Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy

Abstract

GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1-49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age.

Therapy Prospects for Mitochondrial DNA Maintenance Disorders

“…Some clinical trials are currently assessing the safety and efficacy of the treatment with dCtd/dThd in TK2 deficiency (see Table 2 ). The existence of good clinical endpoints, as well as good biochemical biomarkers of the response to the treatment [ 180 ], will facilitate the evaluation of the results.…”

Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study

“…Previous assessment demonstrated that circulating GDF-15 could discriminate between early onset and late-onset cases [7] . In the current analysis, GDF-15 levels did not correlate with disease severity as assessed by age at NIV ( Fig.…”

“…Preclinical studies support GDF-15 as preferentially upregulated in skeletal muscle in response to mitochondrial oxidative stress [47] . Importantly, elevated GDF-15 was a marker of mitochondrial disease, not generalized cytokine responses to inflammation [7] . Previous assessments with early-and late-onset clinical forms of TK2d showed that circulating GDF-15 could differentiate between early-onset and late-onset cases [7] .…”

Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis

“…Recessive mutations in the TK2 gene are responsible for a syndrome of mitochondrial depletion/multiple deletions in mtDNA that can manifest at any age, most often as a pure progressive myopathy [ 2 , 4 , 7 , 8 ]. In patients with TK2d, oral treatment with thymidine and deoxycytidine nucleosides has shown to prolong survival in the most severe infantile cases and halt the progression of the disease in the other clinical forms [ 10 , 17 ]. It is, therefore, essential to achieve an early genetic diagnosis in all patients with TK2d.…”