45
Acute Onset Spinal Muscular Atrophy in Siblings By s. A. Robb*, M. A. McShane,]. Wilson and]. Payan Department of Neurology, Hospital for Siek Children, Great Ormond Si., London WC 1N 3JH, England, *Present address: The Neweomen Centre, Guy's Hospital, St. Thomas Street, London SE 1 9RT, England
Case reports
We describe two sisters who each presented in infancy with acute, severe, generalised weakness and areflexia in association with an intercurrent infection. The clinica! picture resembled acute polyneuritis, but EMG findings and the later clinical features were consistent with a diagno-sis of spinal muscular atrophy. Although symptoms in SMA may be exacerbated by infection, immunisation or trauma, this unusual presentation of the condition in siblings suggests that this may constitute a genetically distinct subgroup of the disorder.
Keywords Spinal muscular atrophy myography - Anterior horn cell disease
Electro-
Introduction The onset of symptoms in the intermediate and mild forms of spinal muscular atrophy (SMA) is usually gradual and difficult to date with certainty, most children presenting with delayed motor milestones with ability to sit but not to walk (intermediate, type 11) or, at a lat~r age, an abnormal gait, frequent falls or difficulty climbing stairs (mild, KugelbergWelander, type 111), (3). The disease follows a variable and often benign course, usually with gradual worsening, but often with long static periods and, occasionally, definite improvement, with many children surviving into adolescence and adulthood (8). The physical signs consist of symmetrical weakness affecting the legs more than the arms and proximal museIes more than distal with reduced or absent tendon reflexes, tongue fasciculation and hand tremor. We describe two siblings who presented in infancy in an unusual way with acute, severe, generalised weakness mimicking acute polyneuropathy, in whom EMG and later clinical findings were consistent with a diagnosis of SMA.
Reeeived April 2, 1990; aeeepted April 25, 1990 Neuropediatries 22 (1991) 45-46 © Hippokrates Verlag Stuttgart
Case 1
This child, the first of two daughters of unrelated parents with no family history of neuromuscular disease, presented at the age of four and a half months with a two week history of pyrexia and misery, constipation followed by diarrhoea and vomiting, a weak cry, difficulty feeding and progressive hypotonia. An E coli urinary tract infection was diagnosed and treated with amoxicillin. Forty-eight hours later she developed an aspiration pneumonia and became profoundly hypotonie. On arrival at this hospital she was alert but lay in a frog position with little spontaneous movement, poor head control, a feeble cry and respiratory stridor. She dribbled saliva and had a poor gag response. Tendon reflexes were absent. She was pink in air with a respiration rat of 46/min, no respiratory distress but inspiratory crepitations in both lung fields, particularly the right. Examination of the heart and abdomen was normal. The following investigations were normal: cranial ultrasound scan, CSF examination, tensilon test, EEG, ECG, renal USS, routine biochemistry, plasma and urine amino acids, urine organic acids, plasma CK, nasopharyngeal aspirate for virology and two urine cultures. Rotavirus was isolated from the stool and the WBC was 6.4x 109/1 with 44% neutrophils showing a left shift. There was consolidation in the right upper and mid zones on ehest x-ray. A micturating cystourethrogram showed left pelviureteric reflux with decreased uptake in the lower pole of the left kidney on DMSA scan but normal IVU. EMG showed (a) a slightly delayed and reduced median nerve action potential (18 uV, 38 m/s), (b) a very sinall and slightly delayed compound museIe action potential (abductor hallucis 0.25 mV, 3.6 ms) and (c) a discrete, or severely reduced pattern of highly unstable voluntary motor unit potentials in tibialis anterior. These findings suggested an early mixed axonal polyneuropathy. She was treated with cefotaxime and remained hypotonie and areflexic but power gradually improved. She was discharged after 1 month and at review 1 month later was clinically weIl with normal tone and power although tendon reflexes were difficult to elicit. Repeated EMG now showed large (6 mV), unstable, discrete voluntary motor unit potentials in tibialis anterior of a kind common in anterior horn cell disorders. The median nerve action potential was unchanged. She was followed at the local hospital and at 9 months was sitting weIl, reaching, transferring and finger feeding. At 22 months she was still bottom shuffling but walked soon afterwards. At four years she still had a waddling gait with a positive Gowers' sign and crawled up and down stairs. Tendon
Downloaded by: National University of Singapore. Copyrighted material.
