Spinal Muscular Atrophy

Author: Bryan Tsao, MD, Associate Professor, Department of Neurology, Loma Linda University; Chair and Service Chief,
Department of Neurology, Loma Linda University Medical Center
Coauthor(s): Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine; Chief, Division of
Neurology, Baystate Medical Center
Contributor Information and Disclosures
Updated: Jan 14, 2009

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 Overview
 Differential Diagnoses & Workup
 Treatment & Medication
 Follow-up

 References
 Keywords

Introduction

Background
The spinal muscular atrophies (SMAs) comprise a group of autosomal-recessive
disorders characterized by progressive weakness of the lower motor neurons.

In the early 1980s, Werdnig and Hoffman described a disorder of progressive

muscular weakness beginning in infancy that resulted in early death, though the age of
death was variable. In pathologic terms, the disease was characterized by loss of
anterior horn cells. The central role of lower motor neuron degeneration was
confirmed in subsequent pathologic studies demonstrating a loss of anterior horn cells
in the spinal cord and cranial nerve nuclei.1

Since then, several types of spinal muscular atrophies have been described based on
age when accompanying clinical features appear. The most common types are acute
infantile (SMA type I, or Werdnig-Hoffman disease), chronic infantile (SMA type II),
chronic juvenile (SMA type III or Kugelberg-Welander disease), and adult onset
(SMA type IV) forms.

The genetic defects associated with SMA types I-III are localized on chromosome
5q11.2-13.3.2,3,4,5

Many classification systems have been proposed and include variants based on
inheritance, clinical, and genetic criteria. Among these are the Emery6 , Pearn7 , and
International SMA Consortium system8 . The ISMAC system is most widely accepted
and is used in this review.
Pathophysiology
In 1995, the spinal muscular atrophy disease-causing gene, termed the survival motor
neuron (SMN), was discovered.9 Each individual has 2 SMN
genes, SMN1 and SMN2. More than 95% of patients with spinal muscular
atrophy have a homozygous disruption in the SMN1 gene on chromosome 5q, caused
by mutation, deletion, or rearrangement. However, all patients with spinal muscular
atrophy retain at least 1 copy ofSMN2, which generates only 10% of the amount of
full-length SMN protein versus SMN1. This genomic organization provides a
therapeutic pathway to promote SMN2, existing in all patients, to function like the
missing SMN1 gene.10
Frequency
United States

The spinal muscular atrophies are the second most common autosomal-recessive
inherited disorders aftercystic fibrosis. The acute infantile-onset SMA (type I) affects
approximately 1 per 10,000 live births; the chronic forms (types II and III) affect 1 per
24,000 births. SMA types I and III each account for about one fourth of cases,
whereas SMA type II is the largest group and accounts for one half of all cases.11

International

The incidence of spinal muscular atrophy is about 1 in 10,000 live births with a carrier
frequency of 1 in 50.7,12
Mortality/Morbidity
The mortality and/or morbidity rates of spinal muscular atrophy are inversely
correlated with the age at onset. High death rates are associated with early onset
disease. In patients with SMA type I, the median survival is 7 months, with a
mortality rate of 95% by age 18 months.

 Respiratory infections account for most deaths.

 In type II SMA, the age of death varies, but death is most often due to
respiratory complications.
 See Prognosis for more information.

Sex
Male individuals are most frequently affected, especially with the early-onset forms of
spinal muscular atrophy, ie, types I and II.13
Age
The ISMAC classification system is based on the age of
onset.8 See Background, History, and Physical for a review of the existing
classification systems and a brief discussion of their relevancy to the role of age in
spinal muscular atrophies.

According to the ISMAC system, the age of onset for spinal muscular atrophies is as
follows:

 SMA type I (acute infantile or Werdnig Hoffman): Onset is from birth to 6

months.
 SMA type II (chronic infantile): Onset is between 6 and 18 months.
 SMA type III (chronic juvenile): Onset is after 18 months.
 SMA type IV (adult onset): Onset is in adulthood (mean onset, mid 30s).

