Spinal Muscular Atrophy (SMA)


Spinal muscular atrophy (SMA) is a group of genetic diseases that lead to progressive muscle weakness and atrophy of the proximal limb muscles caused by the loss of alpha motor neurons.1 Common SMA symptoms include weakness, atrophy, hypotonia, decreased reflexes, trouble chewing and swallowing, tremor, and tongue fasciculations, which vary between the different classifications of SMA. Due to overlap in symptoms with many other disorders affecting the muscular or nervous systems, an SMA differential diagnosis may be necessary. Disorders that should be considered vary depending on the age of onset.

Prenatal To 6 Months Old

Newborns and infants with symptoms of hypotonia, muscle weakness, contractures, respiratory problems, hypo- or areflexia, or tongue fasciculations should be considered candidates for SMA.2 The most common form of SMA, type 1, and the most rare, type 0, would be the most likely to affect this age group.

SMA Variants

For children who exhibit signs in utero to less than 6 months of age, there are a number of other possible causes of hypotonia, or “floppy infant,” that should be considered. In addition to the main classifications of SMA related to mutations or deletions of the SMN1 gene, several variants should be considered, including SMA with regulatory distress 1 (SMARD1), X-linked infantile SMA, and GARS1-related infantile-onset SMA.2

SMARD1, like the traditional forms of SMA, is an autosomal recessive genetic disorder. However, it is due to mutations in the IGHMBP2 gene3 rather than the SMN1 gene and can be differentiated genetically. Overlapping clinical features include weakness, hyporeflexia or areflexia, and respiratory failure.2 SMARD1 can typically be clinically differentiated due to the weakness being more distal and respiratory trouble being related to diaphragm paralysis rather than weak intercostal muscles.3 Infants with SMARD1 may also have sensory and autonomic nervous system involvement not seen in the classic types of SMA.4

Clinical differentiation between X-linked infantile SMA can usually be made with the presence of congenital fractures and/or contractures. Contractures are often present in the digits from birth.5 Genetically, patients have normal SMN1 and mutations in the UBA1 gene.4 Due to its X-linked nature, it is more prevalent in males.

GARS1-related infantile-onset SMA, sometimes referred to as James type of infantile SMA (SMAJI), is very rare and symptoms appear to be heterogeneous between patients described in case studies.6 The heterogeneity of features can make clinical differentiation from classic forms of SMA difficult. Genetic testing would reveal normal SMN1 but with mutations/deletions in GARS1.

Other Genetic Disorders

Several other genetic disorders overlap clinical symptoms with classic forms of SMA that may suggest an SMA differential diagnosis. 

Severe forms of Zellweger spectrum disorders, which include Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease,7 overlap with SMA symptoms of hypotonia. They can be differentiated by central nervous system (CNS) involvement, distinctive facies, malformations, such as chondrodysplasia punctata, and hepatosplenomegaly.7 Zellweger spectrum disorders can also be diagnosed through blood tests for elevated levels of very long-chain fatty acids8 or through genetic tests.

Congenital muscular dystrophy infants display hypotonia and muscle weakness but are differentiable based on ocular and CNS involvement, along with possible increases in creatine kinase (CK) levels in some forms of the disease9 in contrast to normal levels usually seen in SMA type 1.10 Myotonic dystrophy type 1 infants also display hypotonia, weakness, and respiratory insufficiency but the weakness is more general rather than proximal and often includes the face.11 Genetic diagnosis of myotonic dystrophy reveals mutations in the DMPK gene.

Respiratory difficulty and muscle weakness are also present in infants with Pompe disease.12 The largest clinical differentiating factor of Pompe disease from SMA is cardiac problems associated with the infantile form of Pompe disease.12

Muscle weakness and respiratory problems can occur in both congenital myasthenic syndromes and SMA. Congenital myasthenic syndrome can be differentiated based on muscle weakness of the eye, including ophthalmoplegia and ptosis, as well as weakness of the bulbar and facial muscles.13

Prader-Willi syndrome, caused by errors in the paternal chromosome 15, also causes severe hypotonia in infants.14 Respiratory problems are rare in Prader-Willi syndrome patients, however.2

Children 6 Months and Older

SMA type 2 and SMA type 3 typically present in children aged more than 6 months and 18 months, respectively.2 Patients with loss of motor skills after normal development, weakness predominantly in proximal muscles, decreases in tendon responses, and postural tremor in fingers indicate these SMA types as disease candidates. Many of the diseases listed in the above section may present later in infancy or early childhood and should be considered for differential diagnosis with SMA type 2. A number of other diseases should also be considered for differential diagnosis.

