RESUMEN
GDF15 (growth differentiation factor 15) is a marker of cellular energetic stress linked to physical-mental illness, aging, and mortality. However, questions remain about its dynamic properties and measurability in human biofluids other than blood. Here, we examine the natural dynamics and psychobiological regulation of plasma and saliva GDF15 in four human studies representing 4,749 samples from 188 individuals. We show that GDF15 protein is detectable in saliva (8% of plasma concentration), likely produced by salivary glands secretory duct cells. Using a brief laboratory socio-evaluative stressor paradigm, we find that psychosocial stress increases plasma (+3.5-5.9%) and saliva GDF15 (+43%) with distinct kinetics, within minutes. Moreover, saliva GDF15 exhibits a robust awakening response, declining by ~40-89% within 30-45 minutes from its peak level at the time of waking up. Clinically, individuals with genetic mitochondrial OxPhos diseases show elevated baseline plasma and saliva GDF15, and post-stress GDF15 levels in both biofluids correlate with multi-system disease severity, exercise intolerance, and the subjective experience of fatigue. Taken together, our data establish that saliva GDF15 is dynamic, sensitive to psychological states, a clinically relevant endocrine marker of mitochondrial diseases. These findings also point to a shared psychobiological pathway integrating metabolic and mental stress.
RESUMEN
PURPOSE: Glut 1 deficiency syndrome (DS) is defined by hypoglycorrhachia with normoglycemia, acquired microcephaly, episodic movements, and epilepsy refractory to standard antiepileptic drugs (AEDs). Gold standard treatment is the ketogenic diet (KD), which provides ketones to treat neuroglycopenia. Our purpose is (1) to describe epilepsy phenotypes in a large Glut 1 DS cohort, to facilitate diagnosis; and (2) to describe cases in which non-KD agents achieved seizure freedom (SF), highlighting potential adjunctive treatments. METHODS: Retrospective review of 87 patients with Glut 1 DS (45% female, age range 3 months-35 years, average diagnosis 6.5 years) at Columbia University, from 1989 to 2010. KEY FINDINGS: Seventy-eight (90%) of 87 patients had epilepsy, with average onset at 8 months. Seizures were mixed in 68% (53/78): generalized tonic-clonic (53%), absence (49%), complex partial (37%), myoclonic (27%), drop (26%), tonic (12%), simple partial (3%), and spasms (3%). We describe the first two cases of spasms in Glut 1 DS. Electrophysiologic abnormalities were highly variable over time; only 13 (17%) of 75 had exclusively normal findings. KD was used in 82% (64/78); 67% (41/61) were seizure-free and 68% of seizure-free patients (28/41) resolved in <1 week and 76% (31/41) in <1 month. Seven patients achieved SF with broad agents only. SIGNIFICANCE: Glut 1 DS is a genetic metabolic encephalopathy with variable focal and multifocal seizure types and electroencephalographic findings. Infants with seizures, spasms, or paroxysmal events should be tested for Glut 1 DS. Evidence is insufficient to recommend specific AEDs as alternatives to KD. Early diagnosis and initiation of KD and prevention of unnecessary AED trials in Glut 1 DS are important goals for the treatment of children with epilepsy.