Acta ledica Scandlnnvica. Vol. CXXIII, fasc.--V, 1946.

From the Neurological Clinic of the Serafimer Hospital, Stockholm. Head: Professor Nils Antoni.

Contributions to the Symptomntology of Amyotonin Congenittl

(Infantile Spinal Muscular Atrophy). BY

GFUNNAR WOHLF'ART.

(Submitted for publication August 17, 1946.)

Inlroduct ion.

The disease described by Werdnig 1890 and Hoffmann 1893 under the name of hereditary infantile spinal progressive muscu- lar atrophy is now by most neurologists regarded as being iden- tical with amyotonia congenita (Oppenheim 1900). This appre- hension was already asserted by Hoffmann himself according to statements by Slauck 1920. Causes for the identity of the two diseases have been brought up by amongst others Rothmann 1909, Wallgren 1923, Katz 1928, Gjorup and Schroeder 1936, de Lange 1937, Alantar 1938 and Karlstrom and G. Wohlfart 1939. In 1920, Krabbe came to the conclusion after a thorough discus- sion that it was a question of two different diseases, and this point of view was also held by Bielschowsky 1929, and Schild- knecht 1934. In Bumke-Foersters Handbuch der Neurologie B. 16, 1936 the Werdnig-Hoffmann and Oppenheim symptom pictures are described as different diseases, likewise in von Bergmanns Handbuch der Neurologie B. 5, 1939 and in Kinnier Whons large ))Neurology) 1940. The question as to the possible identity between the two diseases has even been discussed by Spiller 1913, Green- field and Stern 1927, Steindler 1935 and Caussade, Karlin and Neimann 1939.

SYMPTOMATOLOQY OF AMYOTONIA CONGENITA. 429

Both diseases can suitably be comprised under the name amyotonia congenita (Morbus Werdnig-Hoffmann-Oppenheim) or expressed as infantile spinal muscular atrophy. Of the disease in question a large number of cases have under the last years been published, so that the symptomatology has been looked upon as being fairly well known. (Amongst cases published under the lat- ter years the following may be noted: Gourse 1939, Weinberg 1939, Andersson and Reeves 1940, Hanisch 1941, Eger and Ohr 1942, Hassin 1942, Lewey 1942, Fossatti and Portillo 1943.)

A considerably greater number of cases have been published under the name of Oppenheim’s disease than under that of Werdnig-Hoffmann’s disease. This fact is surprising, as the disease picture and especially the almost unexceptionally unfavourable course rather should have given motive to the diagnosis of Mor- bus Werdnig-Hoffmann in a very great percentage of the cases published. Among publications over the Werdnig Hoffmann variation are to be mentioned those by Wimmer 1907, Michael 1923, Grinker 1927, Greenfield and Stern 1927, Schildknecht 1934 and Karlstrom and G. Wohlfart 1939. More extensive papers re- garding the Oppenheim variant have been published by Collin and Wilson 1908, Griffith 1910, Reuben 1917, Faber 1917, Krabbe 1920, Greenfield and Stern 1927, Bielschowsky 1929, Karlstrom and G. Wohlfart 1939 and Turner 1940.

Though the number of cases published in the literature is great, it has seemed motivated to describe in the following some cases of amyotonia congenita, which seem in some regards to enrich the knowledge of the symptomatology and prognosis of the disease in question.

Own Investigations. I . The Family 0. The family is of well-to-do farmer stock in southernSweden

(Smbland). The following is a description of a brother and three sisters a t the ages of 6, 8, 10 and 12 years, all suffering from amyotonia congenita. The children a t present 6 and 12 years old respectively, have however the disease in slight degree. Three of the cases have simultaneously atrophy of the optic nerves, two squint.

Heredity: The father, born 1903, is the second of four children, all mainly in good health. The mother, born 1905, is the third of eleven children, even these healthy. Mr. and Mrs 0. have only

430 QUNNAR WOHLFART.

the four offspring described below. No miscarriage. The childrens paternal grandfather and maternal grandfather were cousins, the parents are thus second cousins. Mr. and Mrs. O., who have been examined by the author, showed no signs of organic disease of the nervous system.

As shown in the geneological table, Fig. I, there have been two certain cases of amyotonia congenita, namely that of a cousin to Mr. O., and of the child to a second cousin of his. With regard to the former, the following facts have been ascertained: the child, a boy, lived to the age of 6 months. He was completely limp in

#t = snre cases of amyotonia congenitn in fully developed form.

= snre cases of amyotonia congenitn in rndimentary form.

