by Theodore L. Munsat, M.D.

Director, Neuromuscular Research Unit, New England Medical Center Hospitals, Professor of Neurology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts.

"The Spinal Muscular Atrophies," by Theodore L. Munsat M.D., a long-time MDA Researcher. From CURRENT NEUROLOGY, Chapter 3, Vol. 14, 1994, pp. 55-71. Used by permission of Mosby-Year Book, Inc. Note: Numbers in "(_)" denote footnotes.

DEFINITION AND CLASSIFICATION

This chapter was written as a review of the spinal muscular atrophies (SMAs) for the practicing neurologist. Emphasis in text and references will be placed on developments in the past 5 years on the background of a general review of the subject.

The SMAs constitute a group of neuromuscular disorders defined by a disease process limited to the anterior horn cell (AHC). Other neurologic systems and other organs are rarely involved. Many patients with SMA have a family history of similarly affected individuals, and the phenotypic similarity between familial and nonfamilial cases suggests that the sporadic disease may also be inherited. Most patients with SMA experience clinical onset in childhood and demonstrate autosomal recessive inheritance. A smaller number show autosomal dominant or X-linked inheritance, and onset begins later in life.

A major breakthrough occurred in 1990 when the gene causing the more common autosomal recessive childhood-onset SMA was mapped to the proximal portion of the long arm of chromosome 5.(1) Subsequent work has progressively narrowed the suspect region, and it is anticipated that within the near future the gene will be cloned, its protein product identified, and an effective therapy devised for the first time. Importantly, these developments have already led to reliable prenatal testing.

The search for the SMA gene has necessitated clinical diagnostic criteria that are precise and acceptable to researchers and genetic counselors throughout the world. Recently an international collaborative effort has established diagnostic criteria that are now used for both molecular genetic studies and prenatal diagnosis.(2)

These criteria can be summarized as follows.

1. Weakness is the central feature. The weakness should be symmetrical, proximal more than distal, and accompanied by hypotonia. The trunk is commonly involved. Weakness in the legs is characteristically greater than in the arms.

2. Denervation should be demonstrated by electromyography (EMG), muscle biopsy, and clinical criteria.

3. Several exclusionary criteria must be met. There should be no evidence of central nervous system (CNS) damage (other than to the AHC), arthrogryposis, involvement of other neurologic systems or other organs, sensory loss, eye muscle weakness, or significant facial weakness.

Simultaneously, the International SMA Consortium established the following classification with a clear disclaimer that not all patients will fit the criteria exactly and that at times there will be overlap of clinical features. This is the classification that will be used in this chapter (Table I).

AUTOSOMAL RECESSIVE SPINAL MUSCULAR ATROPHY

Historical Aspects --

Although reports of patients with SMA had been published previously, the first substantive descriptions occurred at the end of the 19th century when Werdnig and Hoffmann characterized the essential clinical and pathologic features of autosomal recessive SMA. Interestingly, their original patients would no longer fit the diagnostic criteria for the disease subsequently known as Werdnig-Hoffmann disease (type I, infantile SMA). Although Werdnig-Hoffmann disease became synonymous with the infantile, severe form of SMA, which has its onset before 6 months and death within a year, the patients they originally described had onset of symptoms in late infancy and lived as long as 5 years. Moreover, there was additional neurologic impairment such as movement disorder and hydrocephalus, which today would clearly exclude the diagnosis of SMA.

TABLE I -- Classification of Spinal Muscular Atrophy

In 1950 Brandt(3) reported 112 cases of "progressive" SMA and noted that one third had disease at delivery and that "transitory improvement" could be observed. Only 7% survived beyond 15 years of age, and 80% died before the age of 4 years. They noted that EMG and muscle biopsy were useful in establishing the diagnosis.

In 1956 Kugelberg and Welander reported several probable patients with SMA under the title "Heredofamilial Juvenile Muscular Atrophy Simulating Muscular Dystrophy."(4) These were patients with later onset and a more prolonged course. Importantly, the authors drew attention to the fact that patients suspected of having muscular dystrophy might in fact have an underlying denervating disorder that only masks as a dystrophy. This issue also occupied the attention of the early students of neuromuscular disease, including Duchenne. In this regard, it is important to remember that the sophisticated EMG and histochemical studies that have become essential in making this distinction precisely were not used routinely until the early l960s.

