Spinal Muscular Atrophies

The spinal muscular atrophies are diseases of the anterior horn cells of the midbrain, pons, medulla, and spinal cord that most often present with muscle weakness in infancy and childhood. They may present with either proximal or distal weakness from the antenatal period onward. The inheritance pattern is most commonly autosomal recessive, but there are forms that are dominant and X linked (l.,Ta.b.!®,.3.6.:2.).

Pathogenesis and Pathophysiology. Information about the molecular basis for these disorders has exploded in the last 5 years. Both the severe and milder forms of

TABLE 36-2 -- TYPES OF SPINAL MUSCULAR ATROPHY

Type

Inheritance Pattern

Age of Onset

Presenting Symptoms

Hallmark

Prognosis

SMA type I (severe infantile SMA, acute or fatal SMA, Werdnig-Hoffman atrophy, Oppenheim disease, amyotonia congenita)

AR

In utero to 6 months

Hypotonia and weakness, problems with sucking, swallowing, and breathing

Never able to sit

Average life expectancy is 8 months, 95% dead before the age of 1 year

SMA type 11 (intermediate)

AR

Generally between 3 and 15 months

Proximal leg weakness, fasciculations, fine hand tremor

Never able to stand, facial muscles spared

Dependent on extent of timing of respiratory

SMA type III (chronic SMA, Kugelberg-Welander disease)

AR, AD

15 months to teen years

Proximal leg weakness, delayed motor milestones

Dependent on extent and timing of respiratory complications

SMA type IV (adult-onset SMA)

AD, AR, or very rarely X-linked recessive

Median age of onset 37 years

Proximal weakness, variable within families, more severe in AD form

Life expectancy not markedly reduced

Distal SMA (progressive SMA, Charcot-Marie-Tooth type-SMA)

AR, AD

AR: birth or infancy; AD: adulthood

Distal weakness

Very slow clinical progression; does not alter lifespan

AD, Autosomal dominant; AR, autosomal recessive.

autosomal recessive SMA have been linked to chromosome 5q11.3-13.1, a region that contains multiple copies of genes and pseudogenes and is characterized by instability. Deletions, truncations, or point mutations in what is now called the gene for survival of motor neurons (SMN) have been identified in SMA types I, II, and III.[10] Its protein product has no known homolog, and its function is not yet known. Although there is no correlation between genotype and phenotype, most affected siblings exhibit the same phenotype, suggesting that there may be additional modifying factors, one of which could be another gene tightly linked to the pathogenic gene. One possibility is the neuronal apoptosis protein gene, located within the linked region, because more severely affected patients have fewer copies of it. y Another possibility is SMN's closely flanking, nearly identical copy gene, c SMN, which can produce an alternatively spliced form that may alter its structure. It is conceivable that the number of copies of c SMN, in addition to individual or tissue-specific influences on its transcription, may determine phenotype when there is a homozygous SMN deletion.y , y Ultimately the amount of SMN gene product may determine the severity of disease.

Epidemiology and Risk Factors. The autosomal recessive SMAs are the most common cause of death in infancy, with incidence estimates of 1 in 10,000 to 25,000 for type I in the Western world. Similar numbers are affected with the milder forms and forms with a later onset. Distal SMA of recessive inheritance is more common with consanguineous parents, whereas the dominant form is rare. The X-linked adult SMA is also rare. y

Clinical Features and Associated Disorders. The three clinical hallmarks of this disorder are hypotonia, weakness, and cranial nerve palsies ( Fig,,...36z2 ).

Generally, SMA has an insidious onset of symmetrical weakness. Proximal muscles are weakened more than distal ones, and the legs become markedly weak before the arms are severely involved. Patients with the later onset forms decline less rapidly than those with earlier onset. An interesting difference between the SMAs and other neurodegenerative disorders is that in the SMAs the greatest decline in muscular power occurs at onset and then slows, implying great loss of motor neurons initially, followed by a stabilization in any

Figure 36-2 A baby with spinal muscular atrophy, showing the flaccid head lag in the supine positi<oFrom Dubowitz V: Muscle Disorders in Childhood. Philadelphia, W.B. Saunders, 1995.)

remaining neurons. This phenomenon results in a large number of complications owing to greater demands on remaining strength, such as scoliosis, contractures, and disuse atrophy, as well as respiratory, nutritional, and sleep problems. Arthrogryposis multiplex congenita, a disorder characterized by congenital limitation of motion in all joints except the temporomandibular and vertebral joints, is sometimes secondary to loss of anterior horn cells. A deletion of SMN has been found in half of such cases examined thus far.y

Progressive bulbar palsy of childhood, or Fazio-Londe disease, involves brain stem motor neuron degeneration that presents most often with stridor followed by ptosis, dysarthria, facial palsy, and dysphagia. Death generally occurs in early childhood.

An autosomal dominant scapuloperoneal SMA has been reported with fasciculations, weakness, and atrophy in that distribution. Autopsy findings included degeneration of anterior horn cells and motor neurons of cranial nerves VII, IX, and X. A few families with adult-onset, autosomal dominant facioscapulohumeral and scapulohumeral distribution SMA have been reported. y

Kennedy's syndrome, a spinobulbar neuropathy with midlife onset, normal lifespan, and gynecomastia that affects males, is caused by the expansion of trinucleotide repeats in the androgen receptor gene located on the X chromosome. y This was a particularly important discovery because it paved the way for identification of trinucleotide repeats as the cause of several other neurological diseases.

Differential Diagnosis and Evaluation. Because many disorders can mimic the clinical picture of the SMAs, it is essential to verify a neurogenic process via EMG and muscle biopsy. In children, the differential diagnosis is particularly wide (..Table SS-S ).

Homozygous deletion of SMN is a sensitive test for confirming the clinical diagnosis in almost all cases, including isolated cases and those with unusual features. After genetic testing, the most revealing studies are EMG and muscle histochemistry, both of which will confirm a neurogenic process involving muscle. Fibrillation and normal-sized residual motor units are commonly seen in the acutely denervated muscle fibers of SMA I. Additionally, there is an abnormal rhythmical motor unit discharge during sleep. SMA II and III produce very large motor units and absence of spontaneous activity. Serum creatine kinase (CK) can be elevated, and it correlates positively with duration of illness.

Management and Future Prognosis. There is no specific treatment for any of the SMAs. A multidisciplinary approach aimed at preventing contractures, skeletal deformities, respiratory complications, and social isolation is imperative. Genetic counseling of parents of young SMA patients or SMA patients approaching childbearing age is appropriate. Thus far, prenatal testing for SMN deletion is available only on a research basis. The prognosis varies according to type, ranging from the early fatality of SMA I to the basically unaltered lifespan of SMA III.

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