Why Is HNPP Misdiagnosed as Multiple Sclerosis (MS)?

It can be deeply confusing and frustrating to be diagnosed with Multiple Sclerosis (MS), only to be told later that your symptoms are caused by Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). Receiving a genetic diagnosis of HNPP changes which causes and treatments need to be considered by your medical team.

The core difference between the two conditions comes down to location: MS is a disease of the central nervous system (the brain, spinal cord, and optic nerves), while HNPP affects the peripheral nervous system (the nerves that run through your arms, legs, and the rest of your body) ^[1][2]. While it is rare, it is also possible for a person to have both conditions at the same time ^[3].

While both conditions involve damage to myelin—the protective covering around your nerves—they are biologically different processes occurring in entirely different bodily systems.

Why the Confusion Happens

HNPP can sometimes be mistaken for MS early in a patient’s journey because the two conditions share overlapping features:

• Relapsing Symptoms: Both conditions can cause episodes of numbness, tingling, and muscle weakness that come and go over time ^[4][5].
• “Demyelination”: Both are categorized as demyelinating diseases. Because MS is the most well-known demyelinating disease, seeing clinical signs of myelin damage can sometimes prompt clinicians to suspect MS first.
• Coincidental or Misleading Test Results: In rare cases, people with HNPP may happen to have non-specific white spots on brain MRIs, mildly elevated protein in their spinal fluid, or delayed visual nerve tests (visual evoked potentials) ^[6][7][2]. These are not characteristic or defining findings of HNPP. However, if a doctor sees these nonspecific results alongside episodes of physical weakness, they might incorrectly suspect MS.

How the Symptoms Differ

While the symptoms can feel similar, examining how and where they happen helps clinicians tell the conditions apart. However, symptoms alone cannot completely distinguish the diseases.

• HNPP Patterns: HNPP symptoms are typically triggered by physical pressure, resting in an awkward position, wearing tight equipment, or minor trauma ^[4]. They affect individual peripheral nerves, often causing localized issues like a “foot drop” (weakness lifting the foot) or a numb hand ^[8]. It is important to note that HNPP can also cause fatigue related to muscle weakness, and balance issues caused by numb feet—which can sometimes be misinterpreted as MS symptoms.
• MS Patterns: MS attacks originate in the brain or spinal cord and are not triggered by external physical pressure on a limb. Symptoms that are more typical of MS (and not standard for HNPP) include severe vision loss (optic neuritis), profound central balance and coordination issues, or new bladder and bowel dysfunction ^[9].

How Doctors Tell Them Apart

Because HNPP and MS affect different parts of the nervous system, doctors use different tools to build a diagnosis. Neither condition is definitively proven by a single MRI or spinal tap; instead, doctors look at the full clinical picture.

Evaluating for Multiple Sclerosis (MS):

• Brain and Spine MRIs: Doctors look for specific patterns of damage (lesions) in the central nervous system that show disease activity spread out in different places and at different times (dissemination in space and time) ^[9].
• Spinal Tap (Lumbar Puncture): This tests the cerebrospinal fluid for specific antibodies called oligoclonal bands. If these bands are absent, or if the MRI lesions are atypical, it lowers the suspicion of MS, though it does not rule it out entirely ^[10].

Evaluating for HNPP:

• EMG and Nerve Conduction Studies: These tests measure electrical signals in your peripheral nerves. In HNPP, they typically show specific patterns of signal slowing at common pressure points (like the elbow or wrist), even in nerves where you haven’t noticed symptoms yet ^[11][12].
• Genetic Blood Test: HNPP is confirmed by testing the PMP22 gene. Most commonly, this requires a specific “copy-number” analysis to look for a missing piece (a deletion) of the gene, as standard genetic sequencing might miss it ^[12][13]. A pathogenic genetic result confirms HNPP, whereas a negative test or a “variant of uncertain significance” does not.

Safety and Next Steps

If you have recently been diagnosed with HNPP after an MS diagnosis, do not abruptly stop your MS disease-modifying therapies or cancel your specialist appointments. Work with a neurologist to carefully review your original MRIs, spinal tap, and genetic report to ensure your new diagnosis fully explains your symptoms.

• Protect Your Nerves: You can help prevent HNPP flare-ups by avoiding prolonged pressure on your nerves. Avoid leaning heavily on your elbows, crossing your legs for long periods, or wearing tight braces. Always inform surgeons and anesthesiologists about your HNPP so they can properly pad your pressure points during medical procedures.
• Family Planning: HNPP is usually an autosomal dominant condition, meaning an affected person has a 50% chance of passing the gene variant to each child. Genetic counseling can help you and your family understand who else might benefit from testing.
• When to Seek Urgent Care: Having HNPP does not protect you from other medical emergencies. You should seek immediate emergency care for sudden one-sided weakness, new severe vision loss, difficulty speaking or swallowing, or sudden loss of bowel and bladder control, as these are not typical pressure palsies and require urgent evaluation.