In 1973 and again in 1978 Pearn published a series of papers from London and Newcastle upon Tyne, England, that must be considered the most important modern documentation of the clinical, epidemiologic, and genetic features of SMA.(5-11) Taking advantage of the British system of organized health care records and of more modern diagnostic techniques, he made several observations that have solidified our current understanding of SMA. For example, he reported that childhood-onset SMA is not an uncommon disease and has an incidence in the range of 4 per 100,000, which makes it at least twice as common as amyotrophic lateral sclerosis (ALS) and the most common genetic cause of neonatal death. He confirmed the autosomal recessive inheritance of childhood SMA and defined the later-onset, more benign autosomal dominant form.

During the 1970s and l980s there was a lively debate regarding the precise nosology of SMA and speculation as to whether SMA was one or more genetic entities. These issues were recently reviewed by Dubowitz.(12) It is hoped that the nosology will soon be resolved to the patient's benefit and researcher's relief. The landmark report by the Columbia University researchers mapping the SMA gene to chromosome 5 (1) has ushered in the molecular genetic phase of attempts to understand and treat SMA. The disease will now be defined by genomic criteria, and genotype-phenotype correlations will be increasingly useful in understanding its pathogenesis.

Epidemiology --

Type I SMA is the most common cause of genetically determined neonatal death, with an incidence of 1 in 25,708 live births.(5) This translates to a gene frequency of about 1 in 160 (q = 0.0063) and a carrier frequency of 1:80.(5) The observed segregation ratio of 0.29 (6) is consistent with autosomal recessive inheritance, as are the vast majority of published pedigrees. Type II SMA accounts for a similar number of patients with a similar carrier frequency.(7) Birth order, parental age, social class, or season do not affect the disease. Almost all epidemiologic studies have observed an unexplained male preponderance, sometimes as high as 2:1.(6)

In Saudi Arabia and other Muslim countries, the incidence of SMA is considerably higher, most likely the result of consanguinity. In the series by Al-Rajeh and coworkers from King Fahd Hospital in Dammam, Saudi Arabia, an incidence of 193 per 100,000 live births for type I SMA was observed,(13) which is almost 50-fold higher than that found elsewhere in the world. In this series parents were consanguineous in 64% of the cases, an incidence comparable to that found in the general population of Saudi Arabia. The phenotype of these patients is identical to that in the Western world. Other endemic areas of high incidence have been reported among the Karaite sect in Israel,(14-15) in the Reunion Islands,(16) and from Tunisia.(17)

Clinical Features --

The cardinal sign of SMA is weakness. The severity and time of onset of weakness is variable. There is a strong correlation between the age of onset and severity of weakness such that the earlier-onset disease is more severe and the prognosis less favorable.(18) In about one third of cases, when the history is carefully obtained and if the mother has had previous normal pregnancies, reduced intrauterine fetal movement is reported."(10) These patients often have severe weakness at birth requiring respiratory support and intubation. Intrauterine onset is also associated with congenital joint contractures, and differentiation from the more benign neurogenic arthrogryposis multiplex congenita may be difficult.

More typically the weakness becomes apparent within the first few weeks or months of life when the family has had an opportunity to observe the child and becomes worried about a lack of normal movement and motor development. Concern may arise when there is a failure to achieve expected motor milestones such as unassisted sitting. Often it is only in retrospect that weakness or decreased muscle tone is fully appreciated. For this reason accurately dating the onset of disease is often a difficult task.

With later onset the course is more insidious and benign. For example, some patients may sit well but then show delayed or impaired walking or may lose the ability to walk after it has been attained.

