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A dietetic approach to circumvent the metabolic failure in GSD5 seems attractive and has been attempted in various forms but with mixed results. We ran a single-blind randomized controlled trial comparing 6\u00a0months of individualized 3:1 low-carbohydrate ketogenic diet (LCKD) to diet as usual in 21 adult patients with GSD5. Primary endpoints were safety and tolerability, and primary outcome was change in peak VO\n                    <jats:sub>2<\/jats:sub>\n                    at incremental exercise test. Secondary outcomes were distance at the12minWT, change in peak work, changes in QoL measured by the SF36 and disability assessed by the WHO-DAS 2.0. Ketosis was monitored by checking blood levels of BOHB with portable glucometers. The LCKD regimen was well tolerated with no dropouts, no SAE related to treatment and only minor and transient subjective adverse events. Blood metabolites remained within the normal range. Six months of LCKD were associated with a significant increase in peak VO\n                    <jats:sub>2<\/jats:sub>\n                    (+\u20092.7\u00a0ml\/min\/Kg,\n                    <jats:italic>p<\/jats:italic>\n                    0.049) and distance covered by the 12minWT (+\u200955\u00a0m\n                    <jats:italic>p<\/jats:italic>\n                    0.049). Peak work showed a marginal increase. There was a nonsignificant trend toward better perceived QoL and decreased disability by SF36 and WHO-DAS 2.0. LCKD is a safe and, once properly individualized, sustainable strategy to improve functioning in GSD5. Five patients in the LCKD study group elected to stay on LCKD and after 3\u00a0years are reporting good impact on functioning.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Trial registration:<\/jats:italic>\n                    n\u00b0: NCT04292938, 3\/25\/2019.\n                  <\/jats:p>","DOI":"10.1007\/s00415-025-13405-5","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T15:18:11Z","timestamp":1760541491000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Low-carbohydrate ketogenic diet in Mc Ardle\u2019s disease: a single-blinded randomized controlled trial"],"prefix":"10.1007","volume":"272","clinical-trial-number":[{"clinical-trial-number":"nct04292938","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0319-3579","authenticated-orcid":false,"given":"A.","family":"Martinuzzi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9208-1527","authenticated-orcid":false,"given":"O.","family":"Musumeci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1715-7410","authenticated-orcid":false,"given":"C.","family":"Stefan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5179-8671","authenticated-orcid":false,"given":"E.","family":"Vinante","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Ferrati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Perillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Pesenti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Toscano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"13405_CR1","first-page":"13","volume":"10","author":"B McArdle","year":"1951","unstructured":"McArdle B (1951) Myopathy due to a defect in muscle glycogen breakdown. 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