Diagnostic Testing and Mimics of HDL1

When a person shows symptoms like involuntary movements and memory loss, the first step is almost always a test for Huntington’s disease (HD) or an evaluation for treatable causes. However, if that standard test comes back negative, it can be a confusing and frustrating time. This is when doctors begin looking for phenocopies—conditions that “copy” or mimic the appearance of Huntington’s disease but are caused by different issues ^[1][2].

The Search for Answers: The Phenocopy Workup

Because many rare diseases look alike, doctors often use a staged approach to testing. It is crucial to remember that a genetic evaluation should also rule out treatable acquired mimics, such as Wilson disease, autoimmune conditions, metabolic disorders, and medication effects.

If the standard HTT gene test for Huntington’s is negative, they may order a phenocopy panel ^[3]. This is a group of genetic tests that check for several mimics at once. However, testing strategies are highly individualized, and a negative panel does not automatically end the evaluation, as no panel covers everything. Mimics include:

• HDL2 (Huntington Disease-Like 2): Caused by a mutation in the JPH3 gene. This mimic is most common in individuals with African ancestry ^[4].
• SCA17 (Spinocerebellar Ataxia 17): Also known as HDL4, this is caused by a mutation in the TBP gene. It often involves balance issues (ataxia) alongside Huntington-like movements ^[5].
• C9orf72: A common genetic cause of frontotemporal dementia and ALS that can sometimes look like Huntington’s disease in its early stages ^[6].

The Definitive Test for HDL1

While other tests can provide clues, targeted PRNP genetic testing is required to confirm a diagnosis of inherited prion disease like HDL1 ^[7]. The test specifically looks for an octapeptide-repeat insertion (OPRI).

It is important to ensure the lab is looking for these “extra repeats.” Standard sequencing can sometimes miss large insertions, so doctors must use specialized methods. The result must then be classified by the laboratory and specialist as pathogenic (disease-causing) rather than a variant of uncertain significance ^[8][9].

Supportive Tests: MRI, EEG, and CSF

Doctors use other tools to see how the disease is affecting the brain, though these tests alone cannot definitively diagnose HDL1, nor does a normal result completely rule it out.

• MRI (Brain Imaging): In HDL1, an MRI may show atrophy (shrinking) of the brain. This is often “diffuse,” meaning it affects many different areas rather than just one ^[10][7]. While it helps rule out other causes like strokes or tumors, the pattern in HDL1 is nonspecific and can look very similar to other neurodegenerative diseases ^[11].
• EEG (Brain Wave Test): This test measures electrical activity in the brain. In many cases of HDL1, the EEG shows nonspecific “background slowing.” While some prion diseases show very specific sharp-wave patterns, these are only found in a minority of some specific mutations (like 5-OPRI) and may not be present at all in others ^[10][11].
• CSF RT-QuIC: This is a specialized test that looks for “prion-seeding activity” (the ability of misfolded proteins to cause normal proteins to misfold) in the spinal fluid ^[9].
  • Variable Sensitivity: The accuracy of this test depends heavily on the specific mutation. It may be highly accurate for standard sporadic prion diseases but can produce false negatives in OPRI-associated diseases or slowly progressing cases ^[9][12].
  • Not a Rule-Out: A negative RT-QuIC result does not mean you do not have HDL1. A validated pathogenic PRNP result interpreted by a specialist, combined with clinical findings, establishes the diagnosis ^[13][7].