Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21.

Essential hypertension is a common multifactorial trait. The molecular basis of a number of rare diseases that after blood pressure in humans has been established, identifying pathways that may be involved in more common forms of hypertension. Pseudohypoaldosteronism type II (PHAII, also known as familial hyperkalaemia and hypertension or Gordon's syndrome; OMIM #145260), is characterized by hyperkalaemia despite normal renal glomerular filtration, hypertension and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis and suppressed plasma renin activity are variable associated findings. The pathogenesis of PHAII is unknown, although clinical studies indicate an abnormality in renal ion transport. As thiazide diuretics are among the most efficacious agents in the treatment of essential hypertension, understanding the pathogenesis of PHAII may be of relevance to more common forms of hypertension. Analysis of linkage in eight PHAII families showing autosomal dominant transmission demonstrates locus heterogeneity of this trait, with a multilocus lod score of 8.1 for linkage of PHAII to chromosomes 1q31-q42 and 17p11-q21. Interestingly, the chromosome-17 locus overlaps a syntenic interval in rat that contains a blood pressure quantitative trait locus (QTL). Our findings provide a first step toward identification of the molecular basis of PHAII.

Human hypertension caused by mutations in WNK kinases.

Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.

Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha.

OBJECTIVE: Pseudohypoparathyroidism type Ia (PHP-Ia) is a hereditary disorder characterized by resistance to multiple hormones that work via cAMP such as PTH and TSH, accompanied by typical skeletal features including short stature and brachydactyly, termed Albright hereditary osteodystrophy (AHO). In affected kindreds, some members may have AHO but not hormone resistance; they are termed as pseudopseudohypoparathyroidism (PPHP). The molecular basis for the disorder is heterozygous inactivating mutation of the Gsalpha gene. In affected families, subjects with both PHP-Ia and PPHP have the same Gsalpha mutations. The skeletal features common to PPHP and PHP-Ia are presumably caused by tissue-specific Gsalpha haploinsufficiency. Other features that distinguish between PPHP and PHP-Ia, such as the multihormone resistance, are presumably caused by tissue-specific paternal imprinting of Gsalpha. This suggests that major differences in phenotype between PHP-Ia and PPHP point to specific tissues with Gsalpha imprinting. One such major difference may be cognitive function in PHP-Ia and PPHP. DESIGN: Description of a large family with PHP-Ia and PPHP. PATIENTS: Eleven affected subjects with PHP-Ia or PPHP in one family. MEASUREMENTS: Cognitive impairment (CI) was defined by a history of developmental delay, learning disability and the Wechsler intelligence scale. RESULTS: CI occurred only in the five PHP-Ia but not in the six PPHP subjects. Hypothyroidism which occurred in all PHP-Ia subjects was apparently not the cause of CI as it was mild, and was treated promptly. Analysis of additional Israeli cases, and the published cases from the literature, all with documented Gsalpha mutations, revealed that CI is prevalent in PHP-Ia [60 of 77 subjects (79%)] but not in PPHP [3 of 30 subjects (10%)] (P < 1 x 10(-6)). CONCLUSION: We suggest that Gsalpha is imprinted in the brain.

Measles epidemic in young adults. Clinical manifestations and laboratory analysis in 40 patients.

Between February and June 1985, 40 military personnel were hospitalized because of measles. Diagnosis in all patients was entirely clinical, and serologic investigations were noncontributory. A transient disturbance in liver function occurred in 70% of patients, and its extent correlated with duration of fever and disease complications. Spontaneously resolving, measles-specific hypocalcemia, which was not associated with hepatic dysfunction, was noted in about one third of the patients. All these patients were asymptomatic, except one patient who developed tetany. The pathophysiologic basis for the hypocalcemia is still unknown. The disease course in three previously immunized patients was benign and uncomplicated.

Proximal renal tubular acidosis: association with familial normaldosteronemic hyperpotassemia and hypertension.

