Brain & Development xxx (2018) xxx–xxx
www.elsevier.com/locate/braindev

Original article

Clinical phenotype of hereditary spastic paraplegia due to
KIF1C gene mutations across life span
Didem Yücel-Yılmaz a, Emrah Yücesan b,1, Dilek Yalnızoğlu c, Kader Karlı Oğuz d,
Mahmut S
ß amil Sağıroğlu e, Uğur Özbek b,2, Esra Serdaroğlu c, Basßar Bilgiç f,
_ßeri b, Hasßmet Hanağası f, Hakan Gürvit f,
Sevim Erdem g, Sibel Aylin Uğur Is
Rıza Köksal Özgül a, Ali Dursun h,⇑
a

Department of Pediatric Metabolism, Institute of Child Health, Hacettepe University, Turkey
Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Turkey
c
Department of Pediatric Neurology, Hacettepe University Faculty of Medicine, Turkey
d
Department of Radiology, Hacettepe University Faculty of Medicine, Turkey
e
_
Informatics and Information Security Research Center, National Research Institute of Electronics and Cryptology, TÜBITAK,
Turkey
f
_
Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul
University Faculty of Medicine, Turkey
g
Department of Neurology, Hacettepe University Faculty of Medicine, Turkey
h
Department of Pediatric Metabolism, Hacettepe University Faculty of Medicine, Turkey
b

Received 1 February 2018; received in revised form 20 February 2018; accepted 23 February 2018

Abstract
Hereditary spastic paraplegias (HSPs) are a group of genetic disorders resulting in pyramidal tract impairment, predominantly in
lower limbs. KIF1C gene has recently been identified as one of the genetic causes of HSP and associated with pure or complicated
HSP. We present three patients with complicated HSP from two unrelated families, who had early onset progressive cerebellar signs
and developed pyramidal tract signs during follow-up. Whole exome sequencing in these patients followed by segregation analysis
identified novel truncating KIF1C mutations (c.463C> T; p.R155* and c.2478delA; p.Ala828Argfs*13). Neuroimaging findings
showed cerebral and upper cervical spinal atrophy, bilateral symmetrical pyramidal tract involvement, and focal cerebral white matter lesions. Patients with KIF1C mutations may present with cerebellar signs and pyramidal findings may emerge later, therefore
complicated HSP should be considered in the differential diagnosis of unidentified cases with cerebellar dysfunction.
Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: KIF1C; Hereditary spastic paraplegia; Ataxia; Kinesin

1. Introduction
⇑ Corresponding author at: Department of Pediatric Metabolism,
Hacettepe University Faculty of Medicine, 06100, Sıhhıye, Ankara,
Turkey.
E-mail address: adursun@hacettepe.edu.tr (A. Dursun).
1
Emrah Yucesan is currently at Institute of Life Sciences and
Biotechnology, Bezmialem Vakıf University.
2
U. Ozbek is currently at Acıbadem University, Faculty of
Medicine, Department of Medical Genetics.

Hereditary spastic paraplegia (HSP) is a group of
inherited disorders characterized by weakness and spasticity of bilateral lower limbs. Genetic mutations cause
neuropathy of the corticospinal tract axons resulting in
progressive weakness and spasticity, extensor plantar
responses and hyperactivity of deep tendon reflexes in

https://doi.org/10.1016/j.braindev.2018.02.013
0387-7604/Ó 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Yücel-Yılmaz D et al. Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across
life span. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.013

2

D. Yücel-Yılmaz et al. / Brain & Development xxx (2018) xxx–xxx

lower extremities [1]. HSPs are clinically classified as
uncomplicated and complicated forms based on neurological manifestations other than pyramidal signs. While
pure HSPs are characterized by slowly progressive lower
extremity spasticity and weakness, complicated HSP
forms are characterized by the presence of additional
neurological or systemic features including peripheral
motor neuropathy and/or distal wasting, cognitive
impairment, ataxia, loss of vision, epilepsy, abnormal
neuroimaging findings or ichthyosis [2]. More than 60
genes have been associated with HSPs, most of which
have roles in cellular trafficking. In addition, mutations
of some genes involved in mitochondrial, cytochrome
p450 and axonal transport pathways have also been
identified in HSPs [3–5]. Mutations in KIF1A and
KIF5A genes encoding kinesin family of proteins functioning as microtubule-based motor proteins were previously reported to cause different forms of HSP [6–9].
Similarly, mutations in KIF1C gene yet another kinesin
family member have been associated with HSP [10–12].
Herein, we report clinical, neuroimaging, and genetic
studies in three patients from two unrelated families
with complicated HSP leading to identification of two
novel KIF1C mutations.
2. Subjects

