PubMed Health⌕ Search

Biomedical subjects

I A Holm

Publications and source records attributed to I A Holm.

9 recordsLinked to original sources
PubMed2001

Phosphate wasting in oncogenic osteomalacia: PHEX is normal and the tumor-derived factor has unique properties.

Oncogenic osteomalacia (OOM) is characterized by renal phosphate wasting and abnormal metabolism of vitamin D, somewhat similar to the phenotype of X-linked hypophosphatemic rickets (HYP). DNA from OOM tumor cells was analyzed for mutations in the PHEX gene, which is mutated in HYP. Screening for mutations by single-strand conformation polymorphism analysis and subsequent sequencing of all the exons revealed no mutations. Conditioned media from long-term cultures of OOM tumor cells were used to further characterize the physical properties of the phosphate-regulating factor and its mechanism of action. Inhibition of OK 3B2 cell renal phosphate transport by conditioned media was dose-dependent and maximal after 20 h. This time course differed from that of parathyroid hormone (PTH). The bioactivity was stable to mild acid and alkali treatment and freeze drying and was retained in the aqueous phase following organic solvent extraction. The activity was not suppressed by heat or by treatment with trypsin but was suppressed by the protease papain and had an apparent molecular weight of < 5000. No change was detected in the expression of type II sodium/phosphate cotransporter (NaPi) mRNA in OK 3B2 cells in response to conditioned media, unlike the reduction seen in Hyp mice. In the presence of colchicine or cytochalasin D, the inhibitory response to conditioned media was reduced, similar to the effect of these agents on the response to PTH. Cycloheximide also suppressed the inhibitory response of conditioned media, but not the response to PTH. These studies indicate that mutations in the PHEX gene are unlikely to be responsible for OOM and suggest that the tumor-derived factor that inhibits phosphate uptake is a small protein that does not downregulate type II NaPi mRNA, and requires an intact cytoskeleton and protein synthesis for activity.

Bone Neoplasms↗
PubMed2001

Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets.

PHEX is the gene defective in X-linked hypophosphatemic rickets. In this study, analysis of PHEX revealed mutations in 22 hypophosphatemic rickets patients, including 16 of 28 patients in whom all 22 PHEX exons were studied. In 13 patients, in whom no PHEX mutation had been previously detected in 17 exons, the remaining 5 PHEX exons were analyzed and mutations found in 6 patients. Twenty different mutations were identified, including 16 mutations predicted to truncate PHEX and 4 missense mutations. Phenotype analysis was performed on 31 hypophosphatemic rickets patients with PHEX mutations, including the 22 patients identified in this study, 9 patients previously identified, and affected family members. No correlation was found between the severity of disease and the type or location of the mutation. However, among patients with a family history of hypophosphatemic rickets, there was a trend toward more severe skeletal disease in patients with truncating mutations. Family members in more recent generations had a milder phenotype. Postpubertal males had a more severe dental phenotype. In conclusion, although identifying mutations in PHEX may have limited prognostic value, genetic testing may be useful for the early identification and treatment of affected individuals. Furthermore, this study suggests that other genes and environmental factors affect the severity of hypophosphatemic rickets.

Adolescent↗
PubMed1999

Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy.

The glycogen storage diseases are caused by inherited deficiencies of enzymes that regulate the synthesis or degradation of glycogen. In the past decade, considerable progress has been made in identifying the precise genetic abnormalities that cause the specific impairments of enzyme function. Likewise, improved understanding of the pathophysiologic derangements resulting from individual enzyme defects has led to the development of effective nutritional therapies for each of these disorders. Meticulous adherence to dietary therapy prevents hypoglycemia, ameliorates the biochemical abnormalities, decreases the size of the liver, and results in normal or nearly normal physical growth and development. Nevertheless, serious long-term complications, including nephropathy that can cause renal failure and hepatic adenomata that can become malignant, are a major concern in GSD-I. In GSD-III, the risk for hypoglycemia diminishes with age, and the liver decreases in size during puberty. Cirrhosis develops in some adult patients, and progressive myopathy and cardiomyopathy occur in patients with absent GDE activity in muscle. It remains unclear whether these complications of glycogen storage disease can be prevented by dietary therapy. Glycogen storage diseases caused by lack of phosphorylase activity are milder disorders with a good prognosis. The liver decreases in size, and biochemical abnormalities disappear by puberty.

Glucosephosphate Dehydrogenase Deficiency↗
PubMed1997

Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets.

