Successful Treatment of Molybdenum Cofactor Deficiency Type A With cPMP

Molybdenum cofactor deficiency (MoCD) is a rare metabolic disorder characterized by severe and rapidly progressive neurologic damage caused by the functional loss of sulfite oxidase, 1 of 4 molybdenum-dependent enzymes. To date, no effective therapy is available for MoCD, and death in early infancy has been the usual outcome. We report here the case of a patient whowas diagnosedwithMoCD at the age of 6 days. Substitution therapy with purified cyclic pyranopterin monophosphate (cPMP) was started on day 36 by daily intravenous administration of 80 to 160 g of cPMP/kg of body weight. Within 1 to 2 weeks, all urinary markers of sulfite oxidase (sulfite, S-sulfocysteine, thiosulfate) and xanthine oxidase deficiency (xanthine, uric acid) returned to almost normal readings and stayed constant (450 days of treatment). Clin-ically, the infant became more alert, convulsions and twitching disap-peared within the first 2 weeks, and an electroencephalogram showe

Favorable Outcome in a Newborn With Molybdenum Cofactor Type A Deficiency Treated With cPMP

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 mu g/kg in the first 12 days reduced the effects of neuro-degenerative 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. Pediatrics 2012; 130: e1005-e101

Synthesis of Cyclic Pyranopterin Monophosphate, a Biosynthetic Intermediate in the Molybdenum Cofactor Pathway

Cyclic pyranopterin monophosphate (<b>1</b>), isolated from bacterial culture, has previously been shown to be effective in restoring normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient mice and human patients. Described here is a synthesis of <b>1</b> hydrobromide (<b>1</b>·HBr) employing in the key step a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one dihydrochloride and d-galactose phenylhydrazone to give the pyranopterin (5a<i>S</i>,6<i>R</i>,7<i>R</i>,8<i>R</i>,9a<i>R</i>)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3<i>H</i>,4<i>H</i>,5<i>H</i>,5a<i>H</i>,6<i>H</i>,7<i>H</i>,8<i>H</i>,9a<i>H</i>,10<i>H</i>-pyrano­[3,2-<i>g</i>]­pteridin-4-one (<b>10</b>) and establishing all four stereocenters found in <b>1</b>. Compound <b>10</b>, characterized spectroscopically and by X-ray crystallography, was transformed through a selectively protected tri-<i>tert</i>-butoxycarbonylamino intermediate into a highly crystalline tetracyclic phosphate ester (<b>15</b>). The latter underwent a Swern oxidation and then deprotection to give <b>1</b>·HBr. Synthesized <b>1</b>·HBr had in vitro efficacy comparable to that of <b>1</b> of bacterial origin as demonstrated by its enzymatic conversion into mature MoCo and subsequent reconstitution of MoCo-free human sulfite oxidase–molybdenum domain yielding a fully active enzyme. The described synthesis has the potential for scale up

Synthesis of Cyclic Pyranopterin Monophosphate, a Biosynthetic Intermediate in the Molybdenum Cofactor Pathway

Cyclic pyranopterin monophosphate (<b>1</b>), isolated from bacterial culture, has previously been shown to be effective in restoring normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient mice and human patients. Described here is a synthesis of <b>1</b> hydrobromide (<b>1</b>·HBr) employing in the key step a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one dihydrochloride and d-galactose phenylhydrazone to give the pyranopterin (5a<i>S</i>,6<i>R</i>,7<i>R</i>,8<i>R</i>,9a<i>R</i>)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3<i>H</i>,4<i>H</i>,5<i>H</i>,5a<i>H</i>,6<i>H</i>,7<i>H</i>,8<i>H</i>,9a<i>H</i>,10<i>H</i>-pyrano­[3,2-<i>g</i>]­pteridin-4-one (<b>10</b>) and establishing all four stereocenters found in <b>1</b>. Compound <b>10</b>, characterized spectroscopically and by X-ray crystallography, was transformed through a selectively protected tri-<i>tert</i>-butoxycarbonylamino intermediate into a highly crystalline tetracyclic phosphate ester (<b>15</b>). The latter underwent a Swern oxidation and then deprotection to give <b>1</b>·HBr. Synthesized <b>1</b>·HBr had in vitro efficacy comparable to that of <b>1</b> of bacterial origin as demonstrated by its enzymatic conversion into mature MoCo and subsequent reconstitution of MoCo-free human sulfite oxidase–molybdenum domain yielding a fully active enzyme. The described synthesis has the potential for scale up

The Hall Technique

The contemporary view of caries management focuses on treating carious lesions using less invasive treatment options. The Hall Technique is an innovative, less invasive, operative management option, in which preformed metal crowns (PMCs) are used to seal carious lesions with dentin involvement in primary molars using a glass ionomer luting cement. Thus, removal of carious tissue, tooth preparation, or the use of local anesthesia are not required for the Hall Technique. The PMCs are simply pushed over the tooth, to isolate and seal the carious lesions from the oral cavity, resulting in reduction of the nutrient supply and consequently carious lesion arrest. This makes the Hall Technique a technically simple procedure to perform, in terms of clinical skills, and is well accepted by dentists, children, and their parents. However, it should not be considered as a quick solution to the problem of treating all carious primary molars in children who are unable to cooperate with more invasive treatment. For success, the Hall Technique requires careful case selection, precise carious lesion and pulpal diagnosis, good patient management, and parental cooperation. The Hall Technique is an effective treatment option for management of asymptomatic dentin carious lesions in primary molars with long-term high success rates and is, with a strong evidence base, recommended as part of our armamentarium for everyday use in pediatric dentistry