Table 1
Demographic, clinical features, investigation findings and follow-up details of the cohort.
| VARIABLES | CASE 1 | CASE 2 | CASE 3 | CASE 4 | CASE 5 | CASE 6 | CASE 7 | CASE 8 |
|---|---|---|---|---|---|---|---|---|
| Demographics | ||||||||
| Age/AAO/Gender | 21y/5y/M | 16y/3y/M | 23y/6y/F | 27y/3y/M | 24y/18y/F | 24y/12y/M | 12y/6y/M | 21y/11y/M |
| FH/Consanguinity | +/– | +/– | –/– | +/– | –/– | +/– | –/– | –/+ |
| Symptoms | ||||||||
| Presenting symptoms | Walking difficulty, slurring of speech, generalized abnormal posturing | Walking difficulty, slurring of speech, generalized abnormal posturing | Generalized abnormal posturing, slurring of speech, walking difficulty | Walking difficult, slurring of speech with generalized abnormal posturing | Walking difficulty, slurring of speech, generalized abnormal posturing | Walking difficulty, slurring of speech with generalized abnormal posturing | Generalized abnormal posturing, slurring of speech, walking difficulty | Walking difficulty, Slurring of speech, abnormal posturing |
| DD/ID | –/+ | –/+ | –/- | –/- | +/– | –/+ | –/– | –/+ |
| Examination findings | ||||||||
| Eye movements | Range, saccades, pursuit normal | Range, saccades, pursuit normal | Mild vertical gaze impairment | Mild gaze restriction, broken pursuit, hypometric saccades, convergent squint | Broken pursuits, Hypometric saccades | Broken pursuits, Hypometric and slow saccades | Normal | Normal |
| Speech | Dystonic and spastic | Dystonic and spastic | Dystonic and spastic | Dystonic and spastic | Dystonic and spastic | Dystonic and spastic | Dystonic and spastic | Dystonia and spastic |
| Dystonia* | + | + | + | + | + | + | + | + |
| Facial twitching | + | + | + | + | + | + | + | + |
| Tone | Spasticity | Spasticity | Spasticity | Spasticity | Rigidity | Spasticity | Normal | Spasticity |
| Deep tendon reflexes | Brisk | Brisk | Brisk | Brisk | Normal | Brisk | Brisk | Brisk |
| Plantar response | Extensor | Extensor | Extensor | Extensor | Flexor | Extensor | Flexor | Extensor |
| Parkinsonism | – | – | – | + | + | – | – | – |
| Contractures | + | + | + | + | – | – | – | + |
| Gait | Dystonic gait Ambulation without support | Dystonic gait Ambulation with support | Dystonic gait Ambulation without support | Dystonic gait Ambulation with support | Dystonic gait Ambulation with support | Dystonic gait Ambulation with support | Dystonic gait Ambulation without support | Dystonic gait. Ambulation with support |
| Additional findings | Kyphoscoliosis | Kyphoscoliosis | Kyphoscoliosis | Kyphoscoliosis | Kyphoscoliosis | – | Kyphoscoliosis | – |
| BFMDRS – Movement | NA | 66 | 85 | NA | NA | NA | NA | NA |
| BFMDRS – Disability | NA | 11 | 24 | NA | NA | NA | NA | NA |
| Imaging | ||||||||
| Ultrasound abdomen | NA | Normal | Normal | Normal | Normal | Normal | Normal | NA |
| X-ray spine | NA | NA | Kyphoscoliosis with C5 partial collapse and sclerosis | Kyphoscoliosis | Kyphoscoliosis | NA | NA | NA |
| Magnetic resonance imaging of the Brain@ | BPPAH & WBP | BPPAH & WBP | BPPAH & WBP | BPPAH & WBP, Diffuse cerebral & cerebellar atrophy | BPPAH & WBP, Diffuse cerebral & cerebellar atrophy | BPPAH & WBP | BPPAH & WBP | BPPAH & WBP |
| Genetic – GLB1: (NM_000404.4) | ||||||||
| Zygosity | CH | CH | CH | CH | CH | HOM | CH | CH |
| Variant-1 ACMG Criteria Consequence/Novelty | c.1325G>A; p.R442Q P(PS3,PM1–3, PP1–5) Missense/No | c.1325G>A; p.R442Q P(PS3,PM1–3,PP1–5) Missense/No | c.1325G>A; p.R442Q P(PS3,PM1–3,PP1–5) Missense/No | c.1325G>A; p.R442Q P (PS3,PM1–3,PP1–5) Missense/No | c.1325G>A; p.R442Q P (PS3,PM1–3,PP1–5) Missense/No | c.146G>A; p.R49H P (PS3PM1,2,5PP2–5) Missense/No | c.1325G>A; p.R442Q P(PS3,PM1–3,PP1–5) Missense/No | c.1325G>A; p.R442Q P (PS3,PM1–3,PP1–5) Missense/No |
| Variant-2 ACMG criteria Consequence/Novelty | c.1022G>T; p.G341V LP (PM1,2,3PP1–4) Missense/Yes | c.1022G>T; p.G341V LP (PM1,2,3PP1–4) Missense/Yes | c.246-2A>G LP(PVS1PM2PP4,5) Splice/No | c.202C>T; p.R68W P (PS3PM1,2,5PP3–5) Missense/No | c.1445G>A; p.R482H P (PS3PM1,2,5,PP2–5) Missense/No | Not applicable | c.1370G>A; p.R457Q P (PS3, PM1,2,PP2–5) Missense/No | c.1369C>T; p.R457* P (PVS1PM2,3PP4,5) Stop-gain/No |
| Treatment and follow-up | ||||||||
| Treatment | THP: 12 mg/d LD/CD: 300 mg/d Baclofen: 20 mg/d Clonaz:0.75 mg/d | THP: 12 mg/d LD/CD: 300 mg/d Baclofen: 20 mg/d | THP: 12 mg/d LD/CD: 300 mg/d Baclofen: 20 mg/d | THP: 6 mg/d LD/CD: 400 mg/d Baclofen: 30 mg/d Clonaz: 1 mg/d | LD/CD: 400 mg/d Clonaz: 1 mg/d Quetiapine: 25 mg/d | LD/CD: 400 mg/d Baclofen: 20 mg/d | LD/CD: 300 mg/d Baclofen: 20 mg/d Clonaz: 0.25 mg/d | LD/CD: 400/100 Baclofen: 60 mg/d THP: 6 mg/d |
| Follow-up | NA | NA | NA | Mild subjective improvement at 9 months | No improvement after 9 months | No improvement after 2 months | Mild subjective improvement at 3 months | No improvement |
[i] +: Present; -: Absent; AAO: Age at onset; ACMG: American College of Medical genetics; BFMDRS: Burke-Fahn-Marsden dystonic rating scale; CH: Compound heterozygous; Clonaz: Clonazepam; d: day; DD: Developmental delay; F: Female; FH: Family history; FLAIR: Fluid attenuated inversion recovery; GP: Globus pallidus; HOM: Homozygous; ID: Intellectual disability; LD: Levodopa/carbidopa; LP: Likely pathogenic; M: Male; NA: Not available; SWI: Susceptibility weighted imaging; P: Pathogenic; THP: Trihexyphenidyl; y: Years.