somal panel, biotinidase, urine and blood amino acids,
urine organic acids, and carnitine-acylcarnitine profile
were all normal. Homocysteine level was 37.7 Â mmo
l/L (N 5.5–17). Neurophysiological studies at 10 years
of age showed normal electroencephalography (EEG)
and electromyography (EMG). He had bilateral prolonged central latencies in brainstem evoked potentials
(BAEP), bilateral prolonged P1 latencies in visual
evoked potentials (VEP). Muscle biopsy showed mild
fiber size variability with scattered atrophic fibers.
Oxidative enzyme stainings including cytochrome oxidase were not compatible with mitochondrial
myopathy.
Brain magnetic resonance imaging (MRI) at 10 years
of age showed T2A hyperintense symmetric lesions more
prominent in the posterior regions involving bilateral
cerebral hemispheres, periventricular white matter, and
centrum semiovale. Bilateral pyramidal tracts showed
hyperintensity, cerebellum and basal ganglia were
spared. Repeat brain MRI at 24 years showed mild atrophy of the cerebral hemispheres especially perirolandic
area brain stem, and upper cervical spinal cord
(Fig. 1a). Very subtle volume loss in the upper vermis
was present. Involvement of the splenium of the corpus
callosum and pyramidal tracts up to the precentral gyri
at the vertex were found as shown by increased T2 signal
intensity (Fig. 1b–d). Spinal MRI was not obtained.

2.1. Patient 1 (Family A, II:1)
2.2. Patient 2 (Family A, II:2)
The first patient, a 25-year-old male, had a normal
prenatal and birth history. Early developmental milestones were met until he started to have progressive tremor following inguinal hernia surgery at 3 years of age.
Neurological evaluation at 10 years of age showed mild
ataxia and wide based gait, borderline IQ. His gait deteriorated around 14 years of age, his speech became
slower and dysarthric. He failed to respond to treatment
with primidone and propranolol. After 15 years of age,
he developed difficulty in walking due to increased tone
and decreased strength in lower extremities. At 18 years,
his weight was 68 kg (50–75p), his height was 185 cm
(90p). He had severe dysarthria, ataxia and tremor with
dystonia in upper extremities, bilateral spasticity,
increased deep tendon reflexes and extensor flexor
responses in lower extremities. Vitamin B12 treatment
resulted in mild improvement (plasma B12 level: 188
pg/ml, N 160–900, homocysteine: 37.7 mmol/, N 5.5–
17). He deteriorated over time with progression of pyramidal and cerebellar signs, he had swallowing difficulty,
decreased joint position sense and was wheel chair
bound at final examination at 24 years of age. He is
on clonazepam and receives physical therapy.
Metabolic screening tests and biochemical tests during follow up including lysosomal enzymes, urine
mucopolysaccharides and oligosaccharides, ceruloplasmin, copper in serum and 24 h collected urine, peroxi-

Second patient is a 19-year-old male, who is the
brother of patient 1, he was also the product of an
uncomplicated pregnancy and uneventful birth history.
He was observed to be a less active infant. He was able
to walk at 18 months. His gait had always been somewhat unsteady, and worsened after 4 years of age. He
was observed to have difficulty in writing due to tremor
of hands at primary school. On neurological examination at 11 years 5 months old, his weight was 56.4 kg
(90p), his height was 157 cm (90–97p). He had a wide
based ataxic gait and difficulty with tandem walking.
He had titubation, upper-limb and lower-limb dysmetria
more on the left side, and dysdiadochokinesia. He had
mild muscle weakness in all extremities more prominent
in lower extremities, and distally in upper extremities.
His deep tendon reflexes were hyperactive in lower
extremities and he had clonus and extensor plantar
responses. After 12 years of age his instability increased
and finally at the age of 14 he started homeschooling
and using a wheel chair outside. At the age of 17, his
titubation and tremors became more evident. He was
able to stand with support. His speech was slower and
dysarthric. Neuropsychological evaluation at 16 years
old showed normal language and cognition level, and
inability to take performance tests due to difficulty in
visual-motor coordination.