Clinical

History
The diagnosis of spinal muscular atrophies includes the following a detailed clinical
history. Obtaining a complete family history facilitates genetic counseling.

Patients with spinal muscular atrophy present with weakness and muscle wasting in
the limbs, respiratory, and bulbar or brainstem muscles. They have no evidence of
cerebral or other CNS dysfunction. Patients with spinal muscular atrophy often have
above-average intelligence quotients (IQs) and demonstrate high degrees of
intelligence.

The clinical manifestations of each particular form of spinal muscular atrophy are
discussed:14,2,15,16,17

 SMA type I - Acute infantile or Werdnig-Hoffman disease

o Patients present before 6 months of age, with 95% of patients having
signs and symptoms by 3 months. They have severe, progressive muscle
weakness and flaccid or reduced muscle tone (hypotonia). Bulbar
dysfunction includes poor suck ability, reduced swallowing, and
respiratory failure. Patients have no involvement of the extraocular
muscles, and facial weakness is often minimal or absent. They have no
evidence of cerebral involvement, and infants appear alert.
o Reports of impaired fetal movements are observed in 30% of cases, and
60% of infants with SMA type I are floppy babies at birth. Prolonged
cyanosis may be noted at delivery. In some instances, the disease can
 cause fulminant weakness in the first few days of life. Such severe
weakness and early bulbar dysfunction are associated with short life
expectancy, with a mean survival of 5.9 months. In 95% of cases, infants
die from complications of the disease by 18 months.
 SMA type II - Chronic infantile form
o This is the most common form of spinal muscular atrophy, and some
experts believe that SMA type II may overlap types I and III.
o Most children present between the ages of 6 and 18 months.
o The most common manifestation that parents and physicians note is
developmental motor delay. Infants with SMA type II often have
difficulties with sitting independently or failure to stand by 1 year of age.
o An unusual feature of the disease is a postural tremor affecting the
fingers. This is thought to be related to fasciculations in the skeletal
muscles.
o Pseudohypertrophy of the gastrocnemius muscle, musculoskeletal
deformities, and respiratory failure can occur.
o The lifespan of patients with SMA type II varies from 2 years to the third
decade of life. Respiratory infections account for most deaths.
 SMA type III - Chronic juvenile or Kugelberg-Welander syndrome
o This is a mild form of autosomal recessive spinal muscular atrophy that
appears after age 18 months.
o SMA type III is characterized by slowly progressive proximal weakness.
Most children with SMA III can stand and walk but have trouble with
motor skills, such as going up and down stairs.
o Bulbar dysfunction occurs late in the disease.
o Patients may show evidence of pseudohypertrophy, as in patients with
SMA type II.
o The disease progresses slowly, and the overall course is mild. Many
patients have normal life expectancies.
 SMA type IV - Adult-onset form
o Onset is typically in the mid 30s.
o In many ways, the disease mimics the symptoms of type III.
o Overall, the course of the disease is benign, and patients have a normal
life expectancy.

