J. Neurol. Neurosurg. Psychiat., 1950, 13, 307

FAMILIAL ATAXIA, DEAF-MUTISM, AND MUSCULAR WASTINGBY

W. B. MATTHEWSFrom the University Department of Neurology at the Manchester Royal Infirmary

The hereditary disorders of the nervous systemare classically presented in eponymous compart-mernts, but it has long been apparent that strictsubdivision is difficult to maintain. The affectedmembers of the family reported here presented, inthe fully developed syndrome, signs of cerebellardysfunction, affection of the posterior and lateralcolumns of the spinal cord, deaf-mutism, andselective muscular wasting. The distribution ofthe affected members can be seen from the accom-panying pedigree.

Case Reports11.3 (No. 130551), a joiner's assistant, aged 39, was

admitted to the Manchester Royal Infirmary under thecare of Dr. F. R. Ferguson in September, 1949, and wasthe member of the family examined in greatest detail.The history of his disease was compiled from the patientand from other members of his family. He was thethird child and was thought to have been normal atbirth. He was backward in learning to speak, but it wasnot until the age of 5 that his parents noticed that hewas deaf. It is now impossible to discover whether hewas born deaf, but in view of his comparatively wellarticulated speech in adult life it seems unlikely, How-ever from early childhood he was, for practical purposes,completely deaf, and attended a special school where helearnt to lip-read.The onset of further symptoms was variously dated

by the patient and his family, but one of his brothersthought that at about the age of 15 the patient's walkingbecame unsteady and slowly deteriorated. The patientdenied any such symptoms until the age of 35 when hislegs rapidly became weak " above the knees ". Thisweakness progressed so that for 10 months beforeadmission he had been unable to work.He first attended hospital in September, 1948, with

synovitis of the right knee, and at that time Wasting ofthe quadriceps was noted. He continued to attend theorthopaedic clinic, and eventually fasciculation was seenin the wasted quadriceps and he was referred for neuro-logical opinion.He was a pleasant and cooperative patient who could

lip-read with some skill and was adept at understandinggesture. There was no obvious defect of intelligenceand he was emotionally stable. His speech wasmonotonous in pitch and accompanied by sibilant ex-piratory sounds, but was seldom unintelligible.

On physical examination no abnormality could befound in the heart, lungs, or abdomen. The bloodpressure was 140/80 mm. Hg. There was no scoliosis,and no deformity of the feet.The sense of smell was intact.The optic fundi were normal and the acuity was 6/6

and Jl in both eyes. The visual fields were full. Theocular movements were normal and there was nonystagmus. The pupils were regular and equal withnormal reflex activity.There was no impairment of sensation over the face.

The temporal fossae appeared unduly hollow, but therewas no detectable weakness of the masticatory muscles.The jaw-jerk was brisk. There was no facial weakness,and the palate and tongue moved normally.For practical purposes he was completely deaf. More

exact testing (Dr. Purcer Smith) showed gross bilateralnerve deafness, with some residual hearing above 512cycles, and a little residue below this pitch at 10-20decibels. The ear-drums were normal. There was fullvestibular response to rotation, but moderate reductionof response to caloric stimulation on the left sideonly.

There was evident muscular wasting in all limbs (Fig. 1).In the arms the wasting was slight and peripheral indistribution, being most marked in the hands, but in thelegs the weakness and wasting were maximal above theknees, particularly in the quadriceps muscles. Thecalves were abnormally thin and the power of the tibialisanterior was reduced on both sides, but there was nodetectable weakness of the peronei or gastrocnemii.The selective distribution of the wasting may be seenfrom the following measurements:

R. L.Maximum circumference of calves 31 cm. 31-5 cm.Circumiiference of thighs 10 cm.above upper border of patella 29-5 cm. 30 cm.

When first seen one of the most striking features of hiscondition was the pronounced fasciculation of the wastedmuscles of the thighs, but this became less obvious onsubsequent examinations, and appeared to be of thenature of "-contraction fasciculation" as it was neverseen in fully relaxed muscles. When present it consistedof rapit fine, flickering contractions evenly distributedthroughout the affected muscle. All muscles respondedto faradism.The tendon reflexes in the arms were uniformly

exaggerated, but Hoffman's sign could not be elicited.The knee jerks were diminished and the ankle jerks

307F

Protected by copyright.

on 30 May 2018 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.13.4.307 on 1 Novem

ber 1950. Dow

nloaded from

308 W. B. MATTHEWS

absent. The abdominal reflexes werepresent, but both plantar reflexes wereextensor.