Bulbar and respiratory involvement is a prominent feature only in early-onset, more severe SMA. Respiratory insufficiency, difficulty sucking and swallowing, accumulation of secretions, and a weak cry frequently accompany type I SMA but are less of a problem in later- onset cases. The intercostal and accessory respiratory muscles are weakened, but the diaphragm is relatively spared, so a characteristic paradoxical breathing pattern and flaring of the lower portion of the rib cage are produced. Tongue fasciculations are commonly seen in type I SMA, whereas in more chronic cases it is less common. Head control is poor. Mild facial weakness can be seen in early-onset SMA, but prominent weakness is currently an exclusion for the diagnosis. Limb weakness is always accompanied by hypotonia and is proportionate to it. In most patients, especially those with earlier onset, reflexes are not obtainable. Sensory testing is normal, as is intellect. In fact, it is commonly observed that patients with SMA are unusually bright and sociable.

A most useful clinical sign in patients with type II and III SMA is the presence of "minipolymyoclonus," a fine, irregular tremor of the outstretched fingers.(19,20) This is a result of denervation followed by reinnervation and the asynchronous firing of restructured and enlarged motor units. It is a much more helpful clinical sign than limb or trunk fasciculations, which are seen infrequently.

Surprisingly little effort has been made to accurately document the clinical course and natural history of SMA. For example. although SMA is considered by most to be a progressive disease, there is no objective evidence of this, and experienced clinicians suggest otherwise. It is more likely that the observed functional deterioration in certain patients is the result of secondary effects such as contractures and scoliosis rather than continued loss of motor units. In type I, the severity of weakness at onset usually leaves little opportunity to determine progression, whereas in types II and III the change, if any, is very slow and difficult to measure. Recent studies that for the first time have used reproducible strength measurement techniques suggest that although patients with SMA do not gain strength at a normal rate, neither do they lose strength, thus suggesting that there may be a defect in maturation rather than continued motor unit deterioration.(21)

Pathology --

AUTOPSY FINDINGS

... The essential, if not sole abnormality in autosomal recessive SMA is degeneration and eventual loss of the AHC. The loss is remarkable in its lack of specificity and leaves little insight into the mechanism of this damage. Various stages of degeneration can be observed that roughly correlate with the clinical deficit. Initially, one observes chromatolysis, dissolution of Nissl substance, and loss of normal staining characteristics. Eventually the cytoplasm undergoes shrinkage and disappears with little if any residual damage to the adjacent neuropil. Neuronophagia may occur, but inflammation is not seen. The changes are symmetrical and correspond to the symmetrical loss of strength.

Electron microscopic studies have been of little help in understanding the mechanism of AHC damage. The changes seen are nonspecific. Fidzianska and coworkers(22) have observed a population of seemingly normal but immature AHCs in addition to those undergoing degeneration. They have also reported that muscle biopsy specimens from patients with type I SMA have a fetal appearance and are morphologically different from other denervating diseases such as ALS.(23) These observations have led them to suggest that type I SMA may be a result of arrested development of the motor unit and not a degenerative process.

Corresponding to the damage and loss of the AHC is a characteristic thinning of the anterior roots of the spinal cord, which is in contrast to the preservation of the posterior sensory roots. Consistent with the lack of clinical upper motor neuron signs, the lateral columns, which are heavily involved in ALS, are spared in SMA. Glial bundles of uncertain pathogenic significance have been described in the proximal portion of the anterior roots.(24)

Although the preponderance of evidence suggests otherwise, occasional reports have shown pathologic changes in tracts and nuclei outside of the AHC. In evaluating the significance of these findings it is important to be aware that almost all autopsy studies have been performed in the more severe type I patients, some of whom have been on respirators and almost all of whom have experienced some degree of caloric and vitamin deprivation. These changes include degeneration in Clarke's column and the thalamus. Carpenter and coworkers(25) have reported degenerative changes in sural nerve biopsy specimens and dorsal root ganglia.

BLOOD STUDIES

... Although serum creatine kinase levels are usually normal in SMA, modest elevation (two to three times normal) can occasionally be seen, particularly in type II but occasionally in type I as well. With later onset and a more benign course, rare cases can have unexplained levels as high as ten times normal.

