Children do not present themselves to their physicians with a diagnosis, such as spinal muscular atrophy, anterior horn cell disease, or similar syndromes; but their parents usually list a chief complaint. The terms used by the family may be "weakness," "delay in sitting and walking," "lack of movement," and so on.
When the physician sees such a child, he needs a certain plan for workup of the patient. Although all parts of the history have to be considered, the examiner must concentrate on certain points in particular. Was the onset of weakness sudden or very gradual? Has the child lost previously reached motor milestones, or is there just slow progress in motor abilities? Diurnal fluctuations of performance have to be investigated; if the child is old enough, queries regarding pain, paresthesias, and dysesthesias have to be made.
Of all physical findings that are elicited and analyzed, the most important one is the presence or absence of deep tendon reflexes. This one physical sign is an intellectual watershed in this clinical investigation. If a weak child has no deep tendon reflexes or they are significantly decreased, he has lower motor neuron disease affecting the anterior horn cell or the peripheral nerves. Other diseases of young children that are characterized by absent tendon reflexes are familial dysautonomia1 and Lowe's syndrome (oculocerebrorenal syndrome).2 These will not be discussed further in this section. Other lower motor syndromes - namely, those of the myoneural junction (myasthenia) and of muscles - present with good tendon reflexes. Patients with muscular dystrophy do not lose these reflexes before the end stages of the disease process.
CLINICAL PICTURES AND TYPES
There are several clinical pictures of a chronic nature that are caused primarily by degeneration of large anterior horn cells in the spinal cord and, to a lesser degree, by the same process in homologous motor nuclei in the brain stem. Depending on the age at onset and the rate of progression, various names are used for these diseases, such as juvenile muscular atrophy simulating muscular dystrophy,3 Werdnig-Hoffmann disease,46 and Kugelberg-Welander disease.7 In order to reduce confusion in the use of eponyms, the editor of this issue has wisely chosen the term spinal muscular atrophy syndromes, which is descriptive and allows for further elucidation of specific syndromes based on metabolic errors or other gene abnormalities.
Spinal muscular atrophy may have clinical onset in utero. In those instances, the mother may notice paucity or absence of fetal movements for some weeks before birth. Weakness will then be apparent at birth or within the first few weeks of extrauterine life. Characteristically, such an infant moves very little, the head falls back floppily, and the extremities cannot overcome gravity. The neonatal grasp, walking, stepping, and placing reflexes are markedly diminished or absent; the lower extremities are held in an externally rotated froglike position; and breathing is primarily abdominal; the child is weak. Deep tendon reflexes are already absent or considerably reduced during the first weeks of life. Because the hypoglossal nucleus is almost universally involved in the disease process, fasciculations of the tongue are usually apparent and certainly should be looked for. The inexperienced examiner, and sometimes the experienced one, may have difficulty differentiating these fasciculations from normal random movements of the tongues of infants. The former are best seen at the lateral edges of the tongue. Fasciculations are not apparent in other skeletal muscles because the muscles are atrophic and are covered by fat and fairly thick skin. Lingual muscles present no such barriers to inspection. Visible atrophy of the muscles of all extremities is usually present soon after the neonatal period.
Because respiration and ventilation are compromised as a result of intercostal muscle weakness and because these infants move little and cough inadequately, they are particularly prone to respiratory infections and aspiration pneumonia, the latter being the precipitating cause of death. During the major part of these children's lives, the function of the diaphragm is either normal or at least adequate. In the presence of marked intercostal muscle weakness, any significant impairment of the diaphragm (spinal level C4) would be incompatible with life. Cases of early diaphragmatic involvement before loss of deep tendon reflexes and other marked weakness have been seen and reported.8
A few young children with spinal muscular atrophy have a fast, fine tremor called minipoiymyoclonus. If present, this movement disorder is highly suggestive of this disease.9
The disease process is progressive and frequently leads to death in infancy or during the first three years.
A second variant or syndrome has its onset anytime in the first year of life but is more slowly progressive. Weakness may be first noted between the fourth and 12th months of age, reflexes will likely be present for a few months, and life expectancy is longer. The presenting complaints are usually delayed sitting and/or standing. Sooner or later the tendon reflexes disappear, and fasciculations of the tongue are present. The clinical course in these children is difficult to predict. Some will live for three to 10 years and then succumb to the usual respiratory complications. Others will appear to make definite clinical progress and may learn to stand with or without orthotic aids, but eventually they will lose some of these motor accomplishments and will retire to wheelchairs. Although the disease appears to be clinically "arrested" for a prolonged time, a fasciculating tongue confirms active denervation.
