Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

S. Ferdinandusse; A.W.M. Zomer; J.C. Komen; C. van den Brink; M. Thanos; F.P.T. Hamers; R.J.A.T. Wanders; P.T. van der Saag; B.T. Poll-The; P. Brites

doi:10.1073/pnas.0806066105

Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

S. Ferdinandusse, A.W.M. Zomer, J.C. Komen, C. van den Brink, M. Thanos, F.P.T. Hamers, R.J.A.T. Wanders, P.T. van der Saag, B.T. Poll-The, P. Brites

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

95 Citations (Scopus)

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.

Original language	English
Pages (from-to)	17712-17717
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	105
Issue number	46
DOIs	https://doi.org/10.1073/pnas.0806066105
Publication status	Published - 2008

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Ferdinandusse, S., Zomer, A. W. M., Komen, J. C., van den Brink, C., Thanos, M., Hamers, F. P. T., Wanders, R. J. A. T., van der Saag, P. T., Poll-The, B. T., & Brites, P. (2008). Ataxia with loss of Purkinje cells in a mouse model for Refsum disease. Proceedings of the National Academy of Sciences of the United States of America, 105(46), 17712-17717. https://doi.org/10.1073/pnas.0806066105

@article{10ff4eda0b494944a39fc727a7e7f007,

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.",

author = "S. Ferdinandusse and A.W.M. Zomer and J.C. Komen and {van den Brink}, C. and M. Thanos and F.P.T. Hamers and R.J.A.T. Wanders and {van der Saag}, P.T. and B.T. Poll-The and P. Brites",

note = "Reporting year: 2008",

year = "2008",

doi = "10.1073/pnas.0806066105",

language = "English",

volume = "105",

pages = "17712--17717",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "46",

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Ferdinandusse, S, Zomer, AWM, Komen, JC, van den Brink, C, Thanos, M, Hamers, FPT, Wanders, RJAT, van der Saag, PT, Poll-The, BT & Brites, P 2008, 'Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 46, pp. 17712-17717. https://doi.org/10.1073/pnas.0806066105

TY - JOUR

T1 - Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

AU - Ferdinandusse, S.

AU - Zomer, A.W.M.

AU - Komen, J.C.

AU - van den Brink, C.

AU - Thanos, M.

AU - Hamers, F.P.T.

AU - Wanders, R.J.A.T.

AU - van der Saag, P.T.

AU - Poll-The, B.T.

AU - Brites, P.

N1 - Reporting year: 2008

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.0806066105

DO - 10.1073/pnas.0806066105

M3 - Article

SN - 0027-8424

VL - 105

SP - 17712

EP - 17717

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 46

ER -

Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

Abstract

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