*: All patients had generalized dystonia with involvement of oromandibular, lingual, Facial, cervical and all four limbs. In addition, all patients had slow facial twitching or dystonic spasms. All patients had normal sensory examination with no apparent weakness. Cerebellar function could not be tested due to significant dystonia.
@: All patients had bilateral symmetrical posterior putaminal atrophy with hyperintensity (BPPAH) on T2 FLAIR and pallidal mineralization on SWI with wish-bone pattern (WBP).
Figure 1
Magnetic resonance imaging of the brain. Axial T2, FLAIR (upper panel) and SWI sequences (Lower panel) of MRI brain of all the seven patients at the level of basal ganglia demonstrating bilateral symmetrical posterior putaminal atrophy and T2/FLAIR hyperintensity (upper panel) and mineralization of bilateral globus pallidi interna in the “wishbone” pattern on the SWI sequence (Lower panel). FLAIR: Fluid attenuated inversion recovery; MRI: Magnetic resonance imaging; SWI: susceptibility weighted imaging.
Video e-1
Video of Case-1. Video demonstrating generalized dystonia involving the face, neck, all four limbs, and trunk. Facial dystonia with slow facial twitching is apparent at rest, which worsens when the patient attempts to speak, along with severe mixed dysarthria.
Video e-2
Video of Case-2. Video demonstrating generalized dystonia involving the face, torticollis, distal hands and legs, and trunk. Facial dystonia with slow facial twitching and mixed dysarthria is apparent when the patient speaks. The patient can walk independently with a dystonic gait.
Video e-3
Video of Case-3. Video demonstrating generalized dystonia involving the face, neck, all four limbs, and trunk, with continuous slow facial twitching, and dystonic gait.
Video e-4
Video of Case-5. Video demonstrating severe cranio-facial dystonia with dysarthria, facial twitching on speaking, and generalized dystonia requiring support to walk.
Table 2
Studies reporting cases with the variant c.1325G>A;p.R442Q.
| STUDY | AGE/AAO/SEX/TYPE* | PRESENTATION | INVESTIGATIONS |
|---|---|---|---|
| Caciotti et al, 2005 | 27/5/NA/Adult | Short stature, ataxia, speech deterioration, bilateral clubfoot, corneal opacity, normal IQ | Other variant: c.985A>G;p.T329A MRI: Mild hyperintensity in the posterior periventricular white matter and mild alteration in the lenticular nuclei GLB1 activity: 4.1 in leukocytes |
| Hofer et al, 2009 | 30/11/NA/Juvenile | CNS and skeletal involvement with no cherry red spot, cardiac involvement, or hepatosplenomegaly | Other variant: c.986C>T;p.T329L MRI: NA GLB1: NA |
| Hofer et al, 2010 | 16/4/NA/Adult | CNS and skeletal involvement with no cherry red spot, cardiac involvement, or hepatosplenomegaly | Other variant: c.1077delA;p.K359Kfs*23 MRI: NA GLB1 activity: 5–15 in leucocytes |
| Caciotti et al, 2011 | 9/4/Female/Juvenile | Dysarthria, tremor, ataxia, borderline IQ, dystonia, stiffness. No eye abnormality/organomegaly | Other variant: c.275G>A;p.W92* MRI: NA GLB1 activity: 2 in leucocytes; 7.5 in fibroblasts |
| Kumar et al, 2016 | 20/Infancy/Female/NA | Spastic limbs, limb dystonia, developmental delay, marked speech disturbance, and unable to mobilise. | Other variant: c.553–2A>G |
| 18/Infancy/Female/NA | Spastic limbs, limb dystonia, developmental delay, marked speech disturbance, unable to mobilise | ||
| 12/Infancy/Male/NA | Spastic gait, limb dystonia, developmental delay, drooling of saliva. No organomegaly or skeletal manifestations | MRI: globus pallid hypointensities were evident on repeat evaluation GLB1 activity: 1.6 in leucocytes |
[i] *: Reported type in the original article.
AAO: Age at onset; CNS: Central nervous system; IQ: Intelligent quotient; MRI: Magnetic resonance imaging; NA: Not available.