dyck 1968

Lower Motor and Primary Sensory NeuronDiseases With Peroneal Muscular Atrophy

I. Neurologic, Genetic, and Electrophysiologic Findingsin Hereditary Polyneuropathies

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

THIS report gives the neurologic, genetic,and electrophysiologic findings of a prospec-tive study of kinships with different heredi-tary neurologic disorders having symmetricneurogenic weakness and atrophy as an ear-ly- and often major manifestation. The studywas undertaken to obtain more reliable in-formation about the natural history of thesedisorders, to test the usefulness of electrophysiologic studies in distinguishing affectedfrom nonaffected persons, to compare the re-sults of nerve biopsies from representativeaffected persons with these disorders, and todevelop a more meaningful classification. Inthis, the first of two articles on the subject,the results of neurologic, genetic, and elec-trophysiologic studies of 67 persons with hy-pertrophic neuropathy of the Charcot-Marie\x=req-\Tooth type, five persons with hypertrophicneuropathy of the Dejerine-Sottas type, and150 unaffected relatives are given. We alsowished to determine whether these syn-dromes were phenotypic variations of oneor several diseases or were separate en-tities on the basis of natural history, inherit-ance, cerebrospinal fluid (CSF) findings,electrophysiologic studies, and histology ofnerves.

Chronic progressive symmetric peronealmuscular atrophy may result from disease ofanterior horn cells, of peripheral nerves, orof muscle. We will discuss only the neurologic disorders with neurogenic peronealmuscular atrophy (not the distal myopathiediseases). Although we have divided the disorders into those affecting the peripheralnerves predominantly (Part I) and into

those affecting anterior horn and dorsal rootganglion cell neurons (Part II), this rigidseparation is not always possible because ofinsufficient information and because bothmay be affected. In diseases causing deathof anterior horn and dorsal root ganglioncells, there will be alteration in structureand in function in the peripheral nerve. Inaddition, disease of the neuron may be expressed distally in the peripheral nerve("dying back"). Furthermore, in severe disease of peripheral nerves, retrograde changesand even death may occur in anterior hornand dorsal root ganglion cells.

Historical Review

Charcot-Marie-Tooth Syndrome.Clinical Features.Prior to Charcot and Marie's1and Tooth's2 papers in 1886, patients withperoneal muscular atrophy had been described by Virchow,3 Eulenburg,4 Friedreich/'and others,68 as recorded by Schultze.9 Thereport by Eichhorst8 in 1873, in particular,should be mentioned because he describedaffected persons in six generations.

In 1886, Charcot and Marie1 described aspecific form of progressive muscular atrophy, often familial, that started in the feetand legs and later involved the hands. Theystated that the illness often afflicted severalsiblings and sometimes the ancestors also(suggesting dominant inheritance). Fascicu-lations and the reaction of degeneration wasfound in atrophie muscles. Vasomotor abnormalities occurred in affected extremities.Sensation was often intact although sometimes affected. They thought that the basisfor the disorder was either a myelopathy ora neuropathy, and they favored the former.

Tooth's2 thesis, at Cambridge University,on the peroneal type of progressive muscu-

Submitted for publication Sept 28, 1967; acceptedJan 8, 1968.

From the Mayo Clinic and Mayo Foundation:Section of Neurology (Dr. Dyck) and Physiology(Dr. Lambert).

Reprint requests to Mayo Clinic, 200 First St SW,Rochester, Minn 55901 (Dr. Dyck).

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lar atrophy was also published in 1886.Tooth concluded that the disease affectedperipheral nerves. There seems little doubtthat the disorders described by Eichhorst,8Charcot and Marie,1 and Tooth2 were alike.

Sensory signs in association with peronealmuscular atrophy were stressed by Hoffmann10 in 1893 and by England and Denny-Brown11 in 1952. Lidge and Chandler12suggested that the disease is self-limiting.Bell13 reviewed the cases in the literatureand concluded that the disease could be inherited as a dominant, recessive, or sex-linked trait and that some cases were sporadic.

Pathologic Features.There are few recentpathologic studies of Charcot-Marie-Toothdisease. Pathologic alterations noted351415include decreased numbers of anterior horncells, decreased numbers of myelinated fibersin peripheral nerve, increased endoneurium,and some posterior column degeneration.More recently, on the basis of muscle biopsies, Haase and Shy16 found myopathiechanges "suggesting primary disease of muscle" in ten of 17 cases of Charcot-Marie-Tooth disease. That the pathologic features which they considered as indicativeof primary disease of muscle can result fromchronic denervation is suggested by a recentstudy by Drachman and associates17 inwhich similar changes were found. In patients with dominantly inherited Charcot-Marie-Tooth disease with low conductionvelocity of nerves, biopsy studies of thegreater auricular and sural nerves by Dyckand co-workers1821 have clearly shown pathologic alterations in peripheral nerve. Thetransverse fascicular area (a good index ofthe size of a nerve trunk) was abnormallylarge, numbers of myelinated nerve fibersper nerve and per unit area of transversesection were decreased, and the largestmyelinated fibers were smaller than normal.Under the electron microscope, small "onion-bulb formations" were seen. Segmentaldemyelinization and remyelinization hasbeen demonstrated2122 in this disorder, andconsiderable variation in the degree of onion-bulb formation from one affected personto the next has been found.