Physical
Patients with disease of the lower motor neurons present with flaccid weakness,
hypotonia, decreased or absent deep tendon reflexes, fasciculations, and muscle
atrophy.
 SMA type I - Acute infantile or Werdnig-Hoffman disease
o Diffuse muscle weakness and hypotonia can be demonstrated with a
variety of bedside maneuvers, including the traction response, vertical
suspension, and horizontal suspension tests.
o In general, infants with SMA type I cannot hold their heads up when
pulled to the sitting position, and they will slip through the examiner's
hands when held vertically. They lay limp in the physician's hand when
held under the abdomen and facing down.
o Weakness is greater in proximal than distal muscles and may mimic
muscle disease (myopathy).
o Findings on sensory examination are normal. Deep tendon reflexes are
absent, as are long-tract signs and sphincteral abnormalities.
o Arthrogryposis, or deformities of the limbs and joints at birth, can be
observed and results from in utero hypotonia. Skeletal deformities
(scoliosis) may be present.
o In the infant or newborn, fasciculations are often restricted to the tongue,
but tongue fasciculations can be difficult to distinguish from normal
random movements unless atrophy is also present.
 SMA type II - Chronic infantile form
o Infants cannot get to a sitting position on their own, though they may
stay upright if placed in that position.
o As with SMA type I, SMA type II cause notable, symmetric proximal
weakness, hypotonia, and fasciculations.
o Findings on sensory examination are normal, and long-tract signs are
absent. When the patient's hands are held out, a characteristic fine
postural tremor may be observed.
 SMA type III - Chronic juvenile or Kugelberg-Welander syndrome
o Children can ambulate, but they have proximal muscle weakness and
various degrees of muscle hypotonia and wasting.
o The lower extremities are often more severely affected than the upper
extremities.
 SMA type IV - Adult-onset form: Patients are similar to those with SMA type
III in presentation and clinical findings, though the overall degree of motor
weakness is less severe in type IV than in type III.
 Spinal muscular atrophy variants
o Juvenile bulbar palsy, or bulbar hereditary motor neuronopathy (HMN)
types I and II: Bulbar HMN I (Vialletto-van Laere syndrome) is an
autosomal recessive syndrome that begins in the second decade of life. It
is characterized by facial weakness, dysphagia and dysarthria followed
by facial weakness and compromised respiratory function. The
 distinguishing feature of this syndrome is the development of bilateral
sensorineural hearing loss.
o Bulbar HMN II (Fazio-Londe disease): This is characterized by
progressive bulbar paralysis in the first decade of life. Patients present
with stridor, dysarthria, and dysphagia. Cranial-nerve involvement leads
to facial diplegia, ptosis, and ophthalmoplegia. Generalized weakness of
the lower motor neurons and rare corticospinal-tract signs are sometimes
observed. Median survival for patients with bulbar HMN II is 18
months.18
o Distal spinal muscular atrophy (spinal CMT or HMN type II): This may
clinically mimic Charcot-Marie-Tooth (CMT) disease, otherwise known
as hereditary motor and sensory neuropathy (HMSN) types 1 and
2: CMT is characterized by peroneal muscular atrophy, weakness, and
wasting in the legs. High foot arches (pes cavus) are often present. Deep
tendon reflexes are reduced or absent. Distal large fiber sensory loss is
found on examination, although patients do not usually present with
complaints of subjective sensory loss. Compared with CMT, patients
with distal spinal muscular atrophy do not have sensory loss and
the electrodiagnostic examination shows sparing of sensory nerves.4
o X-lined recessive bulbospinal muscular atrophy (Kennedy
disease):19 Patients present with bulbar weakness, gynecomastia, and
lower motor neuron weakness beginning at age 20-40 years. Muscles
cramps often precede weakness, and facial and perioral fasciculations are
seen in more than 90% of patients. Increased rates of type 2 diabetes,
infertility, and hand tremor are associated with Kennedy disease. This
condition results from a triple repeat mutation (cytosine-adenine-guanine
[CAG]) in exon 1 of the androgen receptor gene on the X chromosome.
Because of the X-linked nature of Kennedy disease, daughters of
affected patients are obligated carriers; therefore, genetic counseling is
indicated.
o Scapuloperoneal spinal muscular atrophy: Type 1 (AD form) appears at
age 14-26, with weakness, distal leg atrophy, and absent tendon reflexes
and sparing of intrinsic foot muscles. Facial, bulbar, and pectoral
muscles are rarely affected. Progression is slow, with survival into the
seventh or eight decade of life.
o Type 2 (AR form): Patients present between birth and age 5 years, with
weakness and atrophy of the lower extremities and pectoral girdle. The
course is variable, and patients can survive to the fourth decade.20
o X-linked form scapuloperoneal spinal muscular atrophy: This has been
described with an onset before age 10 years. Patients present with
weakness of the pectoral girdle and arms with contractures. Cardiac
 conduction defects and cardiomyopathy are noted. The syndrome is
slowly progressive but stabilizes by age 20 years, and patients survive to
the sixth decade.
o Davidenkow syndrome: This is a form of scapuloperoneal SMA
characterized by weakness of the pectoral girdle and distal leg muscles,
pes equinovarus, and distal sensory loss and fasciculations. Autosomal
dominant (age of onset, 15-30 y) and autosomal recessive (age of onset,
<15 y) forms have been described. The clinical course is slow in the
autosomal dominant form, whereas the course of the autosomal recessive
form is unknown.
o Fascioscapulohumeral (FSH) SMA: Most reports of this disorder are
from Japan. It is an autosomal dominant or sporadic disorder
characterized by limb-girdle and facial weakness occurring before age
20 years. The phenotype of FSH SMA is similar to that of FSH
dystrophy (FSHD), another unrelated muscular dystrophy. However,
FSH SMA does not have the chromosome 4 gene deletion seen in
FSHD. Progression is slow, and the overall prognosis is good.
o Scapulohumeral spinal muscular atrophy: Described initially in a Dutch
family, this autosomal dominant disorder is characterized by the onset of
scapulohumeral weakness and atrophy between the fourth and sixth
decades of life. Progression is rapid, with death from respiratory failure
occurring within 3 years.
o Oculopharyngeal spinal muscular atrophy: This disorder is seen mainly
in people of French-Canadian descent and is characterized by bulbar and
cranial-nerve weakness followed by myopathic weakness of the limbs.
The pattern of inheritance is autosomal dominant with variable
penetrance. The onset is usually in the fourth to fifth decades of life, and
the disease is slowly progressive.
o Ryukyuan spinal muscular atrophy: This is an autosomal recessive
disorder described in men who live in the Japanese community on
Ryukyu Islands. The onset is before age 5 years, and the disease is
characterized by weakness and atrophy of the lower extremities, skeletal
abnormalities (eg, scoliosis), and foot deformities (eg, pes cavus). Deep
tendon reflexes are diminished or absent. The course of disease is
unknown.21
o Other: Other variants have been described, including spinal muscular
atrophy with pontocerebellar hypoplasia (PCH), multiple long-bone
fractures at birth, diaphragmatic paralysis with early respiratory failure,
congenital heart defects, arthrogryposis, segmental amyotrophy, vocal-
cord paralysis (distal HMN type VII), and disease of the anterior horn
cell with agenesis of the corpus callosum.22,23,24,24
Causes

