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.
authors.affiliation: Department of Medical Genetics, Institute of Medical Biochemistry and Genetics, University of Copenhagen, Copenhagen, Denmark. jnielsen@imbg.ku.dk
authors.forename: J E
authors.initials: JE
authors.lastname: Nielsen
authors.forename: B
authors.initials: B
authors.lastname: Johnsen
authors.forename: P
authors.initials: P
authors.lastname: Koefoed
authors.forename: K H
authors.initials: KH
authors.lastname: Scheuer
authors.forename: M
authors.initials: M
authors.lastname: Grønbech-Jensen
authors.forename: I
authors.initials: I
authors.lastname: Law
authors.forename: K
authors.initials: K
authors.lastname: Krabbe
authors.forename: A
authors.initials: A
authors.lastname: Nørremølle
authors.forename: H
authors.initials: H
authors.lastname: Eiberg
authors.forename: H
authors.initials: H
authors.lastname: Søndergård
authors.forename: M
authors.initials: M
authors.lastname: Dam
authors.forename: J F
authors.initials: JF
authors.lastname: Rehfeld
authors.forename: C
authors.initials: C
authors.lastname: Krarup
authors.forename: O B
authors.initials: OB
authors.lastname: Paulson
authors.forename: L
authors.initials: L
authors.lastname: Hasholt
authors.forename: S A
authors.initials: SA
authors.lastname: Sørensen
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D001931:Brain Mapping; D016022:Case-Control Studies; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D003071:Cognition / Q000502:physiology; D003545:Cysteine / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D005071:Evoked Potentials / Q000502:physiology; D005192:Family Health; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009431:Neural Conduction / Q000502:physiology; D009483:Neuropsychological Tests; D010641:Phenotype; D049268:Positron-Emission Tomography / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000074181:Spastin; D013912:Threonine / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D013912:Threonine; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human; D003545:Cysteine