Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.
Spinal muscular atrophy (SMA) is a rare neuromuscular disease that ranges widely in clinical manifestations and severity. It affects approximately 10,000 to 25,000 children and adults in the United States.1 Patients may present with symptoms at any age from birth to adulthood, depending on SMA type.
The disease is characterized by the loss of motor neurons in the anterior horn of the spinal cord, which leads to muscle atrophy and wasting.2 SMA is caused mainly by a homozygous deletion, or by a deletion of one copy and a point mutation in the other copy, of the SMN1 gene, which codes for survival motor neuron protein. This protein is essential for the health of motor neurons.3
The diagnosis of SMA involves a physical examination and review of the family history, nerve conduction studies, and electromyography. Muscle or nerve biopsy may also be used, although this is now rare since a definitive diagnosis can be reached via genetic testing to detect mutations in the SMN1 gene.
The updated consensus statement for standard of care in SMA that was published in 2017 states that muscle biopsy is unnecessary in a typical presentation.4 However, muscle biopsy may be useful in more complex cases or if genetic testing is not available.
General Biopsy Findings
The general histologic features of 5q SMA include large groups of small muscle fibers and clusters of hypertrophic large muscle fibers.5 The small muscle fibers are often rounded and without pyknotic nuclear clumps. They are commonly of type 2, although type 1 or type 2C may also be present. The large muscle fibers are hypertrophic, clustered, and commonly of type 1.
Biopsy Findings by SMA Type
Although the histologic findings cannot clearly distinguish between the different types of SMA, certain histologic features are associated with disease severity.6
For example, patients with SMA type 0 have only type 2C small muscle fibers with moderate variation in size.5
In infants with SMA type 1 or 2, the histologic examination shows large groups of atrophic muscle fibers interspersed with fascicles of hypertrophic and normal fibers.6 The atrophic fibers are of both types 1 and 2 and are round rather than angular. The hypertrophic fibers are usually of type 1.
In type 1 disease, many muscle fibers are small, with a few hypertrophic fibers. In some large and small muscle fibers, glycogen is reduced or absent.5
In SMA type 2, the changes in the patterns of fiber size vary among fascicles. Hypertrophic muscle fibers may be interspersed with small, angular fibers that have no pyknotic nuclear clumps.5 Large and small fibers may show grouped atrophy. Large muscle fibers have a coarse internal architecture. Small muscle fibers may be of various types or mostly of type 2. Large muscle fibers are hypertrophic, clustered, and of type 1.5
In young patients with SMA type 3, larger muscle fibers are not prominently hypertrophic. Fascicle involvement is variable. Axon numbers in the intramuscular nerves are mildly reduced. Neuromuscular junctions are present on large and small muscle fibers. They are large, present mostly around muscle fibers, and not multisegmented. The large fibers have an irregular internal architecture and are predominantly of type 1. Small muscle fibers are predominantly of type 2.5
In milder cases of SMA type 2 or 3, groups of uniformly atrophic muscle fibers of varying size are present between large groups of nonatrophic fibers of a single type (most commonly type 1).6
In adult patients with SMA type 3, regions of grouped atrophy that have very small muscle fibers and pyknotic nuclear clumps are visible. Increased connective tissue and fat are also apparent. Regions of grouped muscle fiber atrophy are also apparent with very small muscle fibers; increased connective tissue and fibrils are seen between muscle fibers. Less involved regions may show hypertrophic muscle fibers, small regions of grouped muscle fiber atrophy, and pyknotic nuclear clumps. Large muscle fibers are predominantly of type 1, whereas most small muscle fibers are of type 2C.5
In SMA type 4, the muscle biopsy findings are similar to those in type 3 disease.6
Underlying the SMA pathology is initial innervation by reduced numbers of motor axons. Functional axons innervate and maintain the size of larger muscle fibers, but the abnormal patterns of activity cause hypertrophy in which larger muscle fibers, which consist predominantly of type 1 fibers, are notably increased in size. In atrophic regions, some muscle fibers may be innervated by nonfunctioning axons. As the disease progresses, axons may become progressively dysfunctional or lost.5
Reviewed by Michael Sapko, MD on 7/1/2021
- About SMA: overview. SMA Foundation. Accessed June 5, 2021.
- Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011;68(8):979-84. doi:10.1001/archneurol.2011.74
- The genetics of 5q spinal muscular atrophy. Spinal Muscular Atrophy UK. Accessed June 5, 2021.
- Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115. doi:10.1016/j.nmd.2017.11.005
- Spinal muscular atrophy (5q). Neuromuscular. August 28, 2019. Accessed June 5, 2021.
- Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157-167. doi:10.1002/mus.24497