MYH7 mutations can cause two main groups of myopathies including myosin storage myopathy and Laing distal myopathy. In this study, we have described a series of patients with genetic confirmed Laing distal myopathy. Up to now, there have been more than 30 articles on Laing distal myopathy, including three reports on Chinese patients [10–12]. So far, this is the largest report on Laing distal myopathy in China. The onset ages are below 10 years old in young patients, but are 20–30 years old in middle-aged patients. This might be explained by the less awareness of weakness in the patients or due to the relatively wide range of onset ages of this disease [9, 16]. The clinical features of this disease are characterized by slowly progressive muscle weakness of ankle dorsiflexion and finger extension . The onset symptom of all six patients in our group is abnormal gait caused by ankle dorsiflexion weakness, suggesting its diagnostic value. Meanwhile, weakness of finger extension is also very common. Axial muscles involvement is another feature of this disease, which is also seen in our patients that five showed weakness of neck flexion and two showed scoliosis [17, 18]. Other orthopedic abnormalities including Achilles tendon contracture, winging scapula, talipes cavus have also been reported in previous researches [5, 19].
None of our patients showed evidence of cardiac involvement, but two presented with obvious sleep apnea, one of whom even needed ventilation assistance during sleep. This symptom has not been reported in previous researches, but should be paid more attention. Therefore, we suggest regular polysomnography test in patients with Laing distal myopathy to detect early sleep apnea. Deep tendon reflexes were absent in two patients, suggesting possible lower motor neuron or peripheral nerve involvement, which was also in accordance with neurogenic lesions on EMGs detected in two patients. High amplitude motor unit potentials and spontaneous activities on EMGs in Laing distal myopathy have also been pointed out in several reports, but without definite explanations [15, 16]. Muscle biopsy in patient 5 showing fiber type grouping further supports the evidence of denervation.
Muscle MRI in our patients shows both similarities and distinctions. In the thigh level, there is a tendency of concentric distribution of fatty infiltration in anterior muscles with vastus intermedius more severe than other quadriceps. Adductor magnus is affected the most among thigh adductor muscles, but posterior thigh muscles are affected differently among patients. This distribution is similar to previous researches that vastus intermedius and lateralis were said to be the most affected muscles followed by biceps femoris and semimembranosus, whereas the rectus femoris, adductor longus, semitendinosus, and gracilis were usually spared [8, 20]. In the calf level, tibialis anterior and extensor hallucis longus are the most severely affected, which is in accordance with clinical features of ankle dorsiflexion weakness and also the typical “hanging big toe” sign [9, 21]. The early involvement of tibialis anterior has also been reported in several researches, but our study further emphasizes extensor hallucis longus is also affected at the early stage . Besides, one of our patient also presented with fatty infiltration of axial muscles, which was also seen in other studies . Meanwhile, the asymmetrical involvement of both limbs is present in our patients, which is also seen in previous reports, and this could be another MRI feature of the disease .
Muscle pathological changes in our patients including type 2 fiber predominance, multi-cores and abnormal mitochondria, were relatively moderate and non-specific, but were in accordance with previous researches [8, 9, 16, 22]. Multi-cores on muscle biopsy of patient 6 were also reported in some previous articles in patients with the same MYH7 mutation p.E1508del [15, 23, 24]. This could be a specific pathological feature of this genotype. Other reported pathological features of the disease include central core, rimmed vacuole et al., suggesting muscle pathology could not be the definite diagnostic criteria of Laing distal myopathy but only provide clues [25, 26]. Muscles selected for biopsy also affect the results that in our study, pathological changes of biceps were relatively slighter than tibialis. Therefore, choosing more severely affected muscles for biopsy in also important, which can be assisted by MRI or other imaging techniques.
In four MYH7 gene mutations detected in our patients, three are in-frame deletions. Referring to published articles on Laing distal myopathy, common mutation types also include missense mutations, and in-frame indels. The p.K1617del and p.E1508del have also been reported in a few studies [5, 6, 8, 9, 12, 15, 19, 23, 24].Besides these in-frame indels in our study, other reported mutations include p.E1687del, p.K1729del, p.E1669del, p.K1729dup, p.L1793del, p.K1784del [5, 9, 11, 16, 26–28]. Therefore, in-frame deletions or duplications are common types of mutations in Laing distal myopathy. One presumable mechanism is similar to those change microsatellite allele size [6, 29].
In conclusion, our study further expands the clinical phenotypes and genotypes of Laing distal myopathy. Besides muscle strengths and cardiac monitoring, we stress the importance of respiratory evaluation, especially polysomnography, in order to find early sleep apnea. Concentric fatty infiltration of anterior thigh muscles together with early involvement of tibialis anterior and extensor hallucis longus on MRI might be an imaging feature of the disease. Meanwhile, in-frame deletions of MYH7 gene are common causes of Laing distal myopathy.