Updated: 12/31/2016

Spinal Muscular Atrophy

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Introduction
  • A disease of progressive motor weakness 
    • significant variability in severity of disease
  • Epidemiology
    • incidence
      • most common genetic disease resulting in death during childhood
      • 1 in 10,000 live births
    • location
      • progressive weakness starts proximally and moves distally
  • Pathophysiology
    • caused by progressive loss of alpha-motor neurons in anterior horn of spinal cord  
  • Genetics
    • inheritance
      • autosomal recessive
    • mutation
      • survival motor neuron (SMN) gene mutation 
        • present in 90% of cases of SMA
        • a telomeric gene deletion 
        • SMN critical to RNA metabolism and is a mediator of apoptosis
        • there are two SMN genes
        • all patients with SMA lack SMN-I protein 
        • severity of disease based on number of functional copies of SMN-II
  • Associated conditions
    • orthopaedic manifestations of SMA
      • hip dislocation and subluxation (see below)
      • scoliosis 
      • lower extremity contractures
  • Prognosis
    • see classification 
Classification

Type
Name
Presentation
Prognosis
Type I Acute Werdnig-Hoffman disease
• Present at < 6 months
• Absent DTR
• Tongue fasciculations
Poor, usually die by 2 yrs.
Type II Chronic Werdnig-Hoffman disease • Present at 6-12 months 
• Muscle weakness worse in LE
• Can sit but cant walk
May live to 5th decade
Type III Kugelberg-Welander disease • Present at 2-15 years 
• Proximal weakness
• Walk as children, wheelchair as adult
Normal life expectancy - may need respiratory support

Presentation
  • Symptoms
    • symmetric progressive weakness that is
      • more profound in lower-extremity than upper extremity
      • more profound proximally than distally
  • Physical exam
    • absent deep tendon reflexes
      • distinguishes from Duchenne's muscular dystrophy where DTR are present
    • fasciculations present 
Imaging
  • Radiographs
    • scoliosis series
    • pelvis
Evaluation
  • Diagnosis based on
    • DNA analysis
    • muscle biopsy
    • prenatal diagnosis is possible
Treatment
  • Nonoperative
    • Nusinersen has been FDA approved for treatment of SMA. It is administered intra-thecally.
  • Operative
    • treat associated orthopaedic disorders (details below)
      • hip dislocation
      • scoliosis 
      • lower extremity contractures
Hip Dislocation
  • Overview
    • hip  subluxation and dislocation occur in 62% with type II SMA, and less frequently in Type III.
  • Treatment
    • nonoperative
      • observation alone (leave dislocated)
        • indications
          • standard of care as dislocations typically remain painless and high recurrence rate if open reduction attempted
Scoliosis
  • Overview
    • the development of scoliosis is almost universal 
    • usually occurs by age 2 to 3 years
    • often progressive
  • Treatment
    • nonoperative
      • bracing
        • indications
          • devices may delay but not prevent surgery in children younger than ten years
    • operative
      • PSF with fusion to pelvis
        • indications
          • progressive curve
        • technique
          • address hip contractures and any other lower extremity contractures before PSF to ensure seating balance
        • outcomes
          • for improved wheelchair sitting
          • may lead to temporary loss of upper extremity function
      • Combined PSF with anterior releases/fusion 
        • indications
          • curves >100 degrees
          • very young child with high risk of crankshaft phenomenon
        • contraindications
          • pulmonary compromise
        • typically not necessary due to the high flexibility of SMA curves 
 Hip, knee, and ankle contractures
  • Overview
    • Common in the hip and knee
    • Nonambulators also develop ankle equinus
  • Treatment
    • Physical therapy
    • Surgical release is controversial as function in nonwalkers is rarely improved and recurrence is common
 

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Questions (9)
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(OBQ12.233) A 3-month-old infant presents to your clinic with difficulty moving his extremities. The child had an uneventful prenatal course and birth, but since birth he has had poor head control and difficulty feeding. On physical exam, he is able to move all extremities, but he moves his upper extremities more than his lower extremities, and his hands more than his shoulders. He has no spasticity, but global weakness. The patient’s deep tendon reflexes are absent, but he has tongue fasciculations. What is the cellular pathology and prognosis for this patient? Review Topic

QID: 4593
1

The patient has a nonprogressive injury to his brain, and he will likely require multiple orthopaedic surgeries in the future as a result of muscle imbalance

9%

(226/2434)

2

The patient has an absent dystrophin protein and will likely require a wheelchair by the age of 15 and will die of cardiorespiratory problems by the age of 20

18%

(428/2434)

3

The child will have a progressive loss of alpha-motor neurons in anterior horn of spinal cord. He will have difficulty walking, but will be able to sit independently and will likely live into the fifth decade of life

15%

(376/2434)

4

The child will have a progressive loss of alpha-motor neurons in anterior horn of spinal cord and will unlikely live past the age of two

56%

(1352/2434)

5

The child will likely go on to develop a cavus foot and hammer toes, but he should live a full healthy life

1%

(25/2434)

ML 4

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

(OBQ13.104) A newborn infant is born with the physical exam finding shown in the video below. In addition, the child has absent deep tendon reflexes and hypotonia. Which of the following abnormalities is most likely responsible for these findings? Review Topic

QID: 4739
FIGURES:
1

Gene mutation in SMN1

61%

(2147/3547)

2

Deficiency of Dystrophin protein

13%

(462/3547)

3

Beta-galactosidase deficiency

16%

(584/3547)

4

Gene mutation in COMP

5%

(171/3547)

5

Gene mutation in COL1A1

4%

(145/3547)

ML 3

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

(SBQ13PE.2) A 12-month-old male presents with symmetric, progressive weakness that is more profound in lower extremity than upper extremity. On physical exam, he can sit but cannot walk. He has tongue fasciculations and absent deep tendon reflexes. Serum creatine phosphokinase and aldolase levels are normal. Which of the following genetic mutations or deletions is responsible for his condition? Review Topic

QID: 4915
1

Dystrophin gene

29%

(1310/4593)

2

PMP22 gene

6%

(280/4593)

3

Androgen receptor gene

1%

(51/4593)

4

SMN-1 gene

54%

(2481/4593)

5

Frataxin gene

10%

(439/4593)

ML 4

Select Answer to see Preferred Response

PREFERRED RESPONSE 4
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