Indian J. Pediat. 34 : 34 1967

INFANTILE SPINAL MUSCULAR ATROPHY*

HARJIT SINGH, L. RAMAKUMAR AND H. L. GUPTA

Rohtak

The clinical triad of hypotonia, muscular weakness and diminished or absent reflcxes in infancy was termed the '"floppy infant syndrome" byGreen- field et al. (1958). Progressive spinal muscular atrophy described indepen- dently by Werdnig in 1891 and Hoff- mann in 1893, constitutes one of the most important causes of this syndrome(Walton, 1956). Oppenheim in the year 1900 described eight cases who presented at birth with hypotonia, areflexia and motor weakness; the infants gradually improved with age. Such cases along with others with hypotonia since birth due to a variety of causes were later included under the common heading of amyotonia congenita.

Although Werdnig-Hoffmann's disease and Oppenheim's amyotonia congenita had been described as separate diseases previously, the work of Greenfield and Stern (I 927), Grinker (1927) and that of Brandt (1950) goes to show that the two conditions represent two extremes of essentially the same pathology. According to Sandifer (1955), if the spinal motor ganglia have been seriously damaged by the time of birth, one sees the picture of amyotonia congenita ; onthe o',her hand if they are damaged later

*From The Department of Pediatrics, Govt. Medical College, Rohtak and Medical College, Patia!a.

the pictureis that of Werdnig-Hoff- mann's disease. Gciler and Geiler (1962) studied the autopsy material of three cases ot Oppenheim's amyotonia congenita and two cases of Werdnig- Hoffmann's disease ; they found similar pathological changes in the two con- ditions and concluded that these are different forms of the same neurological disorder, distinguished only by the d~fferent age of onset. N o distinction has, therefore, been made between the two variants in the present study.

Since the disease was first described in 1891, cases have been reported from all over the world including one from India (Shaw, 1962). Seven cases, reported below, came under our observation during the past few years.

Report of Cases

Case L K . R . , a 6-month-old male child, was admitted to the Medical College Hospilal, Rohlak, wilh the complaint of inability to hold the head. He was cyanosed for a few minutes after birth. He was fourth in order of birth ; one older sibling was suffering from the same disease, one had died of an unknown cause soon after birth, and one female sibling was in good health. Motor milestones bad not been achieved. The child, however, had started smiling and taking an interest in his surroundings. The

SINGH El" AL.~INFANTILE SPINAL MUSCULAR ATROPHY 35

parents of the child were first cousins. On examination the child was moderately nourished. He had marked generalised llypotonia and weakness. Tendon jerks in all the four extremities were markedly diminished. The cranial nerves and sensory system were normal.

Routine investigatmns showed no abnormality. Muscle biopsy which confirmed the diagnosis, showed fibres of diminished size along with normal muscle bundles. There was no increase of fibre-elastic tissue. The total number of muscle fibres appeared to be reduced.

Case 2. V. P., a 4~-year-old male child, was the eider brother of case i. He was brought with the complaints of inability to hold the head and inability to speak. He had been having frequent attacks of upper respiratory infection since infancy. On examina- tion, he was markedly hypotonic and emaciated. Tendon jerks were abse,;t all over. The patient was grossly mentally retarded. Muscle biopsy was compatible with the diagnosis of spinal muscular atrophy.

Case 3. J .K . , a 1�89 female child, was admitted, for inability to hold the head and to sit. The child developed normally till lhe age of 7 montbs and then became progressively weak. She started holding 1he head at three months and sitting at six months. Thereafter, there was a regression in motor achievements (Fig. 1). There was no history of consanguinity and the past history was non-contri- butory. No sat[sfactory history of foetal movements could be elicited.

On ex?.minatlon the child could neilher sit nor hold her head. Mental development was normal. Cranial nerves and sensory systems showed no

abnormality. She was markedly hypo- tonic and Oppenheim's sign was posi- tive. Tendon jerks were absent in all the four extremities. The sensory system showed no abnormality. A biopsy of the calf muscle was com- patible with the diagnosis of spinal muscular atrophy.

Case4. B.K., an 8-month-old child, was a:dmitted with the complaints of weakness of the whole body and inability to hold objects presented to her. The child started holding the head normally at the age of 3 lnonths but thereafter became weak, lost the abiht.y to hold the head and was never able to sit. She was fifth m birth order. The previous four siblings had all died between the age of six months and two years of unknown causes. There was no history of consanguinity.