Further investigation of a family with normaldosteronemic hyperpotassemia and low-renin hypertension showed seven members from three generations, who ranged in age from 4 to 56 years, to be affected. Results of earlier studies had established a normally functioning renin-aldosterone system and normal renal handling of potassium. Constant, albeit mild and asymptomatic, metabolic acidosis in all those affected prompted bicarbonate loading in both the propositus and his brother, which revealed a maximal renal tubular excretory capacity for bicarbonate reabsorption at serum levels of 18 mmole/liter and proved proximal renal tubular acidosis (PRTA). Further, a linear increase in urinary fractional potassium excretion accompanied that of bicarbonate in both, as in normal individuals. Dextrose-insulin infusion in the brother failed to reduce hyperpotassemia. These data support the hypothesis that a generalized cell membrane defect that specifically impedes potassium influx (as opposed to an isolated renal tubular defect) underlies this autosomal dominant disorder.

Familial hyperpotassemia and hypertension accompanied by normal plasma aldosterone levels: possible hereditary cell membrane defect.

Hypertension and hyperpotassemia that were accompanied by normal plasma aldosterone and low renin levels and were responsive to chlorothiazide administration were found in a 29-year-old patient and two decades later in his 21-year-old son. Their renal function is normal, including response to sodium sulfate, mannitol, and aldosterone infusions. Adrenal insufficiency was excluded. The renin-aldosterone system was proved intact by physiological and pharmacologic stress and angiotensin-II infusion. Also normal were values for blood counts, blood volumes, and erythrocyte and exchangeable body potassium. The postulation of a defective cell membrane impeding potassium influx is supported by the failure of glucose and insulin infusions to substantially reduce hyperpotassemia. In the context of a hereditary disorder (the pedigree, compatible with autosomal dominant inheritance, includes five affected in two generations), hypertension is a second phenotypic character of a single defective pleiotropic gene although its pathogenesis remains unclear.

Deficient activity of receptor-cyclase coupling protein in platelets of patients with pseudohypoparathyroidism.

Erythrocytes of patients with pseudohypoparathyroidism exhibit decreased activity of a membrane protein that is required for functional coupling of hormone receptors and catalytic adenylate cyclase. We observed decreased activity of this coupling protein in platelet extracts obtained from two pseudohypoparathyroid subjects, as compared with those of four normal control subjects. These findings support the hypothesis that generalized deficiency of this coupling protein is the primary biochemical defect of pseydohypoparathyroidism.

Familial Albright's hereditary osteodystrophy with hypoparathyroidism: normal structural Gs alpha gene.

Albright's hereditary osteodystrophy (AHO) is a characteristic skeletal phenotype, including short stature, obesity, round face, and brachydactyly. AHO appears in patients with pseudohypoparathyroidism (PHP) who have resistance to PTH and in their eumetabolic family members who have pseudopseudohypoparathyroidism (PPHP). The differential diagnosis of AHO in families without PHP includes brachydactyly E, whose existence as a distinct entity has been questioned. We studied a patient with familial AHO who presented with hypocalcemia. To our surprise, PTH levels were low, and the response to PTH administration was normal. This is the first case of familial AHO with hypoparathyroidism. The proband's family included 22 affected subjects spanning 3 generations, who had variable degrees of AHO manifestations, with an autosomal dominant inheritance trait. The metacarpophalangeal pattern profile was typical of that of PHP-PPHP. As deficient activity and inactivating mutations of Gs alpha were described in PHP as well as in PPHP, we measured the biological activity of Gs in family members, which was normal. To exclude subtle abnormalities in the Gs alpha gene, we sequenced the entire coding region of Gs alpha in the propositus, which was normal. We conclude that hypocalcemia should be adequately evaluated even in the presence of familial AHO, and that familial AHO can occur with a normal coding structural Gs alpha gene. Identification of the molecular defect in familial AHO without PHP will shed light on the pathogenesis of AHO in general.

Presence of insulin-renin-aldosterone-potassium interrelationship in normal subjects, disrupted in chronic hemodialysis patients.

