Clinical features of Parkinson disease cases with GCH1 variants identified in the exome-sequencing study
| Case . | Origin . | Sex/age/age at onset (y) . | GCH1 mutation . | Family history of PD . | Age at l-DOPA start (y) . | Current treatment (mg/day) . | Parkinsonian features . | l-DOPA responsi-veness . | H&Y score . | Cognitive symptoms . | Other non-motor features . | Dystonia . | Levodopa-induced complications . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | USA | F/47/43 | M230I/w | No | / | Pramipexole 0.75 | Asymmetric onset, bilateral involvement with rest and postural tremor, bradykinesia and rigidity, mild gait difficulties | Good | 2 | No | No | No | No |
| 2 | USA | M/55/37 | K224R/w | Yes (father) | NA | NA | Asymmetric onset, moderate bilateral involvement with rest tremor, bradykinesia and rigidity, postural instability and gait difficulties | Good | 3 | No | Fatigue | No | Dyskinesias and wearing-off |
| 3 | Holland | M/49/35 | G217V/w | No | 43 |
| Asymmetric onset, slurred speech, mild L arm rest and postural tremor, moderate bilateral bradykinesia and rigidity, postural instability | Good | 3 | Subjective loss of memory (MMSE 29/30) | Hyposmia, ICD | No | Initial dyskinesias and wearing-off |
| 4 | UK | M/63/32 | V204I/w | Yes (1st degree cousin) | 36 |
| Asymmetric onset, hypomimia, slurred speech, hypophonia, marked bilateral rest and postural tremor, moderate bilateral rigidity and bradykinesia, postural instability | Good | 4 | No | Hyposmia, constipation, RBD | Right foot exercise-induced dystonia at onset | Disabling dyskinesias and on-off fluctuations |
| 5 | Estonia | M/75/61 | V204I/w | Yes (mother) | 61 |
| Asymmetric onset, rest and postural tremor (R>L), bradykinesia and rigidity, mild gait disorder, hypomimia | Good | 3 | Mild cognitive impairment | Hyposmia, fatigue, sleep and bladder disorder | Lower limb off-dystonia | On-off fluctuations (30% of waking day in off-state) |
| 6 | Estonia | M/72/59 | V204I/w | Yes (mother) | 65 |
| Asymmetric onset, bilateral bradykinesia and rigidity (L>R), no tremor. Mild gait difficulties and postural instability | Good | 3 | No | Hyposmia, sleep and bladder disorder | No | Dyskinesias (30-40% of waking day), wearing-off |
| 7 | USA | M/57/52 | D134G/w | Yes (father and paternal aunt) | / | Ropinirole 14 | Asymmetric onset, unilateral left arm rest tremor, bradykinesia and rigidity. Reduced arm swing | Good | 1 | No | NA | No | No |
| 8 | USA | F/59/51 | A120S/wa | Yes (mother) | NA | NA | Asymmetric onset, bilateral bradykinesia and rigidity. No tremor. Mild gait difficulties | Good | 2 | No | NA | No | NA |
| 9 | Portugal | F/73/17 | Q110X/w | Yes (sister; father had tremor) | 49 | l-DOPA 600 Trihexyphenidyl 6 | Bilateral rest and postural tremor (L>R), bilateral rigidity and bradykinesia. Some postural instability | Good | 3 | No | Urinary urgency | Lower limb dystonia at onset | Marked limb and truncal dyskinesias, off phases in the morning |
| 10 | Estonia | M/58/45 | Q110E/w | No | 55 |
| Bilateral severe bradykinesia and rigidity, postural instability, mild tremor, hypomimia | Good | 3 | No | Hyposmia, constipation, fatigue, sleep disorder | No | Mild dyskinesias and wearing-off |
| Case . | Origin . | Sex/age/age at onset (y) . | GCH1 mutation . | Family history of PD . | Age at l-DOPA start (y) . | Current treatment (mg/day) . | Parkinsonian features . | l-DOPA responsi-veness . | H&Y score . | Cognitive symptoms . | Other non-motor features . | Dystonia . | Levodopa-induced complications . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | USA | F/47/43 | M230I/w | No | / | Pramipexole 0.75 | Asymmetric onset, bilateral involvement with rest and postural tremor, bradykinesia and rigidity, mild gait difficulties | Good | 2 | No | No | No | No |
| 2 | USA | M/55/37 | K224R/w | Yes (father) | NA | NA | Asymmetric onset, moderate bilateral involvement with rest tremor, bradykinesia and rigidity, postural instability and gait difficulties | Good | 3 | No | Fatigue | No | Dyskinesias and wearing-off |
| 3 | Holland | M/49/35 | G217V/w | No | 43 |
| Asymmetric onset, slurred speech, mild L arm rest and postural tremor, moderate bilateral bradykinesia and rigidity, postural instability | Good | 3 | Subjective loss of memory (MMSE 29/30) | Hyposmia, ICD | No | Initial dyskinesias and wearing-off |
| 4 | UK | M/63/32 | V204I/w | Yes (1st degree cousin) | 36 |
