Final Diagnosis

Myofibrillar Myopathy

Patient Follow-up

The patient underwent genetic testing. The muscular dystrophy gene panel showed one copy of a possible pathogenic variant, c.5568T > A (p.C1856X), in the SMCHD1 gene. The DUX4 gene expression-permissive 4q35 haplotype was not tested, as his presentation was atypical for facioscapulohumeral muscular dystrophy. There was no mutation detected in the desmin, myotilin, FHL1, or DNAJB6 gene. The other genes, mutations in which could also cause myofibrillar myopathy, including αB-crystallin, Z-line alternatively spliced PDZ motif-containing protein (ZASP), filamin C, and bcl-2-associated athanogene 3 (Bag3) genes were not included in this muscular dystrophy gene panel. Due to the patient’s insurance status, these genes had not been tested. The patient underwent physical therapy, and his weakness slightly progressed over the next 1–1/2 years. But his gait improved after wearing ankle foot orthotic brace (AFO). He was referred to cardiology for cardiac evaluation which revealed a very mild dilated cardiomyopathy, and it was treated. His pulmonary function test was unremarkable.

Discussion

Myofibrillar myopathies are a group of heterogeneous genetic myopathies that share distinct muscle pathology features [1]. They are caused by mutations in the genes that encode proteins in Z line or associated with Z line, which play important roles in maintaining intermyofibrillar architecture . The genes that are primarily involved in myofibrillar myopathies include desmin (DES), αB-crystallin (CRYAB), myotilin (MYOT), ZASP (LDB3), filamin C (FLNC), Bag3 (BAG3), and four-and-a-half-LIM domain 1 protein (FHL1). Many cases are sporadic. The inheritance in the majority of the cases with a positive family history is autosome dominant except for the FHL1-associated cases which are X-linked. Recessive mutations are very rare. A large number of cases with myofibrillar myopathies have no gene mutations found, which indicates that some causative genes have not been identified yet [2–5].

Age of symptom onset in myofibrillar myopathies is variable, ranging from childhood to late adulthood with adult onset being more common [4], especially in the cases with mutations in the LDB3, MYOT, and FLNC genes. Childhood cases are often severe and the progression is rapid. Myofibrillar myopathies can affect skeletal muscles and cardiac muscles. Limb weakness is often distal starting from lower limbs. It gradually progresses to involve upper limb muscles and proximal limb muscles. Some patients may show Achilles and finger contractures and atypical predominant scapuloperoneal weakness. Facial weakness is uncommon. Some older patients may report slurred speech and difficulty swallowing. Cardiac involvement is relatively common in the disease that is caused by mutations in the DES, FLNC, FHL1, or BAG3 gene. Patients may have arrhythmia, conduction defects, and/or dilated or hypertrophic cardiomyopathy. Cardiac involvement is rare in the disease that is caused by mutations in the MYOT or LDB3 gene. Respiratory weakness is mainly seen in early-onset severe cases and is also common in cases with FLNC mutations. Peripheral neuropathy is common especially in patients with BAG3 mutations. Early-onset cataract is a feature associated with CRYAB mutations.

The common causes of distal limb numbness and asymmetrical distal lower limb weakness in an elderly patient like ours include polyradiculopathy, lumbosacral plexopathy, and polyneuropathy. Myofibrillar myopathy is often misdiagnosed with these conditions and a correct diagnosis is often delayed. EMG plays a pivotal role in raising a suspicion for a myopathy. EMG in myofibrillar myopathies usually shows myopathic changes more prominent in the affected distal lower limb muscles as seen in our case. It may also show a coexisting distal polyneuropathy [4]. CK in myofibrillar myopathies is either normal or mildly elevated. The combination of a distal predominant myopathy and a distal polyneuropathy should raise a suspicion for a myofibrillar myopathy. The differential diagnosis in this setting includes sporadic inclusion body myositis (sIBM) and other distal myopathies [6]. For the distal limb muscles, sIBM more affects finger flexors than foot dorsiflexors. The more severe foot and toe plantar flexor weakness seen in our patient is atypical for sIBM. Muscle MRI may show different patterns of muscle involvement in myofibrillar myopathies caused by different gene mutations.

Muscle biopsy plays a key role in making a diagnosis of a myofibrillar myopathy and differentiating it from other distal myopathies. Subsequent genetic testing can identify genetic causes in many patients but not all [3]. As the disease more affects distal limb muscles and the muscle involvement can be asymmetrical, choosing an affected muscle for biopsy based on the clinical weakness, EMG findings, and muscle MRI findings is important as it can increase the biopsy yield.

The defining feature of myofibrillar myopathy is the presence of sarcoplasmic protein aggregates in a background of chronic myopathy. These protein aggregates have been referred to as hyaline structures, spheroid bodies, or Mallory bodies. They are eosinophilic on H&E, dark blue on Gomori trichrome, but pale on mitochondria enzyme stains (NADH-TR, SDH, and COX) and ATPase stains (Fig. 17.1). Cytoplasmic bodies can also be seen in myofibrillar myopathy, but much less specific. Cytoplasmic bodies are usually smaller than hyaline structures, composed of a dark red core surrounded by a pale halo on Gomori trichrome (Fig. 17.2a). On EM, cytoplasmic bodies are composed of an electron dense core surrounded by a halo of radiating filaments that show continuity with myofibrils (Fig. 17.2b). Replicated triads can be prominent (Fig. 17.2b). NADH-TR stain may also reveal widespread myofibrillar disarray (Fig. 17.2c), sometimes referred to as nonhyaline structures [7]. Both hyaline and nonhyaline structures are immunoreactive to desmin (Fig. 17.2d). These aggregates are also reported to be immunoreactive to alpha B crystalline, myotilin and dystrophin [4]. On EM, both hyaline and nonhyaline structures are composed of disintegrated Z band material, electron dense material, and disorganized myofilaments, which are collectively referred to as granulofilamentous material (Fig. 17.2e). Vacuoles containing degenerating membranous organelles can also be seen in some cases of myofibrillar myopathy (Fig. 17.2f); those vacuoles typically lack tubulofilamentous inclusions seen in inclusion body myositis (IBM).

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