Abstract
Neuropediatrics 22 (1991)
S. A. Robb et al
reflexes were all present. Plantar responses were flexor. Repeat nerve conduction studies showed normal evoked sensory and compound museie action potentials but once again EMG showed unequivocal evidence of chronic fallout of motor units present at the anterior horn cellievel.
trauma (1, 2, 4, 8, 11, 14) but it is often unclear whether the illness unmasks a pre-existing, but unrecognised abnormality, or serves to trigger the onset in a genetically predisposed individual (11). These reports have mainly dealt with isolated cases, only one (8) reported acute onset in two female sibs who developed symptoms at 10 months and 3 years respectively following pertussis and pneumonia, but it is not clear whether the weakCase2 ness was as profound as in our patients, or the degree to which it The younger sister of Case 1 was developmen- subsequently improved. tally normal (having sat unaided at 6 months) until she presentThere has been considerable debate as to ed aged 10 months with a two week history of progressive hypo- whether the clinical subtypes of SMA, classified on the basis of tonia and weakness following acute otitis media. Investigations age of onset, degree of progression and age at death, represent at the referring hospital including biochemical screen, CSF ex- separate disease entities (5), or are manifestations of the specamination, arterial blood gases, plasma and urine amino acids trum of a single disease (7). Only type I (acute Werdnigand screen for botulinum toxin were negative. On arrival at this Hoffinann disease) has emerged as a genetically distinct entity hospital she was alert and able to fix and follow but had mild fa- (12, 13). Fried and Emery (6) classified the mild juvenile form cial weakness with drooling and a decreased gag reflex. She was (10, 14) and intermediate type (2) separately, but families have profoundly hypotonie, lying in a frog posture with few sponta- been described in whom siblings showed a very wide variation neous movements of the limbs and areflexia. Examination of in age of onset of symptoms (2, 8). Accordingly, now many conthe heart, lungs and abdomen was normal. sider chronic SMA as a single disease with a clear genetic comThe following investigations were normal: CT ponent but with variable expression perhaps depending on the brain, EEG, CSF examination, FBC, serum immunoglobulins, effect of one or more environmental factors (9). We propose urine organic acids and cultures of urine, sputum, venous blood that the siblings reported here have a genetically distinct suband nose and throat swabs. Nerve conduction studies showed type of SMA in which profound, but substantially reversible normal sural nerve sensory potential, a very small (40 uV) ab- weakness is precipitated in infancy by intercurrent infeetion. ductor hallucis compound museie potential and marginally slowed motor conduction velocity (30 m/s). In tibialis anterior, References deltoid and extensor digitorum communis, therewas no spontaneous activity and the little voluntary activity which could be 1 Brandt, 5.: Werdnig-Hoffmann's Infantile Progressive Muscular Atroprovoked consisted of discrete, simple, rapidly-firing potentials phy. Copenhagen, Munksgaard (1950) 2 Dubowitz, V.: Infantile muscular atrophy. A prospective study with particof about 1 mV. These findings suggest motor unit fallout rather ular reference to a slowly progressive variety. Brain 87 (1964) 707-718 than a mixed polyneuropathy. 3 Dubowitz, V.: Muscle Disorders in Childhood. London, W. B. Saunders Soon after admission this child developed col(1978) lapse and consolidation of the right upper lobe and progressive 4 Dubowitz, V.: Muscle Biopsy, a Practical Approach. Balliere Tindall. (1985) hypoventilation necessitating intubation and artificial ventila5 Emery, A. E. H.: The nosology of the spinal muscular atrophies. J. Med. tion. Several attempts at extubation were unsuccessful and after Genet. 8 (1971) 481-495 two weeks she was treated with continuous negative expiratory 6 Fried, K., A. E. H. Emery: Spinal muscular atrophy type H. Clin. Genet. 2 pressure (CNEP) and thereafter made a steady recovery with (1971) 203-209 gradual increase in museie power, although she remained hypo7 Gamstorp, I.: Progressive spinal museular atrophy with onset in infancy or early ehildhood. Aeta Paediatr. Seand. 