8 9 = deceased in infancy, suspected of being cases of amyotonia congenita.

Fig. 1. Diagram over a part of the family 0.

the whole body, could not move his head. Was moreover said to have had club-feet. The same parents have further had a still- born daughter, a son dead some hours after birth, and a son dead after a few weeks. They have one healthy son, now aged 18. The second case of certain amyotonia congenita was a girl who lived to the age of about 4 years. She is said never to have been able to walk or stand, nor to lift her arms. Was mentally normally developed. The same parents have a healthy son now 6 years old, and have further had a boy who died a t the age of some months.

Lastly can be mentioned that a family from the same district, as known not related to the family 0. have had two children who have died under the diagnosis of Oppenheirns disease.

The remaining members of the family are reported as being or having been of good health and ability. Mrs. O.’s mother was however periodically insane.

SYMPTOMATOLOQY OF AMYOTONIA CONQENITA. 431

Case I. R. O., boy, born 1938. Diagnosis: Atrophia n. optici bilat. Strabismus concomitans divergens. Amyotonia congenita incipiens. Birth weight 4.3 kg. Developed normally during the first years men- tally as well as in respect of general motility. Could sit up a t the age of 7 months, a t 11 months pulled himself upright, and walked round a play-pen. At 1 year 2 months walked without assistance.

At 2 years of age varicellae and rubeola. A t 4 years he began to complain of fatigue during walks and became less persevering. At the same time he started closing the left eye and through a period of some months the eye began to turn outwards. Gradually this eyebegan even to *tremble# (nystagmus). At 4 years it was also noticed that his sight was poor, and becoming worse.

Admitted to the Neurological Clinic of the Serafimer Hospital, 11.3. 1943. (Case No. 28611943.)

S t a t u s . Somatic Examination. For his age a normally developed 4lI2 year-

old boy with a good general condition and fairly well covered. Weight 19.2 kg. Genua valga bilaterally. In lying posture excavated insteps. No signs of past rachitis. Whirl at anterior hair line. No cyanosis or dyspnoea. No oedema.

Oral cavity and throat: Considerable caries. Adenoidal growth in the throat.

Thyroid p o comment. From internal organs notbing abnormal. Normal b6dy temperature. Sedimentation rate according to Wester- gren 2 mm. Wassermann reaction negative in blood. Blood and urine no comment.

Mentality. Lively, normally developed for age. Examination of the Nervous System. Visus (uncertain values, probably too low), right: 2/50, left: hand-

Sciascopical Examination: Right = left = - 0.5. Optic disks pale, especially temporally. Lens: no comment. Pupils

round, likesized, react without comment to light and accomodation. Left eye turns outwards and shows periodically a nystagmus of un- dulating type apparently not of vestibular origin.

Otoneurological examination: no comments. Remaining cranial nerves (I, V, VII, IX, X, XI, XII) no comments. General motility: gross strength good throughout. No visible hypo-

tonia, no atrophy. Can without difficulty do kneebending, raise him- self from backlying and from forward bending. Direct mechanical muscle irritability normal or somewhat weakened. No fibrillary twit- chings, no hyperkinesias.

movements 3 cm.

General sensibility: no comment. Cerebellar tests: no comment. Reflexes: skin and mucous membrane reflexes no comment. No

muscle reflex can be produced. No extensm plantar response. The Rossolimo reflex neg. bilaterally.

No trophical disturbances. Bladder and bowel function: no comment.

432 Q L N X A l t WOHLFART.

X-ray examination of the skull. Cranium of usual form and thick- ness. No suture diastasis. No extended vesselgrooves. No intracranial calcinations. No destructions. Right optical foramen somewhat wider than left. No destructions in their surroundings. (Lysholm). Creatine determination of urine (ordinary mixed diet):

Fig. 2. Case I at the nge of 4% years.

Before glycocoll treatment 33 mg/24 hours (1 determination). During glyocoll treatment 71 mg/24 hours (average of 7 determi-

nations). After discharge from the Serafimer Hospital the patient has de-

veloped in normal manner. With regard to the motility nothing def- initely pathological can be ascertained during the following 11/* years. The sight does not seem to have deteriorated.

Reexamination 19.11.1944. General condition good. Well-nourished

SPMPTOMATOLOQY OF AMYOTONLA CQNQENITA. 433 lively boy of 8 years. Scapula alata bilat. Sway-backed. General mo- tility no comment. Can run faster than any of the three elder sisters. Has a strabismus concomitans divergens. Visus 0.1 bilat. Left eye turns outwards and falls occasionally, as on former examination, in undulating nystagmus. Optic disks strikingly pale, clearly atrophical. Reflex status unchanged since former examination.

