Table 1
Demographic, clinical and radiological features of patients with PLAN.
| TOTAL (n = 26) | INAD (n = 5) | ANAD (n = 3) | DP (n = 5) | DPM (n = 4) | EOP (n = 2) | COMPLEX DYSTONIA (n = 2) | cHSP (n = 5) | |
|---|---|---|---|---|---|---|---|---|
| PARKINSONISM (n = 11) | ||||||||
| Gender (Male: Female) | 15:11 | 3:2 | 2:1 | 1:4 | 3:1 | 1:1 | 1:1 | 4:1 |
| Age at presentation, Year (median, IQR) | 22.5 (6.5–29.0) | 2.0 (1.9–2.7) | 7.0 (5.0–8.0) | 29.0 (25.5–35.0) | 28.5 (25.0–30.5) | 29.0 | 21.0 | 23.0 (18.0–29.0) |
| Age at Onset, Year (median, IQR) | 13.0 (2.7–20.5) | 1.4 (0.75–1.75) | 3.0 (2.0–4.0) | 15.0 (12.0–22.7) | 18.0 (12.0–27.0) | 26.5 | 16.5 | 18.0 (10.5–20.0) |
| Duration of illness, month (median, IQR) | 3.5 (1.5–10.5) | 1.0 (0.50–1.45) | 3.0 (2.0–6.0) | 14.0 (5.2–20.5) | 8.0 (3.3–15.8) | 2.5 | 4.1 | 10.0 (3.0–11.0) |
| Consanguinity (n, %) | 14 (53.8) | 4 (80.0) | 0 | 2 (40) | 2 (50.0) | 1 (50.0) | 2 (100) | 3 (60.0) |
| Positive family history (n, %) | 11 (42.3) | 0 | 0 | 2 (40) | 4 (100.0) | 0 | 2 (100) | 3 (60.0) |
| History of Global Developmental Delay | 9 (34.6) | 4 (80.0) | 2 (66.7) | 0 | 0 | 0 | 2 (100) | 1 (20.0) |
| Dysmorphism | 4 (15.4) | 3 (60.0) | 1 (33.3) | 0 | 0 | 0 | 0 | 0 |
| Symptoms at the onset | ||||||||
| Developmental regression | 6 (23.1) | 5 (100) | 1 (33.3) | 0 | 0 | 0 | 0 | 0 |
| Cognitive decline | 3 (11.5) | 0 | 0 | 0 | 3 (75.0) | 0 | 0 | 0 |
| Behavioural symptoms | 2 (7.7) | 0 | 0 | 2 (40) | 0 | 0 | 0 | 0 |
| Abnormal Posturing | 2 (7.7) | 0 | 0 | 0 | 0 | 0 | 2 (100) | 0 |
| Walking difficulty | 7 (26.9) | 0 | 1 (33.3) | 2 (40) | 0 | 0 | 0 | 4 (80.0) |
| Slowness | 4 (15.4) | 0 | 0 | 1 (20) | 1 (25.0) | 2 (100) | 0 | 0 |
| Change in speech | 2 (7.7) | 0 | 1 (33.3) | 0 | 0 | 0 | 0 | 1 (20.0) |
| Symptomatology | ||||||||
| Behavioural changes | 6 (23.1) | 0 | 0 | 1 (20) | 2 (50.0) | 0 | 0 | 3 (60.0) |
| Cognitive decline | 12 (46.2) | 0 | 2 (66.7) | 2 (40) | 4 (100.0) | 0 | 0 | 4 (80.0) |
| Drooling of saliva | 2 (7.7) | 1 (20.0) | 0 | () | 0 | 0 | 0 | 1 (20.0) |
| Pseudobulbar affect | 4 (15.4) | 0 | 0 | 2 (40) | 0 | 0 | 0 | 2 (40.0) |
| Epilepsy | 4 (15.4) | 0 | 1 (33.3) | 0 | 1 (25.0) | 0 | 0 | 2 (40.0) |
| Examination | ||||||||
| Strabismus | 4 (15.4) | 3 (60.0) | 0 | 1 (20) | 0 | 0 | 0 | 0 |
| Optic atrophy | 1 (3.8) | 1 (20.0) | 0 | 0 | 0 | 0 | 0 | 0 |
| Nystagmus | 3 (11.5) | 2 (40.0) | 1 (33.3) | 0 | 0 | 0 | 0 | 0 |
| Gaze restriction | 11 (42.3) | 2 (40.0) | 0 | 1 (20) | 3 (75.0) | 0 | 2 (100) | 3 (60.0) |
| Speech abnormality | ||||||||
| Mild | 2 (7.7) | 1 (20.0) | 0 | 0 | 0 () | 0 | 0 | 1 (20.0) |