Dahl and Peters(26) reported that late-onset SMA was associated with serum lipid abnormalities, but these were atypical phenotypes that do not fit current diagnostic criteria.

There has been a recent vigorous and at times contentious discussion about the role of antineuronal antibodies in motor neuron diseases. Specifically, it has been suggested that levels of antiganglioside antibodies, especially anti-GM, are elevated in a significant number of patients with motor neuron disease, particularly those who have primarily lower motor neuron involvement, i.e., motor neuropathies or neuronopathies,(27) a clinical picture not too dissimilar from SMA. Furthermore, it has been suggested that these antibodies are representative of an autoimmune attack on motor nerves and that these patients may respond to immunosuppressive therapy. A systematic search for autoantibodies in SMA that meets international diagnostic criteria has not been carried out, and there are no trials of immunosuppression. Nonetheless, there is little to suggest that the disease we are considering in this chapter is relevant to the autoimmune discussion. Spinal muscular atrophy is an inherited disease, whereas immune-mediated motor neuropathies are not. Spinal muscular atrophy is primarily a disease of children, whereas motor neuropathies occur mainly in adults. Motor neuropathies are progressive, often in a subacute manner, whereas SMA appears to be nonprogressive.

CLINICAL NEUROPHYSIOLOGY

... In conjunction with interpretation of muscle biopsy samples, physiologic studies are extremely helpful in establishing a firm diagnosis. The essential findings are those of denervation with reinnervation and normal conduction velocities. However, there are certain aspects of the EMG that are particularly useful in establishing the diagnosis of SMA. In the case of the newborn in whom the EMG is inherently more difficult to interpret, the findings may be modest and difficult to differentiate from a normal pattern. In the older child, evidence of active denervation with fibrillations and positive sharp waves is seen, but the giant polyphasic potentials commonly seen in other chronic denervating diseases are rare. There is a decrease in the interference pattern or even absence of any activity if the muscle is severely damaged. Myopathic motor units may be intermixed with evidence of denervation in chronic, long-standing SMA.

MUSCLE BIOPSY

... A secure diagnosis should not be made without an adequate muscle biopsy specimen processed with histochemical stains. The histologic and histochemical features vary with the type of SMA, which in turn correlates with the age of onset. The earlier the onset, the more severe the disease. Infants who undergo biopsy early pose the greatest problem in identification because the severity and distribution of atrophic fibers characteristic of denervation may not be apparent against the background of small fibers normal for the age. In older children the pattern is quite distinctive, and an experienced pathologist usually can separate SMA from other denervating diseases. The vast majority of fibers are atrophic and of both fiber types, with fiber type grouping the rule. An additional distinctive feature is the presence of a small number of scattered hypertrophic type I fibers presumably resulting from physiologic hypertrophy. In some patients the hypertrophic fibers occur in large groups that often conform to a fascicular distribution. A third population of normal-appearing fibers may be present. In paraffin- embedded sections clumps of darkly staining nuclei may be observed and are thought to represent severely atrophic fibers that have lost all of their myofibrils. Equally important in histologic diagnosis is the absence of significant necrosis, degeneration, regeneration, lipid accumulation, or connective tissue proliferation. However, older patients with long-standing SMA may demonstrate some of these features suggesting a "secondary myopathic" process. Typically, muscle spindles are very prominent and uninvolved. The muscle biopsy does not provide a reliable indication of the future course of the patient.

Pathogenesis --

A detailed understanding of the pathogenesis of SMA will necessarily have to await definition of the gene and its product. For the most part SMA has been considered to be a progressive disease more because of the severity and high mortality of the infantile form than because of objective data. However, clinical observations suggest that the disease process (loss of AHCs) may be active during a relatively short period of time and quite possibly in the prenatal period for type I SMA. Hausmanowa-Petrusewicz and her coworkers in Poland in particular have proposed that type I SMA represents an arrest of normal motor unit development. They observed the immature appearance of both motor neurons and muscle fibers that they innervate,(22,23,28) suggestive of developmental arrest. In an ultrastructural study of muscle in type I SMA(29) they observed membrane-bound muscle cell fragments indicative, in their view, of apoptotic bodies. They suggest that growth-retarded muscle removes the peripheral target of developing AHCs and leads to secondary AHC death.