Case ZI. I(. 0. girl, born 1936. Diagnosis: Amyotonia congenita. Atrophia n. optici bilat.

Birth weight 4.0 kg. During the first months the patient seemed to develop normally, but it soon became apparent that she had not normal muscle power. At 6 months she could roll herself over onto the abdomen, a t 8 months she began to sit up a little. At 10 months she sat on the floor without support. At 11 months she weighed 10.3 kg, her legs could support her a little and she could take short steps when held. At one year of age the patient had a throat infection and rubeola. Delicate for a long time after these illnesses. At 1 year 5 months a reinfection of the throat. Admitted to a local hospital, wbere the diagnosis morbus Oppenheim was given. The muscles of the whole body were then loose and flabby, and when the attempt was made to raise the patient onto her feet she fell completely together.

At 1 year 8 months the patient could raise herself from a stool, a t 1 year 9 months get up on her knees, and it was first a t the age o 2 years 2 months that she could walk properly.

Even during the following years the muscles were markedly slack and weak. Loose shoulders. It was not till the age of 4 that the pa- tient could walk up-stairs. At 6-7 years she began to run, learnt to lift her head when lying flat on her back, and began to be able to raise herself from a forward bent position.

At 6-7 years of age the mother noticed that the patient’s sight was poor. The girl has twice been admitted for examination t o the Neurological Clinic of the Serafimer Hospital.

, 5 year-old girl girl with good general condition and sebmingly nor- mally developed for her age. Well-nourished. Weight 18.9 kg. No visible deformity, no signs of having had rachitis. No spinal deformity. No signs of endocrinal disturbance.

From internal organs nothing of comment. Normal body tempera- ture. Urine without comment. Wassermann reaction negative in the blood.

Mentality. Clear and lucid, calm and compliant. Has a good general knowledge. Knows most of the letters of the alphabet. Seems ordinarily developed for her age.

8 t a t u s. 12.3.1941 (No. 245/1941).

Exanaimztion o/ the Nervous System. Cranial nerves: pupils without comment. The position of the eyes

and their movements without comment. Eye grounds without definite pathological changes. Chewing and sensibility within the trigeminal area without comment. Mimical movements without comment. Can catch a whisper a t a distance of 6 meters bilaterally. No nystagmus.

484 QULNAR WOHLFART.

No gum or throat paresis. Head-turning weak. Cannot lift head when lying down. Shoulder lifting with some difficulty. The position of the tongue and its movements without comment. Speech without comment.

General motility: Obvious hypotonia in the muscles of the extremities with increased range of movements of the joints. On palpation the

Fig. 3. Case I1 at the age of 7 years.

muscles seem somewhat looser than normal. The shoulders can be hunched up considerably higher than normal.

Gross strength strongly reduced throughout in all the muscles. Cannot raise herself from backlying position without having to roll onto the side. Cannot rise up from forward bending without d m b i n g r on her knees. Can stand on toes. Gait generally uncertain, swaying, exerted. Suggestion of a wwaddlelp. Ankles tend to bend inwards. Can- not run. No more definite atrophies. No visible fibrillary twitchings.

BYMPTOMATOLOQY OF AMYOTONIA CONQEBITA. 435 Direct mechanical muscle irritability poor. No certain change of gal- vanic or faradic irritability within the lower leg muscles.

Cough without comment. Breathing without comment, no hyper- kinesias.

General sensibility without comment. Cerebellar tests without comment. Reflexes: Skin and mucous membrane reflexes normal. Muscle re-

flexes lacking. (There are possibly calf reflexes but these are in such case extremely weak.)

No extensor plantar response. Rossolimo neg. bilat. No trophical or vasomotor disturbances. Bladder and bowel func-

tions without comment. Elcctromyogram. (Underarm and thigh muscles.) In repose action

currents occur. Verdict: spontane activity? Fibrillary twitchings? (Dr. Skoglund) .

Creatine decisions 01 the urine: Two tests on ordinary, mixed diet gave the respective values of 204 and 12 mg creatine per 24 hours.

Excision from m. quadriceps dx. Nothing definitely pathological was found in the examined piece of muscle. No dystrophical changes. No interstitial fat deposit.

After discharge the patient was ordinated glycocoll, and took under a period of about 4 months 1 kg of this substance. Marked improve- ment. This continued, however, as mentioned above, without inter- ruption even after the cease of the medication.

Readmitted to the Serafimer Hospital’s Neurological Clinic 11.3. 1943. (Nr. 284143).