| Moderate | 7 (26.9) | 0 | 2 (66.7) | 2 (40) | 1 (25.0) | 0 | 1 (50.0) | 1 (20.0) |
| Severe | 2 (7.7) | 0 | 1 (33.3) | 0 | 0 | 0 | 0 | 1 (20.0) |
| Normal | 15 (57.7) | 4 (80.0) | 0 | 3 (60) | 3 (75.0) | 2 (100) | 1 (50.0) | 2 (40.0) |
| Dysarthria types | ||||||||
| Spastic | 2 (7.7) | 0 | 0 | 0 | 0 | 0 | 1 (50.0) | 1 (20.0) |
| Hyperkinetic | 6 (23.1) | 1 (20.0) | 2 (66.7) | 1 (20) | 1 (25.0) | 0 | 0 | 1 (20.0) |
| Ataxic | 2 (7.7) | 0 | 0 | 2 (7.7) | 0 | 0 | 0 | 0 |
| Anarthria | 2 (7.7) | 0 | 1 (33.3) | 0 | 0 | 0 | 0 | 1 (20.0) |
| Normal speech | 14 (53.8) | 4 (80.0) | 0 | 2 (0) | 0 | 2 (100) | 1 (50.0) | 2 (40.0) |
| Tone | ||||||||
| Rigidity | 12 (46.2) | 1 (20.0) | 0 | 5 (100) | 4 (100.0) | 2 (100) | 0 | 0 |
| Spasticity | 7 (26.9) | 1 (20.0) | 1 (33.3) | 0 | 0 | 0 | 0 | 5 (100.0) |
| Hypotonia | 5 (19.2) | 3 (60.0) | 2 (66.7) | 0 | 0 | 0 | 0 | 0 |
| Brisk muscle stretch reflex | 17 (65.4) | 2 (40.0) | 1 (33.3) | 2 (40) | 4 (100.0) | 1 (50.0) | 2 (100) | 5 (100.0) |
| Positive Babinski sign | 12 (46.2) | 2 (40.0) | 2 (66.7) | 3 (60) | 1 (25.0) | 0 | 0 | 4 (80.0) |
| Extrapyramidal features | ||||||||
| Dystonia | 14 (53.8) | 0 | 0 | 5 (100) | 4 (100.0) | 0 | 2 (100) | 3 (60.0) |
| Generalized | 12 (46.2) | 0 | 0 | 5 (100) | 3 (75.0) | 0 | 2 (100) | 2 (40.0) |
| Lower limb only | 1 (3.8) | 0 | 0 | 0 | 1 (25.0) | 0 | 0 | 0 |
| Finger only | 1 (3.8) | 0 | 0 | 0 | 0 | 0 | 0 | 1 (20.0) |
| Parkinsonism | 11 (42.3) | 0 | 0 | 5 (100) | 4 (100.0) | 2 (100) | 0 | 0 |
| Tremor | 7 (26.9) | 0 | 0 | 3 (60) | 2 (50.0) | 0 | 1 (50.0) | 1 (20.0) |
| Positive cerebellar signs | 14 (53.8) | 4 (80.0) | 3 (100.0) | 3 (60) | 0 | 0 | 1 (50.0) | 3 (60.0) |
| Myoclonus | 6 (23.1) | 0 | 0 | () | 4 (100.0) | 0 | 0 | 2 (40.0) |
| Contractures | 11 (42.3) | 2 (40.0) | 1 (33.3) | 3 (60) | 2 (50.0) | 0 | 0 | 3 (60.0) |
| Gait | ||||||||
| Dystonic | 11 (42.3) | 1 (20.0) | 0 | 5 (10) | 0 | 0 | 1 (50.0) | 0 |
| Ataxic | 6 (23.1) | 2 (40.0) | 2 (66.7) | 0 | 2 (50.0) | 2 (100) | 0 | 2 (40.0) |
| Spastic | 4 (15.4) | 1 (20.0) | 1 (33.3) | 0 | 0 | 0 | 0 | 2 (40.0) |
| Normal | 5 (19.2) | 1 (20.0) | 0 | 0 | 2 (50.0) | 0 | 1 (50.0) | 1 (20.0) |
| EEG (n = 6) | ||||||||
| Abnormal EEG | 4/6 (66.7) | 1/2 (50.0) | 1/1 (100) | 0 | 0 | 0 | 0 | 2/2 (100) |
| Generalized slowing | 2/6 (33.3) | 0 | 1/1 (100) | 0 | 0 | 0 | 0 | 1/2 (50.0) |
| Focal IEDs | 2/6 (33.3) | 1/2 (50.0) | 0 | 0 | 0 | 0 | 0 | 1/2 (50.0) |
| Normal | 2/6 (33.3) | 1/2 (50.0) | 0 | 1/1 (100) | 0 | 0 | 0 | 0 |
| Abnormal nerve conduction study | 2/10 (20.0) | 1/2 (50.0) | 0/1 | 1/4 (25.0) | 0 | 0 | 0/1 | 0/2 |
| MRI | n = 25 | n = 5 | n = 3 | n = 5 | n = 4 | n = 2 | n = 2 | n = 4 |