56 (1967) 408-423 tonie and areflexic. CNEP was discontinued after a further two 8 Gardner-Medwin, D., P. Hudgson,]. N. Walton: Benign spinal muscular weeks and at discharge she was sitting unsupported, able to atrophy arising in ehildhood and adoleseenee. J. Neurol. Sei. 5 (1967) reach above her head but unable to weight bear. She was are121-158 flexic with marktd fasciculation of her tongue and tremor of her 9 Gardner-Medwin, D.: Children with genetie museular disorders. Br. J. outstretched hands. At 16 months she stood holding on and at Hosp. Med. 17 (1977) 314-340 20 months, walked with hands held and was beginning to bot- 10 Kugelberg, E., L. Welander: Heredo-familial juvenile museular atrophy simulating museular dystrophy. Areh. Neurol. Psyehiat. (Chie.) 75 tom shuffle. She had 8 words and was feeding herself. (1956) 500-509 Meadows,]. L., C. D. Marsen, D. G. F. Harriman: Chronic spinal muscular atrophy in adults. Part I - The Kugelberg-Welander Syndrome. J. Neurol. Sei. 9. (1969) 527-550 12 Pearn, ]., C. O. Carter,]. Wilson: The genetie identity of aeute infantile spinal museular atrophy. Brain 96 (1973) 463-470 13 Pearn,]., S. Bundey, C. O. Carter,]. Wilson, D. Gardner-Medwin,]. N. Walton: A genetie study of subacute and chronie spinal muscular atrophy in ehildhood. J. Neurol. Sei. 37 (1978) 227-248 14 Wohlfart, G.,]. Fex, S. Eliasson: Hereditary proximal spinal museular atrophy - a clinieal entity simulating progressive muscular dystrophy. Acta Psyehiat. Scand. 30 (1955) 395-406
11
Discussion The sudden onset of generalised weakness and hypotonia in the first infant initially suggested a metabolie disorder or an acute polyneuropathy. The former was not found and although the latter reeeived some support from EMG and nerve conduction studies, a second investigation when the child was nearly better suggested chronic anterior horn cell fallout. A firm diagnosis was only made when a younger sister presented three years later with a similar, though more severe illness and comparable EMG findings. Re-examination of the older child then revealed mild pelvic girdle weakness, tongue fasciculation and tremor. The onset or exacerbation of symptoms in SMA has been reported to follow infection, immunisation and
S. A. Robb, M.D. The Neweomen Centre Guy's Hospital St. Thomas Street London SE 1 9RT, England
Downloaded by: National University of Singapore. Copyrighted material.
46
Acute Onset Spinal Muscular Atrophy in Siblings By s. A. Robb*, M. A. McShane,]. Wilson and]. Payan Department of Neurology, Hospital for Siek Children, Great Ormond Si., London WC 1N 3JH, England, *Present address: The Neweomen Centre, Guy's Hospital, St. Thomas Street, London SE 1 9RT, England
Case reports
We describe two sisters who each presented in infancy with acute, severe, generalised weakness and areflexia in association with an intercurrent infection. The clinica! picture resembled acute polyneuritis, but EMG findings and the later clinical features were consistent with a diagno-sis of spinal muscular atrophy. Although symptoms in SMA may be exacerbated by infection, immunisation or trauma, this unusual presentation of the condition in siblings suggests that this may constitute a genetically distinct subgroup of the disorder.
Keywords Spinal muscular atrophy myography - Anterior horn cell disease
Electro-
Introduction The onset of symptoms in the intermediate and mild forms of spinal muscular atrophy (SMA) is usually gradual and difficult to date with certainty, most children presenting with delayed motor milestones with ability to sit but not to walk (intermediate, type 11) or, at a lat~r age, an abnormal gait, frequent falls or difficulty climbing stairs (mild, KugelbergWelander, type 111), (3). The disease follows a variable and often benign course, usually with gradual worsening, but often with long static periods and, occasionally, definite improvement, with many children surviving into adolescence and adulthood (8). The physical signs consist of symmetrical weakness affecting the legs more than the arms and proximal museIes more than distal with reduced or absent tendon reflexes, tongue fasciculation and hand tremor. We describe two siblings who presented in infancy in an unusual way with acute, severe, generalised weakness mimicking acute polyneuropathy, in whom EMG and later clinical findings were consistent with a diagnosis of SMA.