On examination the patient was normally built and showed no evidence of muscle wasting. She had marked generalized hypotonia. Tendon jerks were absent in all the four limbs. Oppenheim's sign was positive. The rest of the nervous system examination showed no abnormality. A muscle biopsy was attempted but it showed only fibre-fatty tissue.

Case 5. J. S., a three-month-old male infant, was admitted for gradually progressive weakness of all the four extremities and inability to hold the head. The patient was fourth in birth order. Two other siblings had died of unknown cause at ages of six and nine months respectively.

Exammatio , revealed a moderately built and nourished baby who was markedly hypotonic. All the tendon jerks were absent. The cranial nerves and sensory system showed no abnor- mality. 24-hour urinary excretion of creatine and creatinine was 90 rag.

I N D I A N J O U R N A L O F P E D I A T R I C S P L A T E II

Fig. 1. - Pat ient with infanti le muscu la r spinal a t rophy .

Fig. 2 . - - H y p o t o n i a in pat ient with muscu la r a t rophy .

5INGH ET AL. -INi=ANTILE SPINAL MUSCULAR ATROPHY.

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36 INDIAN JOURNAL OF PEDIATRICS VOL. 34 N o . 229

and 60 mg. respectively. Muscle biopsy was consistent with the diagnosis of Werdnig-Hoffmann's disease.

Case 6. B., a two-year-old child, was admitted with the complaint of progressively increasing weakness for the last I.} years. The onset of the illness followed a febrile episode lasting for a month, at the age of six months. The patient started head holding at three months and never learned to sit up (Fig. 2). He had been having recur- rent respiratory infections. He was the sixth child in the family. Four siblings were healthy ; one had delayed mile- stones and had died at the age of 1�89 years. Muscle biopsy was consistent with the diagnosis of amyotonia congenita (Fig. 3).

Case 7. S., a six-month-old female child, was admitted for progressively increasing weakness of three months' duration. She started head-holding at 2�89 months but never started to sit. She had been getting repeated attacks of upper respiratory infection. The patient was a full term normal delivery, and second in birth order. An older female sibling died of a similar disease at the age of 9 months. On examina- tion, the child was markedly hypotonic,

a n d was unable to hold the head. Tendon jerks wele absent all over. Muscle biopsy was consistent with the diagnosis of amyotonia congenita.

Comments

Hypotonia in infancy can be produced by a variety of neurological and non- neurological disorders (Table 1). Most of the conditions have associated characteristic features whmh make their recognition easy. However, clinical differentiation between the various muscular and neurogenic disorders is

Table 1. Causes o f hypotonia in infano, . *

I. S ys t em ic causes : Rickets Scurvy Malnutrition Arachnodactyly Ehler-Danlos syndrome Familial dysautonomia Mongolism Osteogenesis imperfecta Hypothyroidism Congenital laxity of ligaments Glycogen storage disease

IF. Neurogenic disorders : Werdnig-Hoffmann's disease Mental retardation Poliomyelitis Myasthenia gravis Infantile polyneuritis Friedrich's ataxia

IlI. Myo g en i c causes : Benign congenital hypotonia Polymyositis Infantile muscular dystrophy Central core disease

*After Hardman, R (1961).

not only difficult but may be impossible at times. Walton (1956) followed 109 cases of hypotonia in infancy, who had a provisional label of 'amyotonia congenita' ; only 67 of these were ultimately proved to be infantile spinal muscular atrophy. Greenfield et al. (1958) while stressing the value cf muscle biopsy in arriving at a conclusion, had considered the clinical differentiation between the following conditions difficult :

Infantile spinal muscular atrophY, congenital or infantile muscular

SINGH ET AL.- - INFANTILE SPINAL MUSCULAR ATROPHY 37

dystrophy, central core disease, polymyositis. In addition, a few more disorders like congenital myasthenia gravis, infantile polyneuritis and atonic cerebral palsy may also present with hypotonia in infancy, indistinguishable from the above mentioned causes.

