Shared Sulfur Mobilization Routes for tRNA Thiolation and Molybdenum COFACTOR Biosynthesis in Prokaryotes and Eukaryotes

Modifications of transfer RNA (tRNA) have been shown to play critical roles in the biogenesis, metabolism, structural stability and function of RNA molecules, and the specific modifications of nucleobases with sulfur atoms in tRNA are present in pro- and eukaryotes. Here, especially the thiomodifications xm(5)s(2)U at the wobble position 34 in tRNAs for Lys, Gln and Glu, were suggested to have an important role during the translation process by ensuring accurate deciphering of the genetic code and by stabilization of the tRNA structure. The trafficking and delivery of sulfur nucleosides is a complex process carried out by sulfur relay systems involving numerous proteins, which not only deliver sulfur to the specific tRNAs but also to other sulfur-containing molecules including iron-sulfur clusters, thiamin, biotin, lipoic acid and molybdopterin (MPT). Among the biosynthesis of these sulfur-containing molecules, the biosynthesis of the molybdenum cofactor (Moco) and the synthesis of thio-modified tRNAs in particular show a surprising link by sharing protein components for sulfur mobilization in pro- and eukaryotes.

Leimkuhler, S., Buhning, M., and Beilschmidt, L.,Shared Sulfur Mobilization Routes for tRNA Thiolation and Molybdenum Cofactor Biosynthesis in Prokaryotes and Eukaryotes, Biomolecules, 2017, 7.

Dimerization of the plant molybdenum insertase Cnx1E is required for synthesis of the molybdenum COFACTOR

The molybdenum cofactor (Moco) is a redox active prosthetic group, essentially required for numerous enzyme-catalyzed two electron transfer reactions. Moco is synthesized by an evolutionarily old and highly conserved multistep pathway. In the last step of Moco biosynthesis, the molybdenum center is inserted into the final Moco precursor adenylated molybdopterin (MPT-AMP). This unique and yet poorly characterized maturation reaction finally yields physiologically active Moco. In the model plant Arabidopsis, the two domain enzyme, Cnx1, is required for Moco formation. Recently, a genetic screen identified novel Arabidopsis cnx1 mutant plant lines each harboring a single amino acid exchange in the N-terminal Cnx1E domain. Biochemical characterization of the respective recombinant Cnx1E variants revealed two different amino acid exchanges (S197F and G175D) that impair Cnx1E dimerization, thus linking Cnx1E oligomerization to Cnx1 functionality. Analysis of the Cnx1E structure identified Cnx1E active site-bound molybdate and magnesium ions, which allowed to fine-map the Cnx1E MPT-AMP-binding site.

Krausze, J., Probst, C., Curth, U., Reichelt, J., Saha, S., Schafflick, D., Heinz, D. W., Mendel, R. R., and Kruse, T.,Dimerization of the plant molybdenum insertase Cnx1E is required for synthesis of the molybdenum cofactor, The Biochemical journal, 2017, 474, 163-178.

Identification of a protein-protein interaction network downstream of molybdenum COFACTOR biosynthesis in Arabidopsis thaliana

The molybdenum cofactor (Moco) is ubiquitously present in all kingdoms of life and vitally important for survival. Among animals, loss of the Moco-containing enzyme (Mo-enzyme) sulphite oxidase is lethal, while for plants the loss of nitrate reductase prohibits nitrogen assimilation. Moco is highly oxygen-sensitive, which obviates a freely diffusible pool and necessitates protein-mediated distribution. During the highly conserved Moco biosynthesis pathway, intermediates are channelled through a multi-protein complex facilitating protected transport. However, the mechanism by which Moco is subsequently transferred to apo-enzymes is still unclear. Moco user enzymes can be divided into two families: the sulphite oxidase (SO) and the xanthine oxidoreductase (XOR) family. The latter requires a final sulphurisation of Moco catalysed via ABA3. To examine Moco transfer towards apo-Mo-enzymes, two different and independent protein-protein interaction assays were performed in vivo: bimolecular fluorescence complementation and split luciferase. The results revealed a direct contact between Moco producer molybdenum insertase CNX1, which represents the last biosynthesis step, and members of the SO family. However, no protein contact was observed between Moco producer CNX1 and apo-enzymes of the XOR family or between CNX1 and the Moco sulphurase ABA3. Instead, the Moco-binding protein MOBP2 was identified as a mediator between CNX1 and ABA3. This interaction was followed by contact between ABA3 and enzymes of the XOR family. These results allow to describe an interaction matrix of proteins beyond Moco biosynthesis and to demonstrate the complexity of transferring a prosthetic group after biosynthesis. (C) 2016 Elsevier GmbH. All rights reserved.