The factors regulating aldosterone secretion in normals and in patients on chronic hemodialysis were studied by the determination of the circadian rhythm of plasma aldosterone, renin, cortisol, insulin, potassium, sodium, and glucose. Four normal volunteers and eight normotensive patients on regular dialysis treatment (RDT) were studied during prolonged recumbency on low sodium diet. A definite circadian rhythm for renin could not be demonstrated in RDT patients. The significant simple and multiple correlation coefficients found in normal subjects suggest that insulin participates in the regulation of aldosterone together with the other known factors: ACTH, renin, and potassium. In chronic renal failure, however, when basal conditions were maintained during prolonged recumbency, the correlations of insulin and renin with aldosterone were not found, suggesting that in this condition aldosterone secretion is controlled by ACTH and potassium. As a direct influence of insulin on aldosterone could not be demonstrated by multiple variance analysis, it seems that insulin is related to aldosterone indirectly through renin and/or potassium. The presence of significant correlations between insulin-potassium and potassium-aldosterone in RDT patients, without a significant insulin-aldosterone correlation, suggest that in the normals insulin participates in aldosterone regulation through renin secretion and not through potassium. A correlation between potassium and renin was not found in normals or in RDT patients.

Fibroblast defect in pseudohypoparathyroidism, type I: reduced activity of receptor-cyclase coupling protein.

Erythrocytes of many patients with pseudohypoparathyroidism, type I (PHP-I), exhibit reduced activity of the N protein, a guanine nucleotide-binding regulatory component of hormone-sensitive adenylate cyclase. We compared N and adenylate cyclase activities and the accumulation of cAMP in fibroblasts propagated from skin biopsies of six normal subjects and seven PHP-I patients. N activities were reduced by approximately 40% in fibroblasts as well as erythrocytes of five PHP-I patients. N activities in fibroblasts from two PHP-I patients with normal erythrocyte N activities were within the normal range. These results are consistent with the hypothesis that N deficiency is generalized in tissues of most PHP-I patients and is the primary defect responsible for their resistance to metabolic effects of hormones that work by stimulating adenylate cyclase. Fibroblast N deficiency was not associated with decreases in hormone-stimulated adenylate cyclase or cAMP accumulation in fibroblasts, probably because these activities involve many potentially regulable cellular components in addition to the N protein.

Deficient activity of receptor-cyclase coupling protein is transformed lymphoblasts of patients with pseudohypoparathyroidism, type I.

Erythrocytes of many patients with pseudohypoparathyroidism, type 1 (PHP-I) exhibit quantitatively reduced activity of the N protein, the guanine nucleotide-binding regulatory component of adenylate cyclase. We have designated this group of patients PHP-Ia to distinguish them from PHP-Ib patients, in whom erythrocyte N activity is quantitatively normal. In virus-transformed lymphoblasts of three normal, three PHP-Ia, and two PHP-Ib subjects, we compared N and adenylate cyclase activities, as well as cAMP accumulation and susceptibility to radiolabeling in the presence of [32P]NAD and cholera toxin. In comparison to normal lymphoblasts, N activities were reduced by approximately 50% in lymphoblasts of the PHP-Ia patients, but were not reduced in lymphoblasts from the PHP-Ib patients. Toxin-catalyzed radiolabeling of the 42,000 molecular weight subunit of the N protein was also reduced in lymphoblasts of the PHP-Ia patients. These results are consistent with the hypothesis that N deficiency is generalized in tissues of PHP-Ia patients. Deficient lymphoblast N activity in PHP-Ia was not associated with decreases in adenylate cyclase activity or cAMP accumulation, probably because these activities involve many potential regulable cellular components in addition to the N protein.

High incidence of primary cerebral lymphoma in tumor-induced central neurogenic hyperventilation.

