Review article
Alpha-fetoprotein, a fascinating protein and biomarker in neurology

https://doi.org/10.1016/j.ejpn.2013.09.003Get rights and content

Abstract

Alpha-fetoprotein (AFP) is present in fetal serum in concentrations up to 5,000,000 μg/l. After birth, AFP gene expression is turned down with a subsequent fall of the serum concentrations of this albumin-like protein to ‘adult values’ of circa 0.5–15 μg/l from the age of 2 years onwards. Irrespective of its assumed important functions, individuals with AFP deficiency appear fully healthy. The other way around, the presence of AFP in the circulation after the first years of life doesn't seem to harm, since individuals with ‘hereditary persistence of AFP’ are also without clinical abnormalities. During pregnancy, AFP (in maternal serum) has long been recognized as a marker for congenital anomalies of the fetus. Equally well known is AFP as biomarker for hepatocellular carcinoma and some other malignancies. There are at least four neurodegenerative disorders, all inherited as autosomal recessive traits and characterized by the presence of cerebellar ataxia, abnormal ocular movements, and neuropathy, for which an elevated concentration of serum AFP is an important diagnostic biomarker. The availability of a reliable biomarker is not only important during screening or diagnostic processes, but is also relevant for objective follow-up during (future) therapeutic interventions.

Introduction

The presence of alpha-fetoprotein (AFP) was first demonstrated in the serum of human fetuses in 1956.1 Since then, numerous papers have been published on AFP, with more than 18,000 PubMed hits in April 2013 when searching with “alpha-fetoprotein”. It has become clear that AFP is abundantly present in serum during fetal life, mainly produced by the yolk sac and the fetal liver, while the transcription of the AFP gene rapidly declines after birth. Very low, ‘adult’ serum values below circa 15 μg/l are already reached in the first two years of life. Only under certain physiological and pathological conditions AFP synthesis persists or reappears, leading to high amounts of this fetal protein in serum of children or adults.

Much attention has been paid to AFP as biomarker in prenatal screening programs and the diagnosis of hepatocellular carcinoma. In contrast to these major topics, neurological disorders that can be diagnosed based on the presence of increased serum AFP concentrations have never systematically been discussed in a review paper. Here we give an overview of the physiology of AFP as a protein and describe the relevance of AFP as biomarker in clinical practice with a special focus on neurological disorders, summarizing and integrating the knowledge from a remarkable variety of laboratories and clinical settings like obstetrics, oncology, gastroenterology, genetics, paediatrics and neurology.

Section snippets

Physiology

AFP is a member of the so-called albumin gene family that also contains albumin, vitamin D-binding protein, and afamin (also named alpha-albumin, playing a role in vitamin E transport). The four genes that encode these four proteins are – like the proteins – highly homologous and lie in tandem on the long arm of chromosome 4 (for reviews: Lazarevich, 2000, and Mizejewski 2001 and 2007).2, 3, 4 All four proteins have a role in transport of different ligands, and display other functions including

AFP deficiency

Since AFP is produced in large amounts during fetal life and AFP is thought to play an important role at least as transporter and immune-modulator, it was generally assumed to be essential for normal fetal development. In contradiction to this assumption, an extremely rare condition with genetically determined absence of AFP has been described in three unrelated families.10 All individuals in these families are reported as healthy human beings with normal development. Moreover, it has also been

Hereditary persistence of AFP

As described above, hardly any AFP is synthesized in humans under physiological circumstances after the first two years of life. Elevated serum AFP levels are therefore almost always pointing to an underlying disorder (see next paragraph: AFP as biomarker for disease). Hereditary persistence of alpha-fetoprotein (HPAFP) however, is a rare, benign autosomal dominant condition, in fact a non-disease, in which serum AFP levels remain high throughout life without any clinical signs or symptoms.

Obstetrics

Measurements of maternal serum and amniotic fluid AFP during pregnancy were important and widely applied screening methods for the detection of congenital anomalies of the fetus. Elevated maternal serum AFP concentrations were found in many different fetal disorders, like neural tube defects, omphalocele, gastroschisis, and fetal bowel obstructions. Interestingly, low (instead of high) maternal serum AFP is associated with an increased risk of Down syndrome of the fetus.

Under normal

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