Since the description by Dejerine andSottas2324 of hypertrophie interstitial neuritis, kinships have been described2539 which

had clinical features of the cases of Eich-horst,8 Charcot and Marie,1 and Tooth2but which, on the basis of clinical enlargement or onion-bulb formations of nerves,were placed in the category of Dejerine andSottas' hypertrophie interstitial neuritis.These kinships differed from those of the siblings whose parents were unaffected (probably recessive inheritance) as described byDejerine and Sottas23 in their first report, inthat they had a dominant inheritance, alesser neurologic impairment, and a more favorable prognosis. Recently, it also has beenshown that the onion-bulb formation is notthe hallmark of a single variety of neuropathy.2040 The presence of onion-bulb formations in nerves in both the dominantly andthe recessively inherited disorder thereforedoes not mean that they are the same disorder.

Electrophysiologic Features.Lambert41drew attention to the low conduction velocities of peripheral nerves in chronic familialneuropathies. Similar observations were reported by Gilliatt and Thomas42 and others.4345 Dyck and co-workers46 did a prospective clinical and conduction-velocitystudy on 103 persons of a kinship with dominantly inherited Charcot-Marie-Tooth disease. They were divided into three groups:(1) those with definite signs, (2) those withequivocal signs, and (3) those without signsof the disease. In all of those for whom adefinite clinical diagnosis could be made,conduction velocities were low in all nervestested. In two persons, low conduction velocity was the only evidence of involvement. Infive of 14 persons in the equivocal group,low conduction velocities allowed a definitediagnosis to be made. A similar study wasdone by Amick and Lemmi47 on 28 personsof a 62-member kinship. They also foundlow conduction velocities in the group with"well-developed signs." One of the personsin the mild category had normal conductionvelocity values. However, on later examination of this person by Amick, (written communication from L. Amick, June 27, 1966)no definite evidence of the disease wasfound.

Myrianthopoulos and associates48 didneurologic examinations and conduction velocity measurements on persons from threekinships with peroneal muscular atrophy.


Kinships J and D, although showing dominant inheritance, had other neurologic features, such as corticospinal tract signs,which we think distinguish them from patients with Charcot-Marie-Tooth disease. Inthese two kinships the conduction velocitieswere normal or only slightly low, and theauthors concluded that the disorder was primarily in the spinal cord. In kinship E,conduction velocities were low in affectedpersons, and in these the disorder was primarily in peripheral nerve.

Roussy-Lvy Syndrome.The syndromedescribed by Roussy and Levy49 resembledthat of Charcot and Marie in the followingfeatures: (1) familial nature, (2) clubfoot,(3) weakness and minimal atrophy of thedistal extremity muscles, (4) decreased excitability of muscles to galvanic and faradicstimulation, and (5) some distal sensoryloss. Their cases differed from those ofCharcot and Marie and Tooth because therewas a static tremor of the hands. Roussyand Levy stressed the absence of characteristic cerebellar signs, speech disturbance,Babinski sign, and nystagmus. Recently,Yudell and associates50 described a kinshipsimilar to the kinships of Roussy and Levy.The patients with the fully developed syndrome might be said to have Charcot-Marie-Tooth disease with a superimposedtremor. Genetic review of the kinship didnot bear out the hypothesis that thefull-blown syndrome might be a combination of two nonlinked dominant genes, onefor Charcot-Marie-Tooth disease and theother for tremor. A striking feature was thelow conduction velocity of peripheral nervesin all affected persons, with or without tremor. Because only the older persons had thecomplete syndrome and only the affectedyounger persons who were direct descendants of these had peroneal muscular atrophywithout tremor, it seemed reasonable to assume that the tremor would eventually develop in younger persons.

Dejerine-Sottas Syndrome.In 1893 Dejerine and Sottas23 described two siblingswith a neurologic disorder, beginning in infancy in the case of Fanny Roy and at age14 years in the case of Henri Roy. Thesyndrome included clubfoot, kyphoscoliosis,weakness and atrophy (most severe distal-ly) beginning in the lower extremities and

subsequently appearing in the upper extremities, fasciculation, decreased reactivity ofmuscles to electric stimulation, areflexia,marked sensory loss in all four extremities,incoordination of the arms, Romberg sign,miosis, and nystagmus. Prior to her death atage 45 years, Fanny Roy was unable towalk.

The father of these two siblings died oftuberculosis at age 45 years and was said tobe free of neurologic disease. The motherwas examined at age 61 years and no abnormality was found. Two living siblings of thepatients also had no neurologic abnormality.Five siblings had died during infancy orchildhood. A child of Fanny Roy was alsoexamined and was without abnormality. Onthe basis of this information, recessive inheritance or dominant inheritance with poor expressivity in one of the parents might beinferred.

Portmortem examination of Fanny Royrevealed the following changes in peripheralnerves: nerve trunks were increased in size,the myelin sheath was unusually thin ortotally absent (leaving a denuded axis cylinder) , and a hypertrophie mterstitium of connective tissue with fusiform cells surroundednerve fibers. It was concluded that the lesionwas exclusively interstitial. These peripheralnerve changes were most severe distally;however, similar changes were also observedin the dorsal root and its ganglion. Posteriorcolumn degeneration also occurred.

For substantial accounts of the clinical andpathologic features of hypertrophie neuropathy, the reports of others should beread.365051 In these reports, the criterion forthe diagnosis of hypertrophie neuropathywas the finding of nerve enlargement onneurologic or postmortem examination orthe presence of onion-bulb formations in histologie sections. In the published reports ofcases with hypertrophie neuropathy there isa considerable diversity in the inheritance,clinical syndrome, prognosis, and CSF data.One group of reports24"385253 concerneddominantly inherited cases with hypertrophie neuropathy. In these the clinical syndrome was similar to that described byEichhorst, by Charcot and Marie, and byTooth, but the original descriptions of thissyndrome did not list hypertrophie nerves asa feature. It seems reasonable to believe that


mild nerve enlargement may have been overlooked by these early authors, notwithstanding Dejerine's statement55 that Mariehad not found nerve enlargement in hiscases.

