Molybdenum Cofactor Deficiency in Humans

Abstract

Molybdenum cofactor (Moco) deficiency (MoCD) is characterized by neonatal-onset myoclonic epileptic encephalopathy and dystonia with cerebral MRI changes similar to hypoxic–ischemic lesions. The molecular cause of the disease is the loss of sulfite oxidase (SOX) activity, one of four Moco-dependent enzymes in men. Accumulating toxic sulfite causes a secondary increase of metabolites such as S-sulfocysteine and thiosulfate as well as a decrease in cysteine and its oxidized form, cystine. Moco is synthesized by a three-step biosynthetic pathway that involves the gene products of MOCS1, MOCS2, MOCS3, and GPHN. Depending on which synthetic step is impaired, MoCD is classified as type A, B, or C. This distinction is relevant for patient management because the metabolic block in MoCD type A can be circumvented by administering cyclic pyranopterin monophosphate (cPMP). Substitution therapy with cPMP is highly effective in reducing sulfite toxicity and restoring biochemical homeostasis, while the clinical outcome critically depends on the degree of brain injury prior to the start of treatment. In the absence of a specific treatment for MoCD type B/C and SOX deficiency, we summarize recent progress in our understanding of the underlying metabolic changes in cysteine homeostasis and propose novel therapeutic interventions to circumvent those pathological changes.

A New Pattern of Brain and Cord Gadolinium Enhancement in Molybdenum Cofactor Deficiency: A Case Report

“…Some studies described early MoCd treatment with cPMP, which should be administered before the onset of cystic degeneration to alleviate the patient’s clinical condition without correcting the biochemical defect [ 1 , 3 , 8 ]. This therapy is extremely effective in reducing sulfite toxicity and rebalancing biochemical homeostasis; unfortunately, the clinical outcome depends on the severity of the cerebral lesion identified at the beginning of treatment [ 21 ].…”

Review of childhood genetic nephrolithiasis and nephrocalcinosis

“…MOCS1 encodes for molybdenum cofactor synthesis 1 (MOCS1), which is responsible for the conversion from guanosine triphosphate (GTP) to cyclic pyranopterin monophosphate (cPMP), the first step in the synthesis of molybdenum cofactor (MOCO) ( Reiss and Hahnewald, 2011 ; Johannes et al, 2022 ). MOCO is required to activate XDH and sulfite oxidase (SUOX) ( Reiss and Hahnewald, 2011 ).…”

“…MOCS2 encodes for molybdenum cofactor synthesis 2, which is responsible for the conversion from cPMP to molybdopterin (MPT), the second step in the synthesis of molybdenum cofactor (MOCO) ( Lee et al, 2021 ; Johannes et al, 2022 ). Molybdenum cofactor deficiency B (OMIM phenotype number 252160) is an AR condition due inactivating variants in MOCS2 , resulting in disease onset in infancy with poor feeding, intractable seizures, severe psychomotor retardation, hypouricemia with hypouricosuria, increased sulfite production with urinary excretion of sulfite, and increased xanthine production with xanthinuria and rarely xanthine NL ( Karunakar et al, 2020 ; Lee et al, 2021 ; Johannes et al, 2022 ). There is currently no effective therapy for this condition ( Johannes et al, 2022 ).…”

“…APRT is responsible for converting the purine nucleotide adenine to adenosine monophosphate (AMP), which subsequently is converted to the purine nucleoside adenosine, then to the nucleoside inosine ( Li et al, 2019 ). Insosine is then converted to the purine hypoxanthine and XO facilitates the oxidation of hypoxanthine to xanthine and xanthine to uric acid ( Figure 2 ) ( Li et al, 2019 ; Johannes et al, 2022 ).…”

Interactions of reactive sulfur species with metalloproteins

“… Na 100 g various (nausea, seizures, muscle cramps, etc.) Mg 30 g bone structure; enzyme cofactor – protein and nucleic acid synthesis; ATP hydrolysis; nerve activity in muscles [ 49 ] muscle spasms Fe 5 g electron transfer; O 2 transport and storage; sulfur storage (iron-sulfur clusters, ISCs) anemia, immune disorders, chronic fatigue Zn 2 g acid-base catalysis; structural (zinc fingers); antioxidant (superoxide dismutase 1, SOD1) [ 50 ] growth and immune disorders, skin damage trace elements Cu 100 mg electron transfer; antioxidant (superoxide dismutase 1, SOD1) muscle weakness, hair loss, liver disease Mn 16 mg mitochondrial superoxide dismutase 2 (SOD2) [ 51 ] infertility, skeletal growth disorders Mo 5 mg Moco enzyme cofactor [ 52 ] MoCD is lethal at early age Co 2 mg B 12 – methyl transfer [ 53 ] anemia a Average amounts in a reference person of 70 kg are indicated. …”