| Mineralization | ||||||||
| Caudate | 9 (34.6) | 1 (20.0) | 0 | 3 (60) | 2 (50.0) | 0 | 0 | 3 (75.0) |
| Putamen | 8 (30.8) | 1 (20.0) | 0 | 3 (60) | 1 (25.0) | 0 | 0 | 3 (75.0) |
| GPi | 14 (53.8) | 2 (40.0) | 2 (66.7) | 5 (100) | 1 (25.0) | 1 (50.0) | 0 | 3 (75.0) |
| Substantia nigra | 14 (53.8) | 2 (40.0) | 2 (66.7) | 4 (80) | 1 (25.0) | 1 (50.0) | 0 | 4 (100.0) |
| Atrophy | ||||||||
| Caudate | 4 (15.4) | 0 | 0 | 1 (20) | 2 (50.0) | 0 | 0 | 1 (25.0) |
| Cerebral | 10 (38.5) | 1 (20.0) | 1 (33.3) | 2 (40) | 3 (75.0) | 0 | 0 | 3 (75.0) |
| Frontal predominant | 3 (11.5) | 0 | 0 | 1 (20) | 1 (25.0) | 0 | 0 | 1 (25.0) |
| Corpus callosum | 1 (3.8) | 1 (20.0) | 0 | 0 | 0 | 0 | 0 | 0 |
| Optic nerve | 2 (7.7) | 1 (20.0) | 1 (33.3) | 0 | 0 | 0 | 0 | 0 |
| Cerebellar | 23 (88.5) | 5 (100) | 3 (100.0) | 5 (100) | 3 (25.0) | 1 (50.0) | 2 (100) | 4 (100) |
| White matter signal changes | 12 (46.2) | 2 (40.0) | 2 (66.7) | 4 (80) | 1 (25.0) | 0 | 0 | 3 (75.0) |
| Claval hypertrophy | 10 (38.5) | 4 (80.0) | 1 (33.3) | 2 (40) | 0 | 1 (50.0) | 0 | 2 (50.0) |
| Response to Levodopa | 12/14 (85.7) | 0 | 0 | 5/5 (100) | 4/4 (100.0) | 2/2 (100) | 1/2 (50.0) | 0/1 |
| Levodopa-induced-Dyskinesia | 10/11 (90.9) | 0 | 0 | 4/5 (80) | 4/4 (100.0) | 2/2(100) | 0 | 0 |
[i] aNAD: Atypical neuroaxonal dystrophy; cHSP: Complicated Hereditary spastic paraparesis; DP: Dystonia parkinsonism; DPM: Dystonia parkinsonism myoclonus; EEG: Electroencephalograph; EOP: Early onset Parkinsonism; INAD: Infantile Neuroaxonal Dystrophy; IQR: Inter quartile range.
Figure 1
Magnetic resonance imaging of the brain of selected patients. A: Patient of early-onset parkinsonism (Patient-22). T1 mid-sagittal image showing claval (gracile tubercle) hypertrophy (yellow arrow). B: Patient of infantile neuroaxonal dystrophy (Patient-12). T2 mid-sagittal image showing vertically oriented splenium of the corpus callosum (red dotted circle). C: Patient of atypical neuroaxonal dystrophy (Patient-16). T2 coronal (C-1) and axial (C-2) images showing bilateral optic nerve atrophy (red arrow). D: Patient of complicated hereditary spastic paraparesis (Patient-13). SWI image showing mineralization of bilateral caudate (D-1, yellow arrowhead), putamen, globus pallidi (D-2, red arrow head), and substantia nigra (D-3, green arrow head). E: Patient of complicated hereditary spastic paraparesis (Patient-19). Fluid attenuated inversion recovery (FLAIR) axial image showing atrophy of bilateral caudate and generalized cerebral atrophy (white arrow). It also shows FLAIR hypointensity of bilateral putamen and globus pallidi.
