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Supplementary Table 1. Clinical summary of SPG21 patients
Age at examination, years, sex
Age at onset, years
Patient 1
Patient 2
Mast syndrome
75, male
65, male
31-62, no sex difference
~60
55
childhood ~ early 20's
Initial symptoms
Gait disturbance
Gait disturbance
Milestone delay, cognitive dysfunction, gait disturbance
Severity
Walk with a cart
Walk with a single cane
Unable to walk in the 50's
29
23
Not reported
Increased / Positive
Normal
-/-
Normal / Positive
Normal
-/-
Normal ~ Increased / Not reported
Normal
+
Spastic paraplegia rating scale
Cranial
Jaw jerk / Head retraction reflex
Eye movements
Dysarthria/dysphagia
Upper limbs
Spasticity
Weakness
Tendon reflex
Lower limbs
Spasticity
Weakness (MRC score)
Tendon reflex
Pyramidal signs
Clonus
Sensory disturbance
Increased
Increased
+ in advanced cases
+ in advanced cases
Increased
+
4
Increased
Positive
Unsustained
Pain in the left leg due to LCS
+
4~5
Increased
Positive
Unsustained
Pain in the lower legs due to LCS
+
+
Increased
Positive
+
-
Personality/psychiatric problems
-
-
-~+
Cognitive dysfunction
+
+
+
Apraxia
Ataxia
Extrapyramidal signs
+ (with progression)
-
+ (mild)
-
"Dyspraxia" in two patients
+
+
Normal
Normal
Atetoid movement
Some in advanced cases
+
+ (Progressive)
Only slightly
Not examined
Not examined
Not examined
+
+
+
Slightly decreased amplitude in the sural nerve
Normal
CMCT elongation in the lower legs
Normal
LCS, DM
Not examined
Not examined
Not examined
Not examined
OPLL, LCS
Normal in one patient
Not reported
Not reported
Not reported
Involuntary movement
Bladder function
Neuroradiological examination
Thin corpus callosum
Brain atrophy
White matter changes
Electrophysiological evaluation
NCS
SEP
MEP
Needle EMG
Complication
Abbreviations:: NCS, nerve conduction study; SEP, sensory evoked potentials; MEP, magnetic evoked potentials; EMG, electromyography; LCS, lumbar canal stenosis; DM, diabetes
mellitus; OPLL, ossification of the posterior longitudinal ligament
Supplementary Table 2. Cognitive function of SPG21 patients
Age at examination
MMSE
FAB
WAIS-R
IQ
VIQ
PIQ
Patient 1
Patient 2
75
22/30
13/18
65
20/30
12/18
64
67
66
Not examined
Not examined
Not examined
Abbreviations:
MMSE, Mini-mental state examination
FAB, frontal assessment battery
WAIS-R, Wechsler adult intelligence scale-revised
IQ, intelligence quotient
VIQ, verbal IQ
PIQ, performance IQ
Supplementary Fig. 1: Distribution of age at onset
A
Distribution of age at onset of patients classified on the basis of clinical phenotype
20
n=127
Number of patients
18
16
14
12
Pure
10
8
Complicated
6
4
2
0
0-9
10-19 20-29 30-39 40-49 50-59 60-69
70-
Age at onset
Distribution of age at onset of patients classified on the basis of family history
20
n=127
18
ADHSP
16
Number of patients
B
14
ARHSP
12
10
8
Familial (undetermined
mode of inheritance)
6
4
2
Sporadic
0
0-9
10-19 20-29 30-39 40-49 50-59 60-69
Age at onset
70-
Supplementary Figure 1. Distribution of age at onset according to phenotype and family history
(A) The distribution of age at onset of 127 index patients whose detailed clinical data are obtained is
classified on the basis of clinical phenotype. In pure-form HSP patients, bimodal peaks of the
distribution in the first and the 5th decades are noted, whereas a large peak in the first decade and a
small peak in the 50s and 60s were found in the complicated-form HSP patients.
(B) The distribution of age at onset of 127 patients on the basis of family history. The ages at onset of both
AD-HSP patients and sporadic HSP patients show similar bimodal distributions, whereas AR-HSP
patients tend to show an early onset.
