Table 2. [Genes and Disorders of Interest...]. - GeneReviews®

Gene(s)	DiffDx Disorder	MOI	Features of DiffDx Disorder
ABCD1	Adrenomyeloneuropathy (AMN) (See X-Linked Adrenoleukodystrophy.)	XL	Slowly progressing paraparesis, sphincter control abnormalities, & sexual dysfunction in males & some heterozygous females	~20% of those w/AMN develop rapidly progressive brain involvement. ~85% have symmetric ↑ T₂-weighted signal usually in parieto-occipital region w/contrast enhancement at the advancing margin.	Impaired adrenocortical function in 2/3s of affected persons
ATXN2 ATXN3	SCA2 & SCA3 ¹	AD	Cerebellar gait ataxia, autonomic disturbances, pyramidal involvement, & dysarthria	No specific radiologic changes	Nystagmus, peripheral neuropathy, abnormal movements, & seizures
CSF1R	CSF1R-related adult-onset leukoencephalopathy w/axonal spheroids & pigmented glia	AD	Impaired balance, spasticity, gait apraxia, ataxia, & urinary incontinence.	Bifrontal or bifrontoparietal T₂-weighted hyperintensities often involving periventricular areas. (Unlike LMNB1-related ADLD, periventricular rims are not less affected.) Thin corpus callosum w/T₂-weighted hyperintense lesions; cerebral atrophy manifesting as enlarged ventricles	Frontal lobe syndrome & personality changes (which are not typical in ADLD) are predominant & usually appear early. CT shows calcifications.
DARS2	Leukoencephalopathy w/brain stem & spinal cord involvement & lactate elevation	AR	Progressive spasticity, cerebellar ataxia, dorsal column abnormalities. Dysarthria develops over time.	Lesions w/high T₂-weighted signal intensity in brain stem & spinal cord (usually in the dorsal columns & lateral corticospinal tracts) are typical, but cerebral WM can also be affected.	Personality changes, cognitive impairments, & memory decline
EIF2B1 EIF2B2 EIF2B3 EIF2B4 EIF2B5	Adult onset type of childhood ataxia w/ central nervous system hypomyelination/vanishing white matter	AR	Ataxia, spasticity w/↑ tendon reflexes; rapid deterioration during febrile illnesses	Bilateral confluent cerebral T₂-weighted hyperintensities. Part of the abnormal WM has a signal intensity close to that in CSF w/all sequences. Severe cerebral atrophy can be observed in adult-onset forms w/slow progression.	Cognitive decline & personality changes dominate. Often ovarian failure. Optic atrophy & epilepsy may occur.
GALC	Adult-onset Krabbe disease	AR	Affected persons present w/signs of pyramidal tract dysfunction; spastic paraparesis is a prominent sign. Peripheral neuropathy, dysarthria, & cerebellar ataxia are not unusual. ²	Upper corticospinal tracts are always affected on T₂-weighted images – similar to abnormalities in asymptomatic persons w/LMNB1-related ADLD. However, in adult-onset Krabbe disease, these tracts are less often affected in the brain stem, esp in the medulla oblongata. ↑ T₂-weighted signal intensity is also seen periventricularly along trigonal wall & optic radiations & in posterior corpus callosum. ³ Thus, the abnormalities have a more posterior distribution than in LMNB1-related ADLD.
GBE1	GBE1 adult polyglucosan body disease	AR	Neurogenic bladder, spasticity & weakness from mixed upper & lower motor neuron involvement, sensory loss mainly in distal lower extremities	Paraventricular, subcortical, & deep slowly progressive WM changes that may incl involvement of the upper pons, superior cerebellar peduncles, dentate nuclei, & anterior medulla (incl the olives) often extending to the level of the cervico-medullary junction; slowly progressive cerebral, cerebellar, & spinal cord atrophy
GFAP	Adult form of Alexander disease	AD	Pyramidal signs (spasticity, hyperreflexia, positive Babinski sign), cerebellar ataxia, dysautonomia	Focal T₂-weighted hyperintensities in the brain stem, cerebellar WM, & cervical spinal cord w/mass effect & contrast enhancement in active phases. After the active phase, atrophy develops. Supratentorial WM abnormalities may occur.	Bulbar & pseudobulbar signs are early or only signs in adult-onset Alexander disease but very late signs in LMNB1-related ADLD.