In the only objective longitudinal measurement of motor unit function, the SMA Collaborative Study Group used maximal voluntary isometric contraction to study 37 patients with SMA over a period of 18 months.(21) They noted that no patient lost strength, although 4 lost function, and concluded that motor neuronal cell death may not be a feature of the postnatal disease.

Spinal Muscular Atrophy Variants --

There exists a small but significant number of childhood neuromuscular disorders that fulfill the criteria for the diagnosis of SMA but have added features leading to uncertainty as to whether they are the same or different diseases. Until accurate DNA testing becomes available, it will remain unclear whether these conditions are allelic or nonallelic heterogeneous conditions or possibly whether they are inherited at all. However, the clinical features are such that it seems reasonable for the time being to consider them as separate diseases until proved otherwise. These associated features include joint contractures, congenital cardiac defects, multiple long- bone fractures at birth, diaphragmatic paralysis with early respiratory failure, and pontocerebellar degeneration.

Of particular interest are patients with SMA who are born with joint contractures. It is certain that SMA can develop in utero. In these patients intrauterine motility is reduced, and at birth there is marked weakness and respiratory insufficiency requiring ventilatory and nutritional support. Frequently the deficit is accompanied by fixed joint contractures at elbows, knees, and ankles. Intuitively, since there is evidence that prenatal neuromuscular weakness regardless of cause can lead to contractures,(30) one might consider this a secondary effect of intrauterine denervation. However, confusion exists in separating these cases from neurogenic arthrogryposis multiplex congenita, a nonprogressive disorder with a much more favorable prognosis.(31) Until DNA testing is available, it seems prudent to set these cases aside because they are not appropriate for either gene mapping studies or prenatal testing with linkage analysis.

Congenital heart defects, especially septal defects, occur in about 1% of the general public. Ventricular septal defect occurs in 2.5 to 5 per 100,000 and atrial septal defect in 1 per 1,000 live births. It is thus difficult to consider these congenital defects as part of SMA even when it occurs in an otherwise atypical phenotype. However, recently the concordance of SMA with atrial septal defect has been reported in three siblings.(32)Diaphragmatic weakness is uncommon in SMA. Respiratory insufficiency is typically the result of weakness of the intercostal muscles and accessory muscles of respiration. Occasionally, patients with apparent SMA are seen in the neonatal period with respiratory insufficiency as the primary event.(33) Imaging studies reveal eventration or abnormal motion of the diaphragm. Limb weakness becomes apparent later and is often in an atypical distribution. Electromyographic, muscle biopsy, and autopsy findings have been indistinguishable from those of typical SMA.

Pontocerebellar hypoplasia may be mistaken for neonatal SMA because such patients have profound hypotonia, tongue fasciculations, and neurogenic weakness in the limbs.(34) However, these infants do not have normal intellectual function and may demonstrate other evidence of CNS dysfunction such as increased reflexes. Joint contractures are common. Imaging studies and autopsy reveal atrophy of the cerebellum and brain stem.

The association of SMA-like features has been reported with multiple congenital metaphyseal or epiphyseal long-bone fractures, often with contractures.(35)

Search for the Spinal Muscular Atrophy Gene --

In 1990 mapping of the gene for SMA to chromosome 5q11.2-13.3 was reported(1) and culminated a 3-year search initiated by the Muscular Dystrophy Association. In the initial paper linkage was reported only for chronic cases (types II and III), but shortly thereafter it was shown that type I mapped to the same locus.(36) These observations were almost immediately confirmed by French researchers.(37,38) Subsequently, although the suspect region has been progressively narrowed and the mapping refined,(39,40) as of this writing the gene has not been identified. Although the issue of nonallelic heterogeneity has not been fully resolved, especially for the more chronic cases, it seems likely that most if not all patients who meet the international diagnostic criteria for SMA will map to the same locus on 5q, and it is reasonable to assume, based on experience with other genetic neuromuscular disorders, that allelic differences will account for some of the clinical variation.