S t a t u s . Somatic status: Has grown somewhat since the former examina-

tion. Weight 20.5 kg. General condition good, well nourished. Genua valga bilat. The insteps excavated in lying, normal in standing position.

Oral cavity and throat: Considerable caries. Thyroid not enlarged. From internal organs in general nothing to remark upon. Sedimenta- tion rate on three tests increased: 27, 38 and 35 mm respectively.

Liing X ray neg. Urine normal. Wassermann reaction neg. in blood and liquor. Lumbar liquor without pat.hologica1 changes.

Mentality: Seems well developed for her age. Can read simpler words, thougb she has not yet begun school. No speech defect.

Examination of the Nervous System. Cranial nerves: Sense of smell normal bilaterally. Visus 0.1-0.2 bilat. (refraction - 0.5 bilat.). Pupils round, like-

aized, react normally to light and accomodation. Visual fields, roughly tested, without comment. Optic disks markedly pale temporally. NO lens clouding. The eyes’ position and movements without comment. Mastication, taste, sensibility in face without comment. Mimical muscles without comment. Hearing good. Can discern whisper a t a distance of 8 meters bilaterally. Otoneurological status without comment.

Movements of jaws and throat without comment. -452575. Acta med. acandiirav. Vol. C X I I I I .

436 OUNNAR WOHLIFART.

Headlifting when lying on back possible, though difficult. Likewise

Position and movements of the tongue normal. KO tongue atrophy. General motility: Gross strength rather weak in extremities and

trunk. Cannot raise herself from back lying without rolling over onto her side. Can now rise up from forward bending without *climbing* on the knees. The shoulders now better fixed than formerly. Definite ewaddb. Can run, though with great exertion. Does not lift the legs as high as is normal - it seems as if she was running through mud - and keeps the feet somewhat inwardly rotated.

The muscles of the upper extremities generally somewhat weakly developed and slack on palpation. Remaining muscles normal as t o dimensions but possibly someRhat slack on palpation. No localized atrophies, no fibrillary twitchings. Direct muscle irritability generally poor. Cough and strain without comment. No hyperkinesias.

General sensibility and cerebellar tests without comment. Reflexes: No muscle reflexes can be produced. Skin and mucous

membrane reflexes without comment. No extensor plantar response. Rossolimo neg. bilat.

headtwisting. Shoulder hunching without comment.

Bladder and bowel functions without comment. X ray examination of the skull: Thin, short cap with fairly pro-

nounced impressions. No suture diastasis. No enlarged vessel grooves. No intracranial calcinations. No destructions of the cap or skull base. Right foramen opticum wider than left, but no destructions in their surroundings (Lysholm) .

Creatine h i s i o n s of the urine: (ordinary mixed diet). Before glycocoll treatment: 42 mg/24 hrs (average of 3 decisions). During a u : 56 mg/24 hrs ( a e 7 9 ). Reexaminatzon 19.11.1944: Lively 8 year-old girl with good ge-

neral constitution and well-covered. Scapula alata bilaterally. Walks with the upper body leaning somewhat backwards. Gross strength generally greater (this even relatively, with regard to growth), motility otherwise about the same as on former examination.

Of the muscle reflexes, pronator reflexes can now be produced, par- ticularly on the left side. Remainder still lacking. Walks daily several kilometers to school, but tires considerably faster than form-mates. Can run, but still with visible exertion.

Eye grounds unaltered. The papilli are possibly somewhat paler than before. Psychically well developed. Clever a t school.

Case ZZZ. 11. O., girl, born 1934. Diagnosis Amyotonia congenita. Atrophia n. optici bilaterally.

Was delicate from birth. Has from birth been strikingly slack in all muscles. First a t 8 months she could hold her head upright. At 9-10 months she could neither sit nor herself roll over onto her stomach. Consulted pediatrician diagnosed morbus Oppenheim.

At 1 year of age the patient could sit without support, a t 1 year 1 month she began to be able to support herself a little on legs. At 1 year 5 months she weighed only 10 kg. First a t 2 years could she walk

SYMPTOMATOLOQY OF AMYOTONTA COKQENITA. 437 with support. At 2 years 2 months could walk unsupported. Has how- ever continued being muscle-weak and has tired faster than other children. A t 3-4 years of age the lower extremities could be abducted 90" at the hips and the feet could be placed behind the neck. She has for several years dimbed* with the hands on the thighs when rising from forward bending. For several years she could not run. First a t 8 years of age she began to be able to lift her head when lying on her back. Since the patient began school a t 8 years of age i t has been no- ticed that her sight is poor.

