Table 1.
Pathogenic and likely pathogenic variants detected in known leukodystrophy and leukoencephalopathy genes
| Patient ID | Gene | Variant | Predicted protein effect | Sex | AAO | Family history | Initial syndrome | Additional features |
|---|---|---|---|---|---|---|---|---|
| Vascular leukoencephalopathy | ||||||||
| P1 | NOTCH3 | c.505C > T | p.R169C | M | 30 | AD | Migraine with aura | Parietal ischaemic stroke |
| P2 | NOTCH3 | c.994C > T | p.R332C | M | 37 | AD | Recurrent TIA | Progressive gait deterioration, dysarthria, cognitive decline |
| P3 | NOTCH3 | c.397C > T | p.R133C | F | 36 | No | Migraine with aura | Ischaemic stroke, cognitive decline |
| P4 | NOTCH3 | c.1591T > G | p.C531G | F | 36 | AD | Prepontine SAH | Migraine with aura |
| P28 | CTSA | c.973C > T | p.R325C | F | 42 | AD | Migraine, hypertension | Mild cognitive decline, behavioural change |
| Vanishing white matter disease | ||||||||
| P5 | EIF2B4 | c.[495 + 3delA (;) 623G > A] | p.[? (;) R208Q] | F | 20 | AR | Epilepsy | Spastic tetraparesis, ataxia, cognitive decline |
| P6 | EIF2B5 | c.[338G > A];[380T > C] | p.[R113H];[L127P] | F | 53 | No | Cognitive decline | Migraine, ataxia, personality change |
| P7 | EIF2B5 | c.[338G > A];[913A > T] | p.[R113H];[M305L] | F | 52 | No | Trigeminal neuralgia | Temporal seizures, ataxia, cognitive decline |
| P8 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 31 | No | Slowly progressive hemiparesis | Cognitive decline, ataxia |
| P26 | EIF2B5 | c.[338G > A];[338G > A] | p.[R113H];[R113H] | M | 26 | No | Cognitive decline | Falls, parkinsonism |
| Hypomyelinating disorders | ||||||||
| P9 | PLP1 | c.276C > A | p.Y92* | F | 30 | AD/XLD | Spastic gait, ataxia | Executive dysfunction, impaired visual memory |
| P10 | PLP1 | c.355dupG | p.Q121Pfs*83 | M | 30 | No | Spastic gait, head tremor, | Executive dysfunction, cognitive decline, bladder/bowel disturbance |
| P12 | TUBB4A | c.G538G > A | p.V180M | F | Infancy | De novo | Spasticity, dystonia | Dysarthria, cognitive decline |
| Mitochondrial proteins | ||||||||
| P13 | DARS2 | c.[228‐20_-21 delTTinsC];[1433T > C] | p.[R76Sfs*5];[F479S] | M | 15 | No | LL weakness, neuropathy | Ataxia |
| P14 | DARS2 | c.[228‐20_-21 delTTinsC];[1456C > T] | p.[R76Sfs*5];[L486F] | F | 5 | No | Bilateral UL intention tremor, progressive gait impairment | Cognitive decline, spastic paraplegia, sensory ataxia |
| Genes involved in microglial signalling | ||||||||
| P16 | CSF1R | c.1901T > G | p.L634R | F | 53 | No | Ataxia, spasticity | Cognitive, dyspraxia |
| P17 | CSF1R | c.2570C > T | p.P857L | F | 38 | No | Spastic gait | Severe spastic tetraparesis, dystonia, cognitive decline |
| P18 | CSF1R | c.2381T > C | p.I794T | M | 52 | No | Cognitive decline | UL dyspraxia, alien limb, spasticity, parkinsonism |
| P27 | CSF1R | c.2345G > A | p.R782H | M | 46 | AD | Cognitive decline | Depression, apraxia |
| P19 | TREM2 | c.[377T > G];[377T > G] | p.[V126G];[V126G] | M | 25 | AR | Cognitive decline | Frequent generalized seizures |
| Miscellaneous | ||||||||
| P21 | RNF216 | c.[1482C > A];[1482C > A] | p.[Y494*];[Y494*] | M | 31 | Consang | Cognitive decline | Ataxia, hypogonadotrophic hypogonadism |
AAO = age at onset; AD = autosomal dominant; AR = autosomal recessive; XLD = X-linked dominant; consang = consanguineous relationship; SAH = subarachnoid haemorrhage; TIA = transient ischaemic attack; UL = upper limb; LL = lower limb.