title: Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.
abstract: Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh(-/-) mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.
authors.affiliation: Academic Medical Center, Department of Clinical Chemistry (Laboratory of Genetic Metabolic Diseases), Emma's Children Hospital, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. s.ferdinandusse@amc.uva.nl
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.forename: Anna W M
authors.initials: AW
authors.lastname: Zomer
authors.forename: Jasper C
authors.initials: JC
authors.lastname: Komen
authors.forename: Christina E
authors.initials: CE
authors.lastname: van den Brink
authors.forename: Melissa
authors.initials: M
authors.lastname: Thanos
authors.forename: Frank P T
authors.initials: FP
authors.lastname: Hamers
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Paul T
authors.initials: PT
authors.lastname: van der Saag
authors.forename: Bwee Tien
authors.initials: BT
authors.lastname: Poll-The
authors.forename: Pedro
authors.initials: P
authors.lastname: Brites
mesh_terms: D000818:Animals; D001259:Ataxia / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D001331:Automation; D001522:Behavior, Animal / Q000187:drug effects; D002490:Central Nervous System / Q000002:abnormalities / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005684:Gait / Q000187:drug effects; D018390:Gene Targeting; D005822:Genetic Vectors; D008064:Lipidoses / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000172:deficiency / Q000235:genetics; D010523:Peripheral Nervous System Diseases / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D010831:Phytanic Acid / Q000097:blood; D010836:Phytol / Q000008:administration & dosage / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D012035:Refsum Disease / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D013093:Spermatogonia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
chemical_list: D010831:Phytanic Acid; D010836:Phytol; D006899:Mixed Function Oxygenases; C491170:Phyh protein, mouse