Sensation was intact except in the legs.Postural sense was impaired in the toesof both feet, and vibration sense wasabsent in the left foot. There was no

impairment of cutaneous sensation.There was marked cerebellar ataxia in

all limbs. Alternating movements werepoorly performed, and his writing wasshaky and uncertain. His gait was slow,but he was less incapacitated than mighthave been supposed. The feet were setdown wider apart than normal, and ateach step the heel caught the ground asthe advancing leg passed the horizontal.The foot was then swung clear of theground again and brought down withabnormal force. This unusual gaitappeared to be due in part to his lack ofconfidence in the power of the quadri-ceps to support his weight with the kneeeven slightly flexed.

Further investigation did not addanything of importance. There was noanaemia and the leucocyte count was

m. The cerebrospinal fluid con-tained 1 lymphocyte per c.mm. and 40mg. of protein per 100 mi. The Wasser-mann reaction was negative in bloodand cerebrospinal fluid. The electro-cardiograph was within normal limits.A 24-hour specimen of urine contained

no creatine and 1-4 g. ofi.o ~~~~~~~~~~~~creatinine. Radiographs of

the spine and skull werenormal.

1.1, the father of 11.3, aged69, had been healthy until in-capacitated by silicosis. Hewas examined, and apart fromhis respiratory condition, noabnormality was found. Inparticular his hearing wasnormal, and there was noataxia or muscular wasting.

.........He stated that his threebrothers and two sisters hadben similarly normal, and

.....~~~ ~ ~ ~ ~ ~ ~ that his parents had beenhealthy, his mother havingrecently died at the age of 100.

1.2, the mother of 11.3, aged71, had been healthy apartfrom an abscess behind theleft eye at the age of 30 whichhad left her with a "smalleye ". On examination the.rewas ptosis ofthe left upper eye-

Fio 1.-Distribution of muscular wasting in Case 11.3. lid, but no other abnormality

Protected by copyright.

on 30 May 2018 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.13.4.307 on 1 Novem

ber 1950. Dow

nloaded from

FAMILIAL ATAXIA

of the nervous system could be found, except thatboth ankle jerks were somewhat sluggish. Hearingwas normal and there was no muscular wasting. Shestated that her parents and four sisters had beenhealthy. She was not related to her husband.

11.1, the eldest child of 1.1 and I.2, a man of 44, wasexamined and found to be normal.

II.2, a man aged 42, had never learnt to speak intelli-gibly and had probably been deaf from birth. Soonafter leaving school his gait was noticed to be slow andunsteady, but he was not seriously affected until the ageof 33 when his disabilities began to be incapacitating,and since that time he had steadily deteriorated.He was much less skilled at lip-reading than 11.3, and

his speech was more severely affected, being, in fact,unintelligible. The optic fundi were normal, and therewas no nystagmus. He was severely deaf, but this wasnot analysed in detail. The ear-drums were normal.There was severe wasting of the intrinsic muscles of

the hands and of the lower halves of the forearms, and,in addition, some weakness of the proximal muscles ofthe arms without obvious wasting. The quadricepsmuscles were profoundly wasted, particularly in thelower two-thirds. The calves were abnormally thin butwere not so severely affected as the muscles above theknees. No fasciculation was seen. The tendon reflexesin the arms were uniformly exaggerated; the kneejerks were diminished and the ankle jerks absent. Theabdominal reflexes were present and both plantarreflexes were extensor. There was no intention tremorof the arms, but alternating movements were poorlyperformed. There was gross incoordination of the legs.His gait was similar to that of 11.3, but more ataxic.Vibration sense and sense of passive movement wereimpaired in both feet.

11.4, a woman aged 36, and 11.5, a man aged 34, wereexamined and found to be normal.

I.

11.6, a man aged 32, had been healthy until the age of15, when, following an attack of otorrhoea, he was foundto have perforated ear-drums, and since that time hehad been moderately deaf. Apart from his deafnesshe was thought to be normal, and examination had,therefore, to be unduly rapid, as it was not thoughtdesirable to draw attention to the abnormalities dis-covered. He was found to have a moderately severeconductive deafness, and both ear-drums were scarredand opaque. Speech was normal, and no other ab-normality could be discovered in the cranial nerves.However, there was evident wasting of the thenarmuscles and marked wasting of the quadriceps, butapparently none below the knees. The tendon reflexesin the arms were increased, the knee jerks diminished,and the ankle jerks absent. Both plantar reflexes wereextensor. No incoordination or sensory loss could bedemonstrated.