| Asymmetric onset, hypomimia, slurred speech, hypophonia, marked bilateral rest and postural tremor, moderate bilateral rigidity and bradykinesia, postural instability | Good | 4 | No | Hyposmia, constipation, RBD | Right foot exercise-induced dystonia at onset | Disabling dyskinesias and on-off fluctuations |
| 5 | Estonia | M/75/61 | V204I/w | Yes (mother) | 61 |
| Asymmetric onset, rest and postural tremor (R>L), bradykinesia and rigidity, mild gait disorder, hypomimia | Good | 3 | Mild cognitive impairment | Hyposmia, fatigue, sleep and bladder disorder | Lower limb off-dystonia | On-off fluctuations (30% of waking day in off-state) |
| 6 | Estonia | M/72/59 | V204I/w | Yes (mother) | 65 |
| Asymmetric onset, bilateral bradykinesia and rigidity (L>R), no tremor. Mild gait difficulties and postural instability | Good | 3 | No | Hyposmia, sleep and bladder disorder | No | Dyskinesias (30-40% of waking day), wearing-off |
| 7 | USA | M/57/52 | D134G/w | Yes (father and paternal aunt) | / | Ropinirole 14 | Asymmetric onset, unilateral left arm rest tremor, bradykinesia and rigidity. Reduced arm swing | Good | 1 | No | NA | No | No |
| 8 | USA | F/59/51 | A120S/wa | Yes (mother) | NA | NA | Asymmetric onset, bilateral bradykinesia and rigidity. No tremor. Mild gait difficulties | Good | 2 | No | NA | No | NA |
| 9 | Portugal | F/73/17 | Q110X/w | Yes (sister; father had tremor) | 49 | l-DOPA 600 Trihexyphenidyl 6 | Bilateral rest and postural tremor (L>R), bilateral rigidity and bradykinesia. Some postural instability | Good | 3 | No | Urinary urgency | Lower limb dystonia at onset | Marked limb and truncal dyskinesias, off phases in the morning |
| 10 | Estonia | M/58/45 | Q110E/w | No | 55 |
| Bilateral severe bradykinesia and rigidity, postural instability, mild tremor, hypomimia | Good | 3 | No | Hyposmia, constipation, fatigue, sleep disorder | No | Mild dyskinesias and wearing-off |
NA = information not available; M = male; F = female; PD = Parkinson disease, y = years, ICD = Impulse control disorder, DBS = deep brain stimulation, RBD = REM behavioural sleep disorder, H&Y = Hoehn and Yahr; MMSE = Mini-Mental State Examination.
aThis case also carries in the heterozygous state the GBA E326K variant.
Clinical features of Parkinson disease cases with GCH1 variants identified in the exome-sequencing study
| Case . | Origin . | Sex/age/age at onset (y) . | GCH1 mutation . | Family history of PD . | Age at l-DOPA start (y) . | Current treatment (mg/day) . | Parkinsonian features . | l-DOPA responsi-veness . | H&Y score . | Cognitive symptoms . | Other non-motor features . | Dystonia . | Levodopa-induced complications . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | USA | F/47/43 | M230I/w | No | / | Pramipexole 0.75 | Asymmetric onset, bilateral involvement with rest and postural tremor, bradykinesia and rigidity, mild gait difficulties | Good | 2 | No | No | No | No |
| 2 | USA | M/55/37 | K224R/w | Yes (father) | NA | NA | Asymmetric onset, moderate bilateral involvement with rest tremor, bradykinesia and rigidity, postural instability and gait difficulties | Good | 3 | No | Fatigue | No | Dyskinesias and wearing-off |
| 3 | Holland | M/49/35 | G217V/w | No | 43 |
| Asymmetric onset, slurred speech, mild L arm rest and postural tremor, moderate bilateral bradykinesia and rigidity, postural instability | Good | 3 | Subjective loss of memory (MMSE 29/30) | Hyposmia, ICD | No | Initial dyskinesias and wearing-off |
| 4 | UK | M/63/32 | V204I/w | Yes (1st degree cousin) | 36 |
| Asymmetric onset, hypomimia, slurred speech, hypophonia, marked bilateral rest and postural tremor, moderate bilateral rigidity and bradykinesia, postural instability | Good | 4 | No | Hyposmia, constipation, RBD | Right foot exercise-induced dystonia at onset | Disabling dyskinesias and on-off fluctuations |
| 5 | Estonia | M/75/61 | V204I/w | Yes (mother) | 61 |
| Asymmetric onset, rest and postural tremor (R>L), bradykinesia and rigidity, mild gait disorder, hypomimia | Good | 3 | Mild cognitive impairment | Hyposmia, fatigue, sleep and bladder disorder | Lower limb off-dystonia | On-off fluctuations (30% of waking day in off-state) |
| 6 | Estonia | M/72/59 | V204I/w | Yes (mother) | 65 |
| Asymmetric onset, bilateral bradykinesia and rigidity (L>R), no tremor. Mild gait difficulties and postural instability | Good | 3 | No | Hyposmia, sleep and bladder disorder | No | Dyskinesias (30-40% of waking day), wearing-off |
