Analbuminemia

A number sign (#) is used with this entry because analbuminemia (ANALBA) is caused by homozygous or compound heterozygous mutation in the ALB gene (103600) on chromosome 4q13.

Description

Analbuminemia is a rare autosomal recessive disorder manifested by the presence of a very low amount of circulating serum albumin. Affected individuals have few clinical symptoms other than mild edema, hypotension, fatigue, and, occasionally, a peculiar lower body lipodystrophy (mainly in adult females). The most common biochemical finding is a gross hyperlipidemia, with a significant increase in the total and LDL cholesterol concentrations, but normal concentrations of HDL cholesterol and triglycerides. Analbuminemia often leads to fetal or neonatal death in sibs in families of analbuminemic subjects, which may explain the rarity of the trait (summary by Caridi et al., 2014).

Clinical Features

Analbuminemia, a rare autosomal recessive disorder in which serum albumin is low or absent, was first reported by Bennhold et al. (1954) of Tubingen. See review by Ott (1962). In some reported families analbuminemia is a completely recessive condition; serum albumin has a normal level in heterozygotes. The homozygotes have remarkably little inconvenience attributable to the lack of serum albumin. In the kindreds of Bennhold et al. (1954) and Boman et al. (1976), heterozygotes showed intermediate levels of serum albumin.

Lyon et al. (1998) reported that dye-binding albumin methods employed by clinical laboratories typically found 3 to 18 g/L albumin in serum from analbuminemia patients. As a consequence, the diagnosis of analbuminemia (albumin level of zero) only becomes apparent following measurement of albumin by immunoassay or by electrophoresis.

Kallee (1996) reported 2 sibs with analbuminemia who were followed for 38 years. The female patient received replacement therapy with human serum albumin. Extreme lipodystrophy developed in this patient by the fourth decade of life. She had juvenile osteoporosis, which normalized under albumin replacement. She died from a granulosa cell cancer at age 69. Her brother never received albumin. He suffered from severe osteoporosis with gibbus formation, and died from a colon carcinoma at age 59. Both sibs had chronic insufficiency of the crural veins, with chronic ulcerations of both lower legs but no varicosities of the upper thighs. Despite high cholesterol values and high levels of several blood clotting factors, neither of the patients had severe atherosclerosis or thrombotic events. Kallee (1996) concluded that although patients often fail to exhibit serious clinical signs apart from pathologic laboratory findings, analbuminemia can no longer be regarded as a harmless anomaly.

Cormode et al. (1975) found very low plasma tryptophan in a neonate with analbuminemia who was small for gestational age.

Murray et al. (1983) restudied the family reported by Boman et al. (1976). The proposita showed trace amounts of immunologically normal serum albumin. With cDNA probes for the albumin gene, no deletion could be detected.

Caridi et al. (2019) reported a brother and sister, born to consanguineous Algerian parents, with analbuminemia. The brother was born preterm and was hospitalized during his first month of life with edema and hypoproteinemia. He had a history of hospitalizations for the same reasons until his third year of life. At the time of the report, he was 43 years of age. He had gluten intolerance, fatigue, and felt nauseated and bloated. He had moderate obesity with a body mass index (BMI) of 31.1 and sometimes had edema in the lower part of his legs. His sister did well until age 37 years when she had complications with her first pregnancy. She had an impressive weight gain during her first 2 months of pregnancy. Capillary serum protein electrophoresis showed her to have nearly complete absence of albumin, and she required an albumin infusion. On examination, she had edema and lipodystrophy. At age 38 years, she had a BMI of 36.5. On biochemical measurement, both patients had albumin levels of less than 1 g/L (reference, 40.2-47.6 g/L). Total serum protein levels were close to the lower limit of the normal range because of compensatory increase of other proteins. Both patients had significant hypercholesterolemia, but normal triglycerides. Their mother had an albumin level in the lower half of the normal range.

Inheritance

In a review, Ruffner and Dugaiczyk (1988) stated that of 22 reported analbuminemic individuals, 8 were known to be from consanguineous matings, suggesting autosomal recessive inheritance.

Mapping

Boman et al. (1976) presented data consistent with linkage of the analbuminemia locus and the GC locus (139200).

Molecular Genetics

In a Native American girl with analbuminemia, Ruffner and Dugaiczyk (1988) identified a homozygous splice site mutation in the albumin gene (103600.0027).

In an Italian woman with analbuminemia, Watkins et al. (1994) identified a homozygous mutation in the albumin gene (103600.0040).

In a male newborn of Iraqi extraction with analbuminemia, Campagnoli et al. (2002) identified a homozygous mutation in the ALB gene (103600.0057).

In 2 sibs, born to consanguineous Algerian parents, with analbuminemia, Caridi et al. (2019) identified a homozygous frameshift mutation in the ALB gene (103600.0058). Their mother was heterozygous for the mutation; DNA from the father was not available for testing. The variant was not found in the ExAC or gnomAD databases.

Animal Model

Analbuminemic rats, like analbuminemic humans, are healthy (Nagase et al., 1979). The use of cDNA probes failed to detect serum albumin gene transcripts in liver of these analbuminemic rats (Esumi et al., 1980). Thus, the disorder in the rat and perhaps the human may be the result of gene deletion. On the other hand, the normal levels of albumin in heterozygotes may indicate that the mutation is at a regulatory locus independent of the albumin locus. In the analbuminemic rat, Esumi et al. (1982) found albumin mRNA precursors in nuclei although such were missing from the cytoplasm. From this they concluded that analbuminemia in rats is caused by a unique type of mutation that affects albumin mRNA maturation. In analbuminemia of the rat, Esumi et al. (1983) demonstrated that a 7-bp deletion in an intron interferes with mRNA formation. Shalaby and Shafritz (1990) showed that exon H is skipped in the Nagase analbuminemic rat as a result of the 7-bp deletion at the splice donor site of intron H-I. Mendel et al. (1989) could find no abnormality of thyroxine transport and distribution in Nagase analbuminemic rats.