Infantile spinal musculal atrophy is a disease which is usually familial and transmitted as an autosomal recessive gene, both sexes being involved equally. In the present series of seven cases four were males and three females. A positive family history was available in two cases. In three more cases a history of deaths in the siblings in early infancy was available but the exact cause of death could not be ascertained. A positive family history in two cases and a doubtful history in three cases is in keeping with the general impression of its familial incidence. History of consanguinity in a family (Cases 1 and 2) supports recessive inheritance.

Pathologically, there is a progressive loss of motor neurones beginning and most severe at the caudal end of the spinal cord, progressing cranially and finally involving tlle brain-stem nuclei. Miscroscopically, changes are in the form of disappearance of the dendrites and nuclear degeneration. The cells ultimately shrivel up and disappear altogether. The surrounding tissues show no significant reaction. Abnor- malities of Betz cells in the cerebral cortex are mentioned (Clark, 1959). Recently, Norman and Kay (1965) while reporting some unusual mani- festations of the disease, found on autopsy, neuropathological lesions far more extensive than the clinical picture would suggest. They found changes in the spinal white matter, cerebellum and basal ganglia.

Changes in the muscle are secondary to denervation. The characteristic changes consist of an irregular inter- mixture of small muscle fibres surrounded by numerous sarcolemma nuclei, interspersed among normal or slightly enlarged muscle fibres (Potter, 1952). The diagnostic value of muscle Nopsy in the 'floppy infant' has been stsessed by Greenfield e t al. (1958). A calf muscle biopsy was attempted in all the seven cases in the present series and it was com- patible with the diagnosis in all but one case.

Symptoms may be present at birth or may appear in the early months of extrauterine life. The onset of symp- toms varied from birth to two years in the present series. Limpness and loss of body tone are usually the first symptoms. The infant can usually be folded o1 doubled up into any grotesque posture. However, all cases maynot present with hypotonia. Nor- man and Kay (1965) have reported an unusual case of Werdnig-Hoffmann's disease who had generalised spasticity. Involvement of the respiratory muscles results in respiratory difficulty and recurrent respiratory infections. Mild forms of the disease are compatible with a relatively long life. In the series the oldest case was aged 31 years (Greenfield et al. 1958). Most cases, however, succumb to intercurrent res- piratory infections by the age of one year. The oldest patient in the present series was 4~ years old. All the patients presented with delayed or regressed milestones and limpness of the body. A history of recurrent respiratory infections was available in three cases.

Although widespread pathological changes in the nervous system, including

38 INDIAN JOURNAL OF PEDIATRICS VOL. 34 NO. 229

degenerative changes in the cerebral cortex and brainstem are described in the disease, the association of mental retardation is rare. The presence of mental retardation in one case (Case 2) of the present series is interesting.

Summary

Seven cases of infantile spinal mus- cular atrophy are reported. In one child, mcntal retardation was associated with hypotonia. Similarity between Werdnig-Hoffmann's disease and Oppcnheim's amyotonia congenita is stressed.

The literature is briefly reviewed and the importance of muscle biopsy stressed.

We wish to thank the Principal, Govt. Medical College, Patiala and the Principal, Medical College, Rohtak for their kind permissionto use the hospital data.

R e f e r e n c e s

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Ford, F. R. (1960). Diseases of tile Nervous System in Infancy, Childhood and Adolescence. p. 301. C71arles C. Thomas, Springfieht.

Geiler, G. and Geiler, G. (I 962). The morpho- logy, nosological place and pathogenesis of the amyotonia congenita of Oppenhcim and Werdnig Hoffmann's progressive spinal muscular atrophy of infants. Virchow'sArch.Path. Anat. 335 : 654.

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Greenfield, J. G., Cornman, T. and Shy, G. M. (1958). The progqostic value of muscle biopsy in the floppy infant. Brain, 81 : 461.

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Oppenheim,H.(1900). (Quoted by Shaw, P.M.) Potter, E. L. (1952). Pathology of 111o foetus

and newborn. P. 499. The Year-book Publishers Inc. Chicago.

Sandifer, P.H.(1955). Thedifferential diagno- sis of flaccid paralysis. Prec. roy. Soc. Med. 4r : 186.

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Shy, G. M. and Magrce, K. R. (1956). Quoted by Shaw, P. M.

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Werdnig, G. (1891). Quoted by Shaw, P.M.