TK2D Case 1: Severe Early-Onset Presentation in a Four-Year-Old

This episode, "TK2D Case 1: Severe Early-Onset Presentation in a Four-Year-Old," opens with Dr. Hirano's presentation of the first patient case.

Dr. Hirano opens Case 1, a four-year-old girl who presents to neurology with her parents after a two-and-a-half-year history of hypotonia, feeding difficulties, and progressive motor regression beginning around 18 months. Her motor development plateaued after assisted walking and stair climbing, and she lost the ability to climb stairs by age 3. She carried a working diagnosis of unspecified congenital myopathy for about 18 months. She then developed progressive ptosis, worsening dysphagia, declining respiratory status, and recurrent infections, which prompted expanded genetic testing.

Examination showed no facial weakness but markedly reduced neck flexor strength and proximal shoulder and hip weakness. She could not rise from a seated position or walk without assistance. CK was 800, venous lactate was 3.3 millimolar, and biopsy showed mitochondrial DNA depletion without deletions. Genetic testing found biallelic pathogenic TK2 variants. Management includes a G-tube placed at age 3, physical and occupational therapy, and nocturnal BiPAP started at age 3.5 for hypoventilation.

Dr. Hirano asks for her impressions and whether the patient resembles those in her practice. Dr. Zolkipli-Cunningham calls this a textbook severe early-onset presentation. She points to the age of onset and to motor regression by age 3, when children place more demands on muscle that require more ATP. Progressive ptosis, bulbar symptoms, and declining respiratory status point to a myopathy, and she stresses pursuing potentially treatable conditions quickly. A CK in the 800s is lower than in muscular dystrophies, and a squeezed arm can falsely raise lactate. Depletion points to a mitochondrial DNA depletion disorder, and genetic testing with a geneticist and counselor confirms the diagnosis.

The next episode in this series, "Diagnosing TK2D: Clinical Red Flags and Genetic Testing First," features the experts discussing what this diagnosis means for families, which red flags should prompt testing, and why exome sequencing now comes first.