Progressive Ataxia with Elevated Alpha-Fetoprotein: Diagnostic Issues and Review of the Literature

Abstract

Background: Ataxias represent a challenging group of disorders due to significant clinical overlap. Here, we present a patient with early-onset progressive ataxia, polyneuropathy and discuss how elevation of alpha fetoprotein (AFP) narrows the differential diagnosis. Case report: Ataxia, polyneuropathy, and mild elevation of AFP are features compatible with ataxia with oculomotor apraxia type 2 (AOA2) but also with ataxia with oculomotor apraxia type 4 (AOA4). A genetic analysis demonstrated biallelic mutations in senataxin (SETX), confirming the diagnosis of AOA2. Discussion: Mild elevation of AFP is found in patients with AOA2 and AOA4, and higher levels are commonly seen in ataxia-telangiectasia. AFP is a useful diagnostic tool but not a biomarker for disease progression in AOA2.

Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia

“…Elevated AFP serum levels are also found in ataxia with ocular apraxia types 2 and 4 (AOA2, AOA4). These are differential diagnoses of AT caused by variants in the senataxin (SETX) and the polynucleotide kinase 3′-phosphatase (PNKP) genes [16]. However, patients with AOA2/4 do not exhibit telangiectasia, and our patients did neither carry putatively causative SETX nor PNKP variants.…”

Neurocutaneous Diseases: Diagnosis, Management, and Treatment

“…The diverse range of symptomatology underscores the importance of a comprehensive personal and family history, which can lead a practitioner toward genetic testing to identify the presence of the 11q22–23 mutation in an individual suffering from cerebellar effects [ 115 ]. Moreover, analysis of the patient’s blood may provide key insights in diagnosing AT, revealing the presence of either decreased immunoglobulins or increased alpha-fetoprotein (AFP) levels in adults [ 116 ]. A significant reduction in immunoglobulins in AT results from the lack of mature T cells and the impaired interaction activating B cells [ 117 ].…”

Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?

“…AOA2 is caused by mutations in the SETX gene, encoding for a DNA/RNA helicase protein [ 136 ]. Elevation of AFP is present in 99% of cases and is stable over the course of disease, but it usually do not correlate with disease severity [ 137 ]; elevated CK, mild hypoalbuminemia, or hypercholesterolemia can also be present in AOA2 patients [ 138 ]. Ataxia-telengectasia (AT) is caused by mutation in the ATM gene, that encodes a phosphatidylinositol-3 kinase protein (PI3K).…”

“…Ataxia-telengectasia (AT) is caused by mutation in the ATM gene, that encodes a phosphatidylinositol-3 kinase protein (PI3K). Immunoglobulins (Ig) lare usually reduced in AT and elevation of AFP is progressive [ 138 ]. Conversely, in A-TLD, a rare form caused by mutations in the hMRE11 gene , patients have normal AFP serum concentrations [ 132 , 139 ].…”