Autosomal dominant disorders
|
Alexander disease
|
GFAP
| Bulbar/pseudobulbar signs, ataxia, spasticity | Palatal myoclonus; cognitive function in adults frequently normal; infratentorial atrophy on MRI |
Adult-onset autosomal dominant leukodystrophy
|
LMNB1
| Cognitive impairment, pyramidal & cerebellar signs | Early autonomic dysfunction; a periventricular normal rim on MRI |
CADASIL
|
NOTCH3
| Frontal lobe syndrome, WML | Stroke-like clinical signs; multiple cerebral infarcts & WML incl the characteristic temporal pools |
MAPT-related disorders
|
MAPT
| Progresses over a few years into profound dementia w/mutism | Frontal &/or temporal atrophy w/far fewer WML |
FTD, chromosome 3-linked
|
CHMP2B
| Frontal lobe affected; pyramidal &/or extrapyramidal signs | Frontal &/or temporal atrophy w/far fewer WML |
GRN-related FTD
|
GRN
| Frontal lobe affected; pyramidal/extrapyramidal signs | Frontal &/or temporal atrophy w/far fewer WML |
C9orf72-related FTD
|
C9orf72
| Frontal lobe affected; pyramidal/extrapyramidal signs | Frontal &/or temporal atrophy w/far fewer WML |
Early-onset Alzheimer disease
| APP, PSEN1, PSEN2 | Executive dysfunction & personality changes; similar onset age | Episodic memory loss; WM changes present but much less pronounced |
Autosomal recessive disorders
|
PLOSL (Nasu-Hakola disease) | TREM2, TYROBP | Insidious personality changes, frontal lobe syndrome, motor impairments, dementia & progression to vegetative stage | Pain/tenderness of feet/wrists, polycystic osseous lesions, pathologic fractures; U-fibers partially affected |
Vanishing white matter
| EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5 | Cognitive decline, spastic paraparesis, cerebellar ataxia | Stress-induced deterioration w/minor trauma or infections; more widespread & diffuse WM changes & atrophy than in ALSP; cystic breakdown of the WM |
Adult type of metachromatic leukodystrophy |
ARSA
| Executive dysfunction, personality changes, memory issues, pyramidal signs and seizures | Peripheral neuropathy; spread of WML into the cerebellar region & WM myelin breakdown w/low-density tigroid stripes |
Adult form of Krabbe disease |
GALC
| Pyramidal signs, developing into para- or tetraparesis | Peripheral neuropathy; MRI w/predominance in the posterior part of the WM. MRI detects demyelination in the brain stem & cerebellum. T2-weighted value is progressively prolonged in the occipital deep WM & posterior part of central semiovale in late-onset disease. |
LBSL
|
DARS2
| Slowly progressive pyramidal, cerebellar, & dorsal column dysfunction; deterioration of motor skills | Peripheral neuropathy; WML are either non-homogeneous/spotty or homogeneous & confluent. Signal abnormalities are evident in the medullary pyramids, dorsal columns, & lateral corticospinal tracts. |
AARS2-related ALSP |
AARS2
| Cognitive, neuropsychiatric, & upper motor neuron signs; symmetric leukoencephalopathy w/punctate regions of restricted diffusion | Earlier age of onset of symptoms (mean age 26 yrs); ovarian failure in all women. WM demonstrates rarefaction [Lakshmanan et al 2017]. |
X-linked disorders
|
X-linked adrenoleukodystrophy
|
ABCD1
| Cognitive decline, dementia, spastic paraparesis | Neuropathy & slowly spastic paraparesis. WML are contrast enhancing. Corticospinal tracts are involved from cranial to medulla. |
Fabry disease
|
GLA
| WML | Gray matter pathology |
Mitochondrial disorders (caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA)
|
Leigh syndrome
| mtDNA deletion | Psychomotor regression; WML may be present in adult mt diseases | Strikingly different clinical presentation; brain MRI in mt diseases may demonstrate symmetric T1-weighted hypointense & T2-weighted hyperintense signal abnormalities in deep gray matter; abnormalities are not restricted to vascular territories; lesions often fluctuate over the course of the disease. Varying degrees of cerebral & cerebellar atrophy may also be present. |
MELAS
| MT-TL1 or other mtDNA genes |
Alpers-Huttenlocher syndrome
| POLG 1 |
MNGIE
| TYMP 1 |
Other (complex multifactorial inheritance/sporadic)
|
Primary progressive multiple sclerosis (PPMS) | | WML | Cognitive decline occurs later; callosomarginal lesions occur. Confluent WML in frontoparietal areas are more consistent w/CSF1R-related ALSP than w/PPMS 2. |
Susac syndrome | | Cognitive impairment, behavioral changes | Branch retinal artery inclusions, tinnitus, hearing loss, vertigo; gray matter lesions |
Frontotemporal lobar degeneration | | The combination of FTD & atypical parkinsonism is characterized by multisystem atrophy & progressive supranuclear palsy; the addition of ALS can mimic clinical ALSP. | MRI demonstrates mainly cerebral atrophy w/out the characteristic WML found in CSF1R-related ALSP. |