A second group of reports525657 describeda sporadic or recessively inherited hyper-trophic neuropathy in which the clinical features were similar to those described by Dejerine and Sottas.23 The disorder began ininfancy or early life, was progressive, was asevere mixed polyneuropathy, and was associated with an increased CSF protein content.

A third group of reports285869 described asporadic hypertrophie neuropathy of adultlife which is sometimes called the Roussy-Cornil type. The disorder usually began after the second decade, was usually progressive, and was associated with an increasedCSF protein content.

A fourth group of reports3470"78 was on relapsing cases of hypertrophie neuropathy.The onset was not related to age. The CSFprotein content frequently was high. Thedisorder may begin with peroneal muscularweakness and atrophy and so must be considered with the peroneal muscular atrophies.

Hypertrophie neuropathy has also beenreported by Stewart79 in acromegaly and byThomas and Lascelles80 in diabetes mellitus.The case of hypertrophie neuritis describedby De Bruyn and Stern81 may have beenunrecognized familial amyloid neuropathybecause deposits of amorphous materialwere found in peripheral nerve and becausethe clinical course and inheritance had thefeatures of primary amyloidosis.

Refsum's Syndrome.Refsum82 describeda syndrome strikingly similar to that of Dejerine and Sottas; he called it "heredopathiaatctica polyneuritiformis."83 This also is arecessive disorder, begins in childhood orpuberty, has a grave prognosis, and is oftenassociated with increased CSF protein content. Cammermeyer84 found hypertrophieneuropathy associated with it. Additionalfeatures are retinitis pigmentosa, ichthyosis,and electrocardiographic and bony changes.Additional cases of the Refsum type havebeen described by others.84"87 Klenk andKahlke89 found an inborn error of lipidmetabolism, with large amounts of phytan-

ic acid (3,7,11,15-tetramethylhexadecanoicacid) in urine, serum, liver, kidney, skeletalmuscle, and adipose tissue.8" !'2 In a similarpatient, Kolodny and co-workers93 did notfind phytanic acid in urine, serum, liver, orcornea.

Methods of StudyFive years ago, a prospective study was

begun to delineate the hereditary neurologicdisorders in which symmetric neurogenicperoneal muscular atrophy was present. Theinitial patient, the proband, was referred tothe authors by other neurologic and medicalconsultants in our institution. The patientswere studied by means of neurologic examination, genetic history, nerve conduction velocity measurements, and, in representativecases, by nerve biopsy and CSF examination. In addition, all relatives accompanyingthese patients were examined, includingsimilar conduction velocity determinations.Field trips were made to examine kinships,and relatives were subsequently seen at theMayo Clinic. Biopsy specimens of greaterauricular and sural nerves were obtained inrepresentative cases and studied by quantitative histologie methods and by light, phase-contrast, and electron microscopy.1821

Conduction velocity of motor fibers (A

there were variations in time of onset andseverity of signs. The entire kinship couldalways be placed into one category.

On the basis of inheritance, course, neurologic signs, CSF protein level, electrophysiologic tests, and histologie appearance ofnerve on biopsy, a separation of cases intodistinct syndromes was apparent.

Hypertrophie Neuropathy ofCharcot-Marie-Tooth Type

(Dominant Inheritance)In this category we include kinships such

as those described by Charcot and Marie, byTooth, and by Roussy and Levy. The Rous-sy-Lvy syndrome is included in this category because the inheritance, slow course,distribution of neurologic signs, electrophysiologic characteristics, and histologie abnormality of nerves are the same as those inCharcot-Marie-Tooth disease. Although patients with the Roussy-Lvy syndrome mayhave static tremor of the hands in additionto peroneal muscular atrophy, only a fewwith more advanced disease have exhibitedstatic tremor in some kinships. Consequently, this one inconstant feature did not merita separate diagnostic category.

Two hundred four persons from 21 kinships were evaluated; 38 male and 29 femalepatients had this disorder. Two large kinships previously reported4650 have been included.

Clinical Features.The earliest evidenceof the disorder was usually a foot deformity(Fig 1 and 2). Parents, anticipating the disease in their children, were sometimes ableto recognize this during the first few yearsof life. Many patients said they always hadhigh arches and curled-up toes (hammertoes). Many with these deformities complained of frequent corns and calluses, andmany said that they had been unable to findproperly fitting shoes. Some affected patients, however, had normal arches or evenflat feet (Fig 3). The incidence of pes cavusnoted on examination in the affected groupincreased with age as shown in Table 1. Aspreviously reported,4" a few persons had higharches but no neurologic or electrophysiologic evidence of a neurogenic disorder.Only two of 67 affected persons gave a history of an ulcer of the foot. A few affectedchildren in the latter part of the first decade

Fig 1.Moderate pes cavus in an 18-year-old boy(case III. 12, kinship 9) with dominantly inheritedhypertrophie neuropathy of the Charcot-Marie-Toothtype with low conduction velocities of peripheral nerves.

Fig 2.Muscle atrophy In identical twins (cases IV.20 and 21, kinship 1) with dominantly inherited hyper-trophic neuropathy of the Charcot-Marie-Tooth typewith low conduction velocities of peripheral nerves.Note grooves between metatarsal bones resulting frommuscle atrophy and mild pes cavus. Although theseboys were unable to walk on their heels because ofweakness of the dorsiflexors of the ankles, the degreeof atrophy was not striking.

