Congenital Analbuminemia Research Articles

<i>Congenital Analbuminemia</i>

Congenital analbuminemia (CAA) is a rare autosomal recessive disorder, characterized by the absence or very low level of serum albumin (human serum albumin/HSA) as a result of defect on chromosome 4 which encodes albumin. It is defined as albumin level <1 g/l with normal liver function and the absence of protein loss.1,2 Estimated CAA prevalence is less than 1 in 1 million.A 10-year-old boy suffered from generalized edema that got worsened since last month. The patient had been misdiagnosed with nephrotic syndrome 2 years earlier, and then became protein-losing enteropathy. Neither cough nor diarrhea were reported. The patient had history of food allergy. Physical examination showed moderately ill condition, Glasgow Coma Scale (GCS) score E4 V5 M6, blood pressure 90/50 mmHg, pulse 120 x/min, respiratory rate 30x/min, palpebral edema, shifting dullness, undulation (+), with nonpitting edema on the extremities. Laboratory findings: leukocytosis (neutrophilia), peripheral blood smear showed hypochromic microcytic anisositosis erythrocyte. AAT serum 246 mg/dl, GGT serum: 88 U/l, iron serum 28 µg/dl, TIBC 411 µg/dl, transferrin saturation 7%, total IgE 775,90 U/ml. Serum Protein Electrophoresis (SPE) results were hypoalbuminemia (1,4 g/dl), hypogammaglobulinemia (0,21 g/dl), and total protein 2,91 g/dl. Chest X-ray showed pneumonia with minimal right pleural effusion. Overestimation of serum albumin level was caused by alpha and beta globulin that were detected as albumin in bromocresol green (BCG) methods. CAA aggravated with by allergy caused malnutrition in this patient. These data support the diagnosis of CAA with sepsis and iron deficiency anemia. Suggestion for the management consist of blood culture, procalcitonin level measurement, inguinal lymph node biopsy, DNA sequence analysis, also analysis of pleural and ascites fluid.

Alterations in the Plasma Protein Expression Pattern in Congenital Analbuminemia—A Systematic Review

Albumin is a highly abundant plasma protein with multiple functions, including the balance of fluid between body compartments and fatty acid trafficking. Humans with congenital analbuminemia (CAA) do not express albumin due to homozygosity for albumin gene mutation. Lessons about physiological control could be learned from CAA. Remarkably, these patients exhibit an apparently normal lifespan, without substantial impairments in physical functionality. There was speculation that tolerance to albumin deficiency would be characterized by significant upregulation of other plasma proteins to compensate for analbuminemia. It is unknown but possible that changes in plasma protein expression observed in CAA are required for the well-documented survival and general wellness. A systematic review of published case reports was performed to assess plasma protein pattern remodeling in CAA patients who were free of other illnesses that would confound interpretation. From a literature search in Pubmed, Scopus, and Purdue Libraries (updated October 2022), concentration of individual plasma proteins and protein classes were assessed. Total plasma protein concentration was below the reference range in the vast majority of CAA patients in the analysis, as upregulation of other proteins was not sufficient to prevent the decline of total plasma protein when albumin was absent. Nonetheless, an impressive level of evidence in the literature indicated upregulated plasma levels of multiple globulin classes and various specific proteins which may have metabolic functions in common with albumin. The potential role of this altered plasma protein expression pattern in CAA is discussed, and the findings may have implications for other populations with hypoalbuminemia.