11.7, a man aged 30, had been deaf from birth and hadnever spoken intelligibly, but was otherwise thought tobe normal. On examination he was severely deaf andthe ear-drums were normal. His speech was unintellig-ible, but no other abnormality could be discovered inthe cranial nerves. There was no wasting in the armsor calves, but there was distinct wasting of both quadri-ceps. The tendon reflexes were brisk in the arms, theknee jerks were diminished and the ankle jerks absent.Both plantars were extensor. There was no inco-ordination or sensory loss.

111.1, a man, aged 20, the eldest child of 11.1, was notexamined, but was stated to be normal.

III. 2, 3, and 4, daughters of 11.1, aged 18, 15, and 13,were examined and found to be normal.

111.5, a boy, aged 12, the elder child of 11.3, was notexamined but was stated to be normal.

11.6, a boy, aged 7, the second child of 11.3, wasexamined and found to be normal.

2

I 2 3 41 5I1 6L 7;

12 2 3 4 5 6

= Deaf-mute, with signs of spinal cord affection and muscular wasting.

i = Spinal cord affection, muscular wasting and exogenous deafness.

FIG. 2.-Pedigree of affected family.

I[ .

mn

309

I

Protected by copyright.

on 30 May 2018 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.13.4.307 on 1 Novem

ber 1950. Dow

nloaded from

W. B. MATTHEWS

DiscussionThe four affected members (Fig. 2) of this family

present the features ofa familial disorder reminiscentof Friedreich's ataxia, without pes cavus or scoliosis,but with the addition of deaf-mutism in three andof selective muscular wasting in all. The existenceof acquired deafness in the fourth case is interestingbut probably only coincidental, as no clear pre-disposition to exogenous deafness can be demon-strated in those with a hereditary taint of deaf-mutism (Lindenov, 1945).Hammerschlag (1932) drew a rather laborious

parallel between the Japanece waltzing mouse,which suffers from hereditary deafness, albinism,ocular defects and ataxia, and the human deaf-mute. He postulated a heredopathia acoustico-optico-cerebro-spinalis, the factors being trans-mitted by linked recessive genes. The associationbetween deaf-mutism and retinitis pigmentosa iswell attested (Bell, 1922), and mental deficiencyprobably occurs more frequently than in the generalpopulation. Hammerschlag was, however, onlyable to describe two cases of ataxia associated withhearing defect. In one, ataxia of the Friedreichtype was combined with deaf-mutism, partialalbinism, mental deficiency, and a variety ofdevelopmental defects. The second case presenteda combination of retinitis pigmentosa, nervedeafness of comparatively late onset, and an ataxicgait. No detailed examination of the nervoussystem was recorded.The hypothesis of a linked inheritance of deaf-

mutism and ataxia receives little support froni astudy of the literature of Friedreich's ataxia, as,despite the great variety of neural and extra-neuralanomalies found sporadically in this condition,deafness is uncommon, and deaf-mutism extremelyrare. Thomas and Roux (1901) reported a caseof ataxia of unusual type combined with deafness,the auditory condition not being described in detail,and Variot and Bonniot (1907) described a girlwith cerebellar ataxia and progressive nerve deaf-ness beginning at the age of ten. In neither ofthese cases was there any apparent hereditaryfactor, but Kcennecke (1919) reported a brotherand sister with progressive nerve deafness from anearly age combined with Friedreich's ataxia andgeneralized muscular atrophy. Clauss (1924) de-scribed a case of ataxia of the Marie type withretinitis pigmentosa and a moderate degree of nervedeafness.

Muscular wasting has frequently been describedin Friedreich's ataxia. In many of the reports(for example, those of Rook and Dana, 1890;Whyte, 1898) the wasting has not been selectivebut an atrophy of the limb musculature late in the

disease and possibly due to disuse. However, agreat variety of more distinct forms has beendescribed, ranging from wasting of the intrinsichand muscles (Hodge, 1897) to extensive myopathywith pseudohypertrophy (Spiller, 1910). Spiller'scase came to necropsy, and it was clearly shown thatboth neurogenic and myopathic atrophy occurredin the same patient. The precise form of atrophypresent in the family reported here does not appearto have been described in association with ataxia.Although there are some similarities with peronealmuscular atrophy, there can be no doubt that thewasting first developed above the knees, and thatthe main disability was due to the consequentinstability of the knee joints, and not to weaknessround the ankle joints, as in the classical condition.The association between Friedreich's ataxia and

peroneal muscular atrophy is of particular impor-tance with regard to the general question of theinheritance of disease of the nervous system. Thecoexistence of the two conditions in the samepatient has been described by Greenfield (1912),and Fearnsides (1912), and Spillane (1940) reporteda family in which there was one case of Friedreich'sataxia and three of peroneal muscular atrophy, aswell as many of the syndrome of pes cavus andabsent ankle jerks, which might be regarded asabortive cases of either condition. Roth (1948)recently described two families in which the twoconditions coexisted, and discussed the mode ofinheritance. He concluded that the gene conveyingthe combined syndrome was probably distinct fromthose transmitting the individual diseases. Theinheritance in the present family might be explainedby the existence of two or three recessive genes, threesiblings being homozygous for ataxia, muscularwasting, and deaf-mutism, and the fourth for thetwo former only. It is statistically much moreprobable that a single recessive gene transmittedall three conditions, with lack of penetrance fordeaf-mutism in one case. The exact probabilitycannot be stated as the factor for lack of penetrancecannot be determined on so small a pedigree.