Figure 2
Overview of the variants identified in this cohort. Image depicting the location of the identified variants in the PLA2G6 gene (Transcript ID: NM_003560.4). Novel variants are in italics, pathogenic variants are in red, likely pathogenic variants are in black and variant of uncertain significance are in blue.
Table 2
Details of disease-causing variants (Transcript ID: NM_003560.4).
| FAMILY | PATIENT NO | AGE (YEARS) | GENDER | AAO (YEARS) | FAMILY HISTORY | CONSANGUINITY | FIRST SYMPTOM | CLINICAL PHENOTYPE | EXON | c.DNA | PROTEIN CHANGE | CONSEQUENCE | ACMG CRITERIA | ZYGOSITY | NOVEL |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 1 | 22 | F | 19.5 | – | III | Slowness of ADL | DP | 15 | c.2239C>T | p.Arg747Trp | Missense | Pathogenic (PS3PP5PM1PM2PP2PP3) | Hm | – |
| 2 | 2 | 34 | F | 26 | + | III | Behavioural changes | DP | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 3 | 3 | 1.9 | M | 0.5 | + | No | Developmental regression | INAD | 12 | c.1723delT | p.Thr575 Argfs*8 | Frameshift | Likely pathogenic (PVS1PM2) | Hm | + |
| 4 | 4 | 29 | F | 15 | + | No | Walking difficulty and leg posturing | DP | 5 | c.763C>T | p.Pro255Ser | Missense | VUS-LP (PM2PP2PP4) | Hm | + |
| 5 | 5 | 1.9 | M | 1.4 | – | III | Developmental regression | INAD | 12 | c.1612C>T | p.Arg538Cys | Missense | Pathogenic (PM5PS3PM1PM2PP2PP3PP5) | Hm | – |
| 6 | 6 | 29 | M | 12 | + | II | Cognitive decline | DPM | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 6 | 7 | 24 | F | 12 | + | II | Cognitive decline | DPM | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 7 | 8 | 21 | M | 20 | – | No | Speaking difficulty | cHSP | 3 | c.292T>C | p.Ser98Pro | Missense | VUS–LP (PM2PP2PP4) | Hm | + |
| 8 | 9 | 8 | M | 2 | – | No | Slurring of speech | ANAD | 10 | c.1547C>T | p.Ala516Val | Missense | Pathogenic (PM1PM2PP2PP3PP5) | CH | – |
| 10 | c.1471C>T | p.Leu491Phe | Missense | Likely pathogenic (PM1PM2PP2PP3) | CH | + | |||||||||
| 9 | 10 | 7 | F | 4 | – | No | Walking difficulty | ANAD | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | CH | – |
| 13 | c.1763T>C | p.Leu588Pro | Missense | Likely pathogenic (PM1PM2PP2PP3) | CH | + | |||||||||
| 10 | 11 | 28 | M | 25 | – | No | Slowness of ADL | EOP | 15 | c.2197G>C | p.Asp733His | Missense | Likely pathogenic (PM2PP2PP3PP4) | CH | + |
| 14 | c.1897G>A | p.Ala633Thr | Missense | Likely pathogenic (PM1PM2PM5PP2PP3) | CH | + | |||||||||
| 11 | 12 | 2 | F | 1 | – | II | Regression of milestones | INAD | 5 | c.667C>A | p.Pro223Thr | Missense | Likely pathogenic (PM2PM5PP3PP4) | Hm | + |
| 12 | 13 | 26 | F | 16 | + | II | Toe walking | cHSP | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 14 | 32 | M | 20 | + | II | Ataxia | cHSP | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – | |
| 13 | 15 | 3.5 | F | 2 | – | III | Regression of milestones | INAD | 13 | c.1799G>A | p.Arg600Gln | Missense | Pathogenic (PM1PM2PM5PP2PP3PP5) | Hm | – |
| 14 | 16 | 5 | M | 3 | – | No | Regression of milestones | ANAD | 3 | c.379G>A | p.Val127Met | Missense | VUS–LP (PM2PP2PP4) | Hm | + |
| 15 | 17 | 29 | M | 14 | – | No | Behavioural issues | DP | 6 | c.835delA | p.Ile279SerfsTer26 | Frameshift | Pathogenic (PVS1PM2) | CH | + |
| 7 | c.991G>T | p.Asp331Tyr | Missense | Pathogenic (PM1PM2PM5PP2PP3PP5) | CH | – | |||||||||