Fig 3.Left, Legs and feet of 17-year-old boy (caseIII. 2, kinship 5-10) without pes cavus but with otherclinical features of hypertrophie neuropathy of theCharcot-Marie-Tooth type with low conduction velocitiesof peripheral nerves. Right, The 45-year-old mother(case II. 3, kinship 5-10) also had flat feet. Her neurologic examination gave normal results but conductionvelocities of all peripheral nerves tested were unequivocally low.


Decade2 &34 & later

Table 1.Hypertrophie Neuropathy of the Charcot-Marie-Tooth Type

No. PesAffected CavusPersons (%)

2731

226758

Muscle weakness Tendon reflexes

Peroneal(%)1159

Gastrocnemius Intrinsic AnkleSoleus(%) Hand(%) (%)

0 0 22~7815

261228 81

Knee(%)

05948

Arm(%)115247

EnlargedNerves (%)

114116

Fig 4.Enlarged greater auricular nerve (arrow) in18-year-old boy (case III. 12, kinship 9) with dominantly inherited hypertrophie neuropathy of the Charcot-Marie-Tooth type with low conduction velocities ofperipheral nerves.

had begun walking on the ball of the foot.Surgical procedures for lengthening theAchilles tendon had been performed.

Another early symptom was an abnormal-

ity of gait or of running. This usually developed during the latter part of the first decade or during the second decade. It wasdescribed as awkwardness, clumsiness, "thefamily walk," or frequent tripping. Characteristically, the knees were raised higherthan normal (compensation for the dropfoot) and in this position the feet would assume a marked pes equinovarus deformity.As the foot was brought down, it would slapthe floor. Persons with marked weakness ofthe plantar flexors of the ankles, in additionto weakness of the dorsiflexors, encountereddifficulty in standing still. Some found theycould fix their ankles by standing with theknees bent. Others shifted their feet continuously to maintain balance.

Difficulty in digital manipulations, suchas picking up small objects, buttoning, orsewing, was reported more often by the older affected persons.

There was a striking absence of discomfort. Some patients described an aching,particularly of the leg muscles, after excessive activity. Several women complainedthat their legs ached while they were inactive, but this was promptly relieved by activity (similar to the restless leg syndrome).Not infrequently, patients reported painfrom corns or calluses. Others had pain inthe region of the arch of the foot after muchwalking. None reported burning, prickling,or lancinating pains. Some used words suchas "numbness" when they meant weakness.Coldness of the feet was a rather commoncomplaint.

None of the patients had ichthyosis, retinitis pigmentosa, miosis, nystagmus, or cerebellar ataxia.

Muscle weakness could first be detected inthe peroneal muscles. Weakness of the smallfoot muscles may have developed even earlier, but tests of strength in these musclesare not reliable. Weakness of ankle dorsiflexors was manifested by the patient's in-


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

Type

PersonsConduction velocity(meters/sec) Amplitude* (mv) Distal latency (msec)Mean

Age .(yr) Ulnar Median Peroneal Ulnar Median Peroneal Ulnar Median Peroneal

Hypertrophie neuropathy of the Charcot-Marie-Tooth type (dominant inheritance)Affectedf 64 33.8 23.5 24.0 20.3 4.8 4.5 2.3 7.1 9.2 12.1Unaffectedf 118 27.1 61.6 56.6 50.4 9.9 9.1 5.1 2.6 3.2 4.4Affected 3.0 22.6 22.7 26.3 3.8 3.5 1.9 6.7 7.9 7.9Unaffected} 15 2.4 55.1 47.4 51.5 7.5 7.4 3.4 1.8 2.3 3.1

Hypertrophie neuropathy of the Charcot-Marie-Tooth type (sporadic, dominant inheritance with poorexpressivity, or recessive inheritance)

Affectedf 10 14.1 25.5 25.9 25.4 3.6 4.8 1.2 5.3 7.7 11.3Unaffectedf 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 recording 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^CiiQJQnluloQluSoOouu a

Male.normal conduction velocity C.M.T. disease diagnosed from neurological Female, low conduction velocity

_

examination only0 Neurologic examination negative but no Not available fors^no evidence of CMT diseose

conduction velocity measurements O Not available for study, probably had CMT. disease^Propositus

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


ability to walk on his heels. Other distalmuscles of legs and arms were affected subsequently (Table 1). Muscle atrophy of slightdegree was seen in many patientsfor example, in the intrinsic foot muscles of identical twins (Fig 2). "Stork legs," with virtual absence of all muscles below the knee,was not found in this group. Fasciculationsof weak muscles were seen infrequently.

During the course of the disease, tendonreflexes became diminished in the followingsequence: Achilles, quadriceps, and upperextremity (Table 1). Hyperreflexia and theBabinski sign were not seen.

Sensory impairment was later in onsetand less severe than the motor impairment.The feet, especially the toes, were the firstsites at which sensory loss could be demonstrated; sensory loss was then noted in thefingers and hands. Vibration sense, two-point discrimination, and joint-position sense

were diminished more frequently than wereother modalities. No sensory loss was notedin the nine patients in the first decade(Table 1).

Enlargement and increased firmness ofperipheral nerves (Fig 4) was observed clinically in 17 of 67 affected persons.

Genetic Features.The disorders of the21 kinships of this group were dominantlyinherited (Fig 5). A direct line of inheritance from one generation to the next wasdemonstrated by personal examination ofaffected persons in more than one generation in nine of these kinships and from information supplied by the propositus, hisfamily, or medical records in the 12 otherkinships.

There was considerable variation in expressivity. Three of the 67 persons had noneurologic signs but had the characteristic low conduction velocity of peripheral

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 lowconduction velocities of peripheral nerves. The line represents low limit of normal.