In spite of great variety in detail the hereditarydiseases of the nervous system tend to be curiouslystereotyped in general outline, and the more aberrantforms can often be interpreted as combinations ofwell recognized syndromes. It is also known thatclinical syndromes distinguishable only by time ofonset may be transmitted by different genes, or atleast by differently situated genes. Thus, forexample, peroneal muscular atrophy is known indominant, recessive, and sex-linked forms (Bell,1935), which must imply that this condition may be-transmitted by a gene either on the x-chromosomeor on an autosome. In view of the structural

310

Protected by copyright.

on 30 May 2018 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.13.4.307 on 1 Novem

ber 1950. Dow

nloaded from

FAMILIAL ATAXIA

complexity of the nervous system the comparativelyrestricted range of manifestations of hereditarydisease is surprising. The coexistence of two ormore of these manifestations in the same pedigreeis well-known, and has given rise to the conceptionof a " neuropathic heredity " on a rather ill definedgenetic basis. The pedigree of Friedreich's ataxiareported by Franceschetti and Klein (1941) is ofinterest here. In one offshoot the ataxia wasapparently replaced by labyrinthine hardness ofhearing, and in another by retinitis pigmentosa.These two conditions were regarded as " equivalent "to Friedreich's ataxia, and transmitted by the samegene. The means by which the genes exert theirprofound influence on the soma are largely un-known, but must be fundamentally biochemical.A neuropathic heredity might be explained by avery limited range of genetically influenced meta-bolic aberrations. The clinical results of suchaberrations would in part depend on the stage atwhich the developing nervous system was exposed,which, in turn, might well be modified by theinfluence of the total genetic structure on theabnormal gene. Any such explanation mustremain entirely speculative, as the nature of thegenetically determined lesion that can produce,often after a long latent period, degeneration offormerly normally functioning neurones, remainsquite obscure.

SummaryA family is reported in which four members of a

sibship of seven developed a condition similar toFriedreich's ataxia accompanied by muscular wasting

of unusual distribution. Three of the affectedmembers were deaf-mutes.The literature is reviewed and some speculations

offered on the mode of inheritance.

I am indebted to Dr. Fergus R. Ferguson for permissionto report on Case II.3, and to Dr. C. R. W. Gray forpermission to examine other members of the family:to Dr. H. C. Purcer Smith for his report on the auralcondition of Case 11.3 ; and to Dr. M. D. Milne foradvice on statistics.

REFERENCESBell, J. (1922). Treas. hum. Inher., 2, 17.- (1935). Ibid., 4, 91.Clauss, 0. (1924). Z. ges. Neurol. Psychiat., 93, 294.Fearnsides E. G. (1912). Proc. R. Soc. Med., 5, Neurol.

Sect., p. 144.Franceschetti, A., and Klein, D. (1941). Arch. Klaus-

Stift. Vererb-Forsch., 16, 469.Greenfield, J. G. (1912). Proc. R. Soc. Med., 5, Neurol.

Sect., p. 75.Hammerschlag, V. (1932). Wien. klin. Wschr., 45, 772,

808.Hodge, G. (1897). Brit. med. J., 1, 1405.Koennecke, W. (1919). Z. ges. Neurol. Psychiat., 53,

161.Lindenov, H. (1945). " The Etiology of Deaf-mutism

with Special Reference to Heredity." Copenhagen.Rook, C. W., and Dana, C. L. (1890). J. nerv. ment.

Dis., 17, 173.Roth, M. (1948). Brain, 71, 416.Spillane, J. D. (1940). Ibid., 63, 275.Spiller, W. G. (1910). J. nerv. ment. Dis., 37, 41 1.Thomas, A., and Roux, J. C. (1901). Rev. Mid., 21,

762.Variot, G., and Bonniot, E. (1907). Rev. neurol., 15,

298.Whyte, J. M. (1898). Brain, 21, 72.

311

Protected by copyright.

on 30 May 2018 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.13.4.307 on 1 Novem

ber 1950. Dow

nloaded from