Med 28:2682-2685 (Dec) 1945.
83. Refsum, S.: Heredopathia Atactica Polyneuritiformis: A Familial Syndrome Not Hitherto Described, Acta Psychiat Neurol suppl 38, pp 1-303,
1946.

Cammermeyer, J.: Neuropathologic Changes

Hereditary Neuropathies: Manifestation of the
Syndrome Heredopathia Atactica Polyneuritiformis
in the Presence of Interstitial Hypertrophic Polyneuropathy, J Neuropath Exp Neurol 15:340-361
(July) 1956.
85. Reese, H., and Bareta, J.: Heredopathia
Atactica Polyneuritiformis, J Neuropath Exp Neu84.

in

rol 9:385-395 (Oct) 1950.

86. Clark, D.B.: Heredopathia Atactica Polyneuritiformis (Refsum's Syndrome), Proc Roy Soc Med
44:689-694, 1951.
87. Ashenhurst, E.M.; Millar, J.H.D.; and Milliken, T.G.: Refsum's Syndrome Affecting a Brother
and Two Sisters, Brit Med J 2:415-417 (Aug 16)
1958.
88. Toussaint, D.; Co\l=e"\rs, C.; and Toppet, N.:
Heredopathia atactica polyneuritiformis (syndrome
de Refsum): Constatations cliniques et biopsiques,
Bull Soc Belg Ophtal 122:383-402, 1959.
89. Klenk, E., and Kahlke, W.: \l=U"\berdas Vorkommen der 3.7.11.15-Tetramethyl-hexadecans\l=a"\ure
Phytans\l=a"\ure)in den Cholesterinestern und anderen
Lipoidfraktionen der Organe bei einem Krankheitsfall unbekannter Genese (Verdacht auf Heredopathia atactica polyneuritiformis [Refsum-Syndrom]),
Hoppe Seyler Z Physiol Chem 333:133-139, 1963.
90. Kahlke, W.: \l=U"\ber das Vorkommen von
3,7,11,15-Tetramethyl-hexadecans\l=a"\ureim Blutserum
bei Refsum-Syndrom, Klin Wschr 41:783-785
(Aug) 1963.
91. Richterich, R.; van Mechelen, P.; and Rossi,
E.: Refsum's Disease (Heredopathia Atactica
Polyneuritiformis): An Inborn Error of Lipid Metabolism With Storage of 3,7,11,15-Tetramethyl
Hexadecanoic Acid: I. Report of a Case, Amer J
Med 39:230-236 (Aug) 1965.
92. Kahlke, W., and Richterich, R.: Refsum's
Disease (Heredopathia Atactica Polyneuritiformis): An Inborn Error of Lipid Metabolism With
Storage of 3,7,11,15-Tetramethyl Hexadecanoic
Acid: II. Isolation and Identification of the Storage
Product, Amer J Med 39:237-241 (Aug) 1965.
93. Kolodny, E.H., et al: Refsum's Syndrome:
Report of a Case Including Electron Microscopic
Studies of the Liver, Arch Neurol 12:583-596
(June) 1965.
94. Dawson, G.D., and Scott, J.W.: Recording of
Nerve Action Potentials Through the Skin in Man,
J Neurol Neurosurg Psychiat 12:259-267 (Nov)
1959.
95. Dyck, P.J., and Gomez, M.R.: Segmental Demyelinization in Dejerine-Sottas Disease: Light,
Phase-Contrast, and Electron Microscopic Studies,
to be published.
96. Thomas, P.K., and Lascelles, R.G.: Hypertrophic Neuropathy, Quart J Med 36:223-238 (April)
1967.
97. Nichols, P.C.; Dyck, P.J.; and Miller, D.R.:
Experimental Hypertrophic Neuropathy: Change in
Fascicular Area and Fiber Spectrum After Acute
Crush Injury, to be published.
98. Symonds, C.P., and Shaw, M.E.: Familial
Claw-Foot With Absent Tendon-Jerks: A "Forme
Fruste" of the Charcot-Marie-Tooth Disease, Brain
49:387-403 (Sept) 1926.

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