Kaufholdt, D., Baillie, C. K., Meyer, M. H., Schwich, O. D., Timmerer, U. L., Tobias, L., van Thiel, D., Hansch, R., and Mendel, R. R.,Identification of a protein-protein interaction network downstream of molybdenum cofactor biosynthesis in Arabidopsis thaliana, Journal of Plant Physiology, 2016, 207, 42-50.

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


Higher susceptibility of cerebral cortex and striatum to sulfite neurotoxicity in sulfite oxidase-deficient rats

Patients affected by sulfite oxidase (SO) deficiency present severe seizures early in infancy and progressive neurological damage, as well as tissue accumulation of sulfite, thiosulfate and S-sulfocysteine.

Since the pathomechanisms involved in the neuropathology of SO deficiency are still poorly established, we evaluated the effects of sulfite on redox homeostasis and bioenergetics in cerebral cortex, striatum, cerebellum and hippocampus of rats with chemically induced SO deficiency. The deficiency was induced in 21-day-old rats by adding 200ppm of tungsten, a molybdenum competitor, in their drinking water for 9weeks.

Sulfite (70mg/kg/day) was also administered through the drinking water from the third week of tungsten supplementation until the end of the treatment.

Sulfite decreased reduced glutathione concentrations and the activities of glutathione reductase and glutathione S-transferase (GST) in cerebral cortex and of GST in cerebellum of SO-deficient rats. Moreover, sulfite increased the activities of complexes II and II-III in striatum and of complex II in hippocampus, but reduced the activity of complex IV in striatum of SO-deficient rats. Sulfite also decreased the mitochondrial membrane potential in cerebral cortex and striatum, whereas it had no effect on mitochondrial mass in any encephalic tissue evaluated. Finally, sulfite inhibited the activities of malate and glutamate dehydrogenase in cerebral cortex of SO-deficient rats.

Taken together, our findings indicate that cerebral cortex and striatum are more vulnerable to sulfite-induced toxicity than cerebellum and hippocampus. It is presumed that these pathomechanisms may contribute to the pathophysiology of neurological damage found in patients affected by SO deficiency.

Grings, M., Moura, A. P., Parmeggiani, B., Motta, M. M., Boldrini, R. M., August, P. M., Matte, C., Wyse, A. T., Wajner, M., and Leipnitz, G.,Higher susceptibility of cerebral cortex and striatum to sulfite neurotoxicity in sulfite oxidase-deficient rats, Biochimica et biophysica acta, 2016, 1862, 2063-2074.


Molybdenum deficiency

[SULFITE OXIDASE ACTIVITY DEFICIENCY caused by cofactor molybdenum deficiency: A case of early severe encephalopathy]

Neonatal seizure incidence is approximately 3.5/1000 live births. Inborn metabolic diseases account for approximately 1-4 % of neonatal seizure cases. Among them, the catabolism anomaly of sulfite to sulfate caused by sulfite oxidase or cofactor molybdenum deficiency (MoCD) is a rare metabolic disorder in which neurological damage is similar to that found in neonatal asphyxia.

We report the case of a newborn child with a MoCD. Born of related parents, this child had intrauterine growth retardation predominating on size diagnosed in the third trimester of pregnancy. After an uneventful birth, he presented convulsions at the 12th hour of life, confirmed by an electroencephalogram. Anticonvulsants and adjuvant treatments were ineffective; the child then required intubation at day 5 of life.

The initial biological assessment found an elevated blood lactate level and the chromatography of amino acids showed a significant decrease of cystine and the abnormal presence of sulfocysteine, suggestive of a lack of sulfite oxidase activity.

The uric acid level measured secondarily was low, suggesting a MoCD.

Brain MRI was performed at day 5 for diffuse ischemic injury of different ages.

After limiting acute care, the child died at day 14 of life.

The genetic study of the child found a homozygous mutation c.564+1G>A in the MOCS2 gene, confirming the diagnosis of MoCD, present in the heterozygous state in both parents.

Investigations in a logical sequence quickly suggested the MoCD diagnosis in presence of a low plasma concentration of cysteine, the abnormal presence of sulfocysteine, and low uric acid levels. The diagnosis of sulfite oxidase deficiency was made.

Until now, no treatment has proven effective but a new treatment appears to be effective in cases with a MOCS1 mutation.

Durousset, C., Gay, C., Magnin, S., Acquaviva, C., and Patural, H.,[Sulfite oxidase activity deficiency caused by cofactor molybdenum deficiency: A case of early severe encephalopathy], Archives de pediatrie : organe officiel de la Societe francaise de pediatrie, 2016, 23, 292-296.


