ABSTRACT
Molybdenum cofactor deficiency is an autosomal recessive inborn error of metabolism, which results from mutations in genes involved in Moco biosynthesis. Moco serves as a cofactor of several enzymes, including sulfite oxidase. MoCD is clinically characterized by intractable seizures and severe, rapidly progressing neurodegeneration leading to death in early childhood in the majority of known cases. Here we report a patient with an unusual late disease onset and mild phenotype, characterized by a lack of seizures, normal early development, a decline triggered by febrile illness and a subsequent dystonic movement disorder. Genetic analysis revealed a homozygous c.1338delG MOCS1 mutation causing a frameshift (p.S442fs) with a premature termination of the MOCS1AB translation product at position 477 lacking the entire MOCS1B domain. Surprisingly, urine analysis detected trace amounts (1% of control) of the Moco degradation product urothione, suggesting a residual Moco synthesis in the patient, which was consistent with the mild clinical presentation. Therefore, we performed bioinformatic analysis of the patient's mutated MOCS1 transcript and found a potential Kozak-sequence downstream of the mutation site providing the possibility of an independent expression of a MOCS1B protein. Following the expression of the patient's MOCS1 cDNA in HEK293 cells we detected two proteins: a truncated MOCS1AB protein and a 22.4 kDa protein representing MOCS1B. Functional studies of both proteins confirmed activity of MOCS1B, but not of the truncated MOCS1AB. This finding demonstrates an unusual mechanism of translation re-initiation in the MOCS1 transcript, which results in trace amounts of functional MOCS1B protein being sufficient to partially protect the patient from the most severe symptoms of MoCD.
Subject(s)
Coenzymes/metabolism , Metal Metabolism, Inborn Errors/metabolism , Metalloproteins/metabolism , Nuclear Proteins/metabolism , Peptide Fragments/metabolism , Pteridines/metabolism , Age of Onset , Carbon-Carbon Lyases , Child , Child, Preschool , Diet, Protein-Restricted , Frameshift Mutation , Genetic Predisposition to Disease , HEK293 Cells , Humans , Magnetic Resonance Imaging , Male , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/diet therapy , Metal Metabolism, Inborn Errors/genetics , Molybdenum Cofactors , Nuclear Proteins/genetics , Peptide Fragments/genetics , PhenotypeSubject(s)
Copper/administration & dosage , Copper/deficiency , Dietary Supplements , Iron Overload/diet therapy , Metal Metabolism, Inborn Errors/diet therapy , Copper/blood , Humans , Iron Overload/blood , Iron Overload/diagnosis , Male , Metal Metabolism, Inborn Errors/blood , Metal Metabolism, Inborn Errors/diagnosis , Middle AgedABSTRACT
A 9-year-old Bedlington Terrier was evaluated because of weight loss, inappetence, and hematemesis. Copper storage disease had been diagnosed previously on the basis of high hepatic copper concentration. Treatment had included dietary copper restriction and administration of trientine for chelation of copper. A CBC revealed microcytic hypochromic anemia. High serum activities of liver enzymes, high bile acid concentrations, and low BUN and albumin concentrations were detected. Vomiting resolved temporarily with treatment, but the clinicopathologic abnormalities persisted. Results of transcolonic portal scintigraphy suggested an abnormal shunt fraction. Results of liver biopsy and copper quantification revealed glycogen accumulation and extremely low hepatic copper concentration. Serum and hair copper concentrations were also low. Chelation and dietary copper restriction were tapered and discontinued. Clinical signs and all clinicopathologic abnormalities improved during a period of several months.
Subject(s)
Chelating Agents/adverse effects , Chelation Therapy/veterinary , Copper/deficiency , Dog Diseases/etiology , Metal Metabolism, Inborn Errors/veterinary , Trientine/adverse effects , Animals , Chelating Agents/therapeutic use , Chelation Therapy/adverse effects , Copper/administration & dosage , Copper/metabolism , Diet/adverse effects , Diet/veterinary , Dog Diseases/diet therapy , Dog Diseases/drug therapy , Dogs , Iatrogenic Disease/veterinary , Liver/chemistry , Male , Metal Metabolism, Inborn Errors/diet therapy , Metal Metabolism, Inborn Errors/drug therapy , Time Factors , Trientine/therapeutic useABSTRACT
Idiopathic hypercalciuria (IH) associated with nephrocalcinosis was found in three of six siblings. After the three affected children were maintained on a low-calcium diet, they demonstrated increasing hypercalciuria, parathyroid hormone, and vitamin D3 levels. An oral calcium loading test was not necessary to diagnose renal IH. During treatment with hydrochlorothiazide, the calcium excretion was normalized. These patients are remarkable because nephrocalcinosis is generally regarded as a rare complication of renal IH. Moreover, the fact that three of six siblings are affected raises the question of whether the renal form of IH is genetically distinct from other forms of IH.