Reeeived April 2, 1990; aeeepted April 25, 1990 Neuropediatries 22 (1991) 45-46 © Hippokrates Verlag Stuttgart
Case 1
This child, the first of two daughters of unrelated parents with no family history of neuromuscular disease, presented at the age of four and a half months with a two week history of pyrexia and misery, constipation followed by diarrhoea and vomiting, a weak cry, difficulty feeding and progressive hypotonia. An E coli urinary tract infection was diagnosed and treated with amoxicillin. Forty-eight hours later she developed an aspiration pneumonia and became profoundly hypotonie. On arrival at this hospital she was alert but lay in a frog position with little spontaneous movement, poor head control, a feeble cry and respiratory stridor. She dribbled saliva and had a poor gag response. Tendon reflexes were absent. She was pink in air with a respiration rat of 46/min, no respiratory distress but inspiratory crepitations in both lung fields, particularly the right. Examination of the heart and abdomen was normal. The following investigations were normal: cranial ultrasound scan, CSF examination, tensilon test, EEG, ECG, renal USS, routine biochemistry, plasma and urine amino acids, urine organic acids, plasma CK, nasopharyngeal aspirate for virology and two urine cultures. Rotavirus was isolated from the stool and the WBC was 6.4x 109/1 with 44% neutrophils showing a left shift. There was consolidation in the right upper and mid zones on ehest x-ray. A micturating cystourethrogram showed left pelviureteric reflux with decreased uptake in the lower pole of the left kidney on DMSA scan but normal IVU. EMG showed (a) a slightly delayed and reduced median nerve action potential (18 uV, 38 m/s), (b) a very sinall and slightly delayed compound museIe action potential (abductor hallucis 0.25 mV, 3.6 ms) and (c) a discrete, or severely reduced pattern of highly unstable voluntary motor unit potentials in tibialis anterior. These findings suggested an early mixed axonal polyneuropathy. She was treated with cefotaxime and remained hypotonie and areflexic but power gradually improved. She was discharged after 1 month and at review 1 month later was clinically weIl with normal tone and power although tendon reflexes were difficult to elicit. Repeated EMG now showed large (6 mV), unstable, discrete voluntary motor unit potentials in tibialis anterior of a kind common in anterior horn cell disorders. The median nerve action potential was unchanged. She was followed at the local hospital and at 9 months was sitting weIl, reaching, transferring and finger feeding. At 22 months she was still bottom shuffling but walked soon afterwards. At four years she still had a waddling gait with a positive Gowers' sign and crawled up and down stairs. Tendon
Downloaded by: National University of Singapore. Copyrighted material.
Abstract
Neuropediatrics 22 (1991)
S. A. Robb et al
reflexes were all present. Plantar responses were flexor. Repeat nerve conduction studies showed normal evoked sensory and compound museie action potentials but once again EMG showed unequivocal evidence of chronic fallout of motor units present at the anterior horn cellievel.
trauma (1, 2, 4, 8, 11, 14) but it is often unclear whether the illness unmasks a pre-existing, but unrecognised abnormality, or serves to trigger the onset in a genetically predisposed individual (11). These reports have mainly dealt with isolated cases, only one (8) reported acute onset in two female sibs who developed symptoms at 10 months and 3 years respectively following pertussis and pneumonia, but it is not clear whether the weakCase2 ness was as profound as in our patients, or the degree to which it The younger sister of Case 1 was developmen- subsequently improved. tally normal (having sat unaided at 6 months) until she presentThere has been considerable debate as to ed aged 10 months with a two week history of progressive hypo- whether the clinical subtypes of SMA, classified on the basis of tonia and weakness following acute otitis media. Investigations age of onset, degree of progression and age at death, represent at the referring hospital including biochemical screen, CSF ex- separate disease entities (5), or are manifestations of the specamination, arterial blood gases, plasma and urine amino acids trum of a single disease (7). Only type I (acute Werdnigand screen for botulinum toxin were negative. On arrival at this Hoffinann disease) has emerged as a genetically distinct entity hospital she was alert and able to fix and follow but had mild fa- (12, 13). Fried and Emery (6) classified the mild juvenile form cial weakness with drooling and a decreased gag reflex. She was (10, 14) and intermediate type (2) separately, but families have profoundly hypotonie, lying in a frog posture with few sponta- been