Admitted to the Neurological Clinic of the Serafimer Hospital 11.3. 1943.

S t a t u s 11.3.1943. (Nr. 285/43). Somatic status: General conditon fairly good. Very thin girl of fragile

build, much too small for her age. Weight 18.7 kg. Funnel-chest. Strong loin lordosis with compensative kyphosis of the thoracic spinal column. Walks with the upper part of the body leaning somewhat backwards. Genua valga. Instep excavated on lying, the excavation evened on standing. No cyanosis or dyspnoea. No oedema.

No visible deformity. Considerable dental caries. Otherwise nothing to comment upon

from the internal organs. Blood status without comment. Urine: no albumin, no reducing substance, no urobilinogen. No pathological sedi- ment.

Mentality: Quiet, shy, good. Ordinary intelligence (short intelligence test according to Wiihlh: Intelligence age 9-10 years).

Somewhat smaller fund of knowledge than ordinary on account of late school entrance. No speech defect, no apraxia.

Examination 01 the Nmotcs System. Cranial nerves: Sense of smell without comment bilaterally. Visus 0 . 2 bilat. ( 5 0). No lens sedimentation. Optic disks generally

Pupils without comment. The eyes' positions and movements with-

Chewing muscles without comment. Sensibility in face without com-

Hears whisper a t 6 meters distance bilaterally. No nystagmus. Movements of the soft palate and of the throat normal. Strength very poor on head lifting from dorsal position, head-

The position of the tongue and its movements without comment. No tongue atrophy. General motility: The muscular system poorly developed without

localized atrophies. The gross strength generally poor. Somewhat in- creased movement range in certain joints, e. g. hand and finger joints. Can rise up from downward bent position, can do knee bending, can stand on toes, all of which however with difficulty. Cannot rise up from back-lying without rolling over on her side. Can raise tbe head when lying on back, not however if a slight pressure with the little finger is applied to the forehead. Can only with the exertion of her

palely grey, especially temporally. Visual fields normal.

out comment.

ment.

twisting and shoulder hunching.

438 QUNNAR WOHLFART.

whole strength hoist herself onto a bench reaching to the level of her navel. Walks with the feet somewhat inwardly rotated, no uwaddlea. Runs with visible exertion. No fibrillary twitchings. Direct mechanical muscle irritability generally poor. Cough and strain without comment. No pseudohypertrophias. No Ii yperkinesias.

Fig. 4. Case 111 at the age of 9 years.

General sensibility: no comment. Cerebellur tests: without comment. Rellexes: Skin and mucous membrane reflexes without comment. No muscle reflexes can be produced. No extensor plantar response. Rossolimo neg. bilat. No trophical disturbances. Bladder and bowel junctions without comment. Rkull X-ray. Cap of ordinary form and thickness. No suture diastasis,

SYMPTOMATOLOQY OF AMYOTONIA CONQENITA. 439

on enlarged vessel grooves. No intracranial calcareous deposit. Right foramen opticum somewhat wider than the left, but no destructions in surroundings of these foramina (Lysholm).

Skeleton X ray (upper extremities). No skeletal changes of the hands, underarms or overarms. (Lysholm.)

Creatine decisions of the urine: (ordinary mixed diet). Before glycocoll treatment: 110 mg/24 hrs (average of 3 tests). During H N : 109 mg/24 hrs ( J) D 10 D ). Histological Examination of excision from m. vastus lat. dx. Nothing definitely pathological found in the examined portion. No dystrophical changes, no interstitial fat deposit.

Case ZV. G. 0. girl born 1932. Diagnosis Amyotonia congenita. Strabismus alternans convergens.

Has always been delicate. Has squinted from birth. Learnt to walk first a t 18-20 months. Has always been a little fat and with markedly loose and weak muscles. Has small powers of endurance on bodily exertion. Sight normal.

At the age of 3 a haemangioma was removed from the tip of the nose at the Radium Hospital in Stockholm.

Seems to have a brittle skeleton. Has had fractures of both arms and right lower leg.

Status 19.11.1944: General condition uninfluenced. A rather fat and Nbloatedo 12 year old girl, who psychically does not appear to be so forward as her sisters and brother, but who does quite well a t school. Sway backed, no scoliosis, no scapulae alatae. Cubitus varus bilaterally. Left elbow region deformed through old fracture. The skin of the underarms, thighs and lower legs is of marmoracious appearance. From the internal organs nothing commentable on ordinary physical ex- amination.

