ABSTRACT
Molybdenum cofactor is essential for the activity of multiple enzymes including xanthine dehydrogenase. Molybdenum cofactor deficiencies are rare inborn errors of metabolism. Clinically, they present with intractable seizures, axial hypotonia, and hyperekplexia. They further develop cerebral atrophy, microcephaly, global developmental delay and ectopia lentis. We report a 5-year-old female with clinically, biochemically and genetically confirmed molybdenum cofactor deficiency type B due to compound heterozygous pathogenic variants in the molybdenum cofactor synthesis 2 gene found on whole exome sequencing. The xanthine stones were a key clue towards diagnosis. No mutation was detected in XDH gene. Implementation of a low-purine diet, urine alkalization and hydration lead to a near complete decrease in stone burden. The patient received pyridoxine supplementation with improvement in energy levels and attentiveness. Despite reports of high mortality at a young age, our patient was 9 years old at the time of this writing. Molybdenum cofactor deficiencies should be considered in neonates with early-onset seizures, hypotonia, and feeding difficulties. Screening with serum uric acid levels and empiric treatment may be considered while awaiting genetic results.
Subject(s)
Metal Metabolism, Inborn Errors/diagnosis , Purine-Pyrimidine Metabolism, Inborn Errors/etiology , Child , Humans , Metal Metabolism, Inborn Errors/complicationsABSTRACT
BACKGROUND: Zinc deficiency-like (ZDL) syndrome is an inherited defect of Fleckvieh calves, with striking similarity to bovine hereditary zinc deficiency (BHZD). However, the causative mutation in a phospholipase D4 encoding gene (PLD4) shows no connection to zinc metabolism. OBJECTIVES: To describe clinical signs, laboratory variables, and pathological findings of ZDL syndrome and their utility to differentiate ZDL from BHZD and infectious diseases with similar phenotype. ANIMALS: Nine hospitalized calves with crusting dermatitis and confirmed mutation in PLD4 and medical records from 25 calves with crusting dermatitis or suspected zinc deficiency. METHODS: Prospective and retrospective case series. RESULTS: The 9 calves (age: 5-53 weeks) displayed a moderate to severe crusting dermatitis mainly on the head, ventrum, and joints. Respiratory and digestive tract inflammations were frequently observed. Zinc supplementation did not lead to remission of clinical signs in 4 calves. Laboratory variables revealed slight anemia in 8 calves, hypoalbuminemia in 6 calves, but reduced serum zinc concentrations in only 3 calves. Mucosal erosions/ulcerations were present in 7 calves and thymus atrophy or reduced thymic weights in 8 calves. Histologically, skin lesions were indistinguishable from BHZD. Retrospective analysis of medical records revealed the presence of this phenotype since 1988 and pedigree analysis revealed a common ancestor of several affected calves. CONCLUSIONS AND CLINICAL IMPORTANCE: ZDL syndrome should be suspected in Fleckvieh calves with crusting dermatitis together with diarrhea or respiratory tract inflammations without response to oral zinc supplementation. Definite diagnosis requires molecular genetic confirmation of the PLD4 mutation.
Subject(s)
Cattle Diseases/pathology , Zinc/blood , Animals , Cattle , Cattle Diseases/diagnosis , Cattle Diseases/genetics , Dermatitis/diagnosis , Dermatitis/genetics , Dermatitis/veterinary , Female , Male , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/genetics , Prospective Studies , Retrospective Studies , Syndrome , Zinc/therapeutic useABSTRACT
Transient symptomatic zinc deficiency is a rare disorder clinically indistinguishable from acrodermatitis enteropathica characterized by periorificial and acral dermatitis that usually occurs in exclusively breast-fed infant especially if preterm. We describe a three-month-old breast-fed preterm boy who developed the typical skin lesions. Maternal breast milk zinc was lower than the levels from other 2 mothers of infants at the same gestational age. The disease improved and serum zinc level became normal with oral supplementation of zinc. No recurrence of the dermatosis was observed when the treatment was stopped after weaning.