Covid-19 in a Patient with Congenital Analbuminemia and Coronary Artery Disease: A Case Report

Covid-19 in a Patient with Congenital Analbuminemia and Coronary Artery Disease: A Case Report

Severe hypercholesterolemia in a patient with very low albumin and normal renal function

A 20-year-old male presented with severe elevation in low-density lipoprotein cholesterol (LDL-C). Initial genetic testing for familial hypercholesterolemia was negative. Patient also had low albumin, and further genetic testing showed homozygous variants in the ALB gene, suggesting congenital analbuminemia (CAA) causing severe hyperlipidemia. CAA is an autosomal recessive disorder with incidence of about 1:1,000,000. The gene for albumin is a single autosomal gene, and pathological variants that affect splicing lead to premature stop, nonsense variants, and deletions that result in a defect in albumin synthesis with CAA. CAA can be fatal in the prenatal period and cause infections in early childhood. CAA is tolerated better in adulthood because of compensatory increase in other plasma proteins. Plasma lipoproteins also increase, and CAA can cause gross hyperlipidemia with severe elevations in LDL-C and hypercholesterolemia. Genetic examination of ALB is mandatory to establish the diagnosis. Early diagnosis may be important to initiate lipid-lowering treatments to avoid premature coronary artery disease.

In vitro proliferation and long-term preservation of functional primary rat hepatocytes in cell fibers

Primary hepatocytes are essential cellular resources for drug screening and medical transplantation. While culture systems have already succeeded in reconstituting the biomimetic microenvironment of primary hepatocytes, acquiring additional capabilities to handle them easily as well as to expand them remains unmet needs. This paper describes a culture system for primary rat hepatocytes, based on cell fiber technology, that brings scalability and handleability. Cell fibers are cell-laden core–shell hydrogel microfibers; in the core regions, cells are embedded in extracellular matrix proteins, cultured three-dimensionally, and exposed to soluble growth factors in the culture medium via the hydrogel shells. By encapsulating primary rat hepatocytes within cell fibers, we first demonstrated their proliferation while maintaining their viability and their hepatic specific functions for up to thirty days of subsequent culture. We then demonstrated the efficiency of proliferating primary rat hepatocytes in cell fibers not only as cell-based sensors to detect drugs that damage hepatic functions and hepatocellular processes but also as transplants to improve the plasma albumin concentrations of congenital analbuminemia. Our culture system could therefore be included in innovative strategies and promising developments in applying primary hepatocytes to both pharmaceutical and medical fields.

Congenital Analbuminemia Associated with Hypothyroidism in a Preterm Neonate: The First Case from a Highly Consanguineous Community

AbstractAnalbuminemia is a rare autosomal recessive disease characterized by extremely low or zero levels of circulating serum albumin. The diagnosis is made by ruling out other causes of hypoalbuminemia and should be confirmed by gene mutation analysis. In this article, we describe the clinical findings of a preterm neonate born to a consanguineous family who presented with progressive lower limb edema at the age of 7 days and who was confirmed as having congenital analbuminemia by genetic testing (homozygous mutation ALB NP_000468.1: p. Val78CysfsTer2) and hypothyroidism. This is the first case of congenital analbuminemia to be reported from Jordan.

Analbuminémie congénitale compliquée d’un syndrome coronarien aigu récidivant : à propos d’un cas et revue de la littérature

Congenital analbuminemia (CAA) is a very rare disorder with an estimated prevalence of less than one in one million. This anomaly can be lethal at birth and in early infancy but it's not very symptomatic in adulthood. The clinical signs are edema, lipodystrophy, fatigue… Hypercholesterolemia is the main biological disorder and it predisposes to cardiovascular complications. The mild symptoms of CAA leads to delay diagnosis. That's why clinical and biological signs of this disorder should be known by both of biologist and clinician to establish an early diagnosis in order to prevent cardiovascular complications. We report a new case of congenital analbuminemia complicated by recurrent acute coronary artery disease in 34-year-old man. This complication has been reported only once according to the register of analbuminemia cases.

Congenital analbuminemia caused by a substantial aberrant splicing in the albumin gene

Congenital analbuminemia caused by a substantial aberrant splicing in the albumin gene

Congenital analbuminemia in a patient affected by hypercolesterolemia

Congenital analbuminemia in a patient affected by hypercolesterolemia

Diagnosis, Phenotype, and Molecular Genetics of Congenital Analbuminemia.

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.