70

60 ,\*y, ..-.... > 50

40

- 30

20

10

I "jL-t._

/ r*

o

X

nerves. Two of these were less than 5 yearsold, and subsequent reexamination of onedemonstrated the signs of this syndrome.The third (case II. 3, kinship 5-10), a 45-year-old woman, was carefully examined onseveral occasions and no neurologic signswere found. Conduction velocities of motorfibers (A) of her left ulnar, median, andperoneal nerves were 33, 35, and 34 meter/secall unequivocally low. Her 17-year-old son had definite symptomatic disease, and conduction velocities for his leftulnar, median, and peroneal nerves were 12,14, and 6 meter/sec. This variation of expressivity may explain some of the reportsin the literature of apparently sex-linked inheritance in Charcot-Marie-Tooth disease.13

The penetrance of this gene was calculatedfor completely and incompletely studiedoffspring groups. In a group in which entirefamilies were studied by neurologic examination and conduction velocity determinations, the percentage of affected children from affected parents was determined.Twenty-two (42%) of 53 such children hadevidence of the disorder (83% penetrance).In another group in which sibships wereonly partially examined, 47 (37%) of 128children had evidence of the disorder (73%penetrance).

Conduction Velocity Studies.Low conduction velocities of peripheral nerves werea hallmark of this disorder. The conductionvelocities of the ulnar, median, and peronealnerves of the affected persons were, on theaverage, less than one-half the values in unaffected persons (Table 2). The mean amplitude of the muscle action potential wasalso decreased by more than half. The distallatencies were almost three times greater.No affected persons had a normal conduction velocity (Fig 6). In one clinically normal child the first conduction velocity in theulnar nerve (at age IV2 years) was just below normal, but the distal latency was greatly prolonged; subsequently, clinical signswere evident at age 1/^ years when conduction velocities were 32, 34, and 37 meter/secfor the ulnar, median, and peroneal nerves(well below normal values for that age).

Sensory nerves were also affected. A digital nerve action potential usually could notbe detected by procedures which are uniformly successful in normal persons. If an

action potential was detected, it had a lowamplitude and a long latency. Study of thecompound action potential of the suralnerve in vitro10 has demonstrated low conduction velocity and decreased amplitude ofthe action potential of alpha and delta fiberswithout comparable changes in the actionpotential of C fibers.

Cerebrospinal Fluid.CSF was examinedin three affected persons of this group. Theprotein levels were 16, 35, and 37 mg/100 ccby the sulfosalicylic acid method. Electrophoretic patterns of the proteins were normal in these cases.

Nerve Biopsy Studies.The results ofnerve biopsy have been outlined in severalother communications.1822 The transversefascicular area of nerves was abnormallylarge. The number of myelinated nerve fibers per unit of transverse fascicular areaand per nerve was decreased. The mean diameter of myelinated fibers was less thannormal. On light and phase-contrast microscopy, distinct, large, onion-bulb formationswere seen in transverse sections of somenerves. In other nerves these were not apparent under the light microscope, but theywere seen under the electron microscope. Inteased-fiber preparations, only occasional in-ternodes of myelinated fibers had juxtanod-al or complete demyelinization. There wasa great variation of lengths and diameters ofinternodes of myelinated fibers, a characteristic of disorders with segmental demyelinization and remyelinization. In addition, afew fibers were in various stages of walleriandegeneration.

Hypertrophie Neuropathy ofCharcot-Marie-Tooth Type

Sporadic, Dominant Inheritance WithPoor Expressivity or Recessive Inheritance.In eight patients there was no history of asimilar disorder in the kinship. Twenty-threeunaffected close relatives of seven of thesewere examined. Except for one case, bothparents of each propositus were studied. Theother normal relatives were siblings andgrandparents. In addition, two affected siblings have been included in this group; noclinical or conduction velocity abnormalitywas found in two other siblings or in eitherparent.

Clinical Features.The findings in af-


fected persons were similar to those in thefirst group except that all affected personswere symptomatic and had been brought tothe Mayo Clinic because of the disorder. Allexcept one of the affected persons wereyoung. In every case the chief complaintwas an abnormal gait recognized by parentsas clumsiness, inability to run as fast as other siblings, a tendency to trip or stumble, orawkwardness. Two children began to walkon the ball of the foot at about 2 years ofage. The development of the disorder andthe neurologic signs were similar to those ofthe first group and will not be listed in detail.

Conduction Velocity Studies.The conduction velocity of the motor nerves and theamplitude of the evoked muscle actionpotentials in the affected group were lessthan one half the normal values in the unaffected group (Table 2). In the two affectedpersons tested, no nerve action potentialwas detected over the median nerve afterstimulation of afferent fibers in the fingers.In each of 16 unaffected persons tested, a response was obtained (mean time from stimulus to peak of the action potential was 2.9msec, range 2.2 to 3.9 msec).

Cerebrospinal Fluid.CSF was normal intwo affected persons.

Hypertrophie Neuropathy ofDejerine-Sottas Type

Sporadic or Recessive Inheritance.Inthis category we include kinships such asthose originally described by Dejerine andSottas.23

Five affected and 13 unaffected close relatives from four kinships were evaluated.Four of the five affected persons werebrought to the Mayo Clinic because ofsymptoms of a severe sensory motor poly-neuropathy present since birth. An asymptomatic sibling of one of these four was foundby examination to have a mild form of thesame disorder. None of the parents had evidence of a peripheral neuropathy in the neurologic examination or in conduction velocity studies.

