Table 1.

Lysosomal and peroxisomal disorders with potential to mimic multiple sclerosis

Disorder	Gene(s); biochemical defect	Inheritance mechanism	Neurologic presentations in adult-onset disease	‘Typical’ MRI appearances	Recommended diagnostic testing
Globoid cell leukodystrophy (Krabbe disease)	GALC Galactocerebrosidase (GALC) deficiency; lysosomal accumulation of incompletely metabolized galacto-cerebroside and galacto-sylsphingosine (psychosine)	AR	SP and gait dysfunction, cognitive deterioration, clumsiness; lower extremity paraesthesia and visual loss reported rarely	T2/FLAIR hyperintensities involving CS or pyramidal tracts are characteristic. Symmetric periventricular T2/FLAIR WM hyperintensity, predominantly posterior (parieto-occipital) with common involvement of the splenium of the CC; U-fibres generally spared	GALC activity, lymphocytes (decreased) Molecular testing of GALCa Also consider: Nerve conduction studies (demyelinating or axonal neuropathy with delayed NCV) Protein analysis, CSF (normal or increased)
Metachromatic leukodystrophy	ARSA Arylsulphatase A (ARSA) deficiency; lysosomal accumulation of sulphatides	AR	Neuropsychiatric symptoms with cognitive deterioration progressing to dementia; spasticity and incoordination; visual failure; dystonia; peripheral neuropathy	Symmetrical ‘sheet-like’ areas of abnormal T2/FLAIR WM periventricular hyperintensity, typically with frontal predominance, progressing to involve subcortical WM while sparing the U-fibres; variable involvement of cerebellar, thalamic or projection fibre WM in advanced disease; typically no enhancement	Sulfatide analysis, urine (increased sulfatides) ARSA activity, lymphocytes (decreased)b Molecular testing of ARSA Also consider: Nerve conduction studies (acute/subacute demyelinating polyneuropathy with delayed NCV) Sural nerve/brain biopsy (metachromatic deposits) Fundal examination/retinal photography (perifoveal white patches) Protein analysis, CSF (increased)
X-linked adrenoleukodystrophy/ adrenomyeloneuropathy	ABCD1 Defect of peroxisomal β-oxidation of VLCFA	X-linked	Male hemizygotes: SP with progressive gait, spastic paraparesis and bladder dysfunction; erectile dysfunction; abnormalities of proprioception and vibration sense; headache, hemiparesis and ataxia also reported; primary adrenocortical insufficiency with/without neurologic symptoms; Female heterozygotes: 20–50% eventually develop SP or mild myelopathy, often after middle age; adrenocortical insufficiency rare	In AMN, primary involvement of frontopontine or corticospinal projection fibres; many AMN patients develop cerebral involvement limited to long tracts (posterior limbs internal capsules, brain stem) or with lobar involvement similar in appearance to childhood X-ALD (frontal or parieto-occipital); peripheral enhancement common	VLCFA analysis, plasma (increased C26 and C26:C22 ratio; normal phytanic/pristanic acid)b Molecular testing of ABCD1 Adrenocortical functionc Also consider: Nerve conduction studies (demyelinating or axonal polyneuropathy) Protein analysis, CSF (increased)
Fabry disease	GLA Deficiency of α-galactosidase A (α-gal A); accumulation of globotriasylceramide (gb3) in vascular endothelial cells, cardiomyocytes, and renal podocytes	X-linked	Temperature-sensitive acroparasthesias usually signal clinical onset of disease; anhidrosis; recurrent/chronic abdominal pain; transient TIA/stroke episodes include hemiparesis or vertigo; chronic fatigue, anxiety and depression commond	Non-specific, multifocal, asymmetric T2/FLAIR hyperintense lesions in deep and subcortical WM; progressive WM lesion load over time due to cerebral vasculopathy; T1 hyperintensities of thalamic pulvinar are characteristic but only present in 25% of patients	α-gal A activity, plasma and leucocytes (decreased)e Molecular testing of GLA Also consider: Slit lamp ophthalmologic exam (corneal haziness or opacity/whorled streaking; lenticular opacities in 30% of affected males) Skin exam (angiokeratoma) Urinalysis (proteinuria) Protein analysis, CSF (increased)
Niemann-Pick disease, type C	NPC1, NPC2 Excessive LDL uptake with deficient dysregulated cholesterol biosynthesis/ esterification and trafficking; endosomal accumulation of cholesterol	AR	Partial/generalized seizure disorder with gelastic cataplexy and vertical supranuclear gaze palsy are characteristic; also neuropsychiatric symptoms with cognitive deterioration and dementia; dystonia; dysarthria; peripheral neuropathy reported rarely	Thinning of CC with increased signal in periatrial WM; widespread GM/WM abnormalities; reduced pons:midbrain ratio; cerebellar vermian atrophy (late)	Cholesterol esterification studies/filipin staining, fibroblasts (abnormal intracellular cholesterol esterification and homoeostasis) Molecular testing of NPC1±NPC2 Also consider: Oxysterol quantification, plasmaf Abdominal ultrasound study (subclinical splenomegaly)
Chédiak-Higashi disease	LYST Regulatory defect of lysosomal trafficking; defective membrane targeting of secretory lysosomes	AR	Late-onset disease characterized by SP, spinocerebellar degeneration, parkinsonism, dystonia, cognitive deteriorationg	T2-FLAIR hyperintensity in periventricular WM becoming more prominent with time; global atrophy, especially spinocerebellar atrophy	Peripheral blood smear (abnormal PMNs with enlarged granules) Natural killer cell function (decreased/absent) Molecular testing of LYST Also consider: Skin biopsy (cutaneous amyloid deposition; abnormal pigmentation) Light microscopy of hair shaft (abnormal pigmentary clumping) Nerve conduction studies

AMN = adrenomyeloneuropathy; AR = autosomal recessive; CC = corpus callosum; CS = corticospinal; GM = grey matter; LDL = low-density lipoprotein; NCV = nerve conduction velocities; SP = spastic paraparesis; TIA = transient ischaemic attack; VLCFA = very long chain fatty acids; WM = white matter; X-ALD = X-linked adrenoleukodystrophy.

^a High prevalence of 30 kb deletion allele in Caucasian population.

^b VLCFA analysis normal in 10-20% of female heterozygotes (Moser et al., 1999); VLCFA abnormalities generally correlate poorly with clinical phenotypes.

^c Males only; 70% of adult males with adrenomyeloneuropathy phenotype have adrenal insufficiency.

^d Concurrent evidence of cardiovascular, cerebrovascular, or renal disease common; female heterozygotes can be asymptomatic with normal life expectancy or present similarly to hemizygous males with classic disease, depending on pattern of X-inactivation.

^e Full diagnostic algorithm provided in Gal et al. (2011); both plasma and leucocytes should be assayed as some mutations specifically affect trafficking of enzyme; measure of α-gal A is insufficient for detection of carrier status in females.

^f Limited availability outside of research laboratories at time of submission.

^g Adult-onset patients with mild or subclinical immunodeficiency; pigmentary abnormalities of skin, hair and retina common but less apparent than in infantile onset disease.