Please cite this article in press as: Yücel-Yılmaz D et al. Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across
life span. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.013

D. Yücel-Yılmaz et al. / Brain & Development xxx (2018) xxx–xxx

3

Fig. 1. Brain MRI of the patient 1, elder brother, at the age of 24 years. Sagittal T1 weighted (W) (TR/TE; 550/15 ms) image (a) shows mild atrophy
of the brain stem, upper vermis and upper cervical spinal cord. Axial fluid-attenuated inversion-recovery (FLAIR) (TR/TE/TI; 9000/100/2000 ms)
images (b–d) show hyperintensity in the brain stem (b), internal capsule (c) and perirolandic area (d) along the pyramidal tracts, in the splenium of
the corpus callosum (c) as well as minute hyperintense foci in the cerebral white matter (c, d). Please note more prominent atrophy in the
perirolanding area (d).

Initial metabolic screening tests were normal except
homocysteine level at 46 lmol/L (N: 5.5–17 lmol/L),
vitamin B12 126.4 pg/mL (N: 200–860 pg/mL). Based
on biochemical results, he was treated for vitamin B12
deficiency. Brain MRI at 17 years old revealed a pattern
of involvement very similar to his elder brother. However, atrophy of the cerebrum, marked at the perirolandic area at the vertex and upper cervical spinal cord were
more severe than his elder brother (Fig. 2a–d).
2.3. Patient 3 (Family B, II:1)
Third patient, who is now a 27-year-old woman, is
from a different family. Her first symptom was tremor,
which started at the age of 3. She had a mild motor
developmental delay (walked at the age of 2). She also
complained from difficulty in speech and mild balance
problems leading to infrequent falls. These symptoms
progressed very mildly in the course of the disease.

Neurological examination at the age of 22 showed mild
ataxia, titubation of the head, and significant postural
and kinetic tremor in the upper extremities along with
dysarthria and mild cerebellar signs. Her deep tendon
reflexes were brisk but no Babinski sign was observed.
Vibration sense was found to be diminished in the lower
and upper extremities. Her gait was slightly impaired
due to the ataxia but she was able to walk independently. Her mental status was intact. Cerebrospinal fluid
and EMG analyses were normal. Brain MRI revealed
very similar findings.
Clinical, laboratory and neuroimaging findings of the
patients are summarized in Table 1.
Institutional approval from the Ethics Review Board
for this research project was obtained (Hacettepe
_
University, TBK11/03-37 and Istanbul
University
2012/907-1091). Written informed consent for participation and publication of clinical data was obtained from
the patients and family members.

Please cite this article in press as: Yücel-Yılmaz D et al. Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across
life span. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.013

4

D. Yücel-Yılmaz et al. / Brain & Development xxx (2018) xxx–xxx

Fig. 2. Brain MRI of the patient 2, younger brother of patient 1, at the age of 17 years shows much similar findings with involvement of both
pyramidal tracts, splenium of the corpus callosum, hyperintense cerebral white matter foci (b–d). However in this patient, atrophy of the upper
cervical spinal cord (a) and perirolandic atrophy (d) are more severe.

3. Methods and results
3.1. Whole exome sequencing
Whole exome sequencing was performed in the DNA
samples of patients and their healthy family members
using deep sequencing core facility of The Scientific
and Technical Research Council Marmara Research
_
_
Center (TÜBITAK-MAM,
IGBAM,
Turkey). Illumina
TruSeq Sample Preparation Kit (San Diego, CA) was
used for sample preparation and exonic DNA was captured using Illumina TruSeq Exome Enrichment Kit.
Captured DNA fragments were sequenced on an Illumina HiSeq 2000 system (Illumina, San Diego, California, USA).
Variants were filtered according to their GMAF and
ESP6500 MAF scores being lower than 0.01 in dbSNP
(build 138) and in our in-house database (n = 1003).