The clinical syndromes were alike in thefour probands. Motor development was abnormal. Walking occurred at 15, 33, 36, and48 months. None of the probands was everable 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 theirbest, they experienced great difficulty inwalking short distances. One, a 43-year-oldwoman, has been in a wheelchair since age31 years; another, a 19-year-old girl, although able to take an occasional step,needs to use a wheelchair to get about. Theother two, ages 11 and 12 years, do not usea wheelchair but have a severe disturbanceof gait.

On the basis of the four persons with thewell-developed syndrome, the neurologicdisorder is best characterized as a severemixed polyneuropathy. None had miosis ornystagmus. The 43-year-old woman hadshuddering eye movements and sensorineu-ral hearing loss. Enlargement, increasedfirmness, and insensitivity of greater auricular, cervical, ulnar, median, and peronealnerves was seen in all cases. Weakness andatrophy were greater in the distal muscles,especially of the lower limbs, but were present also in proximal muscles of the limbs.All were areflexic. Sensory loss was mostmarked distally in the limbs in all four patients. All modalities of sensation were affected, but light touch, joint movement, andvibration perception were most abnormal.Locomotor ataxia was apparent in both upper and lower extremities. All patients exhibited some mild truncal instability on sitting. Some had choreiform-like movementsof the fingers of the outstretched hands. Themildly affected 12-year-old brother of one ofthe four probands (case III. 17, kinship 9-16)was asymptomatic but had enlargement ofperipheral nerves and diminished tendon reflexes in the lower extremities without weakness or sensory loss.

All five affected persons had increasedCSF protein content (76, 96, 126, 129, and180 mg/100 cc). The boy with the incompletely developed syndrome had the lowestvalue.

All five had low conduction velocities ofall nerves tested. Three of the five had extremely low conduction velocities (in the ulnar nerves, 3, 4 and 5 meter/sec). In the twoothers the values were 22 and 42 meter/sec,within the range of values seen in cases ofthe Charcot-Marie-Tooth type of neuropathy. The highest value was obtained in theasymptomatic sibling.


Sural nerve biopsies were performed onthe four persons with the well-developedsyndrome. The findings of these studieshave been reported previously.18202295 Enlargement of the nerve was noted at thetime of biopsy in all four cases. In one case,in which the entire nerve trunk was removed for a short distance, the transversefascicular area was approximately threetimes that of healthy nerves. In every casethere was a decrease in the number of myelinated nerve fibers per unit of transversefascicular area. Largest myelinated fibershad a much smaller diameter than seen inhealthy nerves. Segmental demyelinizationwas frequently seen in teased fibers and inlongitudinal sections examined under phase-contrast and electron microscopes. In thenerves studied under the electron microscope,myelin sheaths were abnormally thin anddistinctly different from those of nerves inthe Charcot-Marie-Tooth type of neuropathy.

Report of CasesCase III. 18, kinship 9-16.This 11-year-old

boy, with the diagnosis of hypertrophie neuropathy of Dejerine and Stottas, was referred tothe Mayo Clinic for these studies by Dr. GarthG. Myers, neurologist, of Salt Lake City, Utah.(The quantitative histologie and teased-fibermeasurements on a biopsy specimen of suralnerve from this patient are reported elsewhere.22) His place in the kinship (Fig 7) isindicated by an arrow. His brother, althoughasymptomatic, was found to have a similar disorder. A younger brother of the maternalgrandfather became ill at age 8 years with frequent convulsions and inability to walk. Hedied at age 16 years of an unknown disease.

Neither parent of the proband had any evidence of disease in neurologic and conductionvelocity studies.

The patient was born 6 weeks prematurelyafter an uneventful pregnancy. In infancy, noproblems were encountered, although themother noted that he did not cry like otherbabies when hypodermic injections were given.He did not walk until 2% years of age. He wasalways clumsy in walking, reaching his bestperformance at age 8 or 9 years. His parentsthought that his performance deteriorated after age 9 years; he could ride a bicycle then butcannot now.

His presenting symptoms were poor coordination in walking and writing and weakness ingetting in and out of chairs. He denied havingvisual or auditory symptoms. On neurologic examination, no abnormality of cranial nerveswas observed. He did not have miosis or nystagmus. When sitting on the bedside with hisarms outstretched before him, there was someswaying of the trunk and some irregular cho-reiform movements of his fingers. He had aRomberg sign. He had mild weakness ofshoulder and hip girdle muscles and moderateto severe weakness of distal muscles. Thegreatest weakness occurred in the dorsiflexormuscles of the ankle. Tendon reflexes were absent. Perception of sensory stimuli was decreased, especially distally in the lower extremities. Recognition of touch, joint position, andthe vibrations of a tuning fork was especiallydecreased distally in the feet. There was also aslight decrease in the recognition of painfulstimuli in the feet. The greater auricular andcervical nerves were visible beneath the skinand, on palpation, were abnormally hard. Themedian, ulnar, and peroneal nerves were also enlarged and unusually firm and insensitive. Theconduction velocities of motor fibers of the leftulnar and median nerves were 5 and 6 me-

Fig 7.Kinship with the hypertrophie neuropathy of Dejerine and Sottas, showing recessiveinheritance.

Kinship 9-16

OP,

QS>.2 ^ri n-^ 1~s ye

in

7 ^9 ^ ^^. ^9

~fi 17yr 18 9-22 23-251-5 6 7 9-12 13-16


ter/sec, respectively. No response was obtainedfrom the extensor digitorum brevis muscle after stimulation of the peroneal nerve at theknee and ankle. No action potential could bedetected over median and ulnar nerves at thewrist after stimulation of digital nerves. TheCSF contained 3 lymphocytes per cu mm and96 nig of protein per 100 ml.

