Video 1
PLAN-DP case report. The video shows generalized bradykinesia, masked facies, blepharospasm, jaw-opening dystonia and right ankle clonus. The gait is limited by leg spasticity and dystonia, and balance is severely impaired.
Figure 1
Brain Magnetic Resonance Imaging of Patient with PLA2G6-associated Dystonia–Parkinsonism. (A,B) Axial fluid-attenuated inversion recovery images show frontotemporal atrophy with widened temporal horns of lateral ventricles (arrow in A) and lateral fissure (arrow in B). (C) Mid-sagittal T1 image shows vertically oriented splenium (arrow) and apparent claval hypertrophy (arrowhead). Mild cerebellar vermis atrophy is also visible. (D) SWI demonstrates bilateral hypointensity in the globus pallidus due to iron deposition (arrow).
Table 1
Summary of Demographic and Clinical Findings
| Reference | Patient | Gender/Age at Onset | Presenting Symptom | Parkinsonism | Tremor at Rest | LD/LID | Ataxia | Dystonia | Pyramidal Signs | Poor balance | Myoclonus | Oculomotor Abnormality | Autonomic |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Paisán-Ruiz et al.8 | F1/P1 | F/26 | Cognitive decline | + | + | +/+ | – | + | + | + | +(Facial) | SNGP/LOA | – |
| Paisán-Ruiz et al.8 | F1/P2 | F/10 | Foot drag | + | + | +/+ | – | + | NK | + | NK | NK | NK |
| Paisán-Ruiz et al.8 | F2/P1 | F/18 | Foot drag | + | + | DA/- | – | + | + | + | – | Jerky saccadic | Frequency and nocturia |
| Sina et al.9 | P1 | M/25 | Foot drag | + | + | +/+ | – | + | + | + | – | Fragmented saccades | NK |
| Sina et al.9 | P2 | M/22 | Foot drag | + | + | +/+ | – | + | + | + | – | Fragmented saccades | NK |
| Sina et al.9 | P3 | F/21 | Foot drag | + | + | +/+ | + | + | + | + | – | Fragmented saccades | – |
| Bower et al.10 | P1 | F/18 | Depression | + | – | NM | – | + | + | + | NM | – | NM |
| Bower et al.10 | P2 | F/4 | Dyslexia, stuttering, clumsiness | + | + | NM | + | + | – | + | NM | Saccadic pursuit | NM |
| Yoshino et al.11 | PA | F/20 | Tremor at rest, unsteady gait | + | + | +/+ | – | – | – | + | – | – | Urinary disturbance/Constipation/OH |
| Yoshino et al.11 | PB1 | M/25 | Bradykinesia, gait problem | + | – | +/+ | – | – | – | + | – | – | Urinary disturbance |
| Yoshino et al.11 | PB2 | M/30 | Bradykinesia, gait problem | + | – | +/+ | – | – | – | + | – | – | Urinary disturbance/Constipation/OH |
| Shi et al.12 | P | M/37 | Foot drag | + | + | +/+ | – | – | – | + | – | – | – |
| Virmani et al.13 | P1 | F/25 | Depression and psychosis | + | + | +/– | – | + | + | + | + (Face and limbs) | Jerky pursuit, OGC with levodopa | – |
| Virmani et al.13 | P2 | F/22 | Depression | + | + | +/– | – | + | + | + | – | – | – |
| Agarwal et al.14 | P1 | M/14 | Depression | + | – | + | – | + | + | – | +(Hand) | SNGP/LOA | – |
| Lu et al.15 | P1 | F/30 | Right hand awkwardness | + | – | +/+ | – | – | – | NM | – | – | – |
| Lu et al.15 | P2 | F/8 | Unsteady and slow | + | + | +/+ | + | + | – | NM | – | – | + |
| Lu et al.15 | P3 | F/19 | Unsteady and slow | + | + | +/+ | + | + | – | NM | – | Nystagmus | + |
| Kim et al.16 | P1 | F/22 | Unsteady gait and fall | + | – | +/– | + | + | + | + | – | – | – |
| Kim et al.16 | P2 | M/6 | Unsteady gait and fall | + | – | NK | + | + | – | + | – | – | – |
| Malaguti et al.17 | P | F/27 | Urge incontinence, stiff leg | + | – | +/− | – | + | + | + | – | Slow saccades | Urge incontinence |
| Xie et al.18 | PA | M/36 | Foot drag | + | + | +/NM | – | – | – | + | – | – | – |
| Xie et al.18 | PB | M/36 | Tremor at rest | + | + | +/NM | – | – | – | + | – | – | – |
| Our patient | P | M/16 | Foot drag and blepharospasm | + | + | –/– | – | + | + | + | + (Face, hands) | – | – |
[i] DA, Dopamine agonist; F, Female; F1 and F2, Family 1 and Family 2; LD, Levodopa Response; LID, Levodopa-induced Dyskinesia; LOA, Lid Opening Apraxia; M, Male; NK, Not Known (data not available for the original article’s authors); NM, Not Mentioned (data not mentioned in the original article); OGC, Oculogyric Crisis; OH, Orthostatic Hypotension; P, Patient; PA and PB, Patient A and B; SNGP, Supranuclear Gaze Palsy; +, Positive; –, Negative.
