Recurrent rhabdomyolysis and exercise intolerance: A new phenotype of late-onset thymidine kinase 2 deficiency

Hoz, Carlos de Fuenmayor-Fernández de Pablo la; Morís, Germán; Jiménez-Mallebrera, C.; Badosa, Carmen; Hernández-Laín, Aurelio; Encinar, Alberto Blázquez; Martín, Miguel; Domínguez‐González, Cristina

doi:10.1016/j.ymgmr.2020.100701

Cited by 6 publications

(8 citation statements)

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“…For example, P16 in our study previously was reported to have a phenotype of recurrent rhabdomyolysis and exercise intolerance. Symptoms began at age 16 years, but after 14 years of disease duration, the patient had only mild weakness without respiratory insufficiency [19] . In contrast, other patients in our cohort (eg, P14, with very late disease onset at 50 years) needed ventilatory assistance only 3 years after diagnosis.…”

Section: Article In Pressmentioning

confidence: 99%

“…a Data for 6 patients (P1, P2, P3, P13, P14, P15) have not been previously published. Partial data for patients P4-P12, P16, and P17 were reported in previous publications:[3,4,7,10,17,19] P4 = P25 (Domínguez-González 2020)[7], P8 (Domínguez-González 2019a)[4]; P5 = P26 (Domínguez-González 2020)[7], P6 (Domínguez-González 2019a)[4]; P6 = P78 (Garone 2018)[3] and reported in Laine-Menéndez (2021; case study)[17]; P7 = P18 (Domínguez-González 2020)[7], P3 (Domínguez-González 2019a)[4], P16 (Domínguez-González 2019b)[10]; P8 = P16 (Domínguez-González 2020)[7], P1 (Domínguez-González 2019a)[4], P13 (Domínguez-González 2019b)[10]; P9 = P20 (Domínguez-González 2020)[7], P4 (Domínguez-González 2019a)[4]; P10 = P17 (Domínguez-González 2020)[7], P5 (Domínguez-González 2019a)[4], P15 (Domínguez-González 2019b)[10]; P11 = P22 (Domínguez-González 2020)[7]; P12 = P19 (Domínguez-González 2020)[7], P2 (Domínguez-González 2019a)[4], P14 (Domínguez-González 2019b)[10]; P16 = reported in de Fuenmayor-Fernández de la Hoz (2021; case study)[19]; P17 = P7 (Domínguez-González 2019a)[4]; P4 and P5 were initially administered nucleoside therapy then withdrew from treatment; data were collected after treatment withdrawal. NIV, noninvasive ventilation; mtDNA, mitochondrial DNA; Pt, patient; N, no; ND, not determined; RI, respiratory insufficiency; Y, yes.…”

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confidence: 99%

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

Domínguez‐González

Hernández-Voth

Hoz

et al. 2022

Neuromuscular Disorders

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Section: Article In Pressmentioning

confidence: 99%

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confidence: 99%

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

Domínguez‐González

Hernández-Voth

Hoz

et al. 2022

Neuromuscular Disorders

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“…Exercise-induced rhabdomyolysis has been reported in cases of cytochrome b, cytochrome c oxidase (COX), TK2, and MELAS m.3260A>G mutations. [98][99][100][101] For an illustrative example of a patient with mitochondrial myopathy, see CASE 10-3.…”

Section: Clinical Presentationmentioning

confidence: 99%

Metabolic Myopathies

Tarnopolsky¹

2022

CONTINUUM: Lifelong Learning in Neurology

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PURPOSE OF REVIEW: Metabolic myopathies are disorders that affect skeletal muscle substrate oxidation. Although some drugs and hormones can affect metabolism in skeletal muscle, this review will focus on the genetic metabolic myopathies.RECENT FINDINGS: Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/oxidation (fatty acid oxidation defects), and mitochondrial metabolism (mitochondrial myopathies) represent most metabolic myopathies; however, they often overlap clinically with structural genetic myopathies, referred to as pseudometabolic myopathies. Although metabolic myopathies can present in the neonatal period with hypotonia, hypoglycemia, and encephalopathy, most cases present clinically in children or young adults with exercise intolerance, rhabdomyolysis, and weakness. In general, the glycogen storage diseases manifest during brief bouts of high-intensity exercise; in contrast, fatty acid oxidation defects and mitochondrial myopathies usually manifest during longer-duration endurance-type activities, often with fasting or other metabolic stressors (eg, surgery, fever). The neurologic examination is often normal between events (except in the pseudometabolic myopathies) and evaluation requires one or more of the following tests: exercise stress testing, blood (eg, creatine kinase, acylcarnitine profile, lactate, amino acids), urine (eg, organic acids, myoglobin), muscle biopsy (eg, histology, ultrastructure, enzyme testing), and targeted (specific gene) or untargeted (myopathy panels) genetic tests. SUMMARY: Definitive identification of a specific metabolic myopathy often leads to specific interventions, including lifestyle, exercise, and nutritional modifications; cofactor treatments; accurate genetic counseling; avoidance of specific triggers; and rapid treatment of rhabdomyolysis.

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“…TK2 deficiency manifests predominantly as a progressive myopathy with a broad spectrum of severity ranging from extremely severe and rapidly progressive early-onset forms (with a survival of less than two years) to less severe forms with a childhood, late or very late-onset, and a slower rate of progression, but with an almost invariable respiratory involvement, which appears during disease progression, and shortens life expectancy [ 3 , 4 , 5 ]. The mildest form of the clinical spectrum described so far is a myopathy that manifests only as recurrent rhabdomyolysis and exercise intolerance, for at least the first 10 years of evolution, of which only one case has been described in the literature [ 6 ]. Late-onset TK2 deficiency is the least common form, and its natural history is not well understood.…”

Section: Introductionmentioning

confidence: 99%

Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study

Laine-Menéndez

Domínguez‐González

Blázquez

et al. 2021

IJMS

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Our goal was to analyze postmortem tissues of an adult patient with late-onset thymidine kinase 2 (TK2) deficiency who died of respiratory failure. Compared with control tissues, we found a low mtDNA content in the patient’s skeletal muscle, liver, kidney, small intestine, and particularly in the diaphragm, whereas heart and brain tissue showed normal mtDNA levels. mtDNA deletions were present in skeletal muscle and diaphragm. All tissues showed a low content of OXPHOS subunits, and this was especially evident in diaphragm, which also exhibited an abnormal protein profile, expression of non-muscular β-actin and loss of GAPDH and α-actin. MALDI-TOF/TOF mass spectrometry analysis demonstrated the loss of the enzyme fructose-bisphosphate aldolase, and enrichment for serum albumin in the patient’s diaphragm tissue. The TK2-deficient patient’s diaphragm showed a more profound loss of OXPHOS proteins, with lower levels of catalase, peroxiredoxin 6, cytosolic superoxide dismutase, p62 and the catalytic subunits of proteasome than diaphragms of ventilated controls. Strong overexpression of TK1 was observed in all tissues of the patient with diaphragm showing the highest levels. TK2 deficiency induces a more profound dysfunction of the diaphragm than of other tissues, which manifests as loss of OXPHOS and glycolytic proteins, sarcomeric components, antioxidants and overactivation of the TK1 salvage pathway that is not attributed to mechanical ventilation.

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Recurrent rhabdomyolysis and exercise intolerance: A new phenotype of late-onset thymidine kinase 2 deficiency

Cited by 6 publications

References 6 publications

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

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

Metabolic Myopathies

Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study

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