Case III. 17, kinship 9-16.The 12-year-oldbrother of the preceding patient was asymptomatic. On examination, however, the greaterauricular nerve was enlarged and firmer thannormal. Tendon reflexes in the lower extremities were moderately reduced. Muscle strengthwas normal (he could walk on toes and heelsand could rise from a squat). No sensory abnormality was found. Conduction velocities ofthe motor fibers of the left ulnar, median, andperoneal nerves were 42, 44, and 29 meter/sec,respectively. The initial pressure of the CSFon lumbar puncture was 20 cm. With jugularvein compression, it increased to 33 cm andwith release of compression, it decreasedpromptly to 17 cm. The CSF protein contentwas 76 mg/100 cc.

Case III. 2, kinship 5-13.The clinical,genetic, and electrophysiologic data and resultsof histologie examination of the nerve biopsyof the proband of this kinship have previouslybeen presented.1920

Case IV. 7, kinship 9-15.The clinical, genetic, and histologie data regarding the pro-band of this kinship are being published elsewhere.95

Case II. 5, kinship 8-13.This 43-year-oldwoman had been born at full term after a normal pregnancy. At age 9 months, delayed motor development was recognized. She sat at 9months, crawled at 12 to 14 months, andwalked at 3 years. Mental development, however, was normal. Her best motor skills occurred in high school, when she could walk approximately iy2 blocks. She was never able torun or jump. Walking gradually deteriorateduntil, at age 31 years, she could not even walkwith support. She has been in a wheelchairsince that time. She fell frequently and hadseveral fractures.

There was a shuddering movement of theeyes. Hearing was decreased bilaterally. Therewas moderate weakness of all muscles of thearms; in the legs there was considerable weakness affecting especially muscles below theknee. She was totally areflexic. There wasmarked locomotor ataxia. In addition, therewas severe sensory loss, greatest distally in allextremities but including the trunk and possibly the face. Joint-position sense was absent inthe toes and ankles and at the wrists and el-

bows. Pinprick and temperature sensation wereonly minimally impaired over the face andtrunk. Conduction velocities of motor fibers ofthe left ulnar and median nerves were 22 and12 meter/sec, respectively. Conduction velocityof the left peroneal nerve to the anterior tibialmuscle was 20 meter/sec. A blood smear wasmade for acanthocytes, but none was seen. TheCSF contained 1 lymphocyte per cu mm and aprotein content of 129 mg/100 cc. Results ofelectrophoresis 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 detectedby palpation, but this was not surprising because of the large amount of subcutaneous tissue. Fascicular biopsy of the left sural nerveshowed hypertrophie neuritis and segmentaldemyelinization.

Neurologic examinations and conduction velocity studies of both parents revealed no abnormalities. The maternal great grandparentswere first cousins.

CommentThere is a growing body of evi-

dence2037409897 that hypertrophie neuropathy (clinical enlargement of peripheralnerves, increase in transverse fascicular area,and onion-bulb formations with increase inthe endoneurium) is not a hallmark of onedisease but rather is a histologie reactioncommon to several disorders. In this prospective study of kinships with neurogenicperoneal muscle atrophy, we have encountered two types of inherited hypertrophieneuropathy which we believe to be differentdisorders. A third type of inherited hyper-trophic neuropathy, an example of which wedid not see during this study, is that first described by Refsum8283 and Cammermeyer.84We saw several kinships with dominantlyinherited primary amyloidosis during thecourse of the study but, because symmetricperoneal muscle weakness and atrophy wasnot a distinguishing feature of the disease,this disorder will not be discussed.

The first type of inherited neuropathy inthis report has the natural history, inheritance, and clinical features of the kinshipsdescribed by Eichhorst, Charcot and Marie,Tooth, and Roussy and Levy. We agreewith Symonds and Shaw98 that there is noconvincing evidence that kinships, as originally described by Roussy and Levy, shouldbe set into a separate category. In this type


of inherited neuropathy there is peripheralnerve enlargement and onion-bulb formation. It seems reasonable to designate thisgroup of cases as "hypertrophie neuropathyof the Charcot-Marie-Tooth type."

In the majority of cases in our study, thisdisorder was inherited as a dominant trait.We did not find any cases of sex-linked inheritance, as did others.13 Sex-linked inheritance was suspected in some of our kinshipson the basis of information supplied by thepropositus, but subsequent examination ofthe kinship did not confirm it. There werecases in which dominant inheritance couldnot be established, even with examinationand conduction velocity determinations ofparents and siblings, although these wereconsiderably fewer than the dominantly inherited cases. In these cases, the followingpossibilities must be considered: (1) thecondition was unrelated to the dominantlyinherited variety but had a similar pheno-type; (2) the condition was dominantly inherited but the true parent with the disorderis unidentified; (3) the condition was dominantly inherited but, because of poor expressivity, was unrecognized in the parent; and(4) the condition was recessively inherited.We were unable to obtain evidence to reacha conclusion regarding these possibilities.

The second type of hereditary hypertrophie neuropathy (the hypertrophie neuropathy of the Dejerine-Sottas type) is probablymuch rarer than the first and is probably inherited as a recessive trait. This kind of caseoccurred only sporadically or in siblings,and the parents were sometimes consanguineous but always unaffected (favoring recessive inheritance). In addition, these caseshad a more severe mixed motor and sensoryneuropathy, so that normal motor development was usually not reached. The patientshad a worse prognosis than did the affectedpersons with hypertrophie neuropathy ofthe Charcot-Marie-Tooth type. Also, in allaffected persons, the CSF protein contentwas increased whereas it was not increasedin any case of the Charcot-Marie-Toothtype. Increased protein content was seen ina young boy whose disorder was asymptomatic and who had no blockage of the CSF.Although diffusely low conduction velocitiesof peripheral nerves were seen in both theCharcot-Marie-Tooth and the Dejerine-Sot-

tas types, extremely low values were seenonly in the latter. In three cases of the De-jerine-Sottas type, the conduction velocityof the ulnar nerve was 3, 4, and 5 meter/sec.Such low values were not seen in the Charcot-Marie-Tooth type. There was a difference in the histologie features of nerve.Enlargement of nerve trunks, onion-bulb formations, increased endoneurium, and evidence of segmental demyelinization wereseen in both disorders but were moremarked in the Dejerine-Sottas type. As a result of the increased severity of the segmentai demyelinization, many internodes ofmyelinated fibers were denuded of myelinand most internodes had an unusually thinmyelin sheath (these were considered to beincompletely remyelinated internodes).