| 16 | 18 | 36 | F | 10 | – | No | Toe walking and running since childhood | DP | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 17 | 19 | 23 | M | 18 | + | II | Left leg dragging followed by walking difficulty | cHSP | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 18 | 20 | 28 | M | 24 | + | No | Slowness in daily activity | DPM | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 18 | 21 | 31 | M | 28 | + | No | Memory impairment | DPM | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 19 | 22 | 30 | F | 28 | – | Yes | Slowness of ADL | EOP | 17 | c.2405T>C | p.Leu802Pro | Missense | VUS-LP (PM2PM3PP2PP4) | Hm | + |
| 20 | 23 | 2 | M | 1.5 | – | II | Developmental regression | INAD | 14 | c.1903C>T | p.Arg635Ter | Stop gain | Pathogenic (PVS1PM2PP5) | Hm | – |
| 21 | 24 | 22 | F | 22 | + | II | Posturing and tremulousness of head and right upper limb | cDYT | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 21 | 25 | 20 | M | 11 | + | II | Posturing and tremulousness of head and right upper limb | cDYT | 15 | c.2222G>A | p.Arg741Gln | Missense | Pathogenic (PS3PP5PM1PM2PM5PP2) | Hm | – |
| 22 | 26 | 15 | M | 5 | – | No | Walking difficulty, stiff leg | cHSP | 17 | c.2370T>G | p.Tyr790Ter | Stop gain | Pathogenic (PVS1PS3) | CH | – |
| 17 | c.2405T>C | p.Leu802Pro | Missense | Likely pathogenic (PM2PM3PP2PP4) | CH | + |
[i] +: Yes; –: No.
AAO: Age at onset; ACMG: American College of Medical Genetics; ADL: Activity of daily living; ANAD: Atypical neuroaxonal dystrophy; cDNA: complementary Deoxyribonucleic acid; cDYT: Complex dystonia; CH: Compound heterozygous; cHSP: complicated Hereditary spastic paraparesis; DP: Dystonia parkinsonism; DPM: Dystonia parkinsonism myoclonus; EOP: Early onset Parkinsonism; F: Female; Hm: Homozygous; INAD: Infantile Neuroaxonal Dystrophy; M: Male; PLAN: PLA2G6-associated neurodegeneration; VUS-LP: Variant of uncertain significance probably likely pathogenic.
Video 1
Video of Patient-13 with complicated Hereditary Spastic Paraparesis. Video of Patient-13 demonstrating pseudobulbar affect, mild dysarthria, mild clumsiness in hands, incoordination in left upper limb and bilateral lower limbs with spastic-ataxic gait. In addition, the patient had spasticity and brisk deep tendon reflexes in all four limbs with bilateral extensor plantar response (not shown in the video). Exome sequencing revealed homozygous c.2222G>A;p.Arg741Gln pathogenic missense variant. The video was taken after written informed consent was obtained for video recording, and publication in print and online.
Video 2
Video of Patient-7 with dystonia-parkinsonism-myoclonus phenotype. Video of Patient-7 demonstrating reduced facial expression, left more than right rest tremor, and distal appendicular predominant generalized dystonia. Post-levodopa, the patient developed generalized choreiform dyskinesia with partial improvement in parkinsonism and dystonia. In addition, the patient had facial predominant perioral action-induced myoclonus and pyramidal signs (not shown in the video). Exome sequencing revealed homozygous c.2222G>A;p.Arg741Gln pathogenic missense variant. The video was taken after written informed consent was obtained for video recording, and publication in print and online.
Video 3
Video of Patient-25 with complex dystonia. Video of Patient-25 demonstrating cervical predominant generalized dystonia with left torticollis with frequent spasmodic retrocollis, mild dystonia in outstretched hands with dystonic right thumb tremor, and truncal tilt to right on walking. In addition, the patient had mild cerebellar signs and brisk deep tendon reflexes. Exome sequencing revealed homozygous c.2222G>A;p.Arg741Gln pathogenic missense variant. The video was taken after written informed consent was obtained for video recording, and publication in print and online.
