Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene.
OBJECTIVE
Hereditary spastic paraplegia is a clinically and genetically heterogeneous group of rare, inherited disorders causing an upper motor neuron syndrome with (complex) or without (pure) additional neurological symptoms. Mutations in the KIF1A gene have already been associated with recessive and dominant forms of hereditary spastic paraplegia (SPG30) in a few cases.


METHODS
All family members included in the study were examined neurologically. Whole-exome sequencing was used in affected individuals to identify the responsible candidate gene. Conventional Sanger sequencing was conducted to validate familial segregation.


RESULTS
A family of Macedonian origin with two affected siblings, one with slowly progressive and the other one with a more complex and rapidly progressing hereditary spastic paraplegia is reported. In both affected individuals, two novel pathogenic mutations outside the motor domain of the KIF1A gene were found (NM_001244008.1:c.2909G>A, p.Arg970His and c.1214dup, p.Asn405Lysfs*40) that segregate with the disease within the family establishing the diagnosis of autosomal recessive SPG30.


CONCLUSIONS
This report provides the first evidence that mutations outside the motor domain of the gene can cause (recessive) SPG30 and extends the genotype-phenotype association for KIF1A-related diseases.
Department of Neurology, Medical University of Vienna, Vienna, Austria.
M
http://orcid.org/0000-0003-3026-3082
M
Krenn
Department of Neurology, Medical University of Vienna, Vienna, Austria.
G
G
Zulehner
Department of Neurology, Medical University of Vienna, Vienna, Austria.
C
C
Hotzy
Department of Neurology, Medical University of Vienna, Vienna, Austria.
J
J
Rath
Department of Neurology, Medical University of Vienna, Vienna, Austria.
E
E
Stogmann
Institute of Human Genetics, Technical University Munich, Munich, Germany.|Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
M
M
Wagner
Institute of Human Genetics, Technical University Munich, Munich, Germany.
T B
TB
Haack
Institute of Human Genetics, Technical University Munich, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
T M
TM
Strom
Department of Neurology, Medical University of Vienna, Vienna, Austria.
A
A
Zimprich
Department of Neurology, Medical University of Vienna, Vienna, Austria.
F
F
Zimprich
D005260:Female; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D009154:Mutation; D010264:Paraplegia / Q000151:congenital* / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D010375:Pedigree; D018843:Republic of North Macedonia
C094065:KIF1A protein, human; D016547:Kinesins

KIF1A
; SPG30; hereditary spastic paraplegia; spastic paraparesis; whole-exome sequencing