Spinal Muscle Atrophy Workup

Updated: Aug 11, 2020
  • Author: Ashish S Ranade, MBBS, MS, MRCS; Chief Editor: Jeffrey A Goldstein, MD  more...
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Workup

Laboratory Studies

A simple blood test can confirm whether the child has a mutation that causes spinal muscle atrophy (SMA; also known as spinal muscular atrophy). The SMN1 deletion test is recommended as the first diagnostic step for a patient suspected of having SMA. The deletion status can be tested by using polymerase chain reaction (PCR) to determine if both copies of SMN1 exon 7 are absent, a finding that is noted in 95% of affected individuals. PCR can reliably and accurately measure SMN1 and SMN2 copy numbers over a wide range (ie, 0-8 copies).

If the survival motor neuron (SMN) gene test is positive, the diagnosis is confirmed. However, 5% of children with the symptoms of SMA can have a negative SMN gene test and may require additional diagnostic testing. These tests can include electromyography (EMG), a nerve conduction study (NCS), or muscle biopsy and additional blood tests to help rule out other forms of muscle disease. A congenital hypotonia panel may be ordered to test for SMA. Clinical laboratories may offer panels that include tests for disorders such as SMA, myotonic dystrophy (type 1), Prader-Willi syndrome, Angelman syndrome, and maternal uniparental disomy. [25]

In contrast to findings in patients with Duchenne muscular dystrophy and Becker muscular dystrophy, aldolase and serum creatine kinase (CK) findings are within reference ranges in patients with SMA. In later-onset SMA, these muscle enzymes may be slightly elevated.

Diagnostic delays are common in SMA. A systematic review of the literature conducted to diagnose diagnostic delay reported both age of onset and age at confirmed diagnosis; the delay to diagnosis ranged from months to years. [28] Earlier identification of newborns with SMA will also allow infants to begin treatment even before showing symptoms, when research in human and mouse models suggests it may be most effective.

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Imaging Studies

On anteroposterior (AP) and lateral views of the pelvis, most patients with type II SMA are found to have developed hip dislocations. (See the images below.) The dislocations are only temporarily symptomatic and do not influence function in these patients, because they are nonambulatory.

Spinal muscle atrophy. Anteroposterior radiograph Spinal muscle atrophy. Anteroposterior radiograph of pelvis demonstrating right hip dislocation.
Spinal muscle atrophy. Lauenstein lateral view of Spinal muscle atrophy. Lauenstein lateral view of hips on patient with spinal muscle atrophy type I. Note near-universal pelvic dysmorphology (eg, widened obturator foramina) in addition to dislocated right hip.

A complete spine and scoliosis series is indicated. All patients with type II SMA and most patients with type III SMA develop a long C-shaped scoliotic curve. (See the images below.)

Spinal muscle atrophy. At age 4 years, this boy's Spinal muscle atrophy. At age 4 years, this boy's chest radiograph already reveals presence of significant 32° left thoracic scoliosis. Diagnosis is type I spinal muscle atrophy (Werdnig-Hoffmann disease). This radiograph captures the lumbar curvature incompletely.
Spinal muscle atrophy. By age 6 years, child's cur Spinal muscle atrophy. By age 6 years, child's curve is starting to decompensate. Note development of right-side truncal shift. He now has 40° thoracic curve and 60° lumbar curve.
Spinal muscle atrophy. Spine anteroposterior view. Spinal muscle atrophy. Spine anteroposterior view. Spinal curvature is progressing. Lumbar curve now is 70°, and thoracic curve is 35°. It is now clearly apparent that right hip is dislocated. Also note marked pelvic obliquity in this patient.
Spinal muscle atrophy. By age 9 years, this patien Spinal muscle atrophy. By age 9 years, this patient with type I spinal muscle atrophy now has thoracic curve of 60° and lumbar curve of 110°. Note that patient has tracheostomy tube and nasogastric tube as well.
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Other Tests

Findings from electromyography (EMG) in patients with SMA are characteristic of a neuropathic disorder, revealing fibrillation potentials, denervation, and increased amplitude. However, nerve conduction velocity test results are normal.