 In 1995, the SMN gene, responsible for SMA types I-III, was mapped to the
long arm of chromosome 5. (See Pathophysiology.) 
o Two copies of the SMN gene have been identified on the 5q arm: a
telomeric SMN gene (SMNt,or SMN1) and a centromeric SMN gene
(SMNc, or SMN2). These 2 genes are nearly identical except for base-
pair changes in exons 7 and 8. About 95% of all cases of SMA involve a
homozygous deletion of the SMN1 gene.25
o Expression of SMN1 produces the full-length SMN protein. In contrast,
expression of SMN2produces a truncated version of the SMN protein
that is missing the 16 amino acids from the carboxy terminus. This
truncated protein results from a base-pair switch in exon 7 of
the SMN2gene. This switch leads to alternative splicing
of SMN2 mRNA, with removal of the exon 7 sequence. About 70-80%
of the gene product is in the form of this truncated protein. Only about
10-25% of the protein produced is the full-length functioning form.25
o Deletions or mutations in the SMN1 gene substantially decrease
expression of the SMN protein. Expression of SMN2 alone does not
appear to produce sufficient amounts of SMN protein to permit normal
mRNA processing in the lower motor neurons. Inefficient or abnormal
mRNA processing appears to have a toxic effect on the lower motor
neurons and results in cellular degeneration.26
o SMN protein is part of a multimeric protein complex that plays a critical
role in the assembly of snRNPs. These snRNPs are essential for early
pre-mRNA splicing. The hypothesis is that impaired or reduced
formation of snRNPs impairs mRNA splicing, with a toxic effect on
normal cellular function. Why this mutation results in such selective
degeneration of lower motor neurons is unclear, though the SMN protein
is expressed in many types of neurons and organ systems.27
 Neuronal apoptosis inhibitory protein (AIP), NAIP, gene
o This gene was also identified in 1995. Homozygous deletions of this
gene are found in 45% of patients with SMA type I and in 18% of
patients with SMA types II or III.
o This gene belongs to a class of highly conserved AIPs that help to
regulate programmed cell death. Deletion of this gene appears to be
associated with severe phenotypes of SMA.28
 BFT2p44 gene: Mutations in this gene have been found in 15% of patients with
SMA.29
More on Spinal Muscular Atrophy

