ALB – Congenital Analbuminemia

Congenital analbuminemia (CAA) is a rare autosomal recessive disorder caused by biallelic loss‐of‐function variants in the albumin gene (ALB), leading to severely reduced or absent serum albumin ([PMID:24627724]). Patients often present neonatally with hypoalbuminemia, compensatory hyperlipidemia, and variable edema, although many adults remain asymptomatic due to up‐regulation of other plasma proteins and lipoproteins.

Genetic studies have confirmed over 90 molecularly diagnosed cases worldwide, with >53 probands characterized by sequence analysis revealing 27 distinct loss‐of‐function ALB variants across more than 20 unrelated families ([PMID:31057599]). Segregation in consanguineous pedigrees and sibling clusters—such as the Kayseri exon 3 founder mutation in a three‐sibling Arab family—further supports autosomal recessive inheritance ([PMID:18791744], [PMID:27346974]).

The spectrum of pathogenic ALB variants includes splice‐site defects (e.g., c.1652+1G>A causing exon 12 skipping), frameshift deletions (e.g., c.527delC), nonsense mutations (e.g., c.412C>T (p.Arg138Ter)), and start‐codon disruptions. Most are unique to individual families, although the Kayseri deletion accounts for ~30% of cases, suggesting a founder effect in certain populations.

Clinically, CAA manifests with severe hypoalbuminemia (serum albumin <10 g/L; HP:0003073), hyperlipidemia (HP:0003077), hypercholesterolemia (HP:0003124), fatigue (HP:0012378), hypocalcemia (HP:0002901), and vitamin D deficiency (HP:0100512). Rare complications include recurrent hypoglycemia (HP:0001988), glomerulonephritis, and early‐onset coronary thrombosis.

Functional assays and animal models corroborate a loss‐of‐function mechanism. Splicing defects have been validated via RT‐PCR of patient mRNA, and Nagase analbuminemic rats exhibit exon‐skipping phenotypes that can be rescued by complementary U1 snRNA, underscoring haploinsufficiency as the pathogenic mechanism ([PMID:9790899], [PMID:26543026]).

No major conflicting reports have emerged; all variants consistently reduce albumin synthesis or stability, with compensatory plasma protein upregulation mitigating clinical severity in adulthood.

In summary, congenital analbuminemia is a well‐established autosomal recessive condition with definitive gene–disease validity. Genetic testing of ALB enables early diagnosis, informs carrier screening, and guides supportive management of metabolic and cardiovascular complications. Key Take‐home: Molecular confirmation of ALB loss‐of‐function variants is critical for the diagnosis and personalized care of CAA patients.

References

• Biochemia medica • 2014 • Congenital analbuminemia caused by a novel aberrant splicing in the albumin gene. PMID:24627724
• Frontiers in genetics • 2019 • Diagnosis, Phenotype, and Molecular Genetics of Congenital Analbuminemia. PMID:31057599
• Biochemia medica • 2016 • A nucleotide deletion and frame-shift cause analbuminemia in a Turkish family. PMID:27346974
• Pediatric nephrology • 2009 • Congenital analbuminemia with acute glomerulonephritis: a diagnostic challenge. PMID:18791744
• Case reports in endocrinology • 2020 • Recurrent Hypoglycemia in a Case of Congenital Analbuminemia. PMID:32181025
• Biochemical and biophysical research communications • 1998 • Suppression of the 5' splice site mutation in the Nagase analbuminemic rat with mutated U1snRNA. PMID:9790899
• Annals of clinical biochemistry • 2016 • A novel splicing mutation in the albumin gene (c.270+1G>T) causes analbuminaemia in a German infant. PMID:26543026

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