Molybdenum cofactor deficiency in humans: neurological consequences of sulfite oxidase deficiency

Molybdenum cofactor deficiency in humans: neurological consequences of sulfite oxidase deficiency.

The molybdenum cofactor (MoCo)is an essential component of molybdoenzymes. A deficiency of the co-factor in humans dimimishes the ability to synthesise those enzymes of which the co-factor is a component. Sulfite oxidase deficiency is a particular problem in infants.

Molybdenum cofactor (MoCo) deficiency leads to a combined deficiency of the molybdo-enzymes sulphite oxidase, xanthine dehydrogenase and aldehyde oxidase. This rare disease results in neonatal seizures and other neurological symptoms identical to sulphite oxidase deficiency. No therapy is known. It is inherited autosomal-recessively and leads to early childhood death. Prenatal diagnosis has been performed since 1983 by the measurement of sulphite oxidase activity [Reiss et al., 1999].

Reiss, J., Christensen, E., Dorche, C., Molybdenum cofactor deficiency: First prenatal genetic analysis, Prenatal Diagnosis , 1999, 19 , 386-388.

Classical xanthinuria type 11 is an autosomal recessive disorder characterized by deficiency of xanthine dehydrogenase and aldehyde oxidase activities due to lack of a common sulfido-molybdenum cofactor (MoCo).

Peretz, H., Naamati, M. S., Levartovsky, D., Lagziel, A., Shani, E., Horn, I., Shalev, H., and Landau, D., Identification and characterization of the first mutation (Arg776Cys) in the C-terminal domain of the Human Molybdenum Cofactor Sulfurase (HMCS) associated with type II classical xanthinuria, Molecular Genetics and Metabolism, 2007, 91, 23-29.

Three infants are diagnosed with molybdenum cofactor deficiency characterized by seizures unresponsive to treatment, craniofacial dysmorphic features, hyperexcitability, low blood uric acid levels, and neuroimaging findings. The parents were consanguineous in two of these patients. The diagnosis was established by the presence of low blood uric acid levels, positive urine sulfite reaction, quantitative aminoacid analysis, and high-voltage electrophoresis of the urine sample showing atypical increase of S-sulfo-L-cysteine. Skin fibroblast cultures confirmed the diagnosis. Magnetic resonance imaging findings were suggestive of encephalomalacia with cystic changes due to hypoxic-ischemic encephalopathy. Molybdenum cofactor deficiency must be included in the differential diagnosis of patients presenting with intractable seizures in the newborn period who have computed tomography and magnetic resonance imaging findings reminiscent of those of hypoxic-ischemic encephalopathy. The urine sulfite dipstick test can be a part of the evaluation of these infants in neonatal intensive care units.

Topcu, M., Coskun, T., Haliloglu, G., and Saatci, I., Molybdenum cofactor deficiency: Report of three cases presenting as hypoxic-ischemic encephalopathy, Journal of Child Neurology, 2001, 16, 264-270.

Sulfite oxidase deficiency is a rare inborn error of metabolism which can be easily missed with metabolic screening. Symptoms in the newly born are seizures, severe neurologic disease, and ectopia lentis accompanied by lens subluxation revealed by ophthalmic assessment. The condition is severe and often fatal. Prevention of new cases by proper screening and genetic counselling is paramount. Prenatal diagnosis of molybdenum cofactor deficiency or isolated sulfite oxidase deficiency can be made with an assay of sulfite oxidase activity in uncultured chorionic villus tissue. S-sulfocysteine can be detected in amniotic fluid.

Edwards, M.C., Johnson, J.L., Marriage, B., Graf, T.N., Coyne, K.E., Rajagopalan, K.V., MacDonald, I.M., Isolated sulfite oxidase deficiency - Review of two cases in one family, Ophthalmology , 1999, 106 , 10, 1957-1961.

See also:

Reiss, J., Christensen, E., Dorche, C., Molybdenum cofactor deficiency: First prenatal genetic analysis, Prenatal Diagnosis , 1999, 19 , 4, 386-388.

Molybdenum cofactor (MoCo) deficiency leads to a combined deficiency of the molybdoenzymes sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase. This rare disease results in neonatal seizures and other neurological symptoms identical to those of sulfite oxidase deficiency. It is an autosomal recessive trait and leads to early childhood death.
Effective therapy is not available. The MOCS genes are ideal candidates for a somatic gene therapy approach.

Reiss, J., Genetics of molybdenum cofactor deficiency, Human Genetics, 2000, 106 , 157-163.

