This case was originally published in 2021. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
The patient is a three-year-old girl who presents with generalized hypotonia and weakness, abnormal gait, absent deep tendon reflexes, and a positive Gower’s sign. She passed initial motor milestones, crawling at seven months and walking at ten months of age, but her parents became concerned when she was two years old because she was unable to run. Her fine motor and language skills are normal for age. CPK level is within normal limits. A muscle biopsy is performed to evaluate for a possible underlying neuromuscular disorder.
Right quadriceps muscle
Whole Slide Image
The whole slide image provided is an H&E stain of the right quadriceps muscle biopsy, frozen section.
Which of the following is the most likely diagnosis?
Amyotrophic lateral sclerosis
Duchenne muscular dystrophy
Spinal muscular atrophy
Which of the following additional studies would be most useful to confirm the diagnosis?
Brain and spinal cord MRI
Electromyography/nerve conduction study
Molecular genetic testing
Which of the following histologic features is most useful in distinguishing neuropathic from myopathic conditions?
Focal adipose tissue deposition
Large groups of atrophic fibers
Presence of occasional whorled fibers
Scattered atrophic fibers
Scattered hypertrophic fibers
Discussion and Diagnosis
The clinical history, physical exam, and muscle biopsy findings in this case are most consistent with spinal muscular atrophy (SMA). Molecular genetic testing in this patient identified zero copies of the survival motor neuron 1 (SMN1) gene, which is consistent with a molecular diagnosis of SMA. SMA is a group of inherited neuromuscular disorders characterized by degeneration of the anterior horn motor neurons in the spinal cord with resultant skeletal muscle atrophy and weakness.
The most common type of SMA is an autosomal recessive condition associated with a genetic alteration in the SMN1 gene on chromosome 5q. It is the leading genetic cause of death in infancy, with an incidence of 1 in 10,000 live births. The protein product, SMN, is important in RNA processing and is ubiquitously expressed but may also have a motor neuron specific function given the selective vulnerability of these cells. A second, almost identical gene, also located on chromosome 5q, is SMN2. Alternative splicing of SMN2 results in frequent exclusion of exon 7, which renders the protein product extremely unstable, and it is quickly degraded. A minority of SMN2 transcripts are spliced to include exon 7, which results in a small amount of fully functional SMN protein. The clinical severity of SMA is inversely proportional to the number of copies of SMN2 (one to four copies) that the patient retains and the amount of functional SMN protein produced by SMN2.
SMA represents a clinical spectrum, with patients demonstrating varying degrees of symmetrical, proximal muscle weakness involving the lower extremities greater than the upper. There are three main clinical subtypes. SMA type I (ie, Werdnig-Hoffman disease) is the most severe, with presentation in infancy. Patients display extreme weakness or paralysis and are never able to sit on their own. They usually die from a respiratory infection before their second birthday. SMA type II is an intermediate form in which patients generally present before 18 months, achieve the ability to sit, but are never able to stand or walk. SMA type III (ie, Kugelberg-Welander disease) is the mildest form, with presentation typically from age 18 months to adulthood. These patients achieve the ability to walk unassisted, but may have difficulty jumping or running, as with the patient in this case. Some also recognize a type 0 form, with presentation in utero and an even more severe phenotype than type I. Some clinicians consider adult-onset cases a separate group—SMA type IV, while others lump these patients with SMA type III. These groups again represent a clinical continuum, and it is sometimes difficult to classify a patient into one of these strict groups. Important to note, muscle biopsy features do not determine the type of SMA; subtype is a clinical and genetic classification.
In this modern molecular era, the vast majority of SMA cases, especially those with early onset and severe, classic symptoms, are now diagnosed by molecular genetic testing, and a muscle biopsy is rarely performed. Because 95% of SMA patients have a deletion involving exons 7 and 8 of the SMN1 gene, molecular testing can reliably identify the vast majority of cases. The remaining 5% of cases are designated non-5q SMA and are genetically and clinically heterogeneous.
