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Molybdenum Cofactor Disorders

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Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases

Abstract

Molybdenum (Mo) cofactor deficiency (MoCD) is characterized by neonatal seizures, high-pitch crying, convulsions, and abnormal EEG and MRI findings accompanied by rapidly progressing neurodegeneration. In the absence of treatment, patients usually die within the first years of life and show no neurodevelopmental improvement. The molecular cause of the disease is mainly due to the loss of sulfite oxidase activity, one out of four molybdenum cofactor-dependent enzymes. Sulfite oxidase catalyzes the terminal step in the oxidative degradation of cysteine; a loss of activity results in the accumulation of toxic sulfite, which in turn triggers the alteration of secondary-related metabolites such as S-sulfocysteine, thiosulfate, taurine, hypotaurine, and cystine. Xanthine oxidoreductase catalyzes the catabolism of purines from hypoxanthine to xanthine and further to uric acid, which is reduced in patients while xanthine and to a lesser extent hypoxanthine accumulate. The molybdenum cofactor (Moco) is synthesized by a three-step biosynthetic pathway, which involves gene products of the MOCS1, MOCS2, MOCS3, and GEPH loci. Depending on the mutation, type A, B, and C deficiencies are known. While MoCD types A and B are clinically indistinguishable, MoCD type C has a more severe neurological presentation due to the loss of synaptic inhibition, which is dependent on GEPHYRIN function. Dietary restriction (low cysteine and methionine) has been reported in some case, however, disease improvement was marginal. A first causative therapy has been established for MoCD type A patients and is based on the treatment with cyclic pyranopterin monophosphate, the first intermediate in the molybdenum cofactor pathway. Given the high neurotoxicity of sulfite and its related compounds, early diagnosis has been shown to be the key determinant in the treatment outcome. Patients that were treated shortly after birth and have not been exposed to extensive anticonvulsive therapy showed best clinical and neurodevelopmental outcome.

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Authors and Affiliations

  1. Department of Chemistry, Institute of Biochemistry, University of Cologne, Zülpicher Str. 47, Köln, 50674, Germany

    Günter Schwarz

  2. Colbourne Pharmaceuticals GmbH, Viktoriaweg 7, Niederkassel, 53859, Germany

    Alex Veldman

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  1. Günter Schwarz
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Correspondence to Günter Schwarz .

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Editors and Affiliations

  1. Department of General Pediatrics, University Children's Hospital, Division of Inborn Metabolic Diseases, Heidelberg, Germany

    Nenad Blau

  2. Laboratory Genetic Metabolic Diseases, University of Amsterdam Academic Medical Centre, Amsterdam, The Netherlands

    Marinus Duran

  3. Section of Clinical Pharmacology, Washington State University, Spokane, Washington, USA

    K Michael Gibson

  4. Division of Metabolism, Department of Pediatric Medicine, Bambino Gesù Children’s Research Hospital, Rome, Italy

    Carlo Dionisi Vici

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Schwarz, G., Veldman, A. (2014). Molybdenum Cofactor Disorders. In: Blau, N., Duran, M., Gibson, K., Dionisi Vici, C. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40337-8_12

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