title: Thiamine pyrophosphokinase deficiency causes a Leigh Disease like phenotype in a sibling pair: identification through whole exome sequencing and management strategies.
abstract: We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical course.
authors.affiliation: Pediatrics Residency Program, Children's National Medical Center, Washington, DC, USA; Medical Genetics Training Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Fraser
authors.affiliation: Division of Neurology, Children's National Medical Center, Washington, DC, USA.
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
authors.affiliation: Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Yang
authors.affiliation: Division of Neurology, Children's National Medical Center, Washington, DC, USA.
authors.forename: Taeun
authors.initials: T
authors.lastname: Chang
authors.affiliation: Division of Neurology, Children's National Medical Center, Washington, DC, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Cramp
authors.affiliation: Department of Radiology, Children's National Medical Center, Washington, DC, USA.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Vezina
authors.affiliation: Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
authors.forename: Uta
authors.initials: U
authors.lastname: Lichter-Konecki
authors.affiliation: Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
authors.forename: Kristina P
authors.initials: KP
authors.lastname: Cusmano-Ozog
authors.affiliation: Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
authors.forename: Patroula
authors.initials: P
authors.lastname: Smpokou
authors.affiliation: Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Chapman
authors.affiliation: Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.
authors.forename: Dina J
authors.initials: DJ
authors.lastname: Zand
keywords: Leigh-like disease; Mitochondrial disorder; Thiamine; Thiamine pyrophosphokinase; α-Ketoglutarate