X-linked hypophosphatemic rickets (HYP) is a dominant disorder characterized by renal phosphate wasting and abnormal vitamin D metabolism. PEX, the gene that is defective in HYP and is located on Xp22.1, is homologous to members of the neutral endopeptidase family. However, the complete coding sequence of the PEX cDNA, the structure of the PEX gene, and the role that PEX plays in phosphate transport remain unknown. We determined the genomic structure of the published PEX gene, which was found to be composed of 18 short exons, and demonstrated that the genomic organization of PEX shares homology to members of the family of neutral endopeptidases. Primer sets were designed from the intron sequence, to amplify each PEX exon from genomic DNA of HYP patients. Mutations in PEX were identified in 9/22 unrelated HYP patients, confirming that defects in PEX are responsible for HYP. The mutations detected included three nonsense mutations, a 1-bp deletion leading to a frameshift, a donor splice-site mutation, and missense mutations in four patients. Although the entire PEX gene has not been identified and some mutations may have been missed, the lack of detection of mutations in the remaining 13 patients, especially in 1 patient who has an apparently balanced, de novo 9;13 translocation, implies that there may be other loci involved in the generation of the HYP phenotype.

Adult↗
PubMed1996

Oxidative phosphorylation defect associated with primary adrenal insufficiency.

An 18-month-old girl with an oxidative phosphorylation defect had neonatal onset of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. Chronic lactic acidosis responded to treatment with dichloroacetate. Sequential muscle biopsies demonstrated resolution of the lipid storage myopathy associated with the return to normal muscle free carnitine levels. This case demonstrates a new clinical phenotype associated with a defect in oxidative phosphorylation and the need to consider mitochondrial disorders in the differential diagnosis of primary adrenal insufficiency in childhood.

Acidosis, Lactic↗
PubMed1992

Hypervitaminosis D associated with drinking milk.

BACKGROUND: Vitamin D has been added to milk in the United States since the 1930s to prevent rickets. We report the unusual occurrence of eight cases of vitamin D intoxication that appear to have been caused by excessive vitamin D fortification of dairy milk. METHODS: Medical records were reviewed and a dietary questionnaire was sent to eight patients who had unexplained hypervitaminosis D. Vitamin D analyses with high-performance liquid chromatography were performed on samples of the patients' serum, the dairy milk they drank, and the vitamin D concentrate added to the milk. RESULTS: All eight patients drank milk produced by a local dairy in amounts ranging from 1/2 to 3 cups (118 to 710 ml) daily. All had elevated serum 25-hydroxyvitamin D concentrations (mean [+/- SD], 731 +/- 434 nmol per liter [293 +/- 174 ng per milliliter]). Six of the eight patients had elevated serum vitamin D3 concentrations. Of the eight patients, seven had hypercalcemia and one had hypercalciuria but normocalcemia (mean serum calcium, 3.14 +/- 0.51 mmol per liter [12.6 +/- 2.1 mg per deciliter]). Analysis of the dairy's vitamin D-fortified milk revealed concentrations of vitamin D3 (cholecalciferol) that ranged from undetectable to as high as 232,565 IU per quart (245,840 IU per liter). An analysis of the concentrate that was used to fortify the milk, labeled as containing vitamin D2 (ergocalciferol), revealed that it contained vitamin D3. CONCLUSIONS: Hypervitaminosis D may result from drinking milk that is incorrectly and excessively fortified with vitamin D. Milk that is fortified with vitamin D must be carefully monitored.

Adult↗
PubMed1988

Recurrent hypothermia and thrombocytopenia after severe neonatal brain infection.

Two children with multiple severe disabilities due to brain destruction by neonatal infection had recurrent hypothermia (less than 34 degrees C) with associated thrombocytopenia (less than 50,000), and clinical hemorrhage. They also had milder, less consistent erythroid and myeloid cell line abnormalities. The hypothermia was presumed to be due to hypothalamic dysfunction. Rewarming was always followed by correction of hematologic problems, but normal temperature was difficult to maintain. Recognition of this entity may improve long-term management of some severely disabled children.

Brain Diseases↗
PubMedDate not supplied

Effect of familial hypophosphatemic rickets on dental development: a controlled, longitudinal study.

Familial or X-linked hypophosphatemic rickets (XLHR) is the most common type of rickets in developed countries today. While the dental manifestations of rickets are well reported, there is little information regarding its relationship to dental development and other dental anomalies. This investigation studied the rate of dental development and associated dental anomalies in 19 XLHR subjects compared with 38 race-, age-, and sex-matched control children. The results showed that in both XLHR and control children, no significant differences existed in dental age compared with the respective chronological age, indicating that rickets did not affect the rate of dental development. Longitudinal growth curves of seven XLHR and matched control children substantiated that relationships of dental to chronological ages were comparable in both groups. Male XLHR subjects showed significantly increased tendency for dental taurodontism with mean Crown-Body (CB):Root (R) ratio of 1.1 compared with 1.0 in females and 0.8 in controls (P < 0.02). Male XLHR children also showed significantly increased prevalence (50%) of ectopic permanent canines compared with control children (8%, P < 0.01).

Adolescent↗