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Here, we identified with whole exorne sequencing (WES) a novel frameshift mutation in the\n                    <jats:italic>SPART<\/jats:italic>\n                    gene in 2 brothers presenting an uncharacterized developmental delay and short stature. Functional characterization in an SH\u2010SY5Y cell model shows that this mutation is associated with increased neurite outgrowth. These cells also show a marked decrease in mitochondrial complex I (NADH dehydrogenase) activity, coupled to decreased ATP synthesis and defective mitochondrial membrane potential. The cells also presented an increase in reactive oxygen species, extracellular pyruvate, and NADH levels, consistent with impaired complex I activity. In concordance with a severe mitochondrial failure, Spartin loss also led to an altered intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis that was restored after transient expression of wild\u2010type Spartin. Our data provide for the first time a thorough assessment of Spartin loss effects, including impaired complex I activity coupled to increased extracellular pyruvate. In summary, through a WES study we assign a diagnosis of Troyer syndrome to otherwise undiagnosed patients, and by functional characterization we show that the novel mutation in\n                    <jats:italic>SPART<\/jats:italic>\n                    leads to a profound bioenergetic imbalance.\u2014Diquigiovanni, C., Bergamini, C., Diaz, R., Liparulo, I., Bianco, F., Masin, L., Baldassarro, V. A., Rizzardi, N., Tranchina, A., Buscherini, F., Wischmeijer, A., Pippucci, T., Scarano, E., Cordelli, D. M., Fato, R., Seri, M., Paracchini, S., Bonora, E. A novel mutation in\n                    <jats:italic>SPART gene<\/jats:italic>\n                    causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism. FASEB J. 33, 11284\u201311302 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201802722r","type":"journal-article","created":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T14:25:04Z","timestamp":1563373504000},"page":"11284-11302","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["A novel mutation in\n                    <i>SPART<\/i>\n                    gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism"],"prefix":"10.1096","volume":"33","author":[{"given":"Chiara","family":"Diquigiovanni","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC) University of Bologna Bologna 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