Differential Diagnoses

Amyotrophic Lateral Sclerosis

Congenital Muscular Dystrophy
Congenital Myopathies
Disorders of Carbohydrate Metabolism
Myasthenia Gravis
Primary Lateral Sclerosis

Treatment

Medical Care
The first report of in vivo activation of SMN2 by valproic acid in 2006 led to a clinical
study of 7 patients with genetically-confirmed SMA type III/IV.34,35 The results of
the clinical trial are summarized as follows:

 This was an open-label retrospective trial with examiners blinded to prior

strength testing. Patient age ranged from 17-45 years with a mean age of 33
years.
 Duration of treatment was 8 months at a dose of valproic acid 250 mg twice a
day, which was then increased to 500 mg twice a day after 3 months, as
tolerated.
 Treated patients were found to have a mean increase in quantitative muscle
strength of 16% compared with normal strength and 48% compared with
pretreatment values. Functional benefit was present in 6 of 7 patients; only 1
did not experience any improvement.
 Follow-up at 1 year showed sustained benefit. The onset of improvement was
surprisingly quick, reported within a few months in most with initiation of
valproic acid.
 Common adverse effects included initial sedation and an average weight gain
of 5 lb.
 Larger controlled studies are underway.

Supportive treatment should be aimed at improving the patients' quality of life and
minimizing disability, particularly in patients with slow progression.

 The treatment of patients with adult-onset spinal muscular atrophy is similar to

that for amyotrophic lateral sclerosis (ALS), except that the course and life
span in spinal muscular atrophies is considerably longer.
 o A multidisciplinary approach is essential and encompasses physical,
occupational, speech, and respiratory therapies.
o The use of splints, bracing, and spinal orthoses can be customized to
each patient.36
o The goals are to maximize the patient's independence and quality of life
at each stage of the disease.
o Specific pharmacologic therapy is not available.
o Gene-specific therapy is not yet available.
 Patients and families can also be directed to ongoing clinical trials for the
treatment of spinal muscular atrophies. Descriptions of various trials can be
found at the following Web sites:
o National Institutes of Health
o Families of Spinal Muscular Atrophy
o Spinal Muscular Atrophy Foundation

Surgical Care

 Surgical revision may provide stable correction of the spine, and early
orthopedic intervention may be indicated in patients in whom prolonged
survival is anticipated.
 Noninvasive ventilation and percutaneous gastrostomy reportedly improves the
quality of life with no effect on survival. These modalities may be most
effective in prolonging lifespan in patients with slowly progressive disease,
whereas they may provide comfort care in rapidly progressive infantile forms.37

Consultations
Consultations for ancillary evaluations and treatments are appropriate. Consult the
following specialists as needed: physical therapist, occupational therapist, speech
therapist, dietary or nutritional therapist, social service staff, pulmonologist, and
gastroenterologist.
Diet
Ensuring optimal caloric intake enables patients to use weak muscles to their
maximum capacity without incurring obesity as a comorbid condition.
Activity

 Encourage mobility. The goal of active but nonfatiguing exercises is to

maintain range of motion, increase muscle flexibility, and prevent contractures.
These exercises should not produce pain or exhaustion.
 Preventing spinal deformities (eg, scoliosis) and joint contractures is important.
This goal is accomplished by using range-of-motion exercises, knee-ankle-foot
orthoses, specialized wheelchairs and seats at home and school, and home
assistance devices.