New Insights into the Neuropathogenesis of Molybdenum Cofactor Deficiency

Abstract

91Molybdenum is found in most foods including legumes, dairy products and meats. It is an important element that forms a complex called molybdenum cofactor. Three mammalian enzymes depend on this cofactor for their function. These enzymes are (i) sulphite oxidase, a terminal enzyme, essential for detoxifying sulphites; (ii) xanthine dehydrogenase, which plays a role in purines metabolism and the formation of uric acid from xanthine and hypoxanthine and (iii) aldehyde dehydrogenase, which catalyses the conversion of aldehydes to acids. 1 Molybdenum cofactor deficiency (MOCOD, OMIM# 252150) is a rare, autosomal recessive, neurodegenerative ABSTRACT: Background: Molybdenum cofactor deficiency (MOCOD) is a rare, progressive neurodegenerative disorder caused by sulphite oxidase enzyme deficiency. The neuropathological findings are consistent with a toxic insult to the brain that causes severe neuronal loss, reactive astrogliosis and spongiosis. The mechanisms responsible for these changes are unknown. Methods: The case is a male infant with MOCOD who died at nine months of age from pneumonia. At autopsy, a complete neuropathological examination was performed including conventional immunohistochemical staining. In addition, brain sections were stained cytochemically with shikata and orcein which stain for disulphide bonds. The elemental composition of cortical cells was then analyzed in the scanning electron microscope using backscatter electron imaging and energy dispersive X-ray spectrometry. Results: Neurons demonstrated cytoplasmic staining with shikata and orcein cytochemically when compared to control sections. Energy dispersive X-ray spectrometry analysis of these neurons confirmed the presence of excess sulphur and unexpectedly revealed excess magnesium accumulation. None of these findings was found in an age-matched control. Conclusions: In MOCOD we found abnormal accumulation of sulphur and magnesium in neurons. It is postulated that sulphur-containing compound(s) that are formed as a result of MOCOD cause excitotoxic neuronal injury in the presence of excess magnesium. RÉSUMÉ: Nouveaux concepts dans la neuropathogenèse de la déficience en cofacteur à molybdène.Introduction: La déficience en cofacteur à molybdène (DCOMO) est une maladie neurodégénérative progressive rare causée par une déficience en sulphite oxydase. Les observations neuropathologiques sont compatibles avec une lésion toxique du cerveau qui cause une perte neuronale sévère, une astrogliose et une spongiose réactionnelles. Les mécanismes responsables de ces changements sont inconnus. Observation: Il s'agit d'un enfant mâle atteint de DCOMO qui est décédé à l'âge de neuf mois de pneumonie. À l'autopsie, un examen neuropathologique complet a été effectué, ainsi que des études conventionnelles de coloration immunohistochimiques et des colorations cytochimiques au shikata et à l'orcéine qui colorent les ponts disulphures. La composition élémentaire des cellules corticales a ensuite été analysée au microscope électronique à balayage utilisant la s...

Early Features in Neuroimaging of Two Siblings With Molybdenum Cofactor Deficiency

“…13 In addition, the cortex area near the cysts did not show restricted diffusion; therefore, the insult to areas with subcortical cysts is thought to start before birth. Neuropathological findings of cortical necrosis and extensive cavitating leukoencephalopathy were reminiscent of those in severe perinatal asphyxia, suggesting an etiology of energy deficiency in MoCoD 14 and ISOD. 15 The sulfite oxidase enzyme is located in the mitochondrial intermembranous space and is involved in electron transfer from sulfites into the electron transport chain.…”

A Mechanism of Sulfite Neurotoxicity

“…In other cases of molybdenum cofactor deficiency, which would compromise SO activity, data from magnetic resonance imaging also suggested hypoxic-ischemic encephalopathy (43). It was proposed that neuronal injury was caused by mitochondrial damage by sulfite, which disrupts mitochondrial membrane integrity leading to decreased ATP or energy failure (44). From these noninvasive studies, it was concluded that the underlying cause was a dysfunction of brain mitochondria.…”

“…Glutamine is an abundant amino acid in the brain, and it can be converted to glutamate, which is present in severalfold higher concentrations than the Krebs cycle metabolites; it therefore contributes significantly to mitochondrial respiratory function. Inhibition of GDH by an accumulation of sulfite in the brain of subjects with human SO deficiency would conceivably cause an energy crisis as shown in MR imaging (42)(43)(44). With inhibition of GDH by sulfite, the supply of ␣-ketoglutarate would be curtailed, because in the brain the GDH reaction operates in the direction of oxidative deamination to form ␣-ketoglutarate (48).…”

Sulfite Oxidase Activity of Cytochrome C: Role of Hydrogen Peroxide

“…However, the molecular mechanisms involved are not fully understood. In clinical studies of SO and molybdenum cofactor deficiencies, it was proposed that neuronal toxicity was due to decreased ATP or energy deficit/failure [82,83]. It has also been suggested that excess sulfite might damage mitochondrial function via disruption of membrane integrity [9,84].…”

“…Steroid-dependent asthmatics and children with chronic asthma are especially vulnerable to such toxicity [2]. Sulfite is also toxic to neurons and cardiovascular system [9][10][11][12][13][14]. The level of sulfite in serum was found to be unregulated in several disease conditions, such as pneumonia and end-stage renal failure [15,16].…”