MFMs are rare, hereditary and progressive muscle disorders with clinically and genetically heterogeneous. They are defined by the presence of myofibrillar disorganization commencing at the Z-disk, an accumulation of myofibrillar degradation products, and the ectopic expression of multiple proteins. MFM subtypes are designated according to the affected protein, such as desminopathy, aB-crystallinopathy, Bag3opathy, or filaminopathy. MFM subgroup frequencies vary depending on the cohort, with filaminopathy accounting for around 4% of all MFM patients according to the Mayo clinic cohort.
Filaminopathy is caused by FLNC mutations. Patients with mutations in the FLNC Ig-like domain usually present with weakness in limb-girdle muscles, and typical histological characteristics include focal disintegration of myofibrils and the aggregation of sarcoplasmic proteins in muscle biopsies.[3,10] Another MFM type is caused by missense mutations in the actin binding domain of FLNC, which leads to increased actin binding affinity. These patients were described as having a distal myopathy without typical pathological features of MFMs. A frameshift mutation in the Ig-like domain, resulting in haploinsufficiency in FLNC, was also shown to be causative of distal myopathy.[11-12]
Patients presenting with distal filaminopathy usually onset at the age of 30–40 years. The most common onset symptom is weakness of the upper limbs, with distal extensors typically more severely affected than flexor muscles. Atrophy is seen mostly in interosseus muscles, especially the first dorsal, and asymmetry is noted in about one-third of patients.[13-14] Our patient shared the same characteristics. A previously reported Australian family including nine affected individuals with distal filaminopathy showed slow progression of muscle weakness. Lower extremities were affected around 10 years after disease onset. Progression to the proximal muscles was evident in the fifth decade of life and patients usually required a stick for walking during their sixth decade. Our patient showed a more severe clinical pattern. His lower extremities were affected around 6 months after disease onset, and his ambulation is currently limited. This may have been caused not only by muscular lesions, but also by the involvement of peripheral nerves and motor neurons in the spinal cord that presented as LMN syndromes.
LMN syndromes are clinically characterized by muscle atrophy, weakness, and hyporeflexia without sensory involvement. They may arise from disease processes affecting the anterior horn cell or the motor axon and/or its surrounding myelin. Neurophysiological analysis may help support their diagnosis.[7,15] Our patient’s nerve conduction velocity revealed obviously diminished CMAP amplitudes in the motor nerves, and absent right ulnar nerve F-waves. The presence of chronic denervation was confirmed by long duration, large amplitude, and decreased motor unit recruitment on the EMG. This was observed in the cervical, thoracic, and lumbosacral spinal cord regions, which may indicate that the roots and branches of peripheral nerves, even motor neurons, were damaged. Such neurophysiological findings have not been reported in previous cases of distal filaminopathy, which mainly showed decreased CMAP amplitudes and a myogenic pattern on EMG. Only one patient with distal filaminopathy had mixed myogenic and neurogenic changes in the anterior tibial muscle.[11,13-14] While obvious neuropathic changes on EMG can be observed in MFM patients, genetic testing is nevertheless important to help make a correct diagnosis.
LMN syndromes can be hereditary, sporadic, or immune-mediated, and include multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy, SMAs, Kennedy’s disease, distal hereditary motor neuropathies, and motor neuron disease.[6,15] To carry out a differential diagnosis in our patient, we tested for the presence of peripheral neuropathy antibodies, SMA genes, and the androgen receptor gene, but all were negative. Therefore, we suggest that his LMN syndrome is associated with a FLNC mutation.
Peripheral nerve involvement has been reported in some MFM patients, including those with desminopathy and ZASPopathy. Moreover, axonal spheroidal formations in the spinal cord and spinal roots that were immunoreactive for neurofilaments were detected in a postmortem of a desminopathy patient.[1,16] In a German filaminopathy cohort, a muscle biopsy of a patient with hyperesthesia indicated neurogenic changes although nerve conduction velocities were normal. From our current investigation, we suggest that the peripheral nervous system and even the spinal cord could be involved in filaminopathy, with some patients showing a more severe clinical pattern. However, details of the pathological changes and underlying mechanism of filaminopathy should be confirmed by additional studies such as nerve biopsies.
The MRI of our patient disclosed a markedly increased signal intensity in the bilateral gastrocnemius muscles in TIRM sequences, while only a minor increase was seen in T2 sequences. This suggested that the affected muscles had edema, and that they had deteriorated rapidly. Patients in other studies with longer term courses and slower progress had markedly increased signal intensities in T2, consistent with fat replacement and lack of hyperintensity on TIRM sequences indicating an absence of muscular edema. The distribution of affected muscles in our patient was typical. Muscle imaging of filaminopathy often shows a homogenous pattern of muscle involvement. In patients with proximal muscle weakness, the involvement of the vastus intermedius and medialis, adductor magnus, and semimembranosus and biceps femoris muscles is more pronounced. The tibialis anterior muscles, as well as the gastrocnemius and soleus muscles, are usually involved in patients with distal muscle weakness.[3-4,10-13,17]
FLNC is located on chromosome 7q32-q35 and contains 48 coding exons. Mutation c.7123G>A, p.V2375I in our patient is in the 21st Ig-like domain. Most patients with mutations in FLNC Ig-like domains present with weakness in their proximal muscles and have typical protein aggregation in muscle biopsies, while those with mutations in actin-binding domains present with distal myopathy without typical pathological changes on histopathological examination.[13-14] However, our patient showed the opposite presentation. Despite carrying a mutation in the Ig-like domain, he showed distal myopathy and had typical protein aggregation on muscle biopsy with the presence of large inclusions in the muscle fibers. This suggests that mutations in actin-binding and Ig-like domains cause overlapping clinical symptoms and histopathological changes, but the relationship between genotype and phenotype remains unclear and may be affected by as yet unknown genetic and environmental causes.
In conclusion, we report a middle-aged Chinese male with a heterozygous missense mutation (c.7123G>A, p.V2375I) in the Ig-like domain 21 of FLNC. He showed distal myopathy and lower motor neuron syndrome with a more severe clinical pattern than other reported cases. Obvious muscle edema could be observed on MRI, and typical protein aggregation presented in the pathological study. Our study not only expands the clinical spectrum of filaminopathies, but also extends the histopathologic and genetic heterogeneity of hereditary distal myopathies and lower motor neuron syndromes. Nevertheless, underlying mechanisms and the relationship between the phenotype and genotype need further study.