TK2 Deficiency Epidemiology: Onset Age Defines Clinical Phenotypes

Welcome back to another NeurologyLive Peers & Perspectives series. In "TK2 Deficiency Epidemiology: Onset Age Defines Clinical Phenotypes," moderator Michio Hirano, MD is joined by Zarazuela Zolkipli-Cunningham, MBChB, MRCP to open the series on TK2 deficiency.

Dr. Hirano frames the discussion around recognition, diagnosis, and management of TK2D across the age spectrum. He explains that two real-world patient cases will anchor the conversation, along with multidisciplinary care teams and emerging advances. He then asks Dr. Zolkipli-Cunningham to characterize the epidemiology of the disease.

Dr. Zolkipli-Cunningham describes TK2D as an ultra-rare autosomal recessive mitochondrial myopathy with an estimated worldwide prevalence of 1.64 cases per million people. The disease presents across a broad age and clinical spectrum. Age of onset is an important determinant of severity and progression, which is why the natural history literature divides patients by when symptoms begin. Traditionally, infantile onset means under 1 year, childhood onset spans over 1 year to under 12 years, and late onset means 12 years or older. A 2026 natural history study instead used a cutoff of 12 years or younger versus older than 12. Either way, she stresses that earlier onset brings a more severe phenotype.

Dr. Hirano asks how presenting symptoms differ across groups. Dr. Zolkipli-Cunningham says pattern recognition is essential. Infants typically present with severe hypotonia and muscle weakness, the so-called floppy baby. Children with onset after age 1, for example at age 5, show progressive motor regression, such as gradual loss of walking, along with proximal or generalized weakness. Late-onset patients may have very mild limb weakness or none, then develop slowly progressive weakness with prominent bulbar, ocular, and facial involvement and frequent need for respiratory support.

Dr. Hirano suggests that early respiratory involvement may distinguish this myopathy. She agrees it is possible. She notes that infantile onset is the trickiest group, since spinal muscular atrophy and congenital myopathies sit on the differential. TK2D should now be considered, because it is treatable.

Up next, in "TK2D Natural History, Mitochondrial Mechanism, and Multidisciplinary Care," Dr. Zolkipli-Cunningham reviews survival data, explains the biochemistry that makes muscle fail first, and outlines the care team.

This program was supported by an independent medical education grant from UCB. the content was developed independently by NeurologyLive and the faculty. UCB has no control over the speakers, content, discussion or conclusions presented.