Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis

Abstract

Background and objective: TK2 deficiency (TK2d) is a rare mitochondrial disorder that manifests predominantly as a progressive myopathy with a broad spectrum of severity and age of onset. The rate of progression is variable, and the prognosis is poor due to early and severe respiratory involvement. Early and accurate diagnosis is particularly important since a specific treatment is under development. This study aims to evaluate the diagnostic value of lower limb muscle MRI in adult patients with TK2d.

Methods: We studied a cohort of 45 genetically confirmed patients with mitochondrial myopathy (16 with mutations in TK2, 9 with mutations in other nuclear genes involved in mitochondrial DNA [mtDNA] synthesis or maintenance, 10 with single mtDNA deletions, and 10 with point mtDNA mutations) to analyze the imaging pattern of fat replacement in lower limb muscles. We compared the identified pattern in patients with TK2d with the MRI pattern of other non-mitochondrial genetic myopathies that share similar clinical characteristics.

Results: We found a consistent lower limb muscle MRI pattern in patients with TK2d characterized by involvement of the gluteus maximus, gastrocnemius medialis, and sartorius muscles. The identified pattern in TK2 patients differs from the known radiological involvement of other resembling muscle dystrophies that share clinical features.

Conclusions: By analyzing the largest cohort of muscle MRI from patients with mitochondrial myopathies studied to date, we identified a characteristic and specific radiological pattern of muscle involvement in patients with TK2d that could be useful to speed up its diagnosis.

Keywords: MRI; Mitochondrial myopathy; TK2.

Fig. 1

Heatmap of muscles of the lower limbs in patients with mitochondrial myopathies, disease duration, and MRC scale. A Heatmap showing involvement of pelvic, thigh and leg muscles. Patients and muscles are ordered according to hierarchical clustering with increasing grading in fat replacement severity from the bottom to the top (patients—rows) and from the left to the right (muscles—columns). The score of a muscle in a patient is indicated by the color of the square. Grey squares mean that data are not available. The column in the top left contains information related to the genetic data of the patient (legend in the bottom left). We have also included a column with information about the muscle strength of the patients measured using the MRC scale in red and a column to the far right with information about the disease duration (time from onset of symptom to the MRI in years). B Heatmaps showing the median Mercuri score of the muscles of the pelvis, thigh and leg areas. The three group of diseases and muscles are ordered according to hierarchical clustering. The column in the top right contains information related to the genetic data of the patient (legend in the bottom left). Group 1: mtDNA single large-scale deletion; Group 2: Point mtDNA mutation (MTCO1, MTTL1, MTTK, MTTS1, and MTTN genes); Group 3: Mutation in nuclear genes involved in mtDNA maintenance (POLG, TWNK, RRM2B and TK2 genes). No pattern of muscle involvement was identified in any group

Fig. 2

Heatmap of muscles of the lower limbs in patients with TK2 gene mutations, disease duration, and MRC scale. Heatmap showing involvement of pelvic, thigh, and leg muscles in patients with mutations in the TK2 gene. Patients and muscles are ordered according to hierarchical clustering with increasing grading in fat replacement severity from the bottom to the top (patients—rows) and from the left to the right (muscles—columns). The score of a muscle in a patient is indicated by the color of the square. Grey squares mean that data are not available. The column in the top left contains information related to disease duration (time from onset of symptom to the MRI in years) and the column in the top right provides information about muscle strength of the patients measured using the MRC scale in red. Legends can be found at the bottom on the right

Fig. 3

Muscle MRI pattern of the lower limbs in TK2d patients compared to other myopathies. A Muscle MRI from three TK2d patients with different disease duration and weakness severity showed that the most affected muscles were the gluteus maximus (arrows), the sartorius (arrowheads), and the gastrocnemius medialis muscles (asterisks). B Muscle MRI from patients with other mitochondrial myopathies as the one linked to point mutation in the mitochondrial gene MTTN, or other myopathies with similar clinical characteristics as FSHD or OPMD, showed a very different pattern of muscle involvement, highlighting the full preservation of the sartorius muscles (open arrows), even when other muscles are severely degenerated

Fig. 4

Boxplots showing values of the Mercuri score of muscles of the pelvis, thigh and leg of TK2d, other mitochondrial myopathies, FSHD and OPMD patients. Value of the Kruskal–Wallis test is shown per every comparison and when significant, Wilcoxon test is applied to compare TK2 and the other three diseases

Fig. 5

PCA analysis. TK2d compared to other mitochondrial myopathies (A) showed that gluteus maximus, vastus lateralis, obturator externus, sartorius, and flexor digitorum were the muscles that differentiated most one disease to another. B TK2d compared to FSHD showed that gluteus maximus, obturator externus, sartorius, the short head of biceps femoris, semimembranosus, flexor digitorum, extensor digitorum, and tibialis anterior were the muscles that differentiated most one disease to another. C TK2d compared to OPMD showed that gluteus maximus, vastus lateralis, obturator externus, sartorius, and flexor digitorum were the muscles that differentiated most from one disease to another

Fig. 6

Boxplots showing the difference in Mercuri score between right and left sides of muscles of the pelvis, thigh and leg of FSHD and TK2d. Results of the Wilcoxon test applied to identify significant differences are shown