DOCK8 Deficiency: The Underlying Risk

DOCK8 deficiency is a rare autosomal recessive primary immunodeficiency characterized by impaired T cell and NK cell function, leading to increased susceptibility to viral, bacterial, and fungal infections. Patients often present with severe eczema, recurrent respiratory infections, and an increased risk of malignancies. While progressive multifocal leukoencephalopathy (PML) is not a typical presenting feature, the underlying immune dysregulation creates a permissive environment for JC virus reactivation and subsequent PML development.

Clinical Presentation: Recognizing the Red Flags

Given the rarity of PML in DOCK8 deficiency, clinicians must maintain a heightened awareness for subtle neurological changes. Unlike PML in HIV, where the diagnosis is often considered early due to the high pre-test probability, PML in DOCK8 deficiency may be overlooked initially. Key red flags should include: new-onset or progressive neurological deficits (weakness, clumsiness, speech difficulties, vision changes, cognitive decline) that are disproportionate to other manifestations of DOCK8 deficiency, absence of other readily identifiable causes for neurological symptoms (e.g., bacterial meningitis, stroke), and a history of severe or recurrent viral infections suggesting impaired T cell immunity.

Diagnostic Workup: Confirming PML

When PML is suspected, a rapid and thorough diagnostic workup is essential. This should include:

• MRI of the brain with and without gadolinium: Look for characteristic white matter lesions, typically asymmetric and non-enhancing in early stages.
• Cerebrospinal fluid (CSF) JC virus PCR: A highly sensitive and specific test for PML.
• Brain biopsy (if necessary): In cases where the diagnosis remains uncertain despite MRI and CSF analysis, brain biopsy may be considered to confirm the presence of JC virus and demyelination.

The 2021 European Academy of Neurology/European Federation of Neurological Societies (EAN/EFNS) guidelines recommend considering PML in any patient with progressive neurological deficits and characteristic MRI findings, regardless of HIV status or immunosuppressive history. This case underscores the importance of extending this recommendation to include patients with known or suspected primary immunodeficiencies.

Treatment Strategies: A Multifaceted Approach

Unfortunately, there is no curative treatment for PML. Management strategies focus on: Immune reconstitution: If the patient is receiving immunosuppressive therapies, discontinuation or reduction of these agents is crucial. In DOCK8 deficiency, hematopoietic stem cell transplantation (HSCT) may be considered as a curative option for the underlying immunodeficiency, potentially leading to improved control of JC virus replication. Supportive care: Manage neurological symptoms and prevent complications such as seizures and infections. Experimental therapies: Several antiviral agents (e.g., cidofovir, maraviroc) have been investigated for PML, but their efficacy remains unproven. Clinical trials should be considered when available.

Limitations

This report is a single case study, and while it provides valuable insights, its generalizability is limited. Larger studies are needed to better understand the incidence, risk factors, and optimal management strategies for PML in DOCK8 deficiency. Furthermore, the lack of specific antiviral therapies for PML highlights the urgent need for research in this area. Who is funding these trials, and are they truly unbiased?