The spina bifida peculiarities in the Crimea region

Congenital analbuminemia (OMIM # 616000) is an extremely rare autosomal recessive disorder, caused by variations in the albumin gene (ALB), which is generally thought to be a relatively benign condition in adulthood, but seems to be potentially life threatening in the pre- and peri-natal period. The subject of our study was a consanguineous family, in which we identified two analbuminemic individuals. Mutation analysis of ALB revealed that both are homozygous for a previously unreported insertion in exon 9 (c.1098dupT), causing a subsequent frame-shift with the generation of a premature stop codon, and an aberrant truncated putative protein product, p.Val367fsTer12. This variation is present in heterozygous condition in several other members of the family. The phenotype and the molecular genetics of CAA are discussed.

A novel insertion (c.1098dupT) in the albumin gene causes analbuminemia in a consanguineous family

Congenital analbuminemia (OMIM # 616000) is an extremely rare autosomal recessive disorder, caused by variations in the albumin gene (ALB), which is generally thought to be a relatively benign condition in adulthood, but seems to be potentially life threatening in the pre- and peri-natal period. The subject of our study was a consanguineous family, in which we identified two analbuminemic individuals. Mutation analysis of ALB revealed that both are homozygous for a previously unreported insertion in exon 9 (c.1098dupT), causing a subsequent frame-shift with the generation of a premature stop codon, and an aberrant truncated putative protein product, p.Val367fsTer12. This variation is present in heterozygous condition in several other members of the family. The phenotype and the molecular genetics of CAA are discussed.

Congenital Analbuminemia in Unrelated Algerian and Turkish Families is Caused by the Same Molecular Defect in the Albumin Gene

Congenital Analbuminemia in Unrelated Algerian and Turkish Families is Caused by the Same Molecular Defect in the Albumin Gene

Understanding fetal factors that contribute to preterm birth: Sjögren-Larsson syndrome as a model.

Preterm birth is the world's leading cause of neonatal death. Unfortunately, the pathophysiology of preterm birth remains poorly understood. Sjögren-Larsson syndrome is a rare, neurometabolic disorder caused by a fatty aldehyde dehydrogenase deficiency. A majority of patients with Sjögren-Larsson syndrome is born preterm. Data of all known Dutch patients with Sjögren-Larsson syndrome and all cases reported in literature were analyzed to learn from preterm birth in context of this rare disease. Exact gestational age was known in 33 Dutch patients; 24 (73%) of them were born preterm, with a median gestational age of 36 weeks. The literature search confirmed our findings: 13 (59%) of 22 cases was born preterm. Preterm birth is a hallmark of Sjögren-Larsson syndrome, presumably caused by the abnormal lipid metabolism of the fetus. At least five additional rare genetic disorders (namely Ehlers-Danlos syndrome, ichthyosis prematurity syndrome, congenital analbuminemia, osteogenesis imperfecta type II and restrictive dermopathy) were found in literature that lead to preterm birth of the affected fetus. These disorders are in fact "experiments of nature" and as such they shed new lights on the mechanisms causing preterm birth.

A nucleotide deletion and frame-shift cause analbuminemia in a Turkish family.

Congenital analbuminemia is an autosomal recessive disorder, in which albumin, the major blood protein, is present only in a minute amount. The condition is a rare allelic heterogeneous defect, only about seventy cases have been reported worldwide. To date, more than twenty different mutations within the albumin gene have been found to cause the trait. In our continuing study of the molecular genetics of congenital analbuminemia, we report here the clinical and biochemical findings and the mutation analysis of the gene in two Turkish infants. For the molecular analysis, we used our strategy, based on the screening of the gene by single-strand conformation polymorphism, heteroduplex analysis and direct DNA sequencing. The results showed that both patients are homozygous for the deletion of a cytosine residue in exon 5, in a stretch of four cytosines starting from nucleotide position 524 and ending at position 527 (NM_000477.5(ALB):c.527delC). The subsequent frame-shift inserts a stop codon in position 215, markedly reducing the size of the predicted protein product. The parents are both heterozygous for the same mutation, for which we propose the name Erzurum from the city of origin of the family. In conclusion, our results show that in this family congenital analbuminemia is caused by a novel frame-shift/deletion defect, confirm the inheritance of the trait, and contribute to advance our understanding of the molecular basis underlying this condition.

