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Progressive Neurological Symptoms in a 36-Year-Old Female: Clinical Challenge

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction
POLG-related mitochondrial disorders constitute a rare group of genetic conditions resulting from mutations in POLG, which encodes the mitochondrial DNA polymerase gamma. Pathogenic variants in POLG lead to defects in the replication and repair of mitochondrial DNA, resulting in mitochondrial dysfunction and cellular energy deficits. The clinical presentations of POLG-related disorders are highly variable, often affecting multiple organ systems, and ranging from early-onset forms with severe encephalopathy and liver failure, to milder late-onset forms characterized by myopathy and progressive external ophthalmoplegia. Pathogenic variants in POLG can be inherited in either an autosomal recessive or autosomal dominant pattern, leading to a wide range of clinical manifestations even among family members. Advances in genetic testing have enabled earlier diagnosis, leading to more prompt and effective management, even though a cure has not yet been found.

Case Presentation
We present a 36-year-old female with a complex medical history marked by progressive neurological symptoms. At 17 years old, the patient developed ataxia and peripheral neuropathy, which gradually worsened. At 23 years old, she began experiencing intractable epilepsy that persisted despite multiple antiepileptic medications, accompanied by episodes of urinary incontinence and a noticeable decline in cognitive function. Over the years, she also experienced recurrent psychotic episodes, further complicating her clinical presentation. Serial neuroimaging revealed white matter hyperintensities in the left frontal lobe, right parietal region, and posterior cingulate gyrus. Initially misdiagnosed with multiple sclerosis, the patient’s refractory epilepsy and the unexplained neurologic progression prompted genetic consultation at 36 years of age.

Diagnostic Workup
The patient's history and clinical presentation included several indicators suggesting the need for a mitochondrial workup, including multisystem involvement, refractory epilepsy, and intermittent lactic acidosis. Plasma amino acid, urine organic acid, plasma acyl carnitine, and carnitine profile were non-diagnostic. GDF-15 level came back significantly elevated 5155 pg/mL (normal <=750). Combined Mito genome plus Mito focused nuclear gene panel identified two pathogenic variants in POLG. First variant c.2243 G>C (PM3), and second variant c.1399 G>A (PM3). This result is consistent with an autosomal recessive POLG-related disorder if these variants are on opposite alleles (in trans), but parental testing was not possible.

Treatment and Management
At that time, the patient was in status epilepticus and was receiving several medications known to be toxic to mitochondria, including valproate, propofol, and linezolid. We recommended discontinuing those three medications specifically, which helped control her seizures the following day. To support mitochondrial function, she was started on supplements that serve as mitochondrial antioxidants and enhance Complex I function, though their effectiveness remains uncertain. She was admitted to inpatient rehabilitation for comprehensive interventional therapies directed at preserving daily functioning. Genetic counseling was provided, and we plan to conduct genetic testing for her children.

Outcome and Follow-Up
By the time the POLG-related mitochondrial disorder was diagnosed, the patient had already faced significant and irreversible neurological deterioration, manifesting as cognitive decline, significant muscle weakness, and progressive loss of vision. Her seizures were briefly controlled with a reduced number of medications, but she was readmitted due to another episode of status epilepticus and her seizures have continued to be challenging to control.

Discussion
This case raises the question of when genetic evaluation should have been conducted into her clinical course and how her outcome could have been different particularly when initial treatments failed to control her seizures.

 

Conclusion
It is important to consider mitochondrial disorders in patients with unexplained, treatment-resistant neurological symptoms and to recognize the crucial role genetic testing plays in achieving a timely diagnosis. Early identification of POLG-related mitochondrial disorders is essential for implementing appropriate multidisciplinary management and providing effective genetic counseling.

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