Table 3
Table comparing clinical features between our cohort and the MDSgene cohort.
| CURRENT COHORT (n = 26) (%) | MDS GENE COHORT (n = 161) (%)* | |
|---|---|---|
| Gender | ||
| Male | 15 | 62 |
| Female | 11 | 78 |
| Missing data | 0 | 21 |
| Age at Onset, Year (median, IQR) | 13.0 (2.7–20.5) | 7 (2–24)# |
| Global Developmental Delay | 9 (34.6) | 28/55 (50.9) |
| Symptoms at the onset | ||
| Developmental regression | 6 (23.1) | 12/88 (13.6) |
| Behavioral symptoms | 2 (7.7) | 9/88 (10.2) |
| Dystonia | 2 (7.7) | 1/88 (1.1) |
| Gait disturbances | 7 (26.9) | 6/88 (6.8) |
| Bradykinesia | 4 (15.4) | 5/88 (5.6) |
| Dysarthria | 2 (7.7) | 1/88 (1.1) |
| Symptomatology | ||
| Behavioral changes& | 6 (23.1) | – |
| Psychosis | 4 (15.4) | 18/35 (51.4) |
| Anxiety | 2 (7.7) | 9/20 (45.0) |
| Depression | 2 (7.7) | 17/35 (48.6) |
| Cognitive decline | 12 (46.2) | 82/91 (90.1) |
| Strabismus | 4 (15.4) | 41/52 (78.8) |
| Epilepsy | 4 (15.4) | 34/66 (51.5) |
| Optic atrophy | 1 (3.8) | 47/52 (94.0) |
| Nystagmus | 3 (11.5) | 64/70 (91.4) |
| Gaze restriction | 11 (42.3) | 18/19 (94.7) |
| Dysarthria | 11 (42.3) | 33/44 (75.0) |
| Tone | ||
| Rigidity | 12 (46.2) | 60/73 (82.2) |
| Spasticity | 7 (26.9) | 51/55 (92.7) |
| Hypotonia | 5 (19.2) | 55/55 (100) |
| Brisk muscle stretch reflex | 17 (65.4) | 44/71 (62.0) |
| Positive Babinski sign | 12 (46.2) | 118/121 (97.5) |
| Extrapyramidal features | ||
| Dystonia | 14 (53.8) | 57/99 (57.6) |
| Generalized | 12 (46.2) | 6/44 (13.6) |
| Lower limb | 1 (3.8) | 12/38 (31.6) |
| Parkinsonism | 11 (42.3) | 55/79 (69.6) |
| Tremor | 7 (26.9) | 10/12 (83.3) |
| Positive cerebellar signs | 14 (53.8) | 44/52 (84.6) |
| Myoclonus | 6 (23.1) | 4/4 (100) |
| Gait disturbance | 21 (80.8) | 43/43 (100) |
| Dyskinesia | 10 (38.5) | 30/41 (73.2) |
[i] * Information for all 161 patients was not accessible; every variable exhibited missing data, resulting in a fluctuating denominator for each variable. The denominator does not include missing data and is only sum of positive and negative wherever data was available.
# Missing data = 36 (31.3%).
& Patients exhibited multiple behavioral symptoms, including depression, psychosis, and anxiety, either individually or in combination.
IQR: Inter quartile range.
Table 4
Review of the patients of PLAN with cHSP phenotype.
| CURRENT STUDY (n = 5) | CHENG ET AL. 2022 (n = 1) | KOH ET AL. 2018 (n = 6) | CHEN ET AL. 2018 (n = 2) | OZES ET AL. 2017 (n = 2) | |
|---|---|---|---|---|---|
| Gender (Male: Female) | 4:1 | Female | 2:4 | 1:1 | NA |
| Age, Year (median, IQR) | 23.0 (18.0–29.0) | 13 | NA | 26 (20–32) | NA |
| AAO, Year (median, IQR) | 18.0 (10.5–20.0) | 6 | Infantile = 2 1 year = 2 10 years = 1 66 years = 1 | 19 (7–31) | 9year 21year |
| DOI, month (median, IQR) | 10.0 (3.0–11.0) | 7 years | NA | 7 (1–13) Years | NA |
| Consanguinity (n, %) | 3 (60.0) | NA | NA | NA | NA |
| Positive family history n, %) | 3 (60.0) | 0 | NA | 1 (50) | NA |
| Developmental Delay | 1 (20.0) | NA | NA | 1 (50) | NA |
| Dysmorphism | 0 | 0 | NA | 0 | NA |
| Symptoms at the onset | |||||
