RESUMO
Gonadal dysgenesis with normal male karyotype (46XY) is a sexual differentiation disorder. So far three patients have been reported presenting the association of 46XY gonadal dysgenesis with peripheral neuropathy. Examination of sural nerves revealed minifascicle formation in two of them. In one patient, a mutation was found in desert hedgehog homolog (Drosophila), a gene important in gonadal differentiation and peripheral nerve development. We studied neuropathological and molecular genetic aspects of a patient with 46XY gonadal dysgenesis and peripheral neuropathy. Examination of a sural nerve biopsy specimen revealed an axonal neuropathy with pronounced axonal loss, limited signs of axonal regeneration and no minifascicle formation. A normal male karyotype was found (46XY) without micro-deletions in the Y chromosome. No mutations were found in the sex determining region Y gene, peripheral myelin protein 22, Myelin Protein Zero, Gap-Junction protein Beta 1, Mitofusin 2 or desert hedgehog homolog. The absence of minifascicle formation and the absence of a mutation in desert hedgehog homolog in this patient with gonadal dysgenesis and peripheral neuropathy expand the clinical and genetic heterogeneity of this rare entity.
Assuntos
Predisposição Genética para Doença/genética , Disgenesia Gonadal 46 XY/complicações , Disgenesia Gonadal 46 XY/genética , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Axônios/metabolismo , Axônios/patologia , Biópsia , Comorbidade , Análise Mutacional de DNA , Feminino , Dosagem de Genes/genética , Genitália Feminina/anormalidades , Genótipo , Gônadas/anormalidades , Humanos , Cariotipagem , Pessoa de Meia-Idade , Condução Nervosa/genética , Nervos Periféricos/metabolismo , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Diferenciação Sexual/genética , Nervo Sural/metabolismo , Nervo Sural/patologia , Nervo Sural/fisiopatologia , Degeneração Walleriana/genética , Degeneração Walleriana/patologia , Degeneração Walleriana/fisiopatologiaRESUMO
BACKGROUND: Linezolid is an oxazolidinone antibiotic that is increasingly used to treat drug-resistant, gram-positive pathogens. The mechanism of action is inhibition of bacterial protein synthesis. Optic and/or peripheral neuropathy and lactic acidosis are reported side effects, but the underlying pathophysiological mechanism has not been unravelled. METHODS: We studied mitochondrial ultrastructure, mitochondrial respiratory chain enzyme activity, and mitochondrial DNA (mtDNA) in muscle, liver, and kidney samples obtained from a patient who developed optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after prolonged use of linezolid. In addition, we evaluated mtDNA, respiratory chain enzyme activity, and protein amount in muscle and liver samples obtained from experimental animals that received linezolid or placebo. RESULTS: In the patient, mitochondrial respiratory chain enzyme activity was decreased in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In the experimental animals, linezolid induced a dose- and time-dependent decrease of the activity of respiratory chain complexes containing mtDNA-encoded subunits and a decreased amount of protein of these complexes, whereas the amount of mtDNA was normal. CONCLUSION: These results provide direct evidence that linezolid inhibits mitochondrial protein synthesis with potentially severe clinical consequences. Prolonged courses of linezolid should be avoided if alternative treatment options are available.
