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Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study.

ABSTRACT: 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.

SUBMITTER: Laine-Menendez S

PROVIDER: S-EPMC8199166 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study.

Laine-Menéndez Sara S Domínguez-González Cristina C Blázquez Alberto A Delmiro Aitor A García-Consuegra Inés I Fernández-de la Torre Miguel M Hernández-Laín Aurelio A Sayas Javier J Martín Miguel Ángel MÁ Morán María M

International journal of molecular sciences 20210525 11

Our goal was to analyze <i>post</i><i>mortem</i> 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, an ...[more]

PMID: 34070501

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Project description:ObjectivesThymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive disorder that stems from a perturbation of the mitochondrial DNA maintenance. Nucleoside treatment has recently shown promise as a disease-modifying therapy. TK2d was initially associated with rapidly progressive fatal myopathy in children featuring mitochondrial DNA depletion. Subsequently, less severe variants of the disease were described, with onset of symptoms during adolescence or adulthood and associated with the presence of multiple mtDNA deletions. These less severe phenotypes have been reported in only 15% of the approximately 120 patients described worldwide. However, some reports suggest that these juvenile and adult-onset presentations may be more common. The objective of this study was to describe the clinical phenotype in a sample of patients from Spain.MethodsThis study includes 53 patients harboring biallelic TK2 pathogenic variants, compiling data retrospectively from 7 Spanish centers. We analyzed allele frequency, investigated the most recent common ancestor of core haplotypes, and used the Runs of Homozygosity approach to investigate variant coalescence.ResultsSymptom onset distribution revealed that 32 patients (60%) experienced symptoms beyond 12 years of age. Approximately 30% of patients died of respiratory insufficiency, while 56% of surviving patients needed mechanical ventilation. Genetic analysis identified 16 distinct variants in TK2. Two variants, p.Lys202del and p.Thr108Met, exhibited significantly higher prevalence in the Spanish population than that reported in gnomAD database (86-fold and 13-fold, respectively). These variants are estimated to have originated approximately 16.8 generations ago for p.Thr108Met and 95.2 generations ago for p.Lys202del within the Spanish population, with the increase in frequency attributed to various forms of inbreeding. In late-onset cases, 46.9% carried the p.Lys202del variant.DiscussionThe higher frequency of TK2d in Spain can be partially attributed to the increased prevalence of 2 variants and consanguinity. Notably, in 60% of the cohort, the disease was late-onset, emphasizing the potential underdiagnosis of this subgroup of patients in other regions. Raising awareness of this potentially treatable disorder is of utmost importance because early interventions can significantly affect the quality of life and survival of affected individuals.

Project description:Immune-related neuromuscular disorders are rare and potentially life-threatening adverse events of immune checkpoint inhibitors (ICIs) used in the treatment of cancer. They tend to have a chronic course that usually leads to the permanent discontinuation of immunotherapy. We present a case of pembrolizumab-induced myasthenia gravis that only involved the diaphragm. The patient is a 71-year-old female with a history of stage IV lung adenocarcinoma under maintenance therapy with pemetrexed and pembrolizumab after a complete response to first-line chemo-immunotherapy. She complained of orthopnea since the previous month and was admitted due to hypoxemic respiratory failure. Radiology showed decreased lung volumes and atelectatic areas in both lower lung fields. A subsequent bronchoscopy ruled out infection and cancer recurrence. Pulmonary function tests revealed a mixed disorder with a severe reduction in maximal inspiratory pressure and a large drop in vital capacity in the supine versus the sited position. Ultrasonography of the diaphragm confirmed bilateral diaphragmatic dysfunction, and the patient was initiated on non-invasive ventilation (NIV) during sleep, which led to symptom relief. A neurological physical examination did not reveal any other muscle involvement. Laboratory tests for myasthenic syndromes showed an elevated titer of the anti-acetylcholine receptor antibody, which confirmed the diagnosis of myasthenia gravis. The patient was subsequently treated with corticosteroids, pyridostigmine, and intravenous immunoglobulin and was gradually able to wean off supplemental oxygen. On follow-up, her chest X-ray and spirometry had improved, but she continued sleeping on NIV. Pembrolizumab was stopped, and she is still free of cancer after 9 months. Clinicians treating cancer patients with immunotherapy should be aware of this rare complication and perform timely investigations in any case of orthopnea in the course of ICI therapy to offer specialized management.

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Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study.

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Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study.

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