A third group of children are clinically normal for five to 10 years after birth, but they develop weakness, atrophy, tongue fasciculations, and loss of reflexes after that age. The course of the disease in these patients is much slower, and sometimes no progression is recognizable for several years. A few patients with this variant known to the author are now living with a handicap in their third decade. Other patients have been reported to survive even beyond this age. Because weakness is most marked in the proximal muscles, these children are more likely to be confused with those having muscular dystrophy and other myopathies.
If more than one child in a family is affected, there is a tendency for siblings to run a similar course. The question obviously arises whether we are dealing with one disease or whether these variants are similar clinical and pathologic processes due to different causes. Until we have proof of the latter hypothesis - and until specific, different enzyme abnormalities in cases of spinal muscular atrophies have been discovered and defined - it is probably best and most practical to regard these syndromes as different pictures within the same spectrum. Later revisions of this concept can then be based on firmly established facts.
ASSOCIATED CONDITIONS AND COMPLICATIONS
Children with spinal muscular atrophy syndromes have the same chance of being intellectually normal as the childhood population at large. Owing to their immobility and physical inactivity, they may miss out on cultural and social experiences and their fund of knowledge may be below average in the second decade. Educational and recreational exposures have to be encouraged to minimize this factor.
Clinical experiences at ColumbiaPresbyterian Medical Center suggest a higher incidence of seizures than expected for the age group. Whether this is an associated allelic condition or a complication due to chronic or repeated hypoxia is not clear.
The skeleton is affected by poor strength and tone in various ways. Prolonged inactivity always leads to osteoporosis in older children. Because of osteoporosis, there is an increased risk of fractures, especially of the long bones.
Hip dislocation without sex preference is often seen in lower motor neuron syndromes of prenatal or early postnatal onset. The best examples of this are children with lumbosacral meningomyeloceles and central core myopathy. Uni- or bilateral congenital or early-acquired hip dislocation is also sometimes seen in anterior horn cell disease. The probable explanation for this association is a need for an optimal degree of muscle action around the hip. The acetabulum obtains its normal shape and depth from the proper position of the head of the femur and the normal tone of the surrounding muscles. When tone and strength are significantly decreased at birth, the acetabulum will be too flat.
Normal movement of joints also depends partly on normal intrauterine muscle movement. Arthrogryposis is a term used to describe fixed contractures of several joints at birth. Anterior horn cell disease seems to be one of the causes, if not the most frequent one, of arthrogryposis. Either a few or most of the joints of the extremities may be stiff and contracted. Any child with arthrogryposis should be investigated for lower motor neuron disease with electrodiagnostic studies (see below).
Because trunk muscles are weak, the back tends to be held relatively immobile and is usually not symmetrical in the supine or sitting position. The older the affected child becomes, the greater is the incidence of scoliosis. Scoliosis should be prevented, or its progression slowed by proper appliances.
Inactivity and immobility in paretic children lead to decreased energy expenditure and caloric requirements. If these children eat the same amount as other children of the same age, they become too heavy and sometimes grotesquely obese. The overweight increases their physical handicap and further impairs respiratory function. Not only will normal eating lead to obesity with time, but a paucity of social outlets and extended presence within the home will drive teenagers to overeating and raiding of the easily accessible refrigerator.
The various common laboratory examinations of the urine, serum, and cerebrospinal fluid are usually not helpful in the diagnosis of the anterior horn cell syndromes. With one questionable exception (see below), no enzymatic defect has been described that lends itself to a laboratory test. The muscle enzymes, especially creatine Phosphokinase (CPK), are usually normal. A very high CPK is important because it would exclude neurogenic disease, but slight elevations are common in the more active periods of the disease.
Electrodiagnostic studies, together with evaluation of the other aspects of the neurologic examination, are helpful in the diagnosis of neurogenic and myopathic lower motor neuron diseases. Electromyography is concerned with analysis of duration, amplitude, and configuration of motor unit potentials. The hallmarks of denervation are frequent denervation potentials, increased duration of action potentials, and increased amplitude (giant potentials). These findings are common to diseases of the anterior horn cells and to neuropathies. In pure anterior horn cell syndromes, the nerve conduction velocity is assumed to be normal; if that velocity is significantly decreased, the neurogenic disease is presumably situated in the peripheral nerves. Although this statement is correct, it has to be interpreted carefully. First, slightly decreased nerve conduction velocities are sometimes seen in spinal muscular atrophy. Second, the examiner must be experienced in the electrodiagnostic evaluation of children and familiar with normal values in the various pediatric age groups. Exposure to cool air may also reduce conduction velocity.
