Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation

J E Nielsen; B Johnsen; P Koefoed; K H Scheuer; M Grønbech-Jensen; I Law; K Krabbe; Anne Nørremølle; Hans Rudolf Lytchoff Eiberg; H Søndergård; M Dam; J F Rehfeld; C Krarup; O B Paulson; Lis Frydenreich Hasholt; S A Sørensen

doi:10.1111/j.1468-1331.2004.00888.x

Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation

J E Nielsen, B Johnsen, P Koefoed, K H Scheuer, M Grønbech-Jensen, I Law, K Krabbe, Anne Nørremølle, Hans Rudolf Lytchoff Eiberg, H Søndergård, M Dam, J F Rehfeld, C Krarup, O B Paulson, Lis Frydenreich Hasholt, S A Sørensen

63 Citations (Scopus)

Abstract

Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.

Original language	English
Journal	European Journal of Neurology
Volume	11
Issue number	12
Pages (from-to)	817-24
Number of pages	8
ISSN	1351-5101
DOIs	https://doi.org/10.1111/j.1468-1331.2004.00888.x
Publication status	Published - 2004

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Nielsen, J. E., Johnsen, B., Koefoed, P., Scheuer, K. H., Grønbech-Jensen, M., Law, I., Krabbe, K., Nørremølle, A., Eiberg, H. R. L., Søndergård, H., Dam, M., Rehfeld, J. F., Krarup, C., Paulson, O. B., Hasholt, L. F., & Sørensen, S. A. (2004). Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation. European Journal of Neurology, 11(12), 817-24. https://doi.org/10.1111/j.1468-1331.2004.00888.x

Nielsen, JE, Johnsen, B, Koefoed, P, Scheuer, KH, Grønbech-Jensen, M, Law, I, Krabbe, K, Nørremølle, A, Eiberg, HRL, Søndergård, H, Dam, M, Rehfeld, JF, Krarup, C, Paulson, OB, Hasholt, LF & Sørensen, SA 2004, 'Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation', European Journal of Neurology, vol. 11, no. 12, pp. 817-24. https://doi.org/10.1111/j.1468-1331.2004.00888.x

@article{98628851460d4e4bac375450264fb388,

title = "Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation",

abstract = "Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.",

author = "Nielsen, {J E} and B Johnsen and P Koefoed and Scheuer, {K H} and M Gr{\o}nbech-Jensen and I Law and K Krabbe and Anne N{\o}rrem{\o}lle and Eiberg, {Hans Rudolf Lytchoff} and H S{\o}nderg{\aa}rd and M Dam and Rehfeld, {J F} and C Krarup and Paulson, {O B} and Hasholt, {Lis Frydenreich} and S{\o}rensen, {S A}",

year = "2004",

doi = "10.1111/j.1468-1331.2004.00888.x",

language = "English",

volume = "11",

pages = "817--24",

journal = "European Journal of Neurology",

issn = "1351-5101",

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TY - JOUR

T1 - Hereditary spastic paraplegia with cerebellar ataxia

T2 - a complex phenotype associated with a new SPG4 gene mutation

AU - Nielsen, J E

AU - Johnsen, B

AU - Koefoed, P

AU - Scheuer, K H

AU - Grønbech-Jensen, M

AU - Law, I

AU - Krabbe, K

AU - Nørremølle, Anne

AU - Eiberg, Hans Rudolf Lytchoff

AU - Søndergård, H

AU - Dam, M

AU - Rehfeld, J F

AU - Krarup, C

AU - Paulson, O B

AU - Hasholt, Lis Frydenreich

AU - Sørensen, S A

PY - 2004

Y1 - 2004

N2 - Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.

AB - Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.

U2 - 10.1111/j.1468-1331.2004.00888.x

DO - 10.1111/j.1468-1331.2004.00888.x

M3 - Journal article

SN - 1351-5101

VL - 11

SP - 817

EP - 824

JO - European Journal of Neurology

JF - European Journal of Neurology

IS - 12

ER -

Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation

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