The nucleotide variations were filtered according to a
segregation pattern in family members for autosomal
recessive mode of inheritance. The final remaining
nucleotide
changes
c.463C > T;
p.R155*
and
*
c.2478delA; p.Ala828Argfs 13 in KIF1C gene
(NM_006612.5) were visually inspected by using Integrative Genomics Viewer (IGV). In silico analyses for
the novel mutations detected in these patients were performed by Mutation Taster. The Mutation Taster analyses showed that the mutations are assigned as disease
causing pathogenic variations. None of the nucleotide
changes were found in The Exome Aggregation Consortium (ExAC) and 1000 Genomes.
Detected mutations by exome sequencing analyses in
KIF1C gene were confirmed by direct DNA sequencing.
Nucleotide change c.463C> T; p.R155* in exon 7 of
KIF1C gene was homozygous in the affected children
(Family A, II:1 and II:2) and heterozygous in the

Please cite this article in press as: Yücel-Yılmaz D et al. Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across
life span. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.013

D. Yücel-Yılmaz et al. / Brain & Development xxx (2018) xxx–xxx

5

Table 1
Clinical and neuroimaging findings of patients with KIF1C mutations.
Family A, II:1
Genotype
Origin
Sex
Age at final
examination
(yrs)
Age at onset
First symptom
Increased DTR
(lower
extremity)
Spasticity
(lower
extremity)
Babinski reflex
Vibration defect
Trunkal ataxia
Nystagmus
Dysarthria
Dysmetria
Titubation
Extrapyramidal
signs
Sphincter
disturbance
Cognitive
decline
MRI

Family A, II:2
*

Family B, II:1
*

c.463C> T (p.R155 )
Turkey
Male
23

c.463C> T (p.R155 )
Turkey
Male
17

c.2478delA (p.Ala828Argfs*13)
Turkey
Female
22

3
Tremor
+

4
Unsteady gait, tremor
+

3
tremor
+

+

+

+
?
+
+
+
+
+
Dystonia

+
?
+
+
+
+
+

+
+
+
+
+
+

Cerebral, craniocervical junction and upper
cervical spinal atrophy, pyramidal tract
involvement, parietal posterior periventricular
and occipital subcortical involvement

White matter abnormalities of
periventricular white matter,
capsula interna, brainstem and
cerebellum

Borderline IQ, no decline
Cerebral and upper cervical spinal
atrophy, bilateral symmetrical pyramidal
tract involvement, focal cerebral white
matter lesions

healthy brother and parents (I:1, I:2, II:3) (Fig. 3A).
c.2478delA; p.Ala828Argfs*13 mutation in exon 22 of
KIF1C gene was homozygous in the single affected child
(Family B, II:1) and heterozygous in parents and
healthy brother (I:1, I:2, II:2) (Fig. 3B). These mutations
were absent in public databases.
4. Discussion
We present three new patients from two unrelated
families with complicated form HSP due to KIF1C
mutations (Table1). Our patients were diagnosed with
complicated HSP, based on prominent cerebellar signs.
Early features of the disease were cerebellar, such as
tremor and gait disturbance, manifested at 3–4 years
of age. Of note, two patients had delayed gross motor
development and walked at 18 months (patient 2) and
2 years (patient 3). Pyramidal signs, the hallmark of
HSP, became manifest during the course of the disease
in the second decade. Common MRI findings were
bilateral and symmetrical involvement of the pyramidal
tracts, T2 hyperintense foci in the cerebral white
matter, brain stem and cervical spinal atrophy
(Figs. 1 and 2).

Twenty-one patients from 7 families with KIF1C
mutations have been identified in literature and were
summarized in Supplement Table 1 along with our
patients [10–13]. Majority of the patients had early onset
cerebellar findings similar to our patients. Overall twelve
patients had brain MRI studies, ranging from normal
findings to white matter abnormalities and/or cerebellar
atrophy. Very subtle upper vermian atrophy was just
found in one of our patients (Fig. 1) in MRI investigations. Similarly, Dor et al. reported an 18 years old
patient with cerebellar findings without apparent cerebellar atrophy on MRI; the authors suggested that cerebellar signs in HSP patients with KIF1C mutations
result from lesions of the efferent cerebellar pathways
or their connections and are not due to primary involvement of the cerebellum [11]. Patients with HSP may
sometimes develop cerebellar ataxia; also mild cerebellar
symptoms may be the presenting features of HSP
patients as in KIF1A and KIF5A mutations that belong
to the kinesin family. Patients with KIF1C mutations
reported in literature clinically differ from other HSP
patients as majority of them have early onset prominent
cerebellar signs and symptoms, and pyramidal signs
become evident later in life. Therefore, we suggest that

Please cite this article in press as: Yücel-Yılmaz D et al. Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across
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D. Yücel-Yılmaz et al. / Brain & Development xxx (2018) xxx–xxx

Fig. 3. A Pedigrees of two different Turkish families (Family A and B) with consanguineous marriages. Electropherograms indicating the position
and type of the KIF1C mutations are shown on the right. B Domain structure and localisation of reported KIF1C mutations. Novel mutations
detected in this study are shown by red and previously reported mutations by dark blue. (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article.)

