Genotype-phenotype correlation in von Hippel-Lindau syndrome.

The von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene on human chromosome 3p25. It is characterized clinically by vascular tumors including benign hemangioblastomas of the cerebellum, spine, brain stem and retina. Clear-cell renal cell carcinoma is a frequent cause of death, occurring in up to 70% of patients with VHL. Pheochromocytomas occur in association with specific alleles (usually mutations as opposed to deletions), therefore a family history of pheochromocytoma in association with VHL is an indication for thorough surveillance for pheochromocytoma in affected family members. The VHL gene coding sequence contains three exons. Two isoforms of mRNA exist, reflecting the presence or absence of exon 2. Tumors arise following the loss or inactivation of the wild-type allele in a cell. In initial studies approximately 20% of patients had large germline mutations detectable by Southern blot analysis, 27% had missense mutations and 27% had nonsense or frameshift mutations. Advances in mutation analysis now allow for a 100% mutation detection rate in families with definite VHL. Families may be characterized by the presence [type 2 (7-20% of families)] or absence (type 1) of pheochromocytomas. Most type 2 families are affected by missense mutations, whereas most type 1 families have deletions or premature termination mutations. The prognosis for the lifetime risk of pheochromocytoma can be estimated by determination of the underlying mutation even if there is no family history of VHL.

Safety and effectiveness of Niaspan when added sequentially to a statin for treatment of dyslipidemia.

Niaspan, when added to a stable dose of a statin in 66 subjects, was found to be safe and highly effective in improving lipid parameters. Subgroup analyses demonstrated its effectiveness in lowering low-density lipoprotein cholesterol in persons not at the National Cholesterol and Education Program low-density lipoprotein cholesterol target and in raising high-density lipoprotein cholesterol in persons with levels < 40 mg/dl.

Acute axonal neuropathy in maple syrup urine disease.

A 25-year-old woman with maple syrup urine disease (MSUD) developed generalized weakness over 1 week. She had severe leg and moderate arm weakness, areflexia, and distal sensory loss. Plasma branched-chain amino acid concentrations were elevated, reflecting an acute exacerbation of the disease. Electrodiagnostic studies indicated an acute axonal polyneuropathy and sural nerve biopsy revealed acute wallerian degeneration without inflammation. Peripheral neuropathy, although not identified previously as a clinical feature of MSUD, may become more common as chronic dietary restrictions and improved management of the disease allow survival into adulthood.

Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes.

Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene. We characterize here the genomic structure of the COL11A1 gene. Screening of patients with Stickler, Stickler-like, or Marshall syndrome pointed to 23 novel mutations. Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to a typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes.

Management of lipid disorders.

ASCVD is common in patients with rheumatologic disorders. Reduction of LDL cholesterol and treatment of lipid disorders is proved to reduce the risk of ASCVD and its associated clinical events. Therefore, plasma lipids should be obtained in all patients with rheumatologic disorders and lipid disorders should be aggressively treated in an attempt to reduce cardiovascular risk. The clinical approach is similar to other patients, but care should be taken to avoid side effects and drug-drug interactions, which may be somewhat more likely to occur in patients with rheumatologic disorders.

Von Hippel-Lindau syndrome. A pleomorphic condition.

Von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene mapped to human chromosome 3p25. It is characterized clinically by vascular tumors, including retinal and central nervous system hemangioblastomas (cerebellar, spinal, and brain stem). Hemangioblastomas are benign and do not metastasize. Other features include cysts of the kidneys, liver, and pancreas. Clear cell renal cell carcinoma occurs in up to 70% of patients with VHL and is a frequent cause of death. Pheochromocytomas occur in association with specific alleles of the VHL gene; therefore, a family history of pheochromocytoma in association with VHL is an indication for thorough surveillance for pheochromocytoma in affected family members. Recently, it has been appreciated that patients with VHL may develop endolymphatic sac tumors, which can cause tinnitus or deafness. The diagnosis of VHL may be made in a patient with a family history of VHL based on a single retinal or cerebellar hemangioblastoma, renal cell carcinoma or pheochromocytoma, and, possibly, multiple pancreatic cysts. Renal and epididymal cysts are not sufficient to make the diagnosis of VHL. In the absence of a family history of VHL the presence of two or more retinal or cerebellar hemangioblastomas, or one hemangioblastoma with one visceral tumor, is required for diagnosis. Studies of the natural history of VHL showed a life expectancy less than 50 years before surveillance protocols were developed. Annual assessments (physical and ophthalmologic examinations) should begin in infancy. Imaging of abdominal organs and the brain and spine should be added in teenagers and adults. Renal cysts and tumors should be monitored by computed tomography every 6 months. Mutation analysis has allowed presymptomatic identification of affected family members; those found not to have inherited the gene do not need to be monitored. The VHL gene coding sequence contains three exons, and two isoforms of mRNA exist, reflecting the presence or absence of exon 2. Tumors arise after the loss or inactivation of the wild type allele in a cell. About 20% of patients have large germline mutations detectable by Southern blot analysis, 27% have missense mutations, and 27% have nonsense or frameshift mutations. In about 20% of VHL families no deletion or mutation can be detected. Families may be characterized by the presence (type 2; 7% to 20% of families) or absence (type 1) of pheochromocytomas. Most type 2 families have missense mutations, whereas most type 1 families are affected by deletions or premature termination mutations. Prognostic counseling regarding the lifetime risk of pheochromocytoma can be aided by determination of the underlying mutation in patients without family histories of VHL.

