Pseudohyperkalemia, Familial, 2, Due To Red Cell Leak

A number sign (#) is used with this entry because of evidence that familial pseudohyperkalemia-2 (PSHK2) is caused by heterozygous mutation in the ABCB6 gene (605452) on chromosome 2q35.

Description

'Familial pseudohyperkalemia' (PSHK) is a term that was coined to describe conditions in which a patient presents with pseudohyperkalemia as a result of a temperature-based abnormality in the transport of potassium (K) and sodium (Na) across the red cell membrane, in association with essentially normal hematology. PSHK can be considered to be the clinically benign, nonhemolytic cousin of hereditary stomatocytic leaky-cell, congenital hemolytic anemias (see 194380) (summary by Gore et al., 2002).

For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see 194380.

Clinical Features

Dagher et al. (1989) studied a mother and 2 children from Lille (France) with pseudohyperkalemia (FP Lille). The 65-year-old mother presented with a history of frequent cramps, finger tremors, and weakness, as well as 1 episode of paralysis. She was found to have an elevated serum potassium (K) level, with no significant hemolysis in vitro and normal red cell morphology. Reassessment of her potassium level immediately after blood sampling revealed a normal K concentration, which markedly increased after the blood sample was left standing at temperatures lower than 37 degrees centigrade. Investigation of plasma K concentrations in family members revealed a similar syndrome in 2 of her 3 children. Analysis of cation efflux in red cells demonstrated that when temperatures were decreased, passive permeability of potassium markedly increased and that of sodium (Na) remained unchanged in the patients, whereas in controls a reduction in temperature caused a marked reduction in both K and Na passive permeability. Vantyghem et al. (1991) restudied the family with FP Lille originally reported by Dagher et al. (1989) and noted that the precise dividing line between pseudohyperkalemia and hemolytic anemias such as stomatocytosis/xerocytosis (see 194380), which may also involve membrane cation transport abnormalities with increased active and passive K and Na permeability, was unclear.

Haines et al. (2001) described a family of Austrian origin with pseudohyperkalemia (FP Chiswick), living in Chiswick in the UK. Isotopic tracer studies showed this family to be clearly different from the Edinburgh pedigree reported by Stewart et al. (1979) (see 194380) in that the temperature dependence of the ouabain-plus-bumetanide-resistant potassium flux (reflecting the passive leak) showed a novel 'shoulder' abnormality with a minimum at 25 degrees centigrade rising to a maximum at 10 degrees, followed by a further fall. They also examined a Falkirk (Scotland) family previously studied by Meenaghan et al. (1985) and reported findings similar to those in the Austrian family, except for macrocytosis after 24 hours on ice.

Gore et al. (2002) studied a Welsh pedigree with pseudohyperkalemia (FP Cardiff), first described by Leadbeatter and O'Dowd (1982), in which dominantly inherited, red cell-based, temperature-dependent pseudohyperkalemia was associated with normal hematology. Potassium influx studies demonstrated that, as in other families with pseudohyperkalemia, the net K loss that occurs in the red cells at room temperature or below can be attributed to the disparity in temperature dependence between this 'leak' flux and the opposing NaK pump, which always shows a simple and steep monotonic fall with decreasing temperature. Analysis of red cell membrane proteins revealed that the proportion of ether lipids was increased compared to controls. Gore et al. (2002) noted that this had been observed in 3 previous families with cryohydrocytosis and a similar U-shaped K-flux temperature curve (Coles et al., 1999 and Haines et al., 2001; see 185020), suggesting an association between an excess of ether lipids in the red cell membrane and a U-shaped temperature dependence of K flux. Gore et al. (2002) stated that the phenotype in the FP Cardiff family could be regarded as a mild version of the cryohydrocytosis variant of hereditary stomatocytosis. The authors also emphasized the 'very major heterogeneity' of leaky membrane conditions when studied in detail, citing the U-shaped pattern seen in the Cardiff family, the shallow slope observed in the Edinburgh family as well as the frankly hemolytic Blackburn pedigree (Coles et al., 1999; see 185020), and the shoulder pattern seen in the Falkirk and Chiswick pedigrees.

Gore et al. (2004) reported a family of Bangladeshi origin that presented in East London with pseudohyperkalemia (FP East London). Affected individuals, who exhibited no hemolytic picture, had a 'shoulder' temperature profile similar to that previously seen in the Falkirk and Chiswick pedigrees. Gore et al. (2004) stated that this was the first pseudohyperkalemic pedigree to be identified from the Indian subcontinent.

Temperature-Dependent Potassium Flux Patterns

Carella et al. (2004) noted that 3 clinical forms of pseudohyperkalemia unassociated with hematologic manifestations, based predominantly on the leak-temperature dependence curve, had been reported: (1) pseudohyperkalemia Edinburgh (see 194380), in which the curve has a shallow slope; (2) pseudohyperkalemia Chiswick or Falkirk, in which the curve is shouldered; and (3) pseudohyperkalemia Cardiff, in which the temperature dependence of the leak shows a 'U-shaped' profile with a minimum at 23 degrees C.

Gore et al. (2004) stated that potassium-flux temperature profiles are consistent both from year to year in an individual as well as within affected members of a pedigree.

Mapping

Carella et al. (2004) studied a large kindred of Flemish descent with familial pseudohyperkalemia, designated FP Lille, that was originally reported by Dagher et al. (1989). Although the pseudohyperkalemia was indistinguishable from FP Edinburgh (see 194380), microsatellite analysis excluded the locus for that disorder at 16q23-qter. A genome scan mapped the FP Lille locus to chromosome 2q35-q36 with a lod score of 8.46 for marker D2S1338. Because of the duality of loci, Carella et al. (2004) suggested that the protein mediating the leak in familial pseudohyperkalemia might be a heterodimer.

Molecular Genetics

Andolfo et al. (2013) sequenced the candidate gene ABCB6 in 3 previously studied families segregating autosomal dominant pseudohyperkalemia (Dagher et al., 1989; Meenaghan et al., 1985; Gore et al., 2004), and identified a heterozygous R375Q mutation (605452.0013) in the FP Lille pedigree and a heterozygous R375W mutation (606452.0014) in the FP Falkirk and FP East London pedigrees. The mutations segregated fully with disease in each family, and neither was found in 50 controls or in the 1000 Genomes Project database.

Bawazir et al. (2014) analyzed the ABCB6 gene in a previously reported family with pseudohyperkalemia (FP Cardiff; Leadbeatter and O'Dowd, 1982; Gore et al., 2002) and identified a heterozygous missense mutation (R723Q; 606452.0015) that segregated with disease. Screening of 2 unrelated long-time blood donors who had exhibited pseudohyperkalemia, 1 from London and 1 from Cumbria, revealed that both were also heterozygous for the R723Q variant. Bawazir et al. (2014) noted that R723Q is listed in the dbSNP database (rs14811042); combining data from the 1000 Genomes Project, UK10K, NHLBI Exome Sequencing Project, and ClinSeq databases yielded an overall allele frequency of approximately 1:1,000 in European populations, meaning that heterozygosity for the R723Q variant will be present in approximately 1 in 500 blood donors. Analysis of stored blood from the 2 donors with pseudohyperkalemia revealed plasma potassium levels that were similar in pattern and degree to that previously described for FP Cardiff.

Exclusion Studies

In a large kindred of Flemish descent with familial pseudohyperkalemia (FP Lille) mapping to 2q35-q36, originally reported by Dagher et al. (1989), Carella et al. (2004) excluded mutation in several plausible candidate genes in the linked region, including KCNE4 (607775) and TUBA1 (191110).