Human MoCo deficiency is a fatal disease resulting in severe neurological damage and death in early childhood. Most patients harbour MOCS1 mutations, which prohibit formation of a precursor, or carry MOCS2 mutations, which abrogate precursor conversion to molybdopterin. A gephyrin gene (GEPH) deletion has been identified in a patient with symptoms typical of MoCo deficiency. Biochemical studies of the patient's fibroblasts demonstrated that gephyrin catalyses the insertion of molybdenum into molybdopterin and suggest that this novel form of MoCo deficiency might be curable by molybdate supplementation

Reiss, J., Gross-Hardt, S., Christensen, E., Schmidt, P., Mendel, R. R., and Schwarz, G., A Mutation in the Gene for the Neurotransmitter Receptor-Clustering Protein Gephyrin Causes a Novel Form of Molybdenum Cofactor Deficiency, Am.J.Hum.Genet. , 2001, 68 , 208-213.

In patients with molybdenum cofactor deficiency, the presence of elevated levels of sulfite leads to the formation of S-sulfonated cysteine. An ion peak assigned to S-sulfonated transthyretin (80 D larger than unmodified transthyretin) in electrospray ionization mass spectrometry can be used as a diagnostic marker for molybdenum cofactor deficiency.

Kishikawa, M., Nakanishi, T., Shimizu, A., and Yoshino, M., Detection by mass spectrometry of highly increased amount of S- sulfonated transthyretin in serum from a patient with molybdenum cofactor deficiency, Pediatr.Res., 2000, 47 , 492-494.

See also:

Kishikawa, M., [Diagnosis of neurodegenerative disease by mass spectrometry], Rinsho Byori , 2000, 48 , 430-436.

Molybdenum cofactor deficiency (MoCoD) is an autosomal recessive, fatal neurological disorder, characterized by the combined deficiency of sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase. An excessive occurrence of this fatal disorder among segments of the Arab population in Northern Israel has been observed. The true incidence of MoCoD is probably underestimated in this highly inbred population. This lethal disease can be diagnosed prenatally by assay of sulfite oxidase activity in chorionic villus samples in pregnancies of couples who have had previously affected children (obligatory carriers).

Shalata, A., Mandel, H., Dorche, C., Zabot, M. T., Shalev, S., Hugeirat, Y., Arieh, D., Ronit, Z., Reiss, J., Anbinder, Y., and Cohen, N., Prenatal diagnosis and carrier detection for molybdenum cofactor deficiency type A in northern Israel using polymorphic DNA markers, Prenat.Diagn., 2000, 20 , 7-11.
Kisker, C, Schindelin, H, Pacheco, A, Wehbi, WA, Garrett, RM, Rajagopalan, KV, Enemark, JH, Rees, DC, Molecular basis of sulfite oxidase deficiency from the structure of sulfite oxidase, Cell, 1997, 91, 973-983
Sulphite oxidase enzyme deficiency is associated with abnormal accumulation of sulfur and magnesium in neurons. Sulfur-containing compound(s) that are formed as a result of molybdenum cofactor deficiency may cause excitotoxic neuronal injury in the presence of excess magnesium
Salman, M.S., Ackerley, C., Senger, C., and Becker, L., New insights into the neuropathogenesis of molybdenum cofactor deficiency, Canadian Journal of Neurological Sciences, 2002, 29, 91-96.
Mo deficiency may lead to amino acid intolerance, irritability, elevated urinary xanthine and sulfite, and reduced uric acid and sulfate. Condition cured by 160 microg Mo/d administered.
Aburnrad NN, Schneider AJ, Steel D, Rogers LS. Amino acid intolerance during prolonged total parenteral nutrition reversed by molybdate therapy. Am J Clin Nutr 198 ; 34:2551-2559.

Sulfite oxidase catalyses the terminal reaction in the degradation of sulfur amino acids. Genetic deficiency of sulfite oxidase results in neurological abnormalities and often leads to death at an early age [Garrett et al., 1998]. The mutation in the sulfite oxidase gene responsible for sulfite oxidase deficiency in a 5-year-old girl was a guanine to adenine transition at nucleotide 479 identified by sequence analysis of cDNA obtained from fibroblast mRNA and resulting in the amino acid substitution of Arg-160 to Gin. Recombinant protein containing the R160Q mutation was expressed in Escherichia coli. The mutant protein exhibited 2% of native activity . It contained its full complement of molybdenum and heme. The absorption spectra of the isolated molybdenum domains of native sulfite oxidase and of the R160Q mutant differed in the 480-and 350-nm absorption bands, suggestive of altered geometry at the molybdenum centre. Kinetic analysis of the R160Q protein showed an increase in K-m for sulfite combined with a decrease in k(cat) resulting in a decrease of nearly 1,000-fold in the apparent second-order rate constant k(cat)/K-m. Native sulfite oxidase was rapidly inactivated by phenylglyoxal, yielding a modified protein with kinetic parameters mimicking those of the R160Q mutant. It is proposed that Arg-160 attracts the anionic substrate sulfite to the binding site near the molybdenum.