Examination of the Nervous System: No muscle atrophies or pseudo- hypertrophies. Gross strength generally poor in trunk and extremities. All niuscles of the extremities seem loose and flabby on palpation. Can run, do knee bending, stand on tip toe, raise herself from forward bent position. Moves, however, a little clumsily and uncertainly. Be- comes very breathless on running. Calf reflexes lacking. Brachioradialis, pronator, biceps, triceps, kneebcnding and quadriceps reflexes present bilaterally, though rather weak. No extensor plantar response. Ros- solimo neg. bilat.

General sensibility, cerebellar tests, without comment. Has a strabismus alternans convergens with visus 1. o bilat. Eye grounds show normal findings. Remaining cranial nerves show

nothing definitely pathological.

ZI. Case V . M. P., girl, born l9t2. Diagnosis: Atrophia musculorum progressiva spinalis infantilis hereditaria ( Werdnig-Hoffmann). Atro- phia n. optici bilateralis.

This case will only be described shortly. A cousin to tbe patient (a son of the father’s brother) died 1944 a t

8 months of age under the diagnosis Werdnig-Hoffmanns disease.

440 GUNNAR WOHLFART.

Fig. 5. Case V at the age of 2 years 3 months.

The diagnosis was given a t the pediatric clinic of Norrtulls Hospital in Stockholm. The maternal grandfather died of a brain tumour. There are no further known nervous diseases within the family. The patient has no brothers or sisters.

The patient has always appeared weak in the legs, while she moved the arms and head normally during the first six months. The lower extremities’ motility has decreased afterhand and during the last year she has hardly been able to move them a t all. Since the end of her second half-year the power in the arms has also weakened and the patient has had increasing difficulty in moving her head. The last months it has a.lso been difficult to chew and swallow.

Status 5.10.1944. (The Neurological clinic of the Serafimer Hospital nr. 1029/44): General condition fairly good. Somatically nothing com- mentable except for some rachitic symptoms. Psychically not partic- ularly backward.

Emmination of the Nervous System. No localized muscle atrophies, though the muscles seem generally atonic. No fibrillary twitchings. Can hold her head upright a little while but drops thereafter down onto the chest. (Pig. 6. ) No tongue atrophy. Advanced paresis of the arms, almost complete paralysis of lower extremities. No muscle re- flexes can be produced. No external plasted response. Total electric degeneration reaction of t,he arms, the muscles of the lower extremities

SYMPTOMATOLOQY OF AMYOTONIA CONCENITA. 441 electrically unirritable. On an attempt to take an excision from m. quadriceps dx. only adipose tissue was found in place of the muscle. A test of this was not sent for microsco ic examination.

Special Ophthalmological Examination ( 8 sterberg): Strength of vision a t least 0.5 (5 binocularly).

Both optical discs clearly atrophically coloured. Vessels normal.

Discussion. That the above described three sisters and brother 0. suffer

from Oppenheims disease is seemingly certain. Of these the eldest, a girl, and the youngest, a boy, have the disease in rudimentary form, whilst the two others, both girls, show a fully established if relatively mild morbus Oppenheim.

The four children illustrate here how the disease pictures of morbus Werdnig-Hoffmann and morbus Oppenheim converge into one another. According to earlier general opinion Werdnig-Hoff- mann’s disease appeared in about the second half-year in children who had earlier shown normal development, and consisted of a continuous destruction of peripheral motor neurones. The disease picture should therefore be characterized by progressive muscular atrophies with accompanying muscular weakness. The muscle re- flexes (otendonreflexes))) should be lacking and electric degenera- tion reaction often be provable. The disease should further as a rule be familiar.

Contrary to the above, Oppenheim’s disease should be congen- ital and characterized by a tendency towards a standstill or bet- tering. Muscle atrophy should not be present. The disease should not be familiar.

According to the recently mentioned, older principles these children’s disease should actually correspond to morbus Oppen- heim. The absence of muscle reflexes and the familiar appearance point however to morbus Werdnig-Hoffmann.

With regard to the time of appearance of the symptoms (the period a t which they were observed) this was somewhat different for each of the above described sisters and brother. Whilst the general muscle weakness in cases I11 and TV was discovered soon after birth, i t was observed in the after the other cases born case I1 first a t about 6 months of age. Cases 111 and IV were thus apparently Oppenheim cases, whilst case I1 in this regard was of Werdnig-Hoffmann type.

More recent authors on this matter, whose opinion i t is tha t

442 QUNNAR WOHLFART.

it is a question of separate diseases, e . 9. Schildknecht, confess to the appearance of mixed types and stress the progression as being typical for the Werdnig-Hoffmann variant.