Genotype-Phenotype Correlations --

Definitive correlations and a full understanding of the pathogenesis of SMA will be the first step in devising effective therapeutic intervention. In 1969 we suggested that patients with more prolonged survival and a more benign course had the same disease as those with the more severe Werdnig-Hoffmann disease.(41) This speculation was based on observations that occasional siblings demonstrated both mild and severe forms, that phenotypes formed a spectrum of disease severity without clear demarcation and that the pathologic findings were similar. Others suggested that there were at least three genetically distinct forms of the autosomal recessive disease.(42) In 1990 the first attempt at genotype-phenotype correlation on the basis of 14 families who mapped to chromosome 5q11.2-13.3 was made.(18) Although this was a rough initial effort, certain observations seemed warranted. First, SMA mutations at the 5q locus have a broad continuum of clinical abnormalities. Second, although exceptions occurred, little phenotype variability was noted between affected sibling pairs. Third, when families were ranked by severity of disease and age of onset, a strong correlation was observed between early onset and poor prognosis.

In 1964 Becker(43) suggested that phenotypic variation in SMA may be the result of multiple alleles, one common (90% of the involved population) and the others relatively rare. This hypothesis has recently been reviewed and supported by Emery,(44) who points out that this would explain quite well not only sibship variability but the occasional occurrence of very different phenotypes in different generations that at times can simulate dominant inheritance. This view has not been supported in a recent DNA study of four sibships where the involved members had considerable phenotypic differences.(45)

It is unclear whether carriers (heterozygotes) of the autosomal recessive SMA gene express the disease in a subclinical form. Although modest EMG changes suggestive of denervation were found in parents of patients with types I and II SMA,(46) this has not been studied further. A systematic study assessing strength, EMG, and muscle biopsy in carriers is needed.

Because of certain clinical similarities between SMA and hexosaminidase deficiency(47) and the fact that the gene for both diseases maps to chromosome 5, it has been suspected that they might be allelic disorders. However, recent DNA analysis has shown that adjacent but quite separate genes are involved.(48)

Prenatal Testing --

The recent linkage of autosomal recessive SMA to polymorphic markers on chromosome 5q has allowed the introduction of prenatal diagnosis. Although it is still too early to make firm conclusions about the reliability and utility of testing, certain results may be of interest to the reader. At the time of this writing 112 families had been reviewed for possible prenatal testing by Integrated Genetics of Framingham, Massachusetts. Of the 112 families, 102 had complete information available. Seventy-five met the international criteria for the diagnosis of type I SMA and 7 for type II. Twenty, or approximately 20%, did not meet accepted criteria for the diagnosis. Of these 20, 10 had arthrogryposis multiplex alone or in combination with other dysmorphic features, 4 died before full diagnostic information could be obtained, and 6 had atypical clinical courses. Fifty-six families were found to be genetically informative, and from those, 26 prenatal samples of DNA were available, 21 of which have had prenatal diagnostic testing. Seventy-seven percent of the parents were found to be informative for flanking markers. DNA diagnosis was carried out by chorionic villus biopsy in 18 and amniocentesis in 3 and led to a prediction of 5 affected with SMA, 8 carriers, and 4 noncarriers (normal individuals). The accuracy of prenatal prediction, not involving a recombination, has been calculated to be 88% to 99%, depending on the individual family. This figure was based on a very conservative estimate of 10% nonallelic heterogeneity.

It should be emphasized that at the present time there is no reliable way to determine whether an abortus has SMA because characteristic histologic criteria have not been established for SMA at this early stage.

Therapy --

Although gene replacement strategies are being tested in animals, current treatment for SMA consists of prevention and management of the secondary effect of chronic motor unit loss. In type I SMA, despite the considerable early mortality, an important minority of patients will have a relatively prolonged survival. Since it is not possible to accurately predict which patients will fall into this more favorable group, it is appropriate to be vigorous with patient management. Therapeutic goals and the uncertainty of the immediate future should be discussed with the parents. We have frequently seen patients with SMA who were "written off" only to survive beyond the expected 2-year period with resulting consternation for both physician and parent and a missed opportunity to provide effective supportive and preventive treatment.