described in whom siblings showed a very wide variation neous movements of the limbs and areflexia. Examination of in age of onset of symptoms (2, 8). Accordingly, now many conthe heart, lungs and abdomen was normal. sider chronic SMA as a single disease with a clear genetic comThe following investigations were normal: CT ponent but with variable expression perhaps depending on the brain, EEG, CSF examination, FBC, serum immunoglobulins, effect of one or more environmental factors (9). We propose urine organic acids and cultures of urine, sputum, venous blood that the siblings reported here have a genetically distinct suband nose and throat swabs. Nerve conduction studies showed type of SMA in which profound, but substantially reversible normal sural nerve sensory potential, a very small (40 uV) ab- weakness is precipitated in infancy by intercurrent infeetion. ductor hallucis compound museie potential and marginally slowed motor conduction velocity (30 m/s). In tibialis anterior, References deltoid and extensor digitorum communis, therewas no spontaneous activity and the little voluntary activity which could be 1 Brandt, 5.: Werdnig-Hoffmann's Infantile Progressive Muscular Atroprovoked consisted of discrete, simple, rapidly-firing potentials phy. Copenhagen, Munksgaard (1950) 2 Dubowitz, V.: Infantile muscular atrophy. A prospective study with particof about 1 mV. These findings suggest motor unit fallout rather ular reference to a slowly progressive variety. Brain 87 (1964) 707-718 than a mixed polyneuropathy. 3 Dubowitz, V.: Muscle Disorders in Childhood. London, W. B. Saunders Soon after admission this child developed col(1978) lapse and consolidation of the right upper lobe and progressive 4 Dubowitz, V.: Muscle Biopsy, a Practical Approach. Balliere Tindall. (1985) hypoventilation necessitating intubation and artificial ventila5 Emery, A. E. H.: The nosology of the spinal muscular atrophies. J. Med. tion. Several attempts at extubation were unsuccessful and after Genet. 8 (1971) 481-495 two weeks she was treated with continuous negative expiratory 6 Fried, K., A. E. H. Emery: Spinal muscular atrophy type H. Clin. Genet. 2 pressure (CNEP) and thereafter made a steady recovery with (1971) 203-209 gradual increase in museie power, although she remained hypo7 Gamstorp, I.: Progressive spinal museular atrophy with onset in infancy or early ehildhood. Aeta Paediatr. Seand. 56 (1967) 408-423 tonie and areflexic. CNEP was discontinued after a further two 8 Gardner-Medwin, D., P. Hudgson,]. N. Walton: Benign spinal muscular weeks and at discharge she was sitting unsupported, able to atrophy arising in ehildhood and adoleseenee. J. Neurol. Sei. 5 (1967) reach above her head but unable to weight bear. She was are121-158 flexic with marktd fasciculation of her tongue and tremor of her 9 Gardner-Medwin, D.: Children with genetie museular disorders. Br. J. outstretched hands. At 16 months she stood holding on and at Hosp. Med. 17 (1977) 314-340 20 months, walked with hands held and was beginning to bot- 10 Kugelberg, E., L. Welander: Heredo-familial juvenile museular atrophy simulating museular dystrophy. Areh. Neurol. Psyehiat. (Chie.) 75 tom shuffle. She had 8 words and was feeding herself. (1956) 500-509 Meadows,]. L., C. D. Marsen, D. G. F. Harriman: Chronic spinal muscular atrophy in adults. Part I - The Kugelberg-Welander Syndrome. J. Neurol. Sei. 9. (1969) 527-550 12 Pearn, ]., C. O. Carter,]. Wilson: The genetie identity of aeute infantile spinal museular atrophy. Brain 96 (1973) 463-470 13 Pearn,]., S. Bundey, C. O. Carter,]. Wilson, D. Gardner-Medwin,]. N. Walton: A genetie study of subacute and chronie spinal muscular atrophy in ehildhood. J. Neurol. Sei. 37 (1978) 227-248 14 Wohlfart, G.,]. Fex, S. Eliasson: Hereditary proximal spinal museular atrophy - a clinieal entity simulating progressive muscular dystrophy. Acta Psyehiat. Scand. 30 (1955) 395-406
11
Discussion The sudden onset of generalised weakness and hypotonia in the first infant initially suggested a metabolie disorder or an acute polyneuropathy. The former was not found and although the latter reeeived some support from EMG and nerve conduction studies, a second investigation when the child was nearly better suggested chronic anterior horn cell fallout. A firm diagnosis was only made when a younger sister presented three years later with a similar, though more severe illness and comparable EMG findings. Re-examination of the older child then revealed mild pelvic girdle weakness, tongue fasciculation and tremor. The onset or exacerbation of symptoms in SMA has been reported to follow infection, immunisation and
S. A. Robb, M.D. The Neweomen Centre Guy's Hospital St. Thomas Street London SE 1 9RT, England
Downloaded by: National University of Singapore. Copyrighted material.
46