Garrett, R.M., Johnson, J.L., Graf, T.N., Feigenbaum, A., Rajagopalan, K.V., Human sulfite oxidase R160Q: Identification of the mutation in a sulfite oxidase-deficient patient and expression and characterization of the mutant enzyme, Proceedings Of The National Academy Of Sciences Of The United States Of America, 1998, 95 , 6394-6398.
Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency can be diagnosed prenatally by monitoring sulfite oxidase activity in chorionic villus sampling (CVS) tissue.
Johnson, J.L., Prenatal diagnosis of molybdenum cofactor deficiency and isolated sulfite oxidase deficiency, Prenatal Diagnosis, 2003, 23, 6-8.

See also

Lee, H.J., Adham, I. M., Schwarz, G., Kneussel, M., Sass, J. O., Engel, W., and Reiss, J., Molybdenum cofactor-deficient mice resemble the phenotype of human patients, Human Molecular Genetics, 2002, 11, 3309-3317.
Leimkuhler, S., Freuer, A., Araujo, J. A. S., Rajagopalan, K. V., and Mendel, R. R., Mechanistic studies of human molybdopterin synthase reaction and characterization of mutants identified in group B patients of molybdenum cofactor deficiency, Journal of Biological Chemistry, 2003, 278, 26127-26134.

The crystal structure of chicken liver sulfite oxidase at 1.9 Angstrom resolution reveals that each monomer of the dimeric enzyme consists of three domains. At the active site, the Mo is penta-coordinated by three sulfur ligands, one oxo group, and one water/hydroxo. A sulfate molecule adjacent to the Mo identifies the substrate binding pocket. Four variants associated with sulfite oxidase deficiency have been identified: two mutations are near the sulfate binding site, while the other mutations occur within the domain mediating dimerization [Kisker et al., 1997].

Kisker, C, Schindelin, H, Pacheco, A, Wehbi, WA, Garrett, RM, Rajagopalan, KV, Enemark, JH, Rees, DC, Molecular basis of sulfite oxidase deficiency from the structure of sulfite oxidase, Cell, 1997, 91, 973-983

A one-year old girl and her eight-year old brother suffered from intractable seizures which were traced to sulfite oxidase deficiency. Computed tomography of the brain revealed a low-density area in the white and cortical matter consistent with hypoxic-ischemic injury. Sulfocysteine was present in the urine.

Eyaid, W.M., Al Nouri, D. M., Rashed, M. S., Al Rifai, M. T., and Al Wakeel, A. S., An inborn error of metabolism presenting as hypoxic-ischemic insult, Pediatric Neurology, 2005, 32, 134-136.
Hobson, E.E., Thomas, S., Crofton, P. M., Murray, A. D., Dean, J. C. S., and Lloyd, D., Isolated sulphite oxidase deficiency mimics the features of hypoxic ischaemic encephalopathy, European Journal of Pediatrics, 2005, 164, 655-659.

The structural characterization of mutations in the gene encoding sulfite oxidase is now possible after the chicken sulfite oxidase gene has been synthesized chemically. Due to the high homology to the human enzyme it provides a good model of human sulfite oxidase. The review focuses on the possible effects of the sulfite oxidase deficiency causing mutations based on new structures of recombinant chicken sulfite oxidase

Karakas, E. and Kisker, C., Structural analysis of missense mutations causing isolated sulfite oxidase deficiency, Dalton Transactions, 2005, 3459-3463.
Leimkuhler, S., Charcosset, M., Latour, P., Dorche, C., Kleppe, S., Scaglia, F., Szymczak, I., Schupp, P., Hahnewald, R., and Reiss, J., Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase, Human Genetics, 2005, 117, 565-570.