The major management issue in type I SMA is the prevention and early treatment of respiratory infections. Appropriate antibiotics should be given al the first sign of infection, and all measures should be taken to properly manage secretions and pulmonary insufficiency. Patients requiring intubation and tracheostomy have an extremely poor prognosis and depending on the family's wishes, intubation and tracheostomy might properly be withheld. However, each situation must be managed individually with careful attention to bioethical issues. Gastrostomy is needed less commonly than one might expect but, where appropriate, should be carried out.

Understandably, the therapeutic goals and management of patients with types II and Ill are quite different because they have a much better prognosis and frequently live very satisfying and productive lives. A regular and intensive physical therapy program carried out primarily at home but under the supervision of an experienced physical therapist is indicated. The goals are to maintain joint mobility, prevent contractures maximize respiratory function, and maintain muscle strength.

Most patients with later-onset and slower-evolving SMA experience debilitating contractures which further impairs functional capabilities unless preventive care is undertaken. A standing board or A-frame should be encouraged. Walkers can be both physically and psychologically beneficial.

Spinal scoliosis will develop in the majority of patients with chronic SMA. During early childhood a proper back support should be provided. Now that innovative instrumentation is readily available and the morbidity of surgery acceptably low, surgical spine stabilization will be appropriate in most. The time for surgery must be anticipated, with surgical intervention carefully timed.(49) Rapidly decompensating scoliosis can seriously impair respiratory and cardiac function in a unexpectedly short period of time.

AUTOSOMAL DOMINANT SPINAL MUSCULAR ATROPHY

Autosomal dominant SMA is seen uncommonly in the United States but occurs with apparent greater frequency in Europe. A high incidence of 1 in 100,000 has been reported in England,(8) but these might also include cases of X-linked recessive SMA. Although not yet fully resolved, certain reports of dominant disease, as discussed above, may in fact represent disease caused by multiple alleles and resulting compound heterozygotes. In Pearn's report of 13 patients in 6 families with autosomal dominant SMA(8) it was suggested that two different genes were operative, one causing weakness in early childhood (a very uncommon occurrence by present experience) and another with a mean onset at 37 years of age. Penetrance of both genes was felt to be complete.

More recently autosomal dominant SMA has been analyzed by Rietschel and coworkers in Germany where experience with this form is considerably greater than elsewhere.(50) They conclude that the observed intrafamilial phenotypic variation in some of their families is more consistent with a single-gene hypothesis with variable expressivity and that this must be considered in making management decisions and carrying out genetic counseling in dominant SMA. This group has also recently reported that the gene for autosomal dominant SMA does not map to the same locus as the recessive gene.(51)

X-LINKED RECESSIVE SPINAL MUSCULAR ATROPHY

X-linked SMA has a distinctive phenotype that allows clinical differentiation from autosomal recessive and autosomal dominant SMA. In addition to slowly progressive limb weakness that typically begins in early adulthood in affected males, there is prominent involvement of certain bulbar muscles. Denervation of the facial muscles leads to a characteristic mild facial weakness accompanied by prominent fasciculations, particularly about the mouth. Although the extraocular muscles are spared, the tongue becomes atrophic with fasciculations. Mild dysarthria and dysphagia may be present. Electromyographic and muscle biopsy findings show chronic denervation and reinnervation. These clinical features are distinctly unusual in other forms of SMA that begin in this age group.

Another unique and identifying feature of X-linked recessive SMA is feminization with gynecomastia and other features of androgen insufficiency. The gene responsible for this disease has recently been defined(52) and codes for a protein that is part of the androgen receptor.(53) Although androgen receptors are present on AHCs, it is unclear why this genetic defect causes the AHC to degenerate. Other androgen receptor abnormalities, including total absence of the receptor as in testicular feminization, do not result in AHC damage. It has been suggested that the genetic defect may produce a neurotoxic factor that somehow damages the AHC.