Muscle biopsy should be done as part of the clinical evaluation of a child suspected of having spinal muscular atrophy. Biopsy alone, however, cannot be diagnostic. Before the biopsy is performed, the choice of the muscle for that procedure is important. One should examine a muscle that is definitely, but presumably not severely, affected. With wrong sampling, the resuit may be false-negative or the sampled fibers may be so severely involved that no muscle fibers are found in the sample. The report in a typically affected and well-sampled case would list group lesions of small-diameter fibers interspersed with normal muscle fibers (Figure 1). Histochemical studies of muscle can usually distinguish this disorder from the various congenital myopathies and other entities.
Figure 1. Cross-section of muscle biopsy from patient with infantile progressive spinal muscular atrophy, showing groups of very small fibers, some normal-size fibers, and scattered very large fibers.
Necropsy of the spinal cord reveals a marked loss of the large anterior horn cells, especially in the ventromedial group. Varying numbers of the remaining anterior horn cells are pyknotic and are in some stage of neuronophagia. Gliosis is either absent or minimal. Because there is a particularly large number of anterior horn cells in the cervical and lumbar enlargements of the cord, the typical pathologic changes are best seen in those areas.
The homologous nuclei of the motor cranial nerves are also involved in the process. Clinically and pathologically, the XII nucleus is most commonly and most severely affected. Motor nuclei V, VI, VII, IX, X, and XI show loss of nerve cells at autopsy, but these changes are usually not of major clinical importance.
There is no sex preference in these syndromes, and most, if not all, cases are based on autosomal recessive inheritance. If the parents have had one affected child, they should be told that each succeeding pregnancy has a 25 per cent risk of being affected and a 50 per cent risk of being a carrier. Isolated cases in a family are compatible with that hypothesis or may be due to a new mutation. A few families with the spinal muscular atrophy syndrome with probably dominant inheritance have been observed. This occurrence would be an argument that we are dealing with at least two separate diseases.
The question of etiology can be dealt with briefly in this context. The cause or causes of these syndromes are unknown at this time. One autopsied case of apparently typical progressive anterior horn cell disease has been reported10 in which a deficiency of beta-methylcrotonyl coenzyme A carboxylase was well demonstrated. It is more likely that this affected child had two diseases than that a causative relationship existed. Biochemists should investigate leucine degradation in more children with spinal muscular atrophy.
As we know nothing of the etiology of the spinal muscular atrophy syndromes, there is no rational approach to therapy of the primary process, and we know of no cure.
Life can be prolonged in a state of useful function with the prevention and sound management of respiratory infections. This includes proper choice of antibiotics, when indicated, the recognition of dysfunction and weakness of coughing, and clearing of the airways. Proper positioning and support will maintain adequate, functional vital capacity longer. The management of some of the associated conditions, such as scoliosis and obesity, was discussed earlier.
The physician, together with the parents, should make every effort to keep affected children in school with their peers in spite of the physical handicap. Overactivity and undue fatigue should be avoided. The mental attitude and emotional adjustment of the parents have a great influence on the patient's response to his disease.
The physician should encourage the family and the child, but he should not make false promises. Although the final outcome is certain, the life expectancy is not.
1 . Riley, C. M., et al Central autonomic dysfunction with defective lacrimation. Pediatrics 3 (1949), 468.
2. Lowe, CU., Terrey, M.. and MacLachlan. E. A. Organic-aciduria. decreased renal ammonia production, hydrophthalmos and mental retardation; a clinical entity. Am. J. Dis. Child. 83 (1952). 164.
3. Wohlfart. G., Fex, J-, and Eliasson, S. Hereditary proximal spinal muscular atrophy - clinical entity simulating progressive muscular dystrophy. Arch. Psychiatr. Neurol. Scand. 30 (1955), 395.
4. Werdnig, G. Zwei frühinfantile hereditäre Fälle von progressiver Muskelatrophie unter dem Bilde der Dystrophie. Arch. Psychiatr. Nervenkr. 22 (1891), 437.
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10. Stokke, O., et al. Beta-methylcrotonyl-CoA carboxylase deficiency: A new metabolic error in leucine degradation. Pediatrics 49 (1972), 726.