KIF1C mutations may be considered in the differential
diagnosis of patients who present with early cerebellar
findings without prominent structural cerebellar abnormalities on MRI.
So far 9 different KIF1C mutations including missense, nonsense, splicing or frame shift types were
described in HSP patients (SPG58) (Fig. 3.B) [10–12].
KIF1C mutations described in patients with SPG58
cause dysfunction of microtubule-based motor protein
by disrupting adenosine triphosphate hydrolysis and
microtubule
binding.
The
novel
mutations
(NM_006612.5: c.463C> T; p.R155* and c.2478delA;
p.Ala828Argfs*13) either cause formation of truncated
protein products or absence of any protein product
due to a nonsense mediated RNA decay mechanism,
especially for the former mutation. In the truncation scenario, c.463C> T; p.R155* affects all critical protein
domains particularly the conserved kinesin motor
domain. c.2478delA; p.Ala828Argfs*13 on the other
hand, is located in the 22th exon of KIF1C gene, which
is composed totally of 23 exons. Nevertheless, it still can
cause truncation of almost 250 amino acids in the C terminal of the mature protein.
According to the available data in literature, all
patients with KIF1C mutations have complicated HSP
form and have homozygous state for the mutations.
However, in the series of Oteyza et al., the parents
(THI26001-1 and THI26001-2) carrying a heterozygous

mutation have subclinical phenotype characterized by
mild signs of pyramidal involvement and demyelinating
sensory motor neuropathy each in one patient. On the
other hand, the sibling (IHG25125-3) with a heterozygous mutation presented with complicated HSP [10].
Oteyza et al. proposed that HSP due to KIF1C mutations have a mild dominant and more severe recessive
disease phenotype. Therefore, we evaluated the parents
and the brother with heterozygous c.463C> T mutation
for carrier phenotype. While the mother had normal
neurological examination, the father and 23-year-old
brother had hypoactive deep tendon reflexes in the
upper extremities compared to lower extremities as well
as pes cavus deformity. Their neurological examinations
were otherwise unremarkable. Electroneuromyography
of the father revealed normal nerve conduction velocities as well as normal needle electromyography. Family
members of patient 3 were not available for further
evaluation.
Patients with HSP have a wide spectrum of clinical
phenotype along with genetic and allelic heterogeneity.
Patients presented here are remarkable for early onset
of cerebellar findings long before pyramidal signs
become evident, which is a similar course seen in several
patients with KIF1C mutations reported in the literature. In summary, we proposethat KIF1C mutations
might be considered in the differential diagnosis of
patients who present with cerebellar findings and

Please cite this article in press as: Yücel-Yılmaz D et al. Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across
life span. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.013

D. Yücel-Yılmaz et al. / Brain & Development xxx (2018) xxx–xxx

without remarkable structural cerebellar abnormalities
on MRI. In addition, carriers for KIF1C mutations
may become symptomatic, even later in life. We conclude that all carriers including asymptomatic individuals should be considered for long-term follow up.

Acknowledgements
This work was supported by the grants of The
Scientific and Technology Research Council of Turkey
_
(TÜBITAK)
Project Numbers: 111S217 and UEKAE,
_
BILGEM
K030-T439, Scientific Research Projects
_
Coordination Unit of Istanbul
University, ÖNAP
Project Number: 11021 and The Republic of Turkey
Ministry of Development Infrastructure Grant,
_
TRMOD, 108S420. EY has been a fellow of TÜBITAK
Project Number: 113S331.
We would like to thank to the members of DNA
Bank for Rare Diseases at Hacettepe University and
to Istanbul Development Agency (Project Number:
TR10/15/YNK/0093) for biobanking support. We are
grateful to the patients and their families for their
collaboration.
Appendix A. Supplementary data
Supplementary data associated with this article can
be found, in the online version, at https://doi.org/10.
1016/j.braindev.2018.02.013.
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Please cite this article in press as: Yücel-Yılmaz D et al. Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across
life span. Brain Dev (2018), https://doi.org/10.1016/j.braindev.2018.02.013