Non-immune hydrops fetalis

Non-immune hydrops fetalis (NIHF) refers to hydrops in the absence of maternal circulating red-cell antibodies, and constitutes up to 90% of all described hydrops fetalis cases. One-third of hydropic fetuses are discovered incidentally during prenatal sonography in the first or second trimester of gestation. Although hydrops is a fetal condition, in many cases there are associated maternal findings, such as preeclampsia, polyhydramnios, and mirror syndrome (generalized maternal edema, that ‘mirrors’ the edema of the hydropic fetus and placenta). NIHF should be seen as a symptom or clinical phenotype rather than as a disorder, and considered as a non-specific, end-stage status of a wide variety of disorders. Numerous disorders including fetal disorders, maternal diseases (e.g., severe maternal anemia, diabetes and maternal indomethacin use) and placental/cord abnormalities have been associated with NIHF. Despite extensive investigations, the etiology on NIHF may remain unknown in 15% to 25% of patients, even after an autopsy has been performed. Chromosomal abnormalities are the cause of NIHF in 25-70% of the cases. Therefore, fetal or neonatal chromosome analysis is indicated in all cases of NIHF. Abnormalities of the cardiovascular system are responsible for as many as 40% of cases of NIHF. Thoracic abnormalities increase intrathoracic pressure and can obstruct venous return to the heart, leading to peripheral venous congestion, or they may obstruct the lymphatic duct, resulting in lymphedema. Fetal anemia accounts for 10-27% of hydrops. To evaluate the risk of fetal anemia, Doppler measurement of the middle cerebral artery peak systolic velocity should be performed in all hydropic fetuses after 16 weeks of gestation. Parvovirus B19 is the most common infectious agent associated with hydrops. Even in persistent severe anemia, the prognosis is generally good if the fetus is supported by intrauterine fetal transfusions. The development of hydrops in fetuses with a TORCH infection is a poor prognostic indicator. Although hypoproteinemia is frequently proposed as one of the causes of hydrops fetalis, recent studies show that hypoalbuminemia is unlikely to cause the initial development of hydrops. However, it seems to occur as a secondary effect in the cascade of hydrops, and might be the trigger for mild hydrops to evolve into severe hydrops. In addition, not all infants with hypoproteinemia become hydropic, and hydrops fetalis is uncommon in congenital nephrotic syndrome and congenital analbuminemia. In the pathogenesis, inherited metabolic disorders, especially lysosomal storage diseases, are more common than previously thought. Inherited metabolic disorders must be always thought when investigating cases of recurrent NIHF in the same family. It is very important to examine the placenta carefully in cases where hydrops or ascites are present at birth or detected by ultrasound, especially in the transient form. Even if a family does not agree to autopsy, placental examination may be done. Proceedings of the 10 th International Workshop on Neonatology · Cagliari (Italy) · October 22 nd -25 th , 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgiou

Congenital analbuminemia caused by a novel aberrant splicing in the albumin gene

Introduction:Congenital analbuminemia is a rare autosomal recessive disorder manifested by the presence of a very low amount of circulating serum albumin. It is an allelic heterogeneous defect, caused by variety of mutations within the albumin gene in homozygous or compound heterozygous state. Herein we report the clinical and molecular characterization of a new case of congenital analbuminemia diagnosed in a female newborn of consanguineous (first degree cousins) parents from Ankara, Turkey, who presented with a low albumin concentration (< 8 g/L) and severe clinical symptoms.Materials and methods:The albumin gene of the index case was screened by single-strand conformation polymorphism, heteroduplex analysis, and direct DNA sequencing. The effect of the splicing mutation was evaluated by examining the cDNA obtained by reverse transcriptase - polymerase chain reaction (RT-PCR) from the albumin mRNA extracted from proband’s leukocytes.Results:DNA sequencing revealed that the proband is homozygous, and both parents are heterozygous, for a novel G>A transition at position c.1652+1, the first base of intron 12, which inactivates the strongly conserved GT dinucleotide at the 5′ splice site consensus sequence of this intron. The splicing defect results in the complete skipping of the preceding exon (exon 12) and in a frame-shift within exon 13 with a premature stop codon after the translation of three mutant amino acid residues.Conclusions:Our results confirm the clinical diagnosis of congenital analbuminemia in the proband and the inheritance of the trait and contribute to shed light on the molecular genetics of analbuminemia.

