POLG-related disorders, which share overlapping features with thymidine kinase 2 deficiency (TK2d) as mitochondrial diseases affecting energy production, show striking variability in symptoms and lack clear links between genetic mutations and disease severity, according to a study of 34 patients published recently in Neurology Genetics.
“Genotype-phenotype correlations could not be consistently demonstrated in our cohort, and future studies with larger patient populations will be required to clarify these potential relationships,” explained the authors of this research.
POLG stands for the polymerase gamma gene. It provides instructions for making an enzyme called DNA polymerase gamma, which is essential for copying and repairing mitochondrial DNA.
Blood biomarkers such as GDF15 and neurofilament light chain, also called NF-L, were frequently elevated. However, neither marker correlated with disease type or severity, suggesting they may help flag disease but cannot predict how severe it will become.
For patients, this means diagnosis may remain challenging and often delayed, much like in TK2d, because symptoms can differ widely even among individuals with similar genetic findings. However, growing awareness of common patterns and biomarker signals may help clinicians recognize these conditions earlier.
Read more about signs and symptoms of TK2d
This study included 34 patients aged 0.6 to 71 years from 33 families. Most cases (62%) began between ages 12 and 40, while 26.4% had later onset and 11.8% began before age 12. Inheritance was primarily autosomal recessive (73.5%), meaning patients inherited a mutated gene from both parents. The most common clinical presentations were ataxia-neuropathy spectrum (44%), autosomal recessive progressive external ophthalmoplegia plus (26%) and autosomal dominant forms (15%). These overlapping patterns mirror the clinical diversity seen in TK2d and other mitochondrial disorders.
Common symptoms included drooping eyelids (85%), impaired eye movement (88%) and muscle weakness (68%). Nerve damage was confirmed in 67% of those tested, and about half experienced sensory symptoms or balance problems. Additional issues such as fatigue (26%), exercise intolerance (24%), tremor (24%) and hearing loss (18%) were also reported. More severe complications like seizures (9%) and respiratory insufficiency (6%) were less frequent in this group than in some prior reports.
Muscle testing revealed that mitochondrial DNA levels were reduced to about 76% of normal, and nearly all patients had multiple mitochondrial DNA deletions, pointing to impaired cellular energy production as a central disease mechanism, similar to TK2d.
Overall, these findings reinforce that POLG-related disease, like TK2d, is complex and highly variable. For patients, this underscores the importance of comprehensive evaluation and ongoing monitoring. While current biomarkers cannot yet guide prognosis, they represent promising tools for earlier detection and may support future treatment development as research continues.
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