In patients with later onset, atypical symptoms, or a non-5q form, a diagnosis of SMA may not be as clinically apparent, and a muscle biopsy may still be performed. In the severe and intermediate forms, as well as in some of the milder cases, muscle biopsy shows characteristic neuropathic features including large groups of atrophic fibers and hypertrophic fibers that can also appear in large groups (Image A, Image B, and Image C). Muscle fiber regeneration or necrosis are not commonly identified but can be seen as a secondary myopathic change. The perimysium may appear widened, and there may be focal adipose tissue deposition (Image A), but significant endomysial fibrosis, which is typically present in muscular dystrophies, is not seen (Image E). Hypertrophic fibers are typically type 1, while atrophic fibers are of both types, although may appear to be largely type 2 on ATPase staining due to co-expression of more than one isoform of myosin (Image F). Fiber type grouping is often present in the milder cases, although it is not particularly prominent in this example. IHC shows slow myosin expression in the hypertrophic fibers and expression of fast, slow and fetal myosin in various combinations in the atrophic fibers.
When evaluating a muscle biopsy from a patient with possible SMA, there are several potential pitfalls that should be considered. First, the degree of pathology can vary significantly from one region of the muscle to another, with some areas showing only minimal to no significant pathology. In this case, one column showed classic severe neuropathic features described above, while the second column was predominantly comprised of much milder neuropathic changes, with only scattered acutely angulated atrophic fibers (Image D and Whole Slide Image). Sampling error could therefore produce a “normal” appearing biopsy or one with minimal pathology. In addition to possible sampling error, in some of the milder forms, where a muscular dystrophy may be in the clinical differential, the pathologic findings can show some overlap with a myopathic process with the presence of secondary myopathic features. Finally, in some cases of severe, early-onset SMA, muscle biopsy may show only scattered atrophic and hypertrophic fibers, with no fiber type grouping or grouped atrophy identified; such cases have been termed “pre-pathological” SMA.
There is currently no cure for SMA, but a number of promising therapies are being pursued. These include gene therapy aimed at replacing the SMN1 gene and drugs that act to increase expression of SMN2 or encourage inclusion of exon 7 during splicing of SMN2.
Take Home Points
- Pigmented tumors of the spinal or paraspinal region are diagnostically challenging due to extensive histopathologic overlap. Nevertheless, the entities have distinct genetic underpinnings.
- Several surrogate IHC markers are now available to assist in the differential diagnosis of MMNST, primary meningeal melanoma, and metastatic melanoma, though they are not 100% sensitive. As such, molecular testing is needed in a subset.
- MMNST is much more aggressive than previously appreciated, thus warranting the malignant terminology.
- A subset of MMNSTs are associated with Carney complex, and therefore this syndromic association should be further explored clinically and/or genetically.
- Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51:157-67.
- Dubowitz V, Sewry CA, Oldfors A. Muscle Biopsy: A Practical Approach. 4th ed. Elsevier Limited; 2013.
- Jha NN, Kim JK, Monani UR. Motor neuron biology and disease: a current perspective on infantile-onset spinal muscular atrophy. Future Neurol. 2018;13(3):161-72.
- Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015;33:831-46.
- Pedrotti S, Sette C. Spinal muscular atrophy: a new player joins the battle for SMN2 exon 7 splicing. Cell Cycle. 2010;9(19):3874-9.
- Schmalbruch H, Haase G. Spinal muscular atrophy: present state. Brain Pathol. 2001;11:231-47.
- Wee CD, Kong L, Sumner CJ. The genetics of spinal muscular atrophies. Curr Opin Neurol. 2010;23:450-8.
- Which of the following is the most likely diagnosis?
- A. Amyotrophic lateral sclerosis
- B. Congenital myasthenia
- C. Duchenne muscular dystrophy
- D. Myotubular myopathy
- E. Spinal muscular atrophy
- Which of the following additional studies would be most useful to confirm the diagnosis?
- A. Brain and spinal cord MRI
- B. Electromyography/nerve conduction study
- C. Electron microscopy
- D. IHC
- E. Molecular genetic testing
- Which of the following histologic features is most useful in distinguishing neuropathic from myopathic conditions?
- A. Focal adipose tissue deposition
- B. Large groups of atrophic fibers
- C. Presence of occasional whorled fibers
- D. Scattered atrophic fibers
- E. Scattered hypertrophic fibers