Table 2
Mutations and Ethnicity of Patients with PLA2G6 Associated Dystonia–Parkinsonism
| Report | Patients | Ethnicity/Consanguinity | Mutation | Result |
|---|---|---|---|---|
| Paisán-Ruiz et al.8 | Family 1 | Indian/+1 | c.2222G>A | p.R741Q |
| Paisán-Ruiz et al.8 | Family 2 | Pakistani/+ | c.2239C>T | p.R747W |
| Sina et al.9 | One family | Iranian/+ | c.1894C>T | p.R632W |
| Bower et al.10 | One family | European/– | c.4C>A/Del Ex 3 | p.Q2K/pL71_S142del |
| Yushino et al.11 | Patient A | Japanese/– | c.216C>A/c.1904G>A | p.F72L/p.R635Q |
| Yushino et al.11 | Patients B1,B2 | Japanese/– | c.1354C>T/c.1904G>A | p.Q452X/p.R635Q |
| Shi et al.12 | One patient | Chinese/+ | c.991G>T | p.D331Y |
| Virmani et al.13 | One family | Indian/+ | c.2222G>A | p.R741Q |
| Agarwal et al.14 | One family | Scandinavian/– | c.238G>A | p.A80T |
| Lu et al.15 | Two families | Han Chinese/– | c.991G>T/c.1077G>A | p.D331Y/p.M358IfsX |
| Lu et al.15 | One family | Han Chinese/+ | c.991G>T | p.D331Y |
| Kim et al.16 | One family | Korean/– | c.1039G>A/c.1670C>T | p.G347R/p.S557L |
| Malaguti et al.17 | One family | Italian/– | c.1547C>T | p.A516W |
| Xie et al.18 | Two families | Chinese/+ | c.991G>T | p.D331Y |
| This work | One Family | Pakistani/+ | c.2222G>A | p.R741Q |
Table 3
Summary of Neuropsychiatric Disorders
| Reference | Patient number (if appropriate): Symptoms |
|---|---|
| Paisán-Ruiz et al.8 | P1: Cognitive decline, depression |
| P2: Cognitive decline, frontal execution dysfunction, personality change with aggression | |
| Sina et al.9 | Cognitive decline |
| Bower et al.10 | P1: Depression |
| P2: Behavioral difficulties, delusions, and paranoia | |
| Yoshino et al.11 | A: Frontotemporal dementia, depression, personality/behavioral changes, disordered social conduct, and apathy |
| B1, B2: Dementia | |
| Virmani et al.13 | P1: Depression with psychosis, pseudobulbar affect |
| P2: Depression and cognitive decline | |
| Agarwal et al.14 | Anxiety, obsessive compulsive disorder, depression, frontal executive dysfunction |
| Lu et al.15 | Dementia |
| Kim et al.16 | Low IQ |
| Malaguti et al.17 | Dysphoric and anosognosic behavior, executive dysfunction such as impulsive behavior, reduced strategic planning, inability to use environmental feedback to shift cognitive sets, reduced mental flexibility, and mild memory impairment |
Table 4
Summary of clinical and radiological features of PLAN phenotypes[22]
| INAD | Atypical NAD | PLAN-DP | |
|---|---|---|---|
| Age of onset | 6 months to 3 years | Early childhood; can be as late as end of second decade | 4–36 years |
| Brain MRI | Cerebellar atrophy, cerebellar gliosis, posterior corpus callosum abnormalities (thinning, vertical orientation, elongation), apparent claval hypertrophy, iron deposition in basal ganglia (increases with age) | Iron deposition with or without cerebellar atrophy | Normal imaging, cerebral and/or cerebellar atrophy, iron deposition in basal ganglia (33%), corpus callosum changes similar to INAD (some cases) |
| Disease presentation | Gait disturbance and loss of ambulation, truncal hypotonia with hyper-reflexia and hypertonicity, neuroregression with loss of acquired motor skills | Gait impairment or ataxia; social communication difficulties, such as speech difficulties and autistic trait | Gait impairment, dystonia, Parkinsonism, tremor at rest, speech difficulties, and neuropsychiatric disorders |
| Disease progression | Spastic tetraparesis, with symmetrical pyramidal tract signs and areflexia | Dystonia and dysarthria, neuropsychiatric features, such as hyperactivity, impulsivity, emotional lability, and poor attention | Severe dystonia and/or Parkinsonism, spasticity, myoclonus, autonomic dysfunction, seizure, neuropsychiatric features, and cognitive decline |
| Ocular abnormalities | Strabismus, nystagmus, optic nerve atrophy | Strabismus, nystagmus, optic nerve atrophy | Supranuclear gaze palsy, slow saccades, fragmented saccades, nystagmus, lid opening apraxia |
[i] INAD, Infantile Neuroaxonal Dystrophy; MRI, Magnetic Resonance Imaging; PLAN-DP, PLA2G6-associated Neurodegeneration Dystonia–Parkinsonism.