Video 1
Neurological Examination (Initial Visit, 1-Month and 1-Year Follow up): Initial Visit: The patient is unable to walk and presents with severe resting and postural tremors in both upper limbs, head tremor, and leftward deviation of the head and neck. Fine motor movements in both hands are uncoordinated and significantly slowed. 1-Month and 1-Year Follow up: The patient is able to walk, with significant improvement in head tremor and upper limb tremors. Fine motor coordination and hand speed have also improved. However, the leftward deviation of the head and neck remains pronounced.
Table 1
Demographic and clinical characteristics of affected individuals in the family.
| PATIENT | DIAGNOSIS | AGEa (YEAR) | SEX | AGE AT ONSET (YEAR) | MOTOR SYMPTOMS (DURATION, YEAR) | NON-MOTOR SYMPTOMS (DURATION, YEAR) | MUSCLE TONE | DIURNAL FLUCTUATIONS | BABINSKI SIGN | MEDICATIONS | DAILY LEVODOPA DOSE (MG) | DURATION OF LEVODOPA TREATMENT (YEAR) | LEVODOPA RESPONSE | MOTOR COMPLICATIONS OF LEVODOPA |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| II-3b | Parkinsonism ? | N/A | M | N/A | Rest remor of bilateral upper limbs (N/A) | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
| II-7 | Parkinsonism | 56 | M | 44 | Rest and action tremor of bilateral upper limbs (12) | Hyposmia (8) | Increased | Yes | N/A | Levodopa | N/A | N/A | Yes | No |
| II-10 | DRD Parkinsonism | 50 | F | 27 | Cervical dystonia (23); limb rigidity (>10); bradykinesi (>10); rest and action tremor of bilateral upper limbs (>10) | Neck pain (23) | Increased | Yes | Yes | Levodopa; Pramipexole; Eperisone | 375 | 2 | Yes | No |
| II-12 | DRD Parkinsonism | 46 | F | 11 | Cervical dystonia (35) ; limb rigidity (>20); rest and atcion tremor of bilateral upper limbs (>20) | N/A | Increased | Yes | N/A | Levodopa; Trihexyphenidyl | 250 | 20 | Yes | No |
| III-9 | DRD | 28 | F | 10 | Right foot inversion (18) | No | Increased | Yes | N/A | Levodopa | 62.5 | 10 | Yes | No |
[i] a: Age at examination.
b: According to the family, the patient exhibited rest tremor in bilateral upper limbs but was unable to undergo further examination due to death from trauma.
?: stands for possible.
DRD: dopa-responsive dystonia.
Figure 1
Pedigree analysis of the GCH1 gene in the family. Pedigree illustrating the inheritance pattern, clinical phenotypes, and genotypes of family members. Circles represent females, and squares represent males. Red-filled segments denote individuals diagnosed with dopa-responsive dystonia (DRD), while blue-filled segments indicate individuals diagnosed with parkinsonism. Individuals with both parkinsonism and DRD are shown with a half-blue, half-red symbol. Open symbols indicate unaffected individuals, and dotted symbols represent asymptomatic carriers of the GCH1 variant. The proband is indicated by an arrow. The question mark (?) beside individual II-3 indicates diagnostic uncertainty due to limited clinical information. Numbers in parentheses denote the age (in years, y) of each individual at the clinical examination. Genotype notation: +/+: Wild-type (no GCH1 variant detected); +/–: Heterozygous for the GCH1 variant. Individuals who were not tested for the variant are not labeled with genotypes.
Figure 2
Comparative schematic of normal individual and mutant GCH1 mRNA. The upper panel illustrates the normal individual mRNA with translation initiated at the canonical AUG start codon, enabling efficient synthesis of the full-length functional protein. The lower panel depicts the mutant mRNA harboring a c.–22C > T substitution in the 5’-UTR of the GCH1 gene. This DNA-level substitution (C > T) results in a corresponding RNA change (C > U), creating an upstream AUG (uAUG) codon and initiating an upstream open reading frame (uORF). The presence of the uORF competes with the canonical ORF translation, potentially leading to frameshift variant and a premature stop codon within the coding region. This disruption likely reduces overall protein synthesis, impairs GTP cyclohydrolase 1 production.