| 7 | USA | M/57/52 | D134G/w | Yes (father and paternal aunt) | / | Ropinirole 14 | Asymmetric onset, unilateral left arm rest tremor, bradykinesia and rigidity. Reduced arm swing | Good | 1 | No | NA | No | No |
| 8 | USA | F/59/51 | A120S/wa | Yes (mother) | NA | NA | Asymmetric onset, bilateral bradykinesia and rigidity. No tremor. Mild gait difficulties | Good | 2 | No | NA | No | NA |
| 9 | Portugal | F/73/17 | Q110X/w | Yes (sister; father had tremor) | 49 | l-DOPA 600 Trihexyphenidyl 6 | Bilateral rest and postural tremor (L>R), bilateral rigidity and bradykinesia. Some postural instability | Good | 3 | No | Urinary urgency | Lower limb dystonia at onset | Marked limb and truncal dyskinesias, off phases in the morning |
| 10 | Estonia | M/58/45 | Q110E/w | No | 55 |
| Bilateral severe bradykinesia and rigidity, postural instability, mild tremor, hypomimia | Good | 3 | No | Hyposmia, constipation, fatigue, sleep disorder | No | Mild dyskinesias and wearing-off |
| Case . | Origin . | Sex/age/age at onset (y) . | GCH1 mutation . | Family history of PD . | Age at l-DOPA start (y) . | Current treatment (mg/day) . | Parkinsonian features . | l-DOPA responsi-veness . | H&Y score . | Cognitive symptoms . | Other non-motor features . | Dystonia . | Levodopa-induced complications . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | USA | F/47/43 | M230I/w | No | / | Pramipexole 0.75 | Asymmetric onset, bilateral involvement with rest and postural tremor, bradykinesia and rigidity, mild gait difficulties | Good | 2 | No | No | No | No |
| 2 | USA | M/55/37 | K224R/w | Yes (father) | NA | NA | Asymmetric onset, moderate bilateral involvement with rest tremor, bradykinesia and rigidity, postural instability and gait difficulties | Good | 3 | No | Fatigue | No | Dyskinesias and wearing-off |
| 3 | Holland | M/49/35 | G217V/w | No | 43 |
| Asymmetric onset, slurred speech, mild L arm rest and postural tremor, moderate bilateral bradykinesia and rigidity, postural instability | Good | 3 | Subjective loss of memory (MMSE 29/30) | Hyposmia, ICD | No | Initial dyskinesias and wearing-off |
| 4 | UK | M/63/32 | V204I/w | Yes (1st degree cousin) | 36 |
| Asymmetric onset, hypomimia, slurred speech, hypophonia, marked bilateral rest and postural tremor, moderate bilateral rigidity and bradykinesia, postural instability | Good | 4 | No | Hyposmia, constipation, RBD | Right foot exercise-induced dystonia at onset | Disabling dyskinesias and on-off fluctuations |
| 5 | Estonia | M/75/61 | V204I/w | Yes (mother) | 61 |
| Asymmetric onset, rest and postural tremor (R>L), bradykinesia and rigidity, mild gait disorder, hypomimia | Good | 3 | Mild cognitive impairment | Hyposmia, fatigue, sleep and bladder disorder | Lower limb off-dystonia | On-off fluctuations (30% of waking day in off-state) |
| 6 | Estonia | M/72/59 | V204I/w | Yes (mother) | 65 |
| Asymmetric onset, bilateral bradykinesia and rigidity (L>R), no tremor. Mild gait difficulties and postural instability | Good | 3 | No | Hyposmia, sleep and bladder disorder | No | Dyskinesias (30-40% of waking day), wearing-off |
| 7 | USA | M/57/52 | D134G/w | Yes (father and paternal aunt) | / | Ropinirole 14 | Asymmetric onset, unilateral left arm rest tremor, bradykinesia and rigidity. Reduced arm swing | Good | 1 | No | NA | No | No |
| 8 | USA | F/59/51 | A120S/wa | Yes (mother) | NA | NA | Asymmetric onset, bilateral bradykinesia and rigidity. No tremor. Mild gait difficulties | Good | 2 | No | NA | No | NA |
| 9 | Portugal | F/73/17 | Q110X/w | Yes (sister; father had tremor) | 49 | l-DOPA 600 Trihexyphenidyl 6 | Bilateral rest and postural tremor (L>R), bilateral rigidity and bradykinesia. Some postural instability | Good | 3 | No | Urinary urgency | Lower limb dystonia at onset | Marked limb and truncal dyskinesias, off phases in the morning |
| 10 | Estonia | M/58/45 | Q110E/w | No | 55 |
| Bilateral severe bradykinesia and rigidity, postural instability, mild tremor, hypomimia | Good | 3 | No | Hyposmia, constipation, fatigue, sleep disorder | No | Mild dyskinesias and wearing-off |
NA = information not available; M = male; F = female; PD = Parkinson disease, y = years, ICD = Impulse control disorder, DBS = deep brain stimulation, RBD = REM behavioural sleep disorder, H&Y = Hoehn and Yahr; MMSE = Mini-Mental State Examination.
aThis case also carries in the heterozygous state the GBA E326K variant.
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