Treatment of a patient with congenital analbuminemia with atorvastatin and albumin infusion

Congenital analbuminemia is a rare autosomic recessive inherited disorder characterized by low plasma albumin and hypercholesterolemia, which may increase cardiovascular risk. Patients are essentially asymptomatic, apart from ease of fatigue, minimal ankle oedema and hypotension. There is no accepted strategy for safely treating both hypercholesterolemia and analbuminemia in order to eventually decrease the atherosclerotic risk. We report a case of congenital analbuminemia (1.0 g/dL) in a 38-year-old male with hypercholesterolemia (range: 406-475 mg/dL) and severe arterial dysfunction [no brachial artery flow-mediated dilation (FMD)]. Long-term, cholesterol-lowering treatment with atorvastatin was associated with the appearance of peripheral edema. Two-months of infusion with albumin improved FMD (7%) and reduced serum cholesterol (273 mg/dL), supporting the hypothesis of a compensatory role of hypercholesterolemia. Statin treatment, together with periodical albumin infusions, may contribute to the safe reduction of cardiovascular risk.

A novel mutation in the albumin gene (c.1A&gt;C) resulting in analbuminemia

Analbuminemia (OMIM # 103600) is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous or compound heterozygous subjects. The trait is caused by a variety of mutations within the albumin gene. We report here the clinical and molecular characterisation of two new cases of congenital analbuminemia diagnosed in two members of the Druze population living in a Galilean village (Northern Israel) on the basis of their low level of circulating albumin. The albumin gene was screened by single-strand conformation polymorphism and heteroduplex analysis, and the mutated region was submitted to DNA sequencing. Both the analbuminemic subjects resulted homozygous for a previously unreported c.1 A>C transversion, for which we suggest the name Afula from the hospital where the two cases were investigated. This mutation causes the loss of the primary start codon ATG for Met1, which is replaced by a - then untranslated - triplet CTG for Leu. (p.Met1Leu). The use of an alternative downstream ATG codon would probably give rise to a completely aberrant polypeptide chain, leading to a misrouted intracellular transport and a premature degradation. The discovery of this new ALB mutation, probably inherited from a common ancestor, sheds light on the molecular mechanism underlying the analbuminemic trait and may serve in the development of a rapid genetic test for the identification of a-symptomatic heterozygous carriers in the Druze population in the Galilee.

Perinatal and childhood morbidity and mortality in congenital analbuminemia

Albumin, a serum transport protein, provides 80% of colloid osmotic pressure. Congenital analbuminemia (CAA) is an autosomal recessive disorder characterized by absence of serum albumin. Fifty cases of CAA have been reported throughout the world; however, little is known about its clinical impact. Most reported cases have few clinical signs and symptoms. Twelve local cases from the northwestern central plains region in Saskatchewan were identified and reviewed to ascertain morbidity and mortality related with CAA. All the cases are from two remote First Nations communities. Cases had frequent hospital admissions and recurrent respiratory tract infections. Placental abnormalities included hydropic placentas, placental infarcts and microcalcifications. One-half of the cases were born preterm and one-quarter were small for their gestational age. There were three mortalities in the case series. The present case series suggests increased morbidity and mortality during infancy in patients with CAA. The long-term risks of CAA in this population are unknown and a longitudinal study is recommended.