Symptoms and the Clinical Spectrum

Because PRDM8-related disorders are so rare, scientists are still mapping out the full range of symptoms. Research currently describes a “clinical spectrum”—a range of ways the disease can show up in different people. While every journey is unique, doctors have identified two principal patterns reported so far, which may overlap or change as the disease progresses ^[1].

Two Faces of the Same Disorder

The symptoms of PRDM8-related disorders generally fall into two broad categories based on the limited literature. These are not separate diseases, but rather different “lenses” through which doctors might first view the condition.

1. The PME-like Presentation (Lafora-like)

Some individuals present with a pattern known as Progressive Myoclonus Epilepsy (PME). This presentation is often called “Lafora-like” because it shares many features with Lafora disease, a well-known genetic epilepsy ^[1]. Symptoms in this broader PME category typically include:

• Myoclonus: Brief, shock-like muscle jerks that are involuntary. In generic PME, these can sometimes be triggered by light, touch, or the intent to move.
• Generalized Seizures: Seizures that affect the whole brain and can cause loss of consciousness or convulsions.
• Cognitive and Motor Decline: A gradual loss of previously learned skills, such as speech, memory, or the ability to walk or coordinate movements (ataxia) ^[1].
• Visual and Speech Changes: In some generic PME presentations (extrapolated from broader literature), individuals may experience difficulty speaking (dysarthria) or changes in their vision ^[1].

2. The cHSP-like Presentation

Other individuals are first diagnosed with what looks like Complicated Hereditary Spastic Paraplegia (cHSP) ^[1]. In this presentation, the focus is more on physical stiffness and mobility. Key features include:

• Spasticity: Persistent muscle stiffness, particularly in the legs, which can make walking difficult or lead to a “scissoring” gait.
• Ataxia: Problems with balance and coordination that affect fine motor tasks or walking.
• Neurological Involvement: The term “complicated” means that the leg stiffness is accompanied by other neurological issues, which might include cognitive impairment or vision changes ^[1].

Understanding Clinical Heterogeneity

One of the most confusing aspects of PRDM8-related disorders is clinical heterogeneity. This is a medical term meaning that the “same” genetic condition can look very different from person to person.

• Interfamilial Heterogeneity: This refers to differences between families. For example, one family in Pakistan was reported with the “Lafora-like” PME presentation, while a family in Iran was initially diagnosed with the “cHSP” presentation ^[1]. Even though both families have mutations in the same PRDM8 gene, their primary symptoms were distinct.
• Intrafamilial Heterogeneity: This refers to differences within the same family. Two siblings with the exact same genetic mutation may have different ages of onset, different levels of severity, or different specific symptoms ^[1]. This variability is why it is difficult for doctors to give a “one-size-fits-all” prognosis.

Abnormal Findings on EEG

A critical discovery in PRDM8 research is that the brain may show signs of abnormal electrical activity even if the person isn’t having a visible seizure. In the Iranian family, affected individuals were found to have generalized epileptiform discharges on their EEG (electroencephalogram) ^[1].

Epileptiform discharges are abnormal electrical patterns in the brain. However, these individuals had no reported clinical seizures—these discharges were happening on the brain scan, but no physical seizure was visible ^[1]. This finding is important, but it is crucial to understand that these interictal (between-seizure) discharges are not “silent seizures” that must automatically be stopped. Your neurologist will decide whether these findings require treatment based on clinical events and cognition, rather than just treating the EEG itself.

The Absence of Lafora Bodies

In classic Lafora disease, a skin biopsy often reveals Lafora bodies (abnormal carbohydrate clumps in the cells). However, in the two reported families with PRDM8 mutations, skin biopsies have been negative for these markers ^[1]. This tells researchers that while PRDM8-related disorders can look like Lafora disease on the outside, the underlying cellular markers that define classic Lafora were not present in these cases. However, a negative biopsy is not a mandatory diagnostic criterion for PRDM8, nor does a negative result perfectly rule out Lafora disease. The definitive diagnostic basis is molecular testing ^[1].