Genetic Disorders

A number of different forms of muscular dystrophy have a similar onset of early normal development followed by decreasing muscle strength in similar ages to SMA type 2 and 3.  Muscular dystrophies such as Duchenne or Becker can be distinguished clinically by extremely elevated CK levels15 and can be associated with cardiomyopathy.16 Genetic testing can also differentiate these muscular dystrophies from SMA through mutations in the DMD gene.16

Another genetic disorder with similar symptoms to classic SMA is hexosaminidase A deficiency, also known as Tay-Sachs disease. Differentiation includes an increased startle response, visual attentiveness problems, and possible seizures.17

Fazio-Londe syndrome, a form of riboflavin transporter deficiency neuronopathy, has overlapping symptoms of muscle weakness with SMA. Fazio-Londe syndrome typically affects lower cranial nerves and can result in death within years if not treated, compared18 to the slower onset of SMA types 2 and 3.

Hirayama disease, also known as juvenile muscular atrophy of the distal upper extremity4 or monomelic amyotrophy,2 also results in muscle weakness. The weakness is usually distal in the hand and forearm and is usually unilateral19 rather than symmetrical.

SMA Differential Diagnosis: Other Conditions

Other conditions including autoimmune disorders, infections, and injuries can also lead to symptoms similar to SMA.

Guillain-Barré syndrome is an immune-mediated form of peripheral neuropathy that results in weakness and areflexia similar to SMA. Differentiating symptoms include bulbar involvement, sometimes sensorineural symptoms, and dysfunction of the autonomic nervous system.20

Viral infections such as polio, other enteroviruses, and West Nile virus can affect the anterior horn of the spinal cord and lead to muscle weakness and eventually paralysis.21 Signs and symptoms of infection along with diagnostic laboratory testing can be used for differentiation. Infant botulism may also occur in patients in this age range and is marked by hypotonia and respiratory difficulty similar to SMA.22 Distinguishing features comprise cranial nerve palsies, including bulbar involvement, constipation, slow pupillary reflex, and increased muscle fatigue under repetitive nerve stimulation.22 Diagnosis can be confirmed with testing of stool samples for Clostridium botulinum or related species.22

Adult

Onset of SMA type 4 occurs in adult populations and presents as a mild weakness that can affect gait, which overlaps with symptoms of several other disorders.

As mentioned above for children, Guillain-Barré syndrome should be considered in differential diagnosis for SMA. Multiple sclerosis may also present with muscle weakness and mobility trouble but the symptoms can be episodic and include sensory, vision, and autonomic difficulties.23 Another immune disorder, myasthenia gravis, can result in weakness but other common differentiating symptoms include ptosis, ocular myasthenia, dysarthria, and respiratory trouble24 which, although common in younger-onset forms of SMA, is not a common symptom for SMA type 4.

Other Neurodegenerative Disorders

Symptoms of muscle weakness and gait instability in SMA type 4 overlap with several other neurodegenerative disorders but the progression is generally slower in SMA. A rapid loss in function may be indicative of another disease such as amyotrophic lateral sclerosis (ALS), Parkinson’s, Huntington’s, and Alzheimer’s diseases.25

Spinal and bulbar muscular atrophy (Kennedy’s disease) is another neurodegenerative disorder that presents with muscle weakness as well as fasciculations, similar to SMA.26 Kennedy’s disease is an X-linked disorder and so only affects males. Differential clinical features include androgen insensitivity resulting in testicular atrophy and gynecomastia.26

Infection

As mentioned earlier, infections with West Nile virus and enteroviruses can result in similar features to SMA. An additional virus, the human T-cell leukemia virus-1 (HTLV-1) can also lead to similar features of SMA and should be considered in the differential diagnosis in older patients.27

Reviewed by Michael Sapko, MD on 7/1/2021

References

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