| Developmental regression | 0 | Yes | NA | 0 | 0 |
| Cognitive decline | 0 | Yes | 2 | 1 (50) | 0 |
| Behavioural symptoms | 0 | 0 | 0 | 0 | 0 |
| Abnormal Posturing | 0 | 0 | 0 | 0 | 0 |
| Walking difficulty | 4 (80.0) | Yes | 4 | 1 (50) | Yes |
| Slowness | 0 | 0 | 0 | 0 | 0 |
| Change in speech | 1 (20.0) | 0 | 0 | 0 | 0 |
| Symptomatology | |||||
| Behavioural changes | 3 (60.0) | Yes | NA | 1 (50) | Yes (1/2, 50%) |
| Cognitive decline | 4 (80.0) | Yes | 5 | 1 (50) | 0 |
| Drooling of saliva | 1 (20.0) | 0 | NA | NA | 0 |
| Pseudobulbar affect | 2 (40.0) | 0 | NA | NA | 0 |
| Strabismus | 0 | 0 | NA | 0 | 0 |
| Optic atrophy | 0 | 0 | NA | 0 | 0 |
| Nystagmus | 0 | 0 | NA | 0 | 0 |
| Epilepsy | 2 (40.0) | 0 | NA | 0 | 0 |
| Gaze restriction | 3 (60.0) | 0 | NA | 0 | 0 |
| Speech abnormality | 3 (60.0) | 0 | NA | 1 (50) | 2 (100) |
| Tone | |||||
| Spasticity | 5 (100.0) | 1 (100) | 6 (100) | 2 (100) | 2 (100) |
| Brisk muscle stretch reflex | 5 (100.0) | 1 (100) | 6 (100) | 2 (100) | 2 (100) |
| Positive Babinski sign | 4 (80.0) | 1 (100) | 6 (100) | 2 (100) | 2 (100) |
| Extrapyramidal features | 2 (33.3) | ||||
| Dystonia | 3 (60.0) | 1 (100) | NA | 2 (100) | 0 |
| Generalized | 2 (40.0) | – | NA | NA | – |
| Lower limb only | 0 | – | NA | NA | – |
| Finger only | 1 (20.0) | – | NA | NA | – |
| Parkinsonism | 0 | 0 | NA | NA | 0 |
| Tremor | 1 (20.0) | 0 | NA | NA | 0 |
| Contractures | 3 (60.0) | 0 | NA | NA | 0 |
| Positive cerebellar signs | 3 (60.0) | 0 | 3 (50) | 2 (100) | 1 (50) |
| Gait Dystonic Ataxic Spastic | 0 2 (40.0) 2 (40.0) | 0 0 1 (100) | NA | 0 0 2 (100) | 0 0 2 (100) |
| Myoclonus | 2 (40.0) | 0 | NA | NA | 0 |
| Abnormal EEG | 1/2 (20.0) | ||||
| Generalized slowing | 0 | NA | NA | NA | NA |
| Focal IEDs | 1/2 (20.0) | ||||
| Normal | 1/2 (50.0) | ||||
| Neuropathy | 0 | NA | NA | NA | NA |
| Response to Levodopa | 0 | NA | NA | NA | 1 (50) |
| Dyskinesia | 0 | NA | NA | NA | 0 |
| Neuroimaging | n = 4 | n = 1 | n = 6 | n = 2 | n = 2 |
| Mineralization | 4 (100) | 1 (100) | 2 (33.3) | 1 (50) | 2 (100) |
| Caudate | 3 (75.0) | 0 | 0 | 0 | 0 |
| Putamen | 3 (75.0) | 0 | 0 | 0 | 0 |
| GPi | 3 (75.0) | 1 (100) | 2 (33.3) | 1 (50) | 2 (100) |
| Substantia nigra | 4 (100.0) | 1 (100) | 0 | 1 (50) | 1 (50) |
| Atrophy | |||||
| Caudate | 1 (25.0) | 0 | 0 | 0 | 0 |
| Cerebral | 3 (75.0) | 1 (100) | 0 | 0 | 0 |
| Corpus callosum | 0 | 0 | 0 | 0 | 0 |
| Optic nerve | 0 | 0 | 0 | 0 | 0 |
| Cerebellar | 4 (100) | 1 (100) | 5 (83.3) | 2 (100) | 0 |
| White matter signal changes | 3 (75.0) | 0 | 0 | 0 | 0 |
| Claval hypertrophy | 2 (50.0) | 0 | 0 | 0 | 1 (50) |
| Genetic analysis | c.2222G>A (n = 3, 2 families) c.2370T>G (n = 1) c.292T>C (n = 1) | c.1427 + 2T>A | c.517C>T/c.1634 A>G (n = 2, same family) c.662T>C/c.991G>T (n = 1) c.1187-2A>G/c.1933C>T (n = 2, same family) c.1904G>A (n = 1) | c.1511C>T/ c.1117G>A (n = 1) c.991G>T/ c.1982C>T (n = 1) | c.1786C>T (n = 2, same family) |
[i] AAO: Age at onset; cHSP: Complicated Hereditary spastic paraparesis; DOI: Duration of illness; IQR: Inter quartle range; NA = Not available.
