RESEARCH: HSP caused by SPG4/Spastin mutations

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There were 4 articles published recently on HSP caused

by mutations in the SPG4/Spastin gene. The first is

an editorial in the prestigious Archives of Neurology

by Drs. Fink and Shirley Rainier of the

University of Michigan. There is no abstract of their

editorial.

In the same issue of the Archives of Neurology is an

article by an Italian team of scientists. They

discovered 9 families in Scotland with the same

mutation in the SPG4/Spastin gene. Despite the fact

that they all shared a common mutation, affected

members of the families showed a broad range of age of

onset.

The third article concerns an examination of a large

US family with 23 affected members--all with a

SGG4/Spastin mutation. Symptoms of affected members

are compared amongst themselves, and with unaffected

members of the family.

The last article concerns the first reported

(published) use of prenatal testing to find an HSP

mutation in a fetus.

Mark

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Hereditary spastic paraplegia: spastin phenotype and

function.

Fink JK, Rainier S.

Editorial.

SOURCE: Arch Neurol. 2004 Jun;61(6):830-3.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

5210518 & dopt=Abstract

_________________________________________________

Hereditary spastic paraplegia: clinical genetic study

of 15 families.

Orlacchio A, Kawarai T, Totaro A, Errico A, St

-Hyslop PH, Rugarli EI, Bernardi G.

Laboratorio di Neurogenetica, Istituto di Ricovero e

Cura a Carattere Scientifico, Santa Lucia, Rome,

Italy. a.orlacchio@...

BACKGROUND: Autosomal dominant hereditary spastic

paraplegia (ADHSP) is mainly caused by mutations in

the SPG4 gene, which encodes a new member of the AAA

(adenosine triphosphatases associated with diverse

cellular activities) protein family (spastin).

Accumulation of genotype-phenotype correlation is

important for better understanding of SPG4-linked

hereditary spastic paraplegia. OBJECTIVES: To perform

a clinical and genetic study of families with ADHSP

and to perform the functional analysis of the founder

mutation discovered in the SPG4 gene. DESIGN: Genetic

and clinical study.Patients Fifteen unrelated families

with ADHSP originating from southern Scotland. MAIN

OUTCOME MEASURES: Clinical assessment, linkage

analysis, haplotype study, expression of mutant

spastin protein in cultured cells. RESULTS: Nine

families with ADHSP were linked to the SPG4 locus at

2p21-p24. Sequence analysis of SPG4showed a novel

N386S mutation in all 9 of these families. Expression

of mutant spastin showed aberrant distribution in

cultured cells. Haplotype analysis suggested the

existence of a common founder. Clinical examination of

the affected members carrying the mutation showed

phenotypic variations including broad range of age at

onset and disease duration and additional neurologic

features such as mental retardation. Magnetic

resonance imaging demonstrated unique features,

including thin corpus callosum and atrophy of the

cerebellum in 2 patients. Linkage and sequence

analyses showed no evidence of linkage to the

currently known ADHSP loci in the remaining 6

families. CONCLUSIONS: A founder SPG4 mutation N386S

was identified in the families with ADHSP originating

from southern Scotland. Clinical investigation showed

intrafamilial and interfamilial phenotypic variations.

The genetic study demonstrated evidence of further

genetic heterogeneity in ADHSP.

SOURCE: Arch Neurol. 2004 Jun;61(6):849-55.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

5210521 & dopt=Abstract

___________________________________________

Clinical signs and symptoms in a large hereditary

spastic paraparesis pedigree with a novel spastin

mutation.

AP, O'Hearn E, Holmes SE, Chen DT, Margolis

RL.

Department of Neurology, University of Alabama at

Birmingham and the Birmingham Veterans Administration

Medical Center, Birmingham, Alabama, USA.

The most common form of autosomal dominant hereditary

spastic paraparesis (HSP), SPG4, is caused by

mutations in the spastin gene on chromosome 2p. This

disease is characterized by intra- and interfamilial

phenotypic variation. To determine the predictive

values of clinical signs and symptoms in SPG4, we

examined 43 members of a large pedigree with autosomal

dominant HSP. We then identified the genetic etiology

of the disorder in this family, a novel nonsense

mutation in exon 1 of spastin, carried by 24 of the

examined family members. The best clinical predictors

of positive gene status were the presence of

hyperreflexia in the lower extremities, >2 beats of

ankle clonus, pes cavus, bladder symptoms and

increased tone in the legs. The mean age of onset was

32.2 +/- 7.4 years, but the age of onset was earlier

in children from 10 of 12 child-parent gene-positive

pairs, with a mean difference of 10.8 +/- 3.3 years.

The finding of leg weakness was especially common in

older-onset affected family member with leg

hyperreflexia. These results suggest that specific

clinical signs and symptoms may be of value in

differentiating individuals affected with SPG4 from

family members with nonspecific neurological findings.

Copyright 2004 Movement Disorder Society

SOURCE: Mov Disord. 2004 Jun;19(6):641-8.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

5197701 & dopt=Abstract

_______________________________________________

Prenatal diagnosis of autosomal dominant hereditary

spastic paraplegia (SPG4) using direct mutation

detection.

Nielsen JE, Koefoed P, Kjaergaard S, Jensen LN,

Norremolle A, Hasholt L.

Institute of Medical Biochemistry and Genetics,

Department of Medical Genetics, Section of

Neurogenetics, University of Copenhagen, The Panum

Institute, Copenhagen, Denmark.

OBJECTIVE: To present a report on prenatal diagnosis

using direct SPG4 gene analysis in a family with

autosomal dominant hereditary spastic paraplegia

(AD-HSP). METHODS: Genetic linkage and haplotype

analysis were previously carried out with chromosome

2p markers. DNA was obtained from affected

individuals, the affected father, the mother, and

fetal DNA from an ongoing pregnancy by chorionic

villus sampling (CVS) in the first trimester. The

spastin gene (SPG4) was completely sequenced. RESULTS:

A novel 832insGdelAA frameshift mutation, predicted to

cause loss of functional protein, was identified in

the affected father and in the fetal DNA. CONCLUSIONS:

This is the first report on direct prenatal diagnosis

of chromosome 2p-linked AD-HSP (SPG4). In addition, we

report a novel SPG4-combined small insertion/deletion

mutation in exon 5, which may be the first SPG4

mutational hot spot.

SOURCE: Prenat Diagn. 2004 May;24(5):363-6.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

5164410 & dopt=Abstract