Molybdenum cofactor deficiency: A natural history

Spiegel, Ronen; Schwahn, Bernd; Squires, Liza A.; Confer, Nils

doi:10.1002/jimd.12488

Cited by 14 publications

(11 citation statements)

References 48 publications

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“…Biochemically, all three forms of MoCD are indistinguishable and highly similar to isolated SOX deficiency (iSOD). The latter has been reported in more than 50 cases [ 21 ], whereas over 200 cases of MoCD have been described so far [ 22 ], and many more are known to metabolic clinicians. The diagnostic hallmarks of MoCD and iSOD are the accumulation of sulfite, S-sulfocysteine (SSC), thiosulfate, and taurine, accompanied by a reduction in cystine/cysteine as well as homocysteine.…”

Section: Clinical Presentation Of Molybdenum Cofactor Deficient Patientsmentioning

confidence: 99%

“…A proportion of children develop lens dislocation during infancy and nephrolithiasis has also been reported. Mortality is high due to intercurrent lower respiratory tract infections and seizures, with a reported median survival of 2.4 [ 22 ] or 3 years [ 25 ].…”

Section: Clinical Presentation Of Molybdenum Cofactor Deficient Patientsmentioning

confidence: 99%

“…Increasingly, cases with symptom onset later in childhood and attenuated severity have been described. Occasionally, children present merely with dystonia and speech delay [ 29 , 30 ], and cranial imaging may only show changes to the basal ganglia or even appear normal [ 22 , 31 ]. Attenuated disease probably reflects a slightly higher residual activity of SOX and/or Moco synthesis, and the diagnosis is easily missed if specific diagnostic investigations are not undertaken.…”

Section: Clinical Presentation Of Molybdenum Cofactor Deficient Patientsmentioning

confidence: 99%

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Molybdenum Cofactor Deficiency in Humans

Johannes

Schwarz

2022

Molecules

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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.

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Section: Clinical Presentation Of Molybdenum Cofactor Deficient Patientsmentioning

confidence: 99%

Section: Clinical Presentation Of Molybdenum Cofactor Deficient Patientsmentioning

confidence: 99%

Section: Clinical Presentation Of Molybdenum Cofactor Deficient Patientsmentioning

confidence: 99%

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Molybdenum Cofactor Deficiency in Humans

Johannes

Schwarz

2022

Molecules

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“…Patients presented with a severe range of symptoms as neonates, including difficulty feeding, neurological dysfunction, and eye lens dislocation. Symptoms typically appear within the first week of life, and patients generally die within three years of birth (8). Excitingly, a therapy has been developed to treat a subset of patients suffering from Moco deficiency (9).…”

Section: Introductionmentioning

confidence: 99%

Dietary molybdenum cofactor promotes fitness by increasing Moco content and sulfite oxidase activity in the nematode C. elegans

Oliphant

Fettig

Snoozy

et al. 2022

Preprint

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Molybdenum cofactor (Moco) is a prosthetic group necessary for the activity of 4 unique enzymes, including the essential sulfite oxidase (SUOX-1). Moco is required for life; humans with inactivating mutations in the genes encoding Moco-biosynthetic enzymes display Moco deficiency, a rare and lethal inborn error of metabolism. Despite its importance to human health, little is known about how Moco moves among and between cells, tissues, and organisms. The prevailing view is that cells that require Moco must synthesize Moco de novo. Although, the nematode Caenorhabditis elegans appears to be an exception to this rule and has emerged as a valuable system for understanding fundamental Moco biology. C. elegans has the seemingly unique capacity to both synthesize its own Moco as well as acquire Moco from its microbial diet. However, the relative contribution of Moco from the diet or endogenous synthesis has not been rigorously evaluated or quantified biochemically. We genetically removed dietary or endogenous Moco sources in C. elegans and biochemically determined their impact on animal Moco content and SUOX-1 activity. We demonstrate that dietary Moco deficiency dramatically reduces both animal Moco content and SUOX-1 activity. Furthermore, these biochemical deficiencies have physiological consequences; we show that dietary Moco deficiency alone causes sensitivity to sulfite, the toxic substrate of SUOX-1. This work establishes the biochemical consequences of depleting dietary Moco or endogenous Moco synthesis in C. elegans and quantifies the surprising contribution of the diet to maintaining Moco homeostasis in C. elegans.

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“…Patients presented with a severe range of symptoms as neonates, including difficulty feeding, neurological dysfunction, and eye lens dislocation. Symptoms typically appear within the first week of life and patients generally die within 3 years of birth ( 8 ). Excitingly, a therapy has been developed to treat a subset of patients suffering from Moco deficiency ( 9 ).…”

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confidence: 99%