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Selective mutations from patients were tested for effect on protein function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The characteristic clinical presentation of patients with<jats:italic>PYCR2<\/jats:italic>mutations included failure to thrive, microcephaly, craniofacial dysmorphism, progressive psychomotor disability, hyperkinetic movements, and axial hypotonia with variable appendicular spasticity. Patients did not survive beyond the first decade of life. Brain magnetic resonance imaging showed global brain atrophy and white matter T2 hyperintensities. Routine serum metabolic profiles were unremarkable. Both nonsense and missense mutations were identified, which impaired protein multimerization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p><jats:italic>PYCR2<\/jats:italic>\u2010related syndrome represents a clinically recognizable condition in which<jats:italic>PYCR2<\/jats:italic>mutations lead to protein dysfunction, not detectable on routine biochemical assessments. Mutations predict a poor outcome, probably as a result of impaired mitochondrial function. 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