Table 4.

Non-metabolic leukodystrophies and leukoencephalopathies with potential to mimic multiple sclerosis

Disorder	Gene; biochemical/cellular defect	Inheritance mechanism	Clinical presentation in adult-onset disease	‘Typical’ MRI appearances	Recommended diagnostic testing
Adult-onset Alexander disease	GFAP Mutant glial fibrillary acidic protein causes disordered modulation of the morphology and motility of astrocytes	AD	Bulbar/pseudobulbar signs: palatal myoclonus, dysphagia, dysarthria, spasticity, hyperreflexia, ataxia, nystagmus, dysmetria, incontinence, constipation, orthostatic hypotension, seizures, diplopia	Atrophy and T2 hyperinetnsity of medulla and cervical cord in almost all patients; cerebral T2 WM hyperintensities in most, often with with frontal predominance; hyperintensity and swelling involving basal ganglia and thalami; MRI can be normal	Molecular testing of GFAP Also consider CSF studies (increased αβ-crystallin, heat shock protein 27, and glial fibrillary acidic protein)
Autosomal Dominant Leukodystrophy (ADLD)	LMNB1 Lamin B1 overexpression causing defective oligodendroglial differentiation	AD	Early autonomic dysfunction, cognitive impairment, pyramidal lesions, cerebellar dysfunction, typical onset age 30–50 years	Subtle to extensive symmetrical WM T2 hyperintensities with frontoparietal predominance; may also involve middle cerebellar peduncles, brainstem; typically periventricular WM is spared or less affected than other regions; atrophy of corpus callosum and brain stem	Molecular testing of LMNB1 (for common duplication first; use quantitative PCR or FISH initially)
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL)	DARS2 Dysfunctional mitochondrial aspartyl-tRNA synthetase	AR	Slowly progressive cerebellar ataxia, spasticity, abnormal proprioception/vibration sense, dysarthria; epilepsy and/or learning disability in some patients	Confluent or patchy T2 hyperintensities in cerebral WM, dorsal columns and lateral corticospinal tracts of cord, and medulla; relative sparing of the U-fibres; abnormalities may also be seen in corpus callosum, internal capsule, cerebellar peduncles, spinocerebellar tracts and cerebellar WM	Molecular testing of DARS2 Also consider Magnetic resonance spectroscopy (increased lactate in abnormal cerebral white matter)
Hereditary diffuse leukencephalopathy with spheroid cysts (HDLS)	CSF1R Disordered cell-surface cytokine receptor; dysregulation of survival, proliferation, differentiation, and function of CNS microglia	AD	Executive dysfunction with frontal lobe signs, memory decline, personality changes, motor impairment, seizures; usual age of onset 25–45 years	Bifrontal or bifrontoparietal T2/FLAIR hyperintensities in deep, subcortical, and periventricular WM, often asymmetric and patchy, becoming confluent with time; involvement of corpus callosum and corticospinal tract lesions common; brain stem atrophy and contrast enhancement in brain parenchyma usually absent	Molecular testing of CSF1R Also consider CSF studies (increased neurofilament light protein)
Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL/CARASIL)	NOTCH3; HTRA1 Aggregation and accumulation of mutant Notch3 protein in cerebral vasculature causing multifactorial toxicity	AD (CADASIL) AR (CARASIL)	Progressive cerebrovascular disease from mid-adulthood, progressing to spastic paraplegia and dementia; migraine and mood disturbance	Classically T2-hyperintense WM lesions involving the temporal pole and external capsule; numerous subcortical infarcts; optic nerves and cord typically spared	Molecular testing of NOTCH3 and/or HTRA1 (as determined by mode of inheritance and presence/absence of electron-dense granules in media of arterioles) Also consider Skin biopsy (electron dense granules in arteriolar media seen in CADASIL only)
ClC-2 chloride channel deficiency leukoencephalopathy	CLCN2 Abnormal chloride ion and water homeostasis causing white matter oedema	AR	Cerebellar ataxia, SP, optic neuropathy; cognitive defects, headache, retinopathy	Restricted diffusion with T2 hyperintensity in midbrain cerebral peduncles, middle cerebellar peduncles, and posterior limb of internal capsule; possible WM hyperintensity more diffusely	Molecular testing of CLCN2
X-linked Charcot–Marie–Tooth disease (CMTX)	GJB1 Predicted reduction in number/efficiency of gap junctions between oligodendrocytes and astrocytes in CNS	X-linked	Usually accompanied by demyelinating polyneuropathy with amyotrophy, distal weakness, and pes cavus; episodic or persistent ataxia and dysarthria; sensorineural hearing loss in some families; males generally more severely affected; “relapsing” events triggered by e.g. high altitude	Non-enhancing periventricular, symmetrical, confluent white matter abnormalities with posterior predominance; T1 hypointensity in splenium of CC and middle cerebellar peduncles; new CNS abnormalities may appear acutely, especially at altitude	Molecular testing of GJB1 (connexin 32) Nerve conduction study (demyelinating/axonal polyneuropathy with moderately slowed NCV)

AD = autosomal dominant; AR = autosomal recessive; CC = corpus callosum; FISH = fluorescent in situ hybridization; MRS = magnetic resonance spectroscopy; NCV = nerve conduction velocity; SP = spastic paraparesis; WM = white matter.