Molybdenum cofactor deficiency (MoCD) is a severe autosomal recessive inborn error of metabolism first described in 1978. It is characterized by a neonatal presentation of intractable seizures, feeding difficulties, severe developmental delay, microcephaly with brain atrophy and coarse facial features.

MoCD results in deficiency of the molybdenum cofactor dependent enzymes sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase and mitochondrial amidoxime reducing component. The resultant accumulation of sulfite, taurine, S-sulfocysteine and thiosulfate contributes to the severe neurological impairment.

Recently, initial evidence has demonstrated early treatment with cyclic PMP can turn MoCD type A from a previously neonatal lethal condition with only palliative options, to near normal neurological outcomes in affected patients.

We review MoCD and focus on describing the currently published evidence of this exciting new therapeutic option for MoCD type A caused by pathogenic variants in MOCD1. (C) 2015 Elsevier Inc. All rights reserved.

Atwal, P. S., and Scaglia, F.,Molybdenum cofactor deficiency, Molecular Genetics and Metabolism, 2016, 117, 1-4.

[cPMP, cyclic pyranopterin monophosphate (A) is a precursor to molybdenum cofactor (B)


A                                                             B]

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.

Cerebellar hypoplasia: Differential diagnosis and diagnostic approach
Cerebellar hypoplasia (CH) refers to a cerebellum with a reduced volume, and is a common, but non-specific neuroimaging finding. The etiological spectrum of CH is wide and includes both primary (malformative) and secondary (disruptive) conditions. Primary conditions include chromosomal aberrations (e.g., trisomy 13 and 18), metabolic disorders (e.g., molybdenum cofactor deficiency, Smith-Lemli-Opitz syndrome, and adenylosuccinase deficiency), genetic syndromes (e.g., Ritscher-Schinzel, Joubert, and CHARGE syndromes), and brain malformations (primary posterior fossa malformations e.g., Dandy-Walker malformation, pontine tegmental cap dysplasia and rhombencephalosynapsis, or global brain malformations such as tubulinopathies and -dystroglycanopathies). Secondary (disruptive) conditions include prenatal infections (e.g., cytomegalovirus), exposure to teratogens, and extreme prematurity. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling. Neuroimaging provides key information to categorize CH based on the pattern of involvement: unilateral CH, CH with mainly vermis involvement, global CH with involvement of both vermis and hemispheres, and pontocerebellar hypoplasia. The category of CH, associated neuroimaging findings and clinical features may suggest a specific disorder or help plan further investigations and interpret their results. Over the past decade, advances in neuroimaging and genetic testing have greatly improved clinical diagnosis, diagnostic testing, recurrence risk counseling, and information about prognosis for patients and their families. In the next decade, these advances will be translated into deeper understanding of these disorders and more specific treatments. (c) 2014 Wiley Periodicals, Inc

Poretti, A., Boltshauser, E., and Doherty, D., Cerebellar hypoplasia: Differential diagnosis and diagnostic approach, American Journal of Medical Genetics Part C-Seminars in Medical Genetics, 2014, 166, 211-226.

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


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.

Molybdenum Cofactor Deficiency: Metabolic Link Between Taurine and S-Sulfocysteine

Molybdenum cofactor deficiency (MoCD) is a rare inherited metabolic disorder characterized by severe and progressive neurologic damage mainly caused by the loss of sulfite oxidase activity.

Elevated urinary levels of sulfite, thiosulfate, and S-sulfocysteine (SSC) are hallmarks in the diagnosis of both MoCD and sulfite oxidase deficiency.

Sulfite is generated throughout the catabolism of sulfur-containing amino acids cysteine and methionine. Accumulated sulfite reacts with cystine, thus leading to the formation of SSC, a glutamate analogue, which is assumed to cause N-methyl-D-aspartate receptor-mediated neurodegeneration in MoCD patients.
Recently, we described a fast and sensitive HPLC method for diagnostic and treatment monitoring of MoCD patients based on SSC quantification.

In this study, we extend the HPLC method to the analysis of hypotaurine and taurine in urine samples and no interference with other compounds was found. Besides the known elevation of SSC and taurine, also hypotaurine shows strong accumulation in MoCD patients, for which the molecular basis is not understood. SSC, hypotaurine, and taurine urinary excretion values from control individuals as well as MoCD patients are reported and over 20-fold increase in taurine urinary excretion was determined for MoCD patients demonstrating a direct link between sulfite toxicity and taurine biosynthesis in MoCD.

Belaidi, A. A. and Schwarz, G., Molybdenum Cofactor Deficiency: Metabolic Link Between Taurine and S-Sulfocysteine, Taurine 8, Vol 2: Nutrition and Metabolism, Protective Role, and Role in Reproduction, Development, and Differentiation Se Advances in Experimental Medicine and Biology, 2013, 776, 13-19.