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Here we reported two unrelated young men diagnosed as Hartnup disease, who carried novel compound heterozygote mutations in the <jats:italic>SLC6A19<\/jats:italic> gene and presented with new phenotypes. Other than intermittent encephalopathy and photosensitive rashes, they displayed symptoms and signs of spastic paraplegia and severe peripheral nerve damages. Magnetic resonance imaging showed mild bilateral cerebellar atrophy and thinning of the thoracic spinal cord. Electromyogram detected mixed sensorimotor polyneuropathy in lower limbs. Sural nerve biopsy and pathological study indicated the moderately reduced neural fibers in the periphery nerves. Urinary amino acid analysis showed increased levels of multiple neutral amino acids. Moreover, muscle strengths in the lower limbs and the walking ability have been improved in both cases (MRC 3\/5 to 4\/5 in Patient 1; walking distance elongated from 50 to 100 m in Patient 2) after the treatment with oral nicotinic acid and intravenous injection of multiple amino acids. Exome sequencing revealed and confirmed the existence of the novel compound heterozygous <jats:italic>SLC6A19<\/jats:italic> mutations: c.533G&gt;A (p.Arg178Gln) and c.1379\u20101G&gt;C mutations in patient1, and c.1433delG (p.Gly478AlafsTer44) and c.811G&gt;A (p.Ala271Thr) in patient 2. Taken together, these findings expanded the clinical, neuroimaging, pathology, and genetic spectrum of Hartnup disease. However, the co\u2010existence of HSP and peripheral neuropathy was only inferred based on clinical observations, and pathological and molecular studies are needed to further dissect the underlying mechanisms.<\/jats:p>","DOI":"10.1002\/ajmg.a.62475","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T11:12:06Z","timestamp":1630321926000},"page":"237-242","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hartnup disease presenting as hereditary spastic paraplegia and severe peripheral neuropathy"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8619-1092","authenticated-orcid":false,"given":"Xianling","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6995-8258","authenticated-orcid":false,"given":"Xu\u2010Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases  Beijing China"},{"name":"Institute of Genetics and Developmental Biology Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueshan","family":"Piao","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases  Beijing China"},{"name":"Department of Pathology Xuanwu Hospital of Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guobin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yicong","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cunjiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8784-1002","authenticated-orcid":false,"given":"Chaodong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(56)91914-6"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2010.01.009"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.5420.1290"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2019.100551"},{"key":"e_1_2_9_6_1","volume-title":"Hartnup Disease","author":"Hashmi M. 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