An awake patient presented with central neurogenic hyperventilation induced by a cerebral tumor. Corticosteroid therapy and brain irradiation while the patient was anesthetized and respiration controlled under pancuronium-induced respiratory paralysis were followed by tumor regression and resolution of hyperventilation. Recurrence of tumor 6 weeks later was not accompanied by recurrence of hyperventilation. Cytologic study of cerebrospinal fluid revealed B-cell lymphoma. This patient brings to 10 the number of cases recorded with tumor-induced central neurogenic hyperventilation. Five of the eight patients with known tumor histology had a primary cerebral lymphoma, a rare neoplasm that comprises only 1% of all intracranial neoplasms. The disproportionately high frequency of central neurogenic hyperventilation in patients with cerebral lymphoma has therapeutic implications that are briefly reviewed.

Hepatic infarctions during pregnancy are associated with the antiphospholipid syndrome and in addition with complete or incomplete HELLP syndrome.

Antiphospholipid antibody syndrome (APS) is associated with adverse pregnancy outcomes and maternal complications including thrombotic events and early pre-eclampsia. HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) represents a unique form in the spectrum of pre-eclampsia. This report describes four patients with pregnancy-associated hepatic infarctions. All four had APS and HELLP syndrome, which was complete in one patient and incomplete in three patients, with elevated liver enzymes in all, and either thrombocytopenia or hemolysis in two. In the literature, we found descriptions of an additional 24 patients who had 26 pregnancies with concomitant hepatic infarction. Of the total 28 patients, anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LAC) were assessed in 16 patients, out of whom 15 were found to be positive. Hepatic infartction during pregnancy was associated almost always with APS, with HELLP (2/3 complete, 1/3 incomplete), and only in one-third of the pregnancies with pre-eclampsia (PE).

A convenient method for measuring receptor-cyclase coupling activity in whole blood: application to Duchenne muscular dystrophy.

Activity of the guanine nucleotide-binding regulatory (N protein) component of adenylate cyclase can be measured in extracts of whole blood, using a modification of an assay previously applied to erythrocyte membranes. N protein activities in the blood of three patients with Duchenne muscular dystrophy and eight heterozygous carriers of the disease did not differ significantly from activities measured in blood of seven normal subjects. In contrast, the modified assay showed a 50% deficiency of N protein activity in blood of four patients with pseudohypoparathyroidism, type I, in whom erythrocyte studies had previously demonstrated a comparable degree of N deficiency.

Albright hereditary osteodystrophy with hypothyroidism, normocalcemia, and normal Gs protein activity: a family presenting with congenital osteoma cutis.

The syndrome of Albright hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) is clinically and genetically heterogeneous. Classically, patients with PHP have the skeletal features of AHO, resistance to multiple hormones that work via cAMP such as parathyroid hormone and thyroid stimulating hormone, and deficient activity of Gs protein, the guanine nucleotide-binding protein that stimulates adenylate cyclase. However, patients without hormone resistance but with AHO and Gs deficiency were described (PPHP), as well as patients with multiple hormone resistance but without AHO or Gs deficiency. In a few patients with deficient Gs activity, hypothyroidism rather than hypocalcemia was the initial presentation of the disorder. We describe here a new variant of the syndrome, affecting 5 individuals in a 3 generation family with AHO, normal Gs activity and hypothyroidism. In the first 2 generations, mild features of AHO were present. The 2 sibs in the third generation had severe manifestations of AHO, including mild mental retardation as well as hypothyroidism. Diagnosis of congenital osteoma cutis at birth of the proband led to the diagnosis of the family. Elucidation of the molecular defect will shed light on the relationship between hormone resistance and AHO, as well as on the physiological mechanism of hormonal signal transduction.

Effect of venous obstruction of lower extremities on exercise tolerance.

The effect of venous obstruction on effort tolerance is not well appreciated. We studied a patient with severe lower body venous obstruction (with near normal heart and lung function) who had marked exercise intolerance. Peak O2 uptake for leg exercise was reduced, but peak O2 uptake for upper extremities was normal. This difference indicates that severe venous obstruction can lead to exercise limitation.

