Hereditary spastic paraplegia 3A associated with axonal neuropathy.
OBJECTIVE
To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia.


METHODS
We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4.


RESULTS
In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy.


CONCLUSIONS
We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.
Ivanova
Neviana
N
Laboratory of Molecular Pathology, Sofia Medical University, Sofia, Bulgaria.
Claeys
Kristl G
KG
Deconinck
Tine
T
Litvinenko
Ivan
I
Jordanova
Albena
A
Auer-Grumbach
Michaela
M
Haberlova
Jana
J
Löfgren
Ann
A
Smeyers
Gisele
G
Nelis
Eva
E
Mercelis
Rudy
R
Plecko
Barbara
B
Priller
Josef
J
Zámecník
Josef
J
Ceulemans
Berten
B
Erichsen
Anne Kjersti
AK
Björck
Erik
E
Nicholson
Garth
G
Sereda
Michael W
MW
Seeman
Pavel
P
Kremensky
Ivo
I
Mitev
Vanio
V
De Jonghe
Peter
P
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000577:Amides; D000613:Aminobutyrates; D002087:Butyrates; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011115:Polyneuropathies / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015419:Spastic Paraplegia, Hereditary / Q000150:complications / Q000235:genetics* / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000235:genetics*
C488113:4-((2-oxohexadecanoyl)amino)butanoic acid; D000577:Amides; D000613:Aminobutyrates; D002087:Butyrates; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C513390:ZFYVE27 protein, human