Alpha 2-HS glycoprotein phenotypes and quantitative hormone and bone measures in postmenopausal women.

It has been suggested that inherited traits play a role in the development of osteoporosis by providing a background for the modulation of gene expression. In this study, we examine the influence of the different alleles of alpha 2-HS glycoprotein (AHSG), a protein of the bone matrix, on quantitative estrogens, estrone and estradiol, and bone measures, bone area and density. Estrogens provide a protective effect against fractures in older women and were thus included in the analyses. Isoelectric focusing of AHSG from sera followed by immunoblotting was used to type 163 white postmenopausal women participating in a clinical trial of the effects of walking on bone loss. Plasma hormones were measured by a combination of extraction, column chromatography, and radioimmunoassay; bone measures on the dominant radius were determined with computerized tomography. Analysis of variance was done on estrogen and bone measures after controlling for the effects of age and body mass index. The two major alleles of AHSG result in three phenotypes, designated AHSG 1-1, AHSG 2-1, and AHSG 2-2. The AHSG 1-1 homozygote showed a decreased concentration of estradiol, the AHSG 2-2 homozygote showed an increased concentration, and the AHSG 2-1 heterozygote was intermediate (P = 0.001). Estrone demonstrated a similar pattern in residual analysis although it did not reach statistical significance.

Biochemical and genetic identity of alpha-keto acid reductase and cytoplasmic malate dehydrogenase from human erythrocytes.

We have recently shown that cytoplasmic malate dehydrogenase (MDH-s) from several non-human species catalyses the reduction of aromatic alpha-keto acids in the presence of NADH (Friedrich et al. 1987), an activity previously attributed to the enzyme aromatic alpha-keto acid reductase (KAR E.C.1.1.1.96). Here we present evidence that this also occurs in humans, and that the previously characterized human KAR is not the product of a genetically distinct locus. Human MDH-s and KAR activities co-migrate after starch gel electrophoresis, and electrophoretic variants of human MDH-s exhibited identical variation for KAR. Both enzymes show almost no electrophoretic variation among human populations of diverse origin. The reduction of aromatic alpha-keto acids is substantially inhibited by malate, the end-product of the MDH reaction. Antibodies raised against purified chicken MDH-s equally inhibited both MDH-s and KAR in chickens and humans. The bulk of the KAR activity in human blood appears to be due to MDH-s, with a minor fraction catalysed by LDH, as is the case in most other species studied. The previous assignment of a gene for KAR to human chromosome 12 in human/Chinese hamster somatic cell hybrids is questioned because interspecific hybrid bands of both MDH-s and LDH appear with slightly different mobility approximately midway between the human and hamster controls in somatic cell hybrid studies, and the meaning of this artifact is discussed. The discovery that MDH reacts with intermediate metabolites of phenylalanine and tyrosine has implications in relation to the mechanism by which mental retardation may be produced in phenylketonuria (PKU), and the effect of MDH inhibition on oxidative phosphorylation in the various tyrosinaemias is discussed.

The reduction of aromatic alpha-keto acids by cytoplasmic malate dehydrogenase and lactate dehydrogenase.

This study demonstrates that cytoplasmic malate dehydrogenase (MDH-s) catalyzes the reduction of aromatic alpha-keto acids in the presence of NADH, that the enzyme which has been described in the literature as aromatic alpha-keto acid reductase (KAR; EC 1.1.1.96) is identical to MDH-s, and that the reduction of aromatic alpha-keto acids is due predominantly to a previously unrecognized secondary activity of MDH-s and the remainder is due to the previously recognized activity of lactate dehydrogenase (LDH) toward aromatic keto-acids. MDH-s and KAR have the same molecular weight, subunit structure, and tissue distribution. Starch gel electrophoresis followed by histochemical staining using either p-hydroxy-phenylpyruvic acid (HPPA) or malate as the substrate shows that KAR activity comigrates with MDH-s in all species studied except some marine species. Inhibition with malate, the end product of the MDH reaction, substantially reduces or totally eliminates KAR activity. Genetically determined electrophoretic variants of MDH-s seen in the fresh water bony fish of the genus Xiphophorus and the amphibian Rana pipiens exhibited identical variation for KAR, and the two traits cosegregated in the offspring from one R. pipiens heterozygote studied. Both enzymes comigrate with no electrophoretic variation among several inbred strains of mice. Antisera raised against purified chicken MDH-s totally inhibited both MDH-s and KAR activity in chicken liver homogenates. There is no evidence to suggest that any protein besides MDH-s and LDH catalyzes this reaction with the possible exception of the situation in Xiphophorus, in which a third independent zone of HPPA reduction is observed. In most species the activity formerly described as KAR appears to be due to a previously unsuspected activity of MDH-s toward aromatic monocarboxylic alpha-keto acids. In all species examined the KAR activity is associated only with MDH-s; in tissue homogenates the mitochondrial form of MDH (MDH-m) is not detected after electrophoresis using HPPA as a substrate.

A population study of alpha-keto acid reductase.

An electrophoretic survey of 509 individuals of Japanese, Mexican American, American Negro, Eskimo, Amerindian and Anglo-American origin failed to reveal genetically determined variation at the alpha-keto acid reductase locus by starch gel electrophoresis. Additional screening of 232 individuals by thin layer isoelectric focusing in polyacrylamide gels detected a single phenotype. Interspecific variation at the alpha-keto acid reductase locus is clearly resolved using either method. These results indicate that the alpha-keto acid reductase locus is monomorphic in most human population groups despite earlier results suggesting the existence of genetic polymorphism.