Subject(s)
Acrodermatitis/diagnosis , Breast Feeding , Infant, Premature , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/drug therapy , Trace Elements/therapeutic use , Zinc/deficiency , Zinc/therapeutic use , Diagnosis, Differential , Growth Disorders , Humans , Infant , Infant, Very Low Birth Weight , Male , Milk, Human/chemistry , Treatment OutcomeABSTRACT
α-Amino adipic semialdehyde (α-AASA) accumulates in body fluids from patients with pyridoxine-dependent epilepsy because of mutations in antiquitin (ALDH7A1) and serves as the biomarker for this condition. We have recently found that the urinary excretion of α-AASA was also increased in molybdenum cofactor and sulfite oxidase deficiencies. The seizures in pyridoxine-dependent epilepsy are caused by lowered cerebral levels of pyridoxal-5-phosphate (PLP), the bioactive form of pyridoxine (vitamin B(6)), which can be corrected by the supplementation of pyridoxine. The nonenzymatic trapping of PLP by the cyclic form of α-AASA is causative for the lowered cerebral PLP levels. We describe 2 siblings with clinically evident pyridoxine-responsive seizures associated with increased urinary excretion of α-AASA. Subsequent metabolic investigations revealed several metabolic abnormities, all indicative for molybdenum cofactor deficiency. Molecular investigations indeed revealed a known homozygous mutation in the MOCS2 gene. Based upon the clinically evident pyridoxine-responsive seizures in these 2 siblings, we recommend considering pyridoxine supplementation to patients affected with molybdenum cofactor or sulfite oxidase deficiencies.
Subject(s)
2-Aminoadipic Acid/analogs & derivatives , Aldehyde Dehydrogenase/genetics , Consanguinity , Epilepsy/diagnosis , Epilepsy/genetics , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/genetics , 2-Aminoadipic Acid/urine , Brain/metabolism , Brain/pathology , Child, Preschool , DNA Mutational Analysis , Developmental Disabilities/diagnosis , Developmental Disabilities/drug therapy , Developmental Disabilities/genetics , Developmental Disabilities/urine , Diagnosis, Differential , Diffusion Magnetic Resonance Imaging , Electroencephalography/drug effects , Epilepsy/drug therapy , Epilepsy/urine , Exons/genetics , Female , Genetic Carrier Screening , Homozygote , Humans , Infant , Infant, Newborn , Leucovorin/therapeutic use , Male , Metal Metabolism, Inborn Errors/drug therapy , Metal Metabolism, Inborn Errors/urine , Molybdoferredoxin/genetics , Molybdoferredoxin/urine , Neurologic Examination/drug effects , Pyridoxal Phosphate/deficiency , Pyridoxal Phosphate/metabolism , Pyridoxine/therapeutic use , Sequence Analysis, DNA , Sulfurtransferases/geneticsSubject(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 AgedSubject(s)
Copper/metabolism , Dog Diseases/diagnosis , Fanconi Syndrome/veterinary , Liver Diseases/veterinary , Metal Metabolism, Inborn Errors/veterinary , Animals , Chelation Therapy/veterinary , Chemical and Drug Induced Liver Injury , Dog Diseases/chemically induced , Dog Diseases/therapy , Dogs , Fanconi Syndrome/diagnosis , Fanconi Syndrome/therapy , Kidney/pathology , Liver/pathology , Liver Diseases/diagnosis , Male , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/therapyABSTRACT
Deficiency of dietary Zn rapidly reduces both appetite and growth, the latter effect being apparently caused by a failure of cell replication. Diagnosis of presymptomatic Zn deficiency depends largely on estimation of plasma Zn concentration but is complicated by reductions of it during a range of stressful conditions. In the latter cases, the decrease in plasma Zn concentration does not appear to be associated with inadequate Zn intake. Only two genetic defects of Zn metabolism are known in animals. One is associated with lethally inadequate concentrations of Zn in the milk of mice, the other with the A46 trait in Friesian cattle. A46 is a recessively inherited defect of Zn absorption which is lethal in the absence of major Zn supplementation of the diet. The characteristics of the disease are very similar to those of acrodermatitis enteropathica in man.