Gene(s)

DiffDx Disorder

MOI

Features of DiffDx Disorder

Overlapping w/LMNB1-related ADLD

Distinguishing from LMNB1-related ADLD

MRI Findings

Other Features

ABCD1

Adrenomyeloneuropathy (AMN) (See X-Linked Adrenoleukodystrophy.)

Slowly progressing paraparesis, sphincter control abnormalities, & sexual dysfunction in males & some heterozygous females

~20% of those w/AMN develop rapidly progressive brain involvement. ~85% have symmetric ↑ T₂-weighted signal usually in parieto-occipital region w/contrast enhancement at the advancing margin.

Impaired adrenocortical function in 2/3s of affected persons

ATXN2
ATXN3

SCA2 & SCA3 ¹

Cerebellar gait ataxia, autonomic disturbances, pyramidal involvement, & dysarthria

No specific radiologic changes

Nystagmus, peripheral neuropathy, abnormal movements, & seizures

CSF1R

Impaired balance, spasticity, gait apraxia, ataxia, & urinary incontinence.

Bifrontal or bifrontoparietal T₂-weighted hyperintensities often involving periventricular areas. (Unlike LMNB1-related ADLD, periventricular rims are not less affected.) Thin corpus callosum w/T₂-weighted hyperintense lesions; cerebral atrophy manifesting as enlarged ventricles

Frontal lobe syndrome & personality changes (which are not typical in ADLD) are predominant & usually appear early.
CT shows calcifications.

DARS2

Leukoencephalopathy w/brain stem & spinal cord involvement & lactate elevation

Progressive spasticity, cerebellar ataxia, dorsal column abnormalities. Dysarthria develops over time.

Lesions w/high T₂-weighted signal intensity in brain stem & spinal cord (usually in the dorsal columns & lateral corticospinal tracts) are typical, but cerebral WM can also be affected.

Personality changes, cognitive impairments, & memory decline

EIF2B1
EIF2B2
EIF2B3
EIF2B4
EIF2B5

Adult onset type of childhood ataxia w/ central nervous system hypomyelination/vanishing white matter

Ataxia, spasticity w/↑ tendon reflexes; rapid deterioration during febrile illnesses

Bilateral confluent cerebral T₂-weighted hyperintensities. Part of the abnormal WM has a signal intensity close to that in CSF w/all sequences. Severe cerebral atrophy can be observed in adult-onset forms w/slow progression.

Cognitive decline & personality changes dominate. Often ovarian failure. Optic atrophy & epilepsy may occur.

GALC

Adult-onset Krabbe disease

Affected persons present w/signs of pyramidal tract dysfunction; spastic paraparesis is a prominent sign. Peripheral neuropathy, dysarthria, & cerebellar ataxia are not unusual. ²

Upper corticospinal tracts are always affected on T₂-weighted images – similar to abnormalities in asymptomatic persons w/LMNB1-related ADLD. However, in adult-onset Krabbe disease, these tracts are less often affected in the brain stem, esp in the medulla oblongata. ↑ T₂-weighted signal intensity is also seen periventricularly along trigonal wall & optic radiations & in posterior corpus callosum. ³ Thus, the abnormalities have a more posterior distribution than in LMNB1-related ADLD.

GBE1

GBE1 adult polyglucosan body disease

Neurogenic bladder, spasticity & weakness from mixed upper & lower motor neuron involvement, sensory loss mainly in distal lower extremities

Paraventricular, subcortical, & deep slowly progressive WM changes that may incl involvement of the upper pons, superior cerebellar peduncles, dentate nuclei, & anterior medulla (incl the olives) often extending to the level of the cervico-medullary junction; slowly progressive cerebral, cerebellar, & spinal cord atrophy

GFAP

Adult form of Alexander disease

Pyramidal signs (spasticity, hyperreflexia, positive Babinski sign), cerebellar ataxia, dysautonomia

Focal T₂-weighted hyperintensities in the brain stem, cerebellar WM, & cervical spinal cord w/mass effect & contrast enhancement in active phases. After the active phase, atrophy develops. Supratentorial WM abnormalities may occur.

Bulbar & pseudobulbar signs are early or only signs in adult-onset Alexander disease but very late signs in LMNB1-related ADLD.

From: LMNB1-Related Autosomal Dominant Leukodystrophy

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Adam MP, Feldman J, Mirzaa GM, et al., editors.

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