Sulfite oxidase deficiency in rats was established by feeding rats a low molybdenum diet and adding to their drinking water 200 ppm tungsten. Sulfite (25 mg/kg) was administered to the animals in their drinking water. The results showed that sulfite treatment caused an increase in the lipid peroxidation process that was accompanied by changes in visual evoked potentials. Vitamin E has the potential to prevent sulfite induced changes arising from dysfunction of the sulfite oxidase enzyme.

Kucukatay, V., Hacioglu, G., Savcioglu, F., Yargicoglu, P., and Agar, A., Visual evoked potentials in normal and sulfite oxidase deficient rats exposed to ingested sulfite, Neurotoxicology, 2006, 27, 93-100.
Tan, W.H., Eichler, F. S., Hoda, S., Lee, M. S., Baris, H., Hanley, C. A., Grant, E., Krishnamoorthy, K. S., and Shih, V. E., Isolated sulfite oxidase deficiency: A case report with a novel mutation and review of the literature, Pediatrics, 2005, 116, 757-766.

Molybdenum deficiency – neurological damage

In humans, four molybdoenzymes are known: aldehyde oxidase, mitochondrial amidoxime reducing component (mARC), xanthine oxidoreductase, and sulfite oxidase. Mutations in the genes encoding the biosynthetic MoCo [molybdenum cofactor] pathway enzymes abrogate the activities of all molybdoenzymes and result in MoCo deficiency, which is clinically similar to isolated sulfite oxidase deficiency. Both deficiencies are inherited as an autosomal-recessive disease and result in progressive neurological damage and early childhood death.

The majority of mutations leading to MoCo deficiency have been identified in the genes MOCS1 (type A deficiency), MOCS2 (type B deficiency), with one reported in GPHN. For type A deficiency an effective substitution therapy has been described recently. Hum Mutat 32:10-18, 2011.
Reiss, J. and Hahnewald, R., Molybdenum Cofactor Deficiency: Mutations in GPHN, MOCS1, and MOCS2, Human Mutation, 2011, 32, 10-18.

Sulfite oxidase

Deficiency

Analysis of alpha-aminoadipic semialdehyde is an important tool in the diagnosis of antiquitin deficiency (pyridoxine-dependent epilepsy). However continuing use of this test has revealed that elevated urinary excretion of alpha-aminoadipic semialdehyde is not only found in patients with pyridoxine-dependent epilepsy but is also seen in patients with molybdenum cofactor deficiency and isolated sulphite oxidase deficiency. This should be taken into account when interpreting the laboratory data. Sulphite was shown to inhibit alpha-aminoadipic semialdehyde dehydrogenase in vitro

Mills, Philippa B., Footitt, Emma J., Ceyhan, Serkan, Waters, Paula J., Jakobs, Cornelis, Clayton, Peter T., and Struys, Eduard A., Urinary AASA excretion is elevated in patients with molybdenum cofactor deficiency and isolated sulphite oxidase deficiency, Journal of inherited metabolic disease, 2012, 35, 1031-1036.

Molybdenum cofactor deficiency

Molybdenum cofactor deficiency (MoCD) is a lethal autosomal recessive inborn error of metabolism with devastating neurologic manifestations. Currently, experimental treatment with cyclic pyranopterin monophosphate (cPMP) is available for patients with MoCD type A caused by a mutation in the MOCS-1 gene. Here we report the first case of an infant, prenatally diagnosed with MoCD type A, whom we started on treatment with cPMP 4 hours after birth. The most reliable method to evaluate neurologic functioning in early infancy is to assess the quality of general movements (GMs) and fidgety movements (FMs). After a brief period of seizures and cramped-synchronized GMs on the first day, our patient showed no further clinical signs of neurologic deterioration. Her quality of GMs was normal by the end of the first week. Rapid improvement of GM quality together with normal FMs at 3 months is highly predictive of normal neurologic outcome. We demonstrated that a daily cPMP dose of even 80 mug/kg in the first 12 days reduced the effects of neurodegenerative damage even when seizures and cramped-synchronized GMs were already present. We strongly recommend starting cPMP treatment as soon as possible after birth in infants diagnosed with MoCD type A

Hitzert, Marrit M., Bos, Arend F., Bergman, Klasien A., Veldman, Alex, Schwarz, Guenter, Santamaria-Araujo, Jose Angel, Heiner-Fokkema, Rebecca, Sival, Deborah A., Lunsing, Roelineke J., Arjune, Sita, Kosterink, Jos G. W., and van Spronsen, Francjan J., Favorable Outcome in a Newborn With Molybdenum Cofactor Type A Deficiency Treated With cPMP, Pediatrics, 2012, 130, e1005-e1010.