Antibodies to Bordetella pertussis adenylate cyclase are produced in man during pertussis infection and after vaccination.

Bordetella pertussis produces several potential virulence factors. One of these is an adenylate cyclase which penetrates eukaryotic cells, is activated by calmodulin and generates high levels of intracellular cAMP. We have found that pertussis infection in man leads to production of high titres (2000-8000) of anti-B. pertussis adenylate cyclase antibodies. Such antibodies also are produced after pertussis vaccination. They persist into adulthood, cross the placenta and disappear a few months after birth. The anti-adenylate cyclase antibodies found in human serum during pertussis infection do not neutralise the catalytic and penetrative activities of the enzyme.

Prolonged oral morphine therapy for severe angina pectoris.

Patients with intractable angina pectoris despite optimal drug therapy, who are not candidates for revascularization procedures, pose a very difficult problem. We evaluated the role of chronic opioid therapy in four such patients. The patients (mean age 79.5 years) were treated by low doses (mean 40 mg/day) of controlled-release oral morphine (CRM) for 1 to 5 years. The treatment was followed by a marked decline in the rate of admissions and hospitalization periods. The number of admissions decreased from a mean of 6 during the year prior to CRM therapy to 1.5 the following year. The duration of hospitalization for angina pectoris during these periods decreased from a mean of 42 +/- 35 days to 6 +/- 10 days (p < 0.05). Side effects were negligible and consisted mainly of lactulose-responsive constipation. We suggest that prolonged oral morphine therapy may be administered with good efficacy and no significant side effects in selected patients with intractable angina pectoris.

Prolonged therapy by the combination of furosemide and thiazides in refractory heart failure and other fluid retaining conditions.

The efficacy and side effects of the combination therapy of thiazide and furosemide administered to patients with refractory heart failure, for a prolonged period of time, were assessed. Thirty-two patients were hospitalized during the years 1985-1991. Left heart failure (left ventricular ejection fraction (LVEF = 22.4% +/- 6.6%) was present in 26 patients, right heart failure in 3 patients, chronic renal failure, cirrhosis and bilateral pleural effusion were present each in one patient. Chlorothiazide 0.5 g daily was added to conventional therapy. Patients were monitored closely during hospitalization and later as outpatients. During hospitalization, addition of chlorothiazide caused a reduction of 4.8 +/- 4.0 kg in patients' weight, serum potassium decreased from 4.4 +/- 0.6 to 4.0 +/- 0.5 mmol/l (P < 0.005) and serum sodium from 139.0 +/- 4.7 to 136.8 +/- 5.5 mmol/l (P < 0.05). The duration of the combined therapy was 17.2 +/- 19.1 months. Thirteen patients had short treatment (1.6 +/- 0.8 months) and 19 patients had prolonged treatment (26.5 +/- 19.0 months). No specific characteristics distinguished patients in both groups. Thiazides were discontinued in 19 patients, 10 of which had side effects. In only 5 of the 19 patients treated for the prolonged period had thiazides to be discontinued because of side effects. Addition of thiazides to furosemide is efficacious in severe heart failure. The combination should be started during hospitalization. Many patients can be maintained on this combination for a prolonged period of time on an ambulatory basis.

Successful treatment by cyclooxyenase-2 inhibitor of refractory hypokalemia in a patient with Gitelman's syndrome.

Gitelman's syndrome is manifested by hypokalemic alkalosis, hypomagnesemia, hypocalciuria, normotensive hyperreninemia and hyperaldosteronism. Hypokalemia can at times be refractory to treatment. We present a patient refractory to a variety of drugs including indomethacin, the nonspecific COX inhibitor. Rofecoxib, a specific COX 2 inhibitor, promptly elevated serum potassium concentration with normalization of plasma aldosterone and near normalization of renin without a change in serum magnesium. Our patient also had rhabdomyolysis, a rarely reported complication, which was also ameliorated by COX 2 inhibition.