In point of fact i t is apparent on closer study of the several single cases of Werdnig-Hoffmann’s or Oppenheim’s disease which have been published throughout the years, that mixed forms are more usual than typical cases. The author’s right to a classification of the cases can often be discussed, and i t has oc- curred that the same case has by one author been referred to one type of disease, and by another author to the other. This holds good even, as de Lange emphasizes, for a couple of the cases published by Bielschowsky on which this researcher grounded his opinion that the two diseases must be separated.

It has even occurred that in brothers and sisters (Bibergeil 1914) and even in twins (Pearce 1920) the two diseases have ap- peared.

As introductively stressed, it must be regarded as certain tha t Werdnig-Hoffmann’s and Oppenheim’s diseases are identical. This holds good even for the anatomical findings (Karlstrom and G . Wohlfart).

It is a problem how the opinion that Oppenheim’s disease should have a good prognosis ever has been reached. Reuben (1917) states the fact, in a record of 6 personal cases and 136 cases from the literature, that ))the prognosis as to recovery is absolutely bad; there is no record of complete recovery in a single case . . . Of 84 cases, in which the final outcome was stated, 45 are known to have died.)) Practically every one of these cases died before the age of 7. According to some authors, e. g. Winter 1930, those suffering from amyotonia congenita never reach puherty. Kinnier Wilson writes in his large text book (1940) that the oldest known certain case uptil then was one described by Haushalter, the patient then being 131/8 years old. Block published in 1909 a doubtful case of an 18-year-old.

Meanwhile Turner described in 1940 a family in which several members with amyotonia congenita have reached adult age.

The four children of the family 0. described above will in a1 probability also reach adult age and even reach a fair working ability, inasmuch as their visual defects lay no hinders in the way. The family 0. seems thercfore t o be the second known family in the world with amyotonia congenita of such a benign course. A short article about the family described by Turner would with

SYMPTOMBTOLOQY OF AMYOTONIA CONOENITA. 443 regard to this fact be of interest. This was composed of nine girls and four boys, of which three girls and one boy had amyo- tonia congenita. The parents were healthy and there was no known case of nervous or muscular disease amongst their relatives. Besides the thirteen recently mentioned offspring the parents had had one still-born child (the presentation was a breach and the child was strangled during delivery) and a miscarriage at 3112 months. The affected children seem to have been typical cases of amyotonia congenita. They owere perfectly limp after birth and could easily be doubled up. Their heads used to loll about in an unusual way. They never used their legs till they were about 18 months old and when they were about two they started to crawl about in a sitting posture.)) One of these children (a girl) died of measles a t the age of three. The other children were a t the time of the last eaxmination 18-29 years old. They had during the growing period improved after hand and were on examination fully working able. One of the children, a girl, had a healthy child a t the age of 29. All of the cases showed localized atrophies and weakness in certain muscle groups of somewhat dif- fering extension in the separate cases. Especially the shoulder muscles and sternocleidomastoid were affected. Three of the cases showed a slight lumbar lordosis and certain muscle reflexes were weak or lacking in some. Nothing is mentioned as to the presence of any defect of the visual fields in any case. None of them showed signs of myotonia, fibrillary twitchings, pseudohypertrophia or sensibility disturbances.

The diagnosis seems to have been true with regard to the Turner cases. It seems probable that the more affected of the children 0. described in this article will in adult age come to show a picture resembling that of the cases described by Turner, that is, possibly remaining atrophies, lumbar lordosis, weakening or absence of certain muscular reflexes.

That several members of the same family of brothers and sisters can be affected by amyotonia congenita can now, since the relationships between the Werdnig-Hoffmann and Oppenheim diseases have been made clear, not in any way be regarded atyp- ical but as a usual fact. (Cf. e . 9 . Moe 1930, Looft 1931, Thums 1938.) It is on the other hand less usual that the disease has ap- peared amongst other relatives. The family 0. showed, as men- tioned, a sure positive heredity for Oppenheim’s disease. Besides the cases recorded in the geneological table (Fig. l ) , it lies near

444 QUNNAR WOHLBART.

a t hand to presume that those of the father’s cousins who died in infancy probably suffered from the same disease. I n most families with amyotonia congenita i t is namely recorded that one or se- veral other children have died of ))general weakness)) or such like, already during the first weeks or months of life.

Lastly is to note that incipient cases of amyotonia congenita as e . 9. case I above, have not earlier been described.