Table 5
Review of the patients of PLAN with homozygous c.2222G>A variant.
| VARIABLE (N, % UNLESS SPECIFIED) | CURRENT STUDY (N = 12, 8 FAMILIES) | REVIEW OF LITERATURE (N = 19) |
|---|---|---|
| Clinical | ||
| Phenotype | cHSP = 3; DPM = 4; DP = 2; ANAD = 1; cDYT = 2 | DP = 16 EOP = 3 |
| Gender (Male: Female) | 6:6 | 9:10 |
| Age, Year (median, IQR) | 27.0 (22.25–31.75) | 28.0 (24.0–33.0) |
| AAO, Year (median, IQR) | 17.0 (11.25–23.5) | 22.0 (16.0–25.0) |
| DOI, month (median, IQR) | 12.0 (3.25–12) | 6.5 (3.0–11.3) |
| Consanguinity | 5/8 families (62.5) | 13 (72.2) |
| Positive family history | 10 (83.3) | 15 (78.9) |
| Developmental Delay | 3 (25) | 1/10 (10) |
| Dysmorphism | 0 | – |
| Symptoms at the onset | * | |
| Cognitive decline | 3 (25) | 1 (5.6) |
| Behavioural symptoms | 1 (8.3) | 12 (66.7) |
| Abnormal Posturing | 2 (16.7) | 0 |
| Walking difficulty | 5 (41.7) | 3 (16.7) |
| Parkinsonism | 1 (8.3) | 2 (11.1) |
| Symptomatology | ||
| Behavioural changes | 5 (41.7) | 17/18 (94.4) |
| Cognitive decline | 6 (50) | 18/18 (100) |
| Pseudobulbar affect | 3 (25) | 10/16 (62.5) |
| Speech abnormality | 3 (25) | 10/14 (66.7) |
| Optic atrophy | 0 | 2/2 (100) |
| Gaze restriction | 8 (66.7) | – |
| Tone | ||
| Rigidity | 6 (50) | 16 (88.9) |
| Spasticity | 3 (25) | 2 (11.1) |
| Hypotonia | 1 (8.3) | NA = 1 |
| Brisk muscle stretch reflex | 10 (83.3) | 16/16 (100) |
| Positive Babinski sign | 6 (50) | 7/15 (46.7) |
| Extrapyramidal features | ||
| Dystonia | 9 (75) | 14 (73.7) |
| Generalized | 8 (66.7) | – |
| Lower limb only | 1 (8.3) | – |
| Finger only | 0 | – |
| Parkinsonism | 6 (50) | 19 (100) |
| Tremor | 6 (50) | 10/18 (55.6) |
| Positive cerebellar signs | 6 (50) | 2/16 (12.5) |
| Myoclonus | 5 (41.7) | 6/17 (35.3) |
| Contractures | 6 (50) | |
| Gait | ||
| Dystonic | 6 (50) | – |
| Ataxic | 1 (8.3) | – |
| Spastic | 3 (25) | |
| Response to Levodopa | 1 (11.1) | 18/18 (100) |
| Levodopa-induced Dyskinesia | 4 (44.4) | 12/18 (66.7) |
| Neuroimaging | ||
| Mineralization | ||
| Caudate | 6/11 (54.6) | 2/16 (12.5) |
| Putamen | 5/11 (45.5) | 3/16 (18.8) |
| GPi | 4/11 (36.4) | 3/16 (18.8) |
| Substantia nigra | 5/11 (45.5) | 2/16 (12.5) |
| Atrophy | ||
| Caudate | 4/11 (36.4) | – |
| Cerebral | 6/11 (54.6) | 14/18 (77.8) |
| Frontal predominant | 3/11 (27.3) | 4/18 (22.2) |
| Optic nerve | 0 | 2/16 (12.5) |
| Cerebellar | 10/11 (90.9) | 11/18 (61.1) |
| White matter signal changes | 5/11 (45.5) | 1/18 (5.6) |
[i] cHSP: Complicated Hereditary spastic paraparesis, DPM: Dystonia parkinsonism myoclonus.
DP: Dystonia parkinsonism, EOP: Early onset Parkinsonism, ANAD: Atypical neuroaxonal dystrophy.
*Based on the availability of the information, denominators are variable, in this case data of 15 patients were available for analysis.
NA = Not available.