Diagnosis, Phenotype, and Molecular Genetics of Congenital Analbuminemia

Abstract

Congenital analbuminemia (CAA) is an inherited, autosomal recessive disorder with an incidence of 1:1,000,000 live birth. Affected individuals have a strongly decreased concentration, or complete absence, of serum albumin. The trait is usually detected by serum protein electrophoresis and immunochemistry techniques. However, due to the existence of other conditions in which the albumin concentrations are very low or null, analysis of the albumin ( ALB ) gene is necessary for the molecular diagnosis. CAA can lead to serious consequences in the prenatal period, because it can cause miscarriages and preterm birth, which often is due to oligohydramnios and placental abnormalities. Neonatally and in early childhood the trait is a risk factor that can lead to death, mainly from fluid retention and infections in the lower respiratory tract. By contrast, CAA is better tolerated in adulthood. Clinically, in addition to the low level of albumin, the patients almost always have hyperlipidemia, but they usually also have mild oedema, reduced blood pressure and fatigue. The fairly mild symptoms in adulthood are due to compensatory increment of other plasma proteins. The condition is rare; clinically, only about 90 cases have been detected worldwide. Among these, 53 have been studied by sequence analysis of the ALB gene, allowing the identification of 27 different loss of function (LoF) pathogenic variants. These include a variant in the start codon, frame-shift/insertions, frame-shift/deletions, nonsense variants, and variants affecting splicing. Most are unique, peculiar for each affected family, but one, a frame-shift deletion called Kayseri, has been found to cause about one third of the known cases allowing to presume a founder effect. This review provides an overview of the literature about CAA, about supportive and additional physiological and pharmacological information obtained from albumin-deficient mouse and rat models and a complete and up-to-date dataset of the pathogenic variants identified in the ALB gene.

Recurrent Hypoglycemia in a Case of Congenital Analbuminemia

“…Because low serum albumin can have causes other than CAA, the clinical diagnosis of this disorder requires confirmation by mutation analysis of the ALB gene [1]. Genomic DNA from the proband and from two unrelated healthy volunteers, used as controls, was extracted from whole blood, as described by Watkins et al [11].…”

“…Congenital analbuminemia (CAA; OMIM # 616000) is a rare, autosomal recessive inherited disorder that is usually characterized by mutations in the albumin gene (ALB; NCBI Genomic Sequence: NC_00004.12), which lead to undetectable or low levels of the circulating protein [1]. Despite the condition being easily detected by routine serum protein electrophoresis, it is very rare, with only ∼90 cases having so far been identified worldwide [1].…”

“…us, the estimated prevalence is <1 in 1 million [1]. CAA is relatively well tolerated in adulthood but can lead to serious consequences in the pre-and perinatal periods, during which it can cause preterm birth or neonatal or early childhood death [1]. Typical clinical findings in CAA include lower extremity edema and lipodystrophy, which are more obvious in women, and orthostatic hypotension.…”

“…Hypercholesterolemia can be reversed by administration of albumin indicating an interplay between albumin and lipid metabolism [2]. Total serum calcium is usually low, while ionized calcium is in the normal range, and symptomatic hypocalcemia has not been described in CAA [1]. e effects of analbuminemia on glucose and lipid metabolism have previously been studied in a rat model.…”

“…Individuals with CAA are vulnerable to the adverse effects of drugs that have high protein-binding affinities and that are acidic due to alterations in the pharmacokinetics and bioavailability of these drugs [1]. Hypoglycemia is a recognized side effect of fluoroquinolones, such as moxifloxacin, and is due to a blockade of pancreatic islet ion channels, which causes an increase in insulin secretion [6,7].…”