In addition to these inherited forms, wehave seen sporadic cases starting in later life(similar to the cases described by Roussyand Cornil)80 and sporadic relapsing caseswith onset at any age. Because of their different natural history, such sporadic caseshave not been included with the inheritedtypes.

SummaryIn a prospective study of neurologic dis

orders with symmetric peroneal muscularweakness or atrophy, 67 persons with hyper-trophic neuropathy of the Charcot-Marie-Tooth type, five persons with hypertrophieneuropathy of the Dejerine-Sottas type, and150 unaffected relatives have been evaluatedby neurologic, genetic, and electrophysiologic studies. The hypertrophie neuropathy ofthe Charcot-Marie-Tooth type usually hasthe following characteristics: dominant inheritance, onset with foot or gait symptomsin the first or second decade, pes cavus, avariable amount of clinically apparent nerveenlargement, weakness and mild atrophyonly in distal muscles of the limbs beginningin the peroneal muscle group, areflexia orhyporeflexia beginning with the Achilles reflex, mild sensory loss distally in the limbs,normal CSF protein content, low conductionvelocity of peripheral nerves, and increasein transverse fascicular area and a variabledegree of onion-bulb formation. The prognosis is favorable, and confinement to wheelchair is uncommon. We have not found sufficient reasons to designate as a separate


disorder those kinships with the additionalfeature of static tremor of the hands (likethe kinship described by Roussy and Levy).

In the hypertrophie neuropathy of theDejerine-Sottas type, the usual characteristics are probably recessive inheritance, onsetin infancy, delayed motor development, severe gait disturbances, severe mixed poly-neuropathy affecting the limbs, ataxia,marked enlargement of nerves, increasedCSF protein content, often extremely lowconduction velocity of nerves, and very

marked degrees of segmental demyelinization, onion-bulb formation, and thin myelinsheaths. Such patients often become confined to wheelchairs in the third and laterdecades.

Patients with the inherited hypertrophieneuropathy of the Refsum type were notseen in this study.

This investigation was supported in part by research grant NB-5811 from the National Institutesof Health, Public Health Service.

J. Isabell Dyck and Dr. R. E. Espinosa helped intranslation of articles from the French literature.

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88. Toussaint, D.; Co\l=e"\rs,C.; and Toppet, N.:Heredopathia atactica polyneuritiformis (syndromede Refsum): Constatations cliniques et biopsiques,Bull Soc Belg Ophtal 122:383-402, 1959.

89. Klenk, E., and Kahlke, W.: \l=U"\berdas Vor-kommen der 3.7.11.15-Tetramethyl-hexadecans\l=a"\urePhytans\l=a"\ure)in den Cholesterinestern und anderenLipoidfraktionen der Organe bei einem Krankheits-fall unbekannter Genese (Verdacht auf Heredopath-ia atactica polyneuritiformis [Refsum-Syndrom]),Hoppe Seyler Z Physiol Chem 333:133-139, 1963.

90. Kahlke, W.: \l=U"\berdas Vorkommen von3,7,11,15-Tetramethyl-hexadecans\l=a"\ureim Blutserumbei Refsum-Syndrom, Klin Wschr 41:783-785(Aug) 1963.

91. Richterich, R.; van Mechelen, P.; and Rossi,E.: Refsum's Disease (Heredopathia AtacticaPolyneuritiformis): An Inborn Error of Lipid Me-tabolism With Storage of 3,7,11,15-TetramethylHexadecanoic Acid: I. Report of a Case, Amer JMed 39:230-236 (Aug) 1965.

92. Kahlke, W., and Richterich, R.: Refsum'sDisease (Heredopathia Atactica Polyneuritifor-mis): An Inborn Error of Lipid Metabolism WithStorage of 3,7,11,15-Tetramethyl HexadecanoicAcid: II. Isolation and Identification of the StorageProduct, Amer J Med 39:237-241 (Aug) 1965.

93. Kolodny, E.H., et al: Refsum's Syndrome:Report of a Case Including Electron MicroscopicStudies of the Liver, Arch Neurol 12:583-596(June) 1965.

94. Dawson, G.D., and Scott, J.W.: Recording ofNerve 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 De-myelinization in Dejerine-Sottas Disease: Light,Phase-Contrast, and Electron Microscopic Studies,to be published.

96. Thomas, P.K., and Lascelles, R.G.: Hyper-trophic Neuropathy, Quart J Med 36:223-238 (April)1967.

97. Nichols, P.C.; Dyck, P.J.; and Miller, D.R.:Experimental Hypertrophic Neuropathy: Change inFascicular Area and Fiber Spectrum After AcuteCrush Injury, to be published.

98. Symonds, C.P., and Shaw, M.E.: FamilialClaw-Foot With Absent Tendon-Jerks: A "FormeFruste" of the Charcot-Marie-Tooth Disease, Brain49:387-403 (Sept) 1926.


dyck 1968

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