The optical atrophy from which three of the four cases suffer is unique in that this symptom never earlier has been described in definite cases of amyotonia congenita. It is true that Gordon wrote in 1913 an extremely short account of, according to his judgement, a case of amyotonia congenita with double sided op- tical atrophy. The case had, however, even a positive Wassermann reaction and it, is well known that optical atrophy even can occur in connection with congenital syphilis. Spiller, who had the op- portunity of himself seeing the Gordon case, was furthermore of the opinion that this could not be classified as amyotonia con- genita a t all.

One cannot however conclude, from the fact that optical atrophy has not earlier been observed in connection with the disease in question, that the symptom is extremely rare. It is namely quite logical tha t optical atrophy can have been over- looked in several of those cases which have died during the first year of life, and these compose the greater part of the cases de- scribed in the literature. Only a few authors get a definitely ne- gative result as to eye ground examination, amongst these Krab- be, who in 3 of 7 cases mentions tha t eye ground examinations gave normal findings.

That atrophy of the optic nerve can be more usual than one a t present has reason to suppose in connection with amyotonia con- genita, is indicated by its presence in a lately treated case a t the Serafimer Hospital’s Neurological Clinic, above shortly described as case V. Even this case showed a positive heredity for amyo- tonia congenita.

In future attention must be focused on the eye ground findings in all cases of Werdnig-Hoffmann and Oppenheim diseases.

As known, atrophy of the optic nerve is a leading point on certain hereditary nervous diseases, especially the heredoataxias. According to T. Sjogren 1943 optical atrophy was present in 22 of 139 examined cases of heredoataxia. In progressive neural muscular atrophy (Morbus Charcot-Marie-Tooth) occasionrtlly

SYMPTOMATOLOQY OF AMTOTONIA CONGENITA 445

even optical atrophy occurs. This is stated by, amongst others, Bodechtel 1939. Two brothers with progressive neural muscular atrophy and optical atrophy have further recently been described by Milhorat (1943). In the just mentioned diseases, optical atrophy is as a rule slowly progressibe, whilst in Leber’s hereditary optical atrophy i t often takes on a subacute or acute form.

In light of the above, the appearance of optical atrophy even in amyotonia congenita is not surprising. As the history of the disease shows, this has in the above described cases been of the extremely slow progressive type, possibly with periods of stand- still.

Two of the above described children 0. squinted, in the one case of divergent, in the other of convergent type. This symptom has earlier been described several times in amyotonia congenita. (Orbison 1909, Haberman 1910, Guinon and Gauducheau 1911, Spiller 1913, Reuben 1917 etc.) One can, as Wilson, perhaps con- sider that ))occasional squint is doubtless incidental)). It must however be noted that squinting, as well as eye muscle pareses, is not unusual even in heredoataxias, especially such of cerebellar type.

There is no reason for going into detail with regard to the histo-pathological discoveries in amyotonia congenita. The author intends giving a detailed account in this connection in a following article. The muscle excisions from two of the above described cases showed on examination no pathological changes, a fact which is hardly surprising, as the changes present are in all probability distributed spotwise, and can therefore not be found in every excision. The excisions are nevertheless of value in that they show the absence of dystrophical muscular changes. That the above described cases are not t o be assigned to the progressive muscular dystrophy group is fully shown by the dis- ease history. This latter disease does not appear so early and does not retreat so obviously as in the named cases. There is further a complete lack of pseudohypertrophia, the typical increase in creatinuria on glycocoll medication etc.

Summary.

1. Werdnig-Hoffmann’s and Oppenheim’s diseases are to be considered as one disease, amyotonia congenita = infantile spinal muscular atrophy = morbus Werdnig-Hoffmann-Oppenheim.

44 (i QUNNAR WOIILYART.

2. A family with several cases of amyotonia congenita is de- scribed. Of especial interest is a thoroughly examined quartet of brother and sisters in ages ranging from 6 t o 12 years. Of these 2 suffer from amyotonia congenita in fully pronounced form, b u t with since several years retreating symptoms, so tha t both children will in all probability reach adult age, and even become fairly u-orking able as concerns motility. The two other children have the same disease in rudimentary form. Three of the four children suffer further from optical atrophy, a symptom which has earlier been overlooked, and which probably occurs in a certain percentage in this disease. The circumstantially benign course as regards niotility in the described cases is also extremely unusual in tha t only one similar family has earlier been described.

3. In a case of amyotonia congenita of type Werdnig-Hoff- mann, optical atrophy was present, which fact gives strength t o the conclusion tha t this symptom is more usual in the disease in question than would be supposed from a study of the literature.

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SYMPTOMATOLOGY Oh' AUYOTONIA CONGENITA. 447

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