Antenatal DNA analysis is available to diagnose the deletion of arm 5q. [29, 30]

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Biopsy

In patients with SMA, incisional muscle biopsies reveal a uniform smaller diameter of all fibers. This contrasts with biopsy findings for other muscular dystrophies, which consist of degenerating muscle with variable muscle-fiber sizes. Biopsies in patients with hypotonic cerebral palsy reveal normal muscle fibers.

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Histologic Findings

Two subtypes of SMA deserve special mention with regard to their typical histologic appearance. The first, Werdnig-Hoffmann disease (type I SMA), is typically diagnosed in patients from birth to age 6 months. Its histologic pattern is usually one of extremely small and reasonably uniform small muscle fibers (see the images below).

Spinal muscle atrophy, Werdnig-Hoffman disease. Sm Spinal muscle atrophy, Werdnig-Hoffman disease. Small muscle fibers within separate muscle fascicles.
Spinal muscle atrophy, Werdnig-Hoffman disease. Ma Spinal muscle atrophy, Werdnig-Hoffman disease. Marked variation in muscle fiber size, as well as relative increase in associated connective tissue.

The second subtype, Kugelberg-Welander disease (type III SMA), is usually diagnosed in patients aged 2-15 years. The same tendency toward small muscle fiber diameter is seen but with much less uniformity (see the images below). Substantial variation, with intermixing of larger and smaller muscle fibers, may be observed.

Spinal muscle atrophy, Kugelberg-Welander disease. Spinal muscle atrophy, Kugelberg-Welander disease. Marked variation in muscle fiber size, along with increased perimysial connective tissue.
Spinal muscle atrophy, Kugelberg-Welander disease. Spinal muscle atrophy, Kugelberg-Welander disease. Muscle-fiber variation with some demonstrating internal nuclei.

In both forms of SMA, substantial increases in muscular connective tissue lead to both characteristic histologic findings and clinical findings (eg, increased muscle firmness). Centrally migrated or otherwise internalized nuclei are considered pathologic if they are present in more than about 3% of muscle fibers. Such nuclear findings are common in a variety of muscle diseases, including SMA.

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Staging

Once diagnosis has been made, the natural progression of SMA can be assessed by age- and ability-appropriate motor functional scales and electrophysiologic measurement of motor-unit health. [25]

The Hammersmith Infant Neurological Examination (HINE) was designed to be a simple and scorable method for evaluating infants aged 2 months to 2 years. It includes the following three sections, which contain 26 items that assess different aspects of neurologic function:

  • Section 1 - Neurologic examination assessing cranial nerve function, posture, movements, tone, reflexes, and reactions
  • Section 2 - Developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking)
  • Section 3 - Behavioral assessment (state of consciousness, emotional state, social orientation)

The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) was developed by evaluating infants with type I SMA and has been shown to be valid for the assessment of children ranging in age from 3.8 months to over 4 years who have an infant's repertoire of motor skills. It includes 16 items used to assess motor skills, each of which is graded on a scale of 0 to 4 (0 = no response, 4 = complete response; total score, 0-64).

The Hammersmith Functional Motor Scale–Expanded (HFMSE) was developed to evaluate motor function in nonambulatory and ambulatory individuals with later-onset SMA. It has been used in several clinical trials to evaluate the motor function of individuals with later-onset (types II and III) SMA.

The Upper Limb Module (ULM) was developed to assess aspects of function related to everyday life in nonambulatory individuals with SMA. These skills might only be partly captured by the HFMSE in weaker patients.

The 6-Minute Walk Test (6MWT) is an objective evaluation of exercise capacity that may be used to assess function in ambulatory individuals with later-onset SMA.

Electrophysiologic measurementsmay be used to assess the health of motor neurons, as follows:

  • Compound muscle action potential (CMAP) response - This is a measure of the electrophysiologic output from a specific muscle or muscle group following stimulation of the innervating nerve
  • Motor-unit number estimation (MUNE) - This is a method for estimating the number of motor units involved in the contraction of a specific muscle

Measurement and monitoring of quality of life for children with SMA and their families represent an implementable priority for care teams. [31, 32]

Quantitative measurement of lower-extremity contractures may be useful. Minimal hip and knee joint contractures have been associated with diminished motor ability. [33]

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