(C) Distribution of the age at onset in SPG4 patients (n=38) according to the type of mutation. In addition
to index patients, we include affected family members when precise clinical information is available. The
age at onset does not seem to correlate with the type of mutation in SPAST.
Supplementary Fig. 2: Mutations in SPAST identified in the present study
A
Rearrangements
Del ex1
Null
mutations
Dup ex5-7
*
*
Del ex2-17
*
*
* *
* **
* *
*
Del ex17*
Del ex17
*
*
Exon 1
342
599 616
AAA casette
*
*
B
H.
P.
R.
M.
G.
X.
D.
D.
Frameshift mutations
Exon 17
1
Missense
mutations
Nonsense mutations
*
* * *
Y52C
sapiens
troglodytes
norvegicus
musculus
gallus
tropicalis
rerio
melanogaster
PPPESPH-KRNLYYFSYPLF
PPPESPH-KRNLYYFSYPLF
PAPGSPH-KRNLYYFSYPLV
PAAGSPP-KRNPSSFSSPLV
AAAASPH-KRNLYYFSYPLF
LAPPSLH-KRNLYLFSYPLL
----SARGNRLLFYTRSLSR
----SVH-KQNLYVVSFPII
#E43Q
#P41L
#P45Q
#S44L
previously described
missense mutations in exon 1
*
Splicing mutations
Missense mutations
* Novel mutations
T369P
L549P
PELFTGLRA
PELFTGLRA
PELFTGLRA
PELFTGLRA
PELFTGLRA
PELFTGLRA
PELFTGLRA
PELFTGLRA
SGSDLTALA
SGSDLTALA
SGSDLTALA
SGSDLTALA
SGSDLTALV
SGSDITALA
SGSDLTSLA
SGSDLTALA
Supplementary Figure 2. Mutations in SPAST identified in the present study
(A) Spastin is a 616-amino-acid protein, transcribed from 17 exons. Positions of nonsense (green
squares), frameshift (blue circles), splicing (purple diamonds), missense (light blue triangles), and
rearrangement (orange lines) mutations detected in this study are indicated. Nineteen novel
mutations detected in the study were indicated by a star. Nonsense, frameshift, or splice site
mutations (24/32 families) are distributed throughout the genes, whereas most missense mutations
in SPAST (7/8 families) are located in ATPase associated with various cellular activities (AAA) domain.
(B) Analysis of evolutionally conserved sequences in spastin and comparison with novel mutations
(Y52C, T369P, and L549P) detected in this study (underlined). Two mutations in the AAA domain
(T369P and L549P) affect highly conserved amino acids. Y52 is outside the AAA domain, located near
four previously reported amino acid substitutions in exon 1 of SPAST (indicated by sharps). Y52C
involves an evolutionally conserved amino acid among chimpanzees, rats, chickens, and zebrafish,
and is located in a putative nuclear export signal. The patient with the heterozygous Y52C
substitution, born to consanguineous parents, suffered from cervical canal stenosis, and the
symptoms gradually progressed even after a neck surgery. One of the healthy parents carried the
heterozygous Y52C substitution. Y52C was neither present in the controls nor reported in the dbSNP
database (http://www.ncbi.nlm.nih.gov/snp), raising a possibility that it is a mutation with reduced
penetrance. However, we cannot completely exclude the possibility that Y52C is a rare variant with
little relevance to the patient’s neurological conditions.
Abbreviations:
Dup, duplication; Del, deletion
Supplementary Fig. 3: Distribution of age at onset of HSP in patients with
SPG4 and SPG11
Patients with mutations in SPAST (SPG4)
Number of patients
A
10
9
8
7
6
5
4
3
2
1
0
n=38
Missense
Splice site
Truncating
/rearrangement
0-9
B
10-19 20-29 30-39 40-49 50-59 60-69
70-
Age at onset
Patients with mutations in SPG11 (SPG11)
Number of patients
4
3
2
1
0
0-9
10-19 20-29 30-39 40-49 50-59 60-69
70-
Age at onset
(A) Age at onset of HSP in patients with SPG4 showed bimodal distribution. In addition to data of all the index
patients, those of the family members whose clinical information was available were included (n=38). Types of
mutations did not correlate with age at onset.
(B) The ages at onset of HSP in patients with SPG11 were under 30 years old.