In common with myotonic muscular dystrophy (MMD) and the fragile X syndrome, the genetic mutation in X-linked SMA results in abnormal tandem repeats of a CAG sequence in the gene. The length of the repeated CAG sequence seems to correlate with the severity of the disease.

RESTRICTED FORMS OF SPINAL MUSCULAR ATROPHY

Certain forms of AHC disease meet all the criteria for SMA except for the distribution of involvement. Spinal muscular atrophy, as defined by international criteria, requires the weakness to be symmetrical and greater in the proximal muscles than the distal ones. However there are patients and families who meet all diagnostic criteria except that the denervation is focal and restricted in distribution. It is currently unclear whether these represent allelic variants, nonallelic heterogeneity, or possibly disease that is not inherited.

Spinal muscular dystrophy affecting the distal ports of the extremities was reported by McLeod and Prineas in 1971 (54) in six patients, three of whom had a positive family history. All demonstrated involvement of the legs, whereas in two the arms were affected as well. Hirayama and coworkers(55) and Sobue and coworkers(56) have reported SMA primarily involving the distal ends of the upper extremities, a form that appears to be particularly common in Asian countries. Similar neuromuscular weakness has recently been reported in identical Caucasian twins.(57) Spinal muscular atrophy in a facioscapulohumeral(58) and scapuloperoneal distribution(59) has also been reported.

Spinal muscular atrophy limited to parts of a limb or even parts of a muscle is not uncommon and must often be differentiated from early ALS or a spinal cord mass lesion. Originally documented by Riggs and coworkers(60) and designated "benign focal amyotrophy," this condition has a course indicated by that descriptive title. Events typically evolve insidiously, with weakness and atrophy first noted in a limited portion of a limb. The leg is more commonly involved than the arm. Progression is characteristically very slow, first spreading to the homologous group of AHCs on the other side of the spinal cord. "Patches" of lower motor neuron deficit may appear elsewhere simultaneously or at a later date. The electrophysiologic and morphologic changes are those of chronic denervation and are limited in distribution, although subclinical lesions may be detected with EMG, muscle biopsy, or isometric strength testing in seemingly normal muscles. Life span is unaffected, and rarely are these patients significantly impaired functionally.

THE FUTURE

The new age of molecular biology has had a profound effect on our understanding of the spinal muscular atrophies. Within a remarkably short period of time genes have been mapped, reliable prenatal diagnosis made available, and genotype-phenotype correlation begun. An international collaborative effort has narrowed the gene locus of autosomal recessive SMA to a very small region on the short arm of chromosome 5, and it is anticipated that the gene itself will be defined shortly. Following this, the defective gene product will be identified and its function explored to achieve a true understanding of pathogenesis, which is the first step in devising effective treatment.

Although human studies that attempt to directly replace defective genes have already begun in other diseases, it is likely that gene replacement for SMA will require many more years of investigation before it can be applied to humans. Nonetheless, animal studies have already begun. For example, it is interesting to note that motor neuron terminals are capable of taking up proteins from the systemic circulation and by retrograde transport carry them to the cell body in the anterior horn.(61) Sahenk and coworkers(62) have explored the direct injection of gene constructs into peripheral nerve and motor points in animals with considerable success.

The new age of molecular biology has also provided us with an increasing number of human proteins made by recombinant DNA techniques that have motor neurotrophic effects. These agents include ciliary neurotrophic factor (CNTF), insulin-like growth factor (IGF-1), and brain-derived neurotrophic factor (BDNF). Because of promising results in tissue culture experiments and animal models, CNTF and IGF- 1 are currently undergoing preliminary therapeutic trials in ALS. It is likely that additional drugs with even more promise will be developed in the near future. At the time of this writing plans are under way to initiate therapeutic trials with these agents in SMA.

The future is most promising, and it is quite likely that within the next few years we will have the first effective specific treatment for the SMA.

Acknowledgment -- I would like to thank Drs. Lester Adelman and Jerry Mendell for their helpful review of this manuscript.

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