Patient 1Patient 2Mast syndrome Age at examination, years, sex75, male65, male31-62, no sex...
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Transcript of Patient 1Patient 2Mast syndrome Age at examination, years, sex75, male65, male31-62, no sex...
Patient 1 Patient 2 Mast syndrome
Age at examination, years, sex 75, male 65, male 31-62, no sex difference
Age at onset, years ~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
Spastic paraplegia rating scale 29 23 Not reported
Cranial Jaw jerk / Head retraction reflex Increased / Positive Normal / Positive Normal ~ Increased / Not reported Eye movements Normal Normal Normal Dysarthria/dysphagia - / - - / - +Upper limbs Spasticity - - + in advanced cases Weakness - - + in advanced cases Tendon reflex Increased Increased IncreasedLower limbs Spasticity + + + Weakness (MRC score) 4 4~5 + Tendon reflex Increased Increased Increased Pyramidal signs Positive Positive Positive Clonus Unsustained Unsustained +Sensory disturbance Pain in the left leg due to LCS Pain in the lower legs due to LCS -
Personality/psychiatric problems - - - ~ +Cognitive dysfunction + + +Apraxia + (with progression) + (mild) "Dyspraxia" in two patientsAtaxia - - +Extrapyramidal signs - - +Involuntary movement - - Atetoid movementBladder function Normal Normal Some in advanced casesNeuroradiological examination Thin corpus callosum + Not examined + Brain atrophy + (Progressive) Not examined + White matter changes Only slightly Not examined +Electrophysiological evaluation NCS Slightly decreased amplitude in the sural nerve Not examined Normal in one patient SEP Normal Not examined Not reported MEP CMCT elongation in the lower legs Not examined Not reported Needle EMG Normal Not examined Not reportedComplication LCS, DM OPLL, LCS
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 1. Clinical summary of SPG21 patients
Patient 1 Patient 2
Age at examination 75 65MMSE 22/30 20/30FAB 13/18 12/18WAIS-R IQ 64 Not examined VIQ 67 Not examined PIQ 66 Not examined
Abbreviations:MMSE, Mini-mental state examinationFAB, frontal assessment batteryWAIS-R, Wechsler adult intelligence scale-revisedIQ, intelligence quotientVIQ, verbal IQPIQ, performance IQ
Supplementary Table 2. Cognitive function of SPG21 patients
A Distribution of age at onset of patients classified on the basis of clinical phenotype
B Distribution of age at onset of patients classified on the basis of family history
Age at onset
Age at onset
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Supplementary Fig. 1: Distribution of age at onset
n=127
n=127
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.
Nonsense mutations
Frameshift mutations
Splicing mutations
Missense mutations
A
H. sapiens PPPESPH-KRNLYYFSYPLF PELFTGLRA SGSDLTALAP. troglodytes PPPESPH-KRNLYYFSYPLF PELFTGLRA SGSDLTALAR. norvegicus PAPGSPH-KRNLYYFSYPLV PELFTGLRA SGSDLTALAM. musculus PAAGSPP-KRNPSSFSSPLV PELFTGLRA SGSDLTALAG. gallus AAAASPH-KRNLYYFSYPLF PELFTGLRA SGSDLTALVX. tropicalis LAPPSLH-KRNLYLFSYPLL PELFTGLRA SGSDITALAD. rerio ----SARGNRLLFYTRSLSR PELFTGLRA SGSDLTSLAD. melanogaster ----SVH-KQNLYVVSFPII PELFTGLRA SGSDLTALA
B Y52C
Supplementary Fig. 2: Mutations in SPAST identified in the present study
T369P L549P
Exon 1 Exon 17
1 616
AAA casette342 599
Del ex1*Del ex2-17*
Del ex17*Del ex17*Dup ex5-7*
*
* * * ***
* * * * * * **
Missense mutations
Nullmutations
Rearrangements
* * * Novel mutations
#E43Q
#S44L
#P45Q
#P41Lpreviously described
missense mutations in exon 1
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
A Patients with mutations in SPAST (SPG4)
Age at onset
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n=38
Supplementary Fig. 3: Distribution of age at onset of HSP in patients with SPG4 and SPG11
B Patients with mutations in SPG11 (SPG11)
Num
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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.