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Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease - treatable motor neuron diseases of childhood

2011; Wiley; Volume: 54; Issue: 4 Linguagem: Inglês

10.1111/j.1469-8749.2011.04179.x

1469-8749

Carlotta Spagnoli, Carlos de Sousa,

Infectious Encephalopathies and Encephalitis

Fazio-Londe disease and Brown-Vialetto-Van Laere syndrome belong to a spectrum of progressive motor neuron diseases, classically distinguished by the presence of sensorineural deafness in the latter.1, 2 Brown-Vialetto-Van Laere syndrome is characterized by onset in late childhood or early adulthood with sensorineural hearing loss, followed by other lower cranial nerve (VIIth–XIIth) involvement and lower motor neuron signs in the limbs (upper motor neuron signs are less frequently described) as well as respiratory insufficiency. Earlier-onset cases (traditionally referred to as Fazio-Londe disease) show a more rapidly progressive course with stridor, respiratory distress, ptosis, and facial and limb weakness (particularly in the upper limbs), leading to death in a 6- to 18-month period due to respiratory failure, either because of infection or respiratory muscle paralysis. Until recently, diagnosis was solely one of exclusion, supported by electromyography findings of anterior horn cell involvement in the cranial nerve nuclei and more variably in the spinal cord. Major advances have recently been made in the understanding of these conditions, with the discovery of mutations in the C20orf54 gene as an underlying aetiology for Brown-Vialetto-Van Laere syndrome2 and the successful administration of riboflavin as a substitutive therapy in patients showing clinical pictures diagnostic of both ‘variants’.3 The C20orf54 gene, located in 20p13, encodes a highly conserved transmembrane protein. Interestingly, its rat ortholog (rRFT2) is a riboflavin transporter in the small intestine and the protein is highly conserved through evolution.4 Riboflavin deficiency usually leads to a different clinical presentation dominated by dermatological signs, and thus a maintenance function in the central nervous system was hypothesized as a possible alternative explanation. Riboflavin is a precursor of the co-factors FAD and FMN, necessary for various redox reactions in carbohydrate, protein, and lipid metabolism and in oxidative phosphorilation. They have also been involved in apoptosis and DNA repair. Riboflavin administration to three patients was based on the similarities between their biochemical abnormalities and multiple acyl-CoA dehydrogenase deficiency (MADD), previously proven to be riboflavin-responsive when caused by a defect in the electron transfer flavoprotein dehydrogenase (ETFDH).3 As the patients were found to be flavin-defective despite a normal intake and MADD was excluded, a riboflavin transporter defect was suspected and C20orf54 was tested with positive results. The biochemical similarities to MADD are explained by the role of FAD as an electron acceptor for acyl-CoA dehydrogenation reactions involved in mitochondrial fatty acid oxidation and branched amino-acids catabolism. It is very intriguing to link this biochemical background to the notion of previous patients with Fazio-Londe disease being diagnosed with mitochondrial cytopathy (two siblings with evidence of respiratory chain defects in complexes I and II) and another family in which the index case showed ragged red fibres on muscle biopsy.5 Although these preliminary therapy approaches give rise to understandable enthusiasm because of promising results in a previously unrelenting condition, some theoretical issues need to be considered. Riboflavin therapy could result simply in a delay in progression. In an attempt to significantly change natural history, early treatment is crucial to avoid long periods of riboflavin shortage or increased needs during intercurrent illnesses. The neuropathological correlates of Fazio-Londe disease/Brown-Vialetto-Van Laere syndrome in post-mortem examinations are those of widespread degeneration of the motor cranial nerve nuclei of the brainstem, with chromatolysis and gliosis, and anterior horn cell degeneration. For treatment with riboflavin to be most effective in preventing irreversible damage it will need to commence at the earliest stage in the disease. Many new challenges are now arising. Firstly, in the pathophysiological field where mechanisms of action of riboflavin in Fazio-Londe disease/Brown-Vialetto-Van Laere syndrome compared with other riboflavin deficiencies need further elucidation. Why does neuronal death and gliosis occur only in some disorders and how does riboflavin treatment prevent progressive neurological damage in others? Could the answers reside in the mitochondrion? Secondly, in the clinical follow-up to see to what extent this progression is actually prevented. What is undeniable is that we now have a quite simple tool for the treatment of Fazio-Londe disease/Brown-Vialetto-Van Laere syndrome, the use of which should be promoted in the hope of preventing death and reducing disability.