This study reported a cohort of the patients with MADD, in which some clinical features and genetic mutations were expanded. The muscle MRI of lower limb revealed that edema-like change and fatty infiltration exhibited distinct patterns of muscle involvement in the patients with MADD. The combination of either SO+/GA– sign in the leg or BFL+/ST– sign in the thigh had a good sensitivity and specificity for the diagnosis of late-onset MADD.
Different from the scarcity of late-onset MADD in Western countries, a large number of patients with MADD with late-onset muscle type were identified by general neurologists in China recently.[3,5,19] The age at onset of muscle-type MADD usually varied from adolescent to adulthood, only a few number of young children with late-onset muscle-type MADD were reported.[2,7] No newborn-onset cases with pure muscle type were described up to now, because newborn-form patients usually died of severe metabolic disturbance or encephalopathy in the neonatal period. Most intriguingly, this study found a newborn-onset case in this cohort of patients with MADD. The patient presented with isolated myopathy phenotype, and gradually got better with age. The disease progression mimicked that of congenital myopathy.
Abnormalities of peripheral neuropathy were recently reported in patients with late-onset MADD. This study confirmed the existence of the variant phenotype of late-onset MADD in four patients presenting with proximal limb weakness and loss of sensations in the distal limbs. Most patients only complained of hypoesthesia, but some patients presented with severe sensory ataxia and poor prognosis. In the first 15 cases of this cohort of patients, hyperhomocysteinemia was found in some patients by chance. Hereafter we consecutively measured the level of serum homocysteine in the last ten cases. To our surprise, the level of serum homocysteine was significantly elevated in the patients with late-onset MADD. The hyperhomocysteinemia would be neutralized by supplement of riboflavin that is an important cofactor of methylenetetrahydrofolate reductase in folate metabolism cycle for homocysteine metabolism. However, the underlying mechanism how the defects of ETF:QO cause hyperhomocysteinemia still needs to be investigated.
In the past a few years, there were increasing evidence that distinctive muscle MRI changes were useful to diagnose neuromuscular disorders showing specific patterns of muscle involvement.[10,12] However, the characteristics of muscle MRI about the late-onset muscle type of MADD was insufficient up to now. Rosenbohm and colleagues in 2014 found an increase subcutaneous fat but normal visceral fat in a young patient with ETFDH gene mutation through whole-body MRI. Liu and colleagues in 2016 reported that late-onset patients with MADD showed mild to severe fat infiltration and atrophy in the muscles of medial and posterior thigh compartment, as well as gluteus, but relatively sparing of the anterior thigh compartment. Moreover muscle edema pattern was not found in all those patients. Different from Liu et al's study, our study and Zhao et al's study evaluated each muscle in the thigh level, and identified that the fat infiltration mainly involved in femoris longus, semimembranosus, and adductor magnus muscles. Moreover, the edema-like change represented by STIR high signal was also found in the three muscles in more than half of our patients. The differences might be originated from the disputed edema-like change score scale, because no good consensus about muscle edema-like change was currently reached.
The edema-like change in the soleus and tibialis posterior muscles, as well as the BFL and semimembranosus muscles were obviously observed in our patients. However, the detailed mechanism of STIR indicative edema-like change was still elusive. Given the lipid metabolic disorder of MADD happening at mitochondria, the STIR high signal might be associated with alteration in the mitochondrial metabolism that caused cytotoxic edema due to the dysfunction of Na-K-ATPase pump. The STIR high signal faded more quickly than that of fat infiltration after riboflavin treatment. The phenomenon might suggest that muscle edema-like change had great contributions to muscle weakness in the pathologic process of MADD, and STIR signal might be potentially considered a biomarker of treatment response.
Most intriguingly, the muscles with edema-like change were generally identical to those with fat infiltration. Therefore, we suggested that the distinct patterns of selective muscle involvement, that is, a combination of either “SO+/GA–” sign or “BFL+/ST–” sign had a good sensitivity and specificity for the diagnosis of late-onset MADD. To support the diagnostic values of the signs, muscle MRI characteristics should be differentiated from multiple muscular disorders. Mitochondrial myopathy exhibited a similarity with MADD, and also had a positive SO edema-like change and a negative GA edema-like change, but fat infiltration signal was unusually detected in both muscles. The specificity of “SO+/GA–” sign or “BFL+/ST–” sign was high compared with other neuromuscular disorders, but if only compared with mitochondrial myopathy, the specificity would be decreased. Therefore, the signs should be cautiously differentiated in the metabolic myopathies. Dystrophinopathy showed a positive BFL fat infiltration and a negative ST fat infiltration, but no edema-like change can be simultaneously observed in both muscles. Flaminoapthy displayed a positive SO or BFL fat infiltration and a negative GA or ST fat infiltration, but edema-like change cannot be simultaneously found in these muscles. Therefore, both of edema-like change and fat infiltration signals simultaneously consistent with “SO+/GA–” and “BFL+/ST–” might facilitate a correct decision to molecular screening of late-onset MADD.
This study had some limitations that need to be explicitly acknowledged. First, it was a small-sample retrospective study; thus, some clinical data were incomplete that would lower the statistical power. A large-sample, prospective study of the muscle MRI characteristics should be conducted in the future. Second, the fact that the disease controls were quite heterogeneous undermined the reliability of the sensitivity and specificity of diagnostic signs. Confounders such as the age at onset, duration of illness, and CK level might have produced some bias with respect to results. Overall, the outcomes of this study should be cautiously interpreted. However, it seemed to indicate that the sensitivity and specificity of “SO+/GA–” sign or “BFL+/ST–” sign were higher compared with other neuromuscular disorders, and the regression models supported these results.
In conclusion, this study expands the clinical and genetic spectrums of late-onset MADD. The muscle MRI characteristics in the late-onset MADD shows distinct patterns and highlightes the diagnostic values. The dynamic change of STIR signal in the affected muscles might be potentially considered a biomarker of treatment response.
The authors appreciate the patients and their families for their enthusiasm and participation in this study.
This work was supported by a grant from the National Natural Science Foundation of China (No. 81460199).
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