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Título

Sensory neuronopathy in multiple acyl-coenzyme A dehydrogenase deficiency (MADD)

Resumo

Introduction: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a recessive disorder due to ETFA, ETFB, and ETFDH pathogenic variants. Typical late-onset presentation includes exercise intolerance, cyclical vomiting, and progressive muscle weakness. Only a few reports of sensory neuronopathy were associated with MADD, with variable improvement after riboflavin supplementation.
Goals/methods: We aim to describe MADD-associated sensory ganglionopathy from a cohort of MADD patients in a tertiary neuromuscular center. This retrospective study presents clinical, molecular and response characteristics after treatment.
Results: We identified five cases with myopathy and genetically confirmed MADD. Three patients manifested with sensory neuronopathy. All these cases were female, aged 34, 67 and 74. Physical examination was remarkable for severe sensory ataxia and global weakness. Two patients were unable to walk, complained of fluctuating hoarseness, and had a dropped head on examination. Electrodiagnostic studies were consistent with a ganglionopathy in all cases, but two patients also had a superimposed myopathy. Serum CK levels were high in only one patient. Muscle MRI of the three patients had fat substitution or edema. Acylcarnitine profiles were collected in two patients, with only one test consistent with MADD. Muscle biopsies of all patients showed lipidic droplets and mild mitochondrial disfunction. A next-generation sequencing panel for myopathies led to different heterozygous ETFDH pathogenic variants in the patients. Riboflavin, coenzyme Q10, and L-carnitine were supplemented in all patients with a significant response in motor function, and variable response in sensory symptoms. One patient regained the capacity to walk.
Conclusions: MADD, a curable myopathy, is often missed in its typical presentation. An atypical presentation as presented here is even more ignored, and probably missed. Despite extensive investigations, many sensory ganglionopathies remain idiopathic, therefore, we propose MADD should be in differential diagnosis of sensory neuronopathy, especially with the phenotype here described. All three patients had a heterozygous variant, and we could not conclude whether there is a dominant inheritance related to this atypical manifestation, or the second variant was not found. In author’s experience, the motor function has a better response than sensory symptoms, but further studies and phenotype characterization are needed.