Table 6.

Genes of Interest in the Differential Diagnosis of the Neonatal, Infantile, and Juvenile Forms of Alexander Disease

Gene(s)DisorderFeatures of Differential Diagnosis Disorder
Overlapping w/
Alexander disease		Distinguishing from Alexander disease
ABCD1 X-linked adrenoleukodystrophy (X-ALD)
  • Male children present w/regression in motor & cognitive skills.
  • Spasticity & gait abnormalities
MRI: mostly sparing of subcortical WM; involvement of deep WM primarily (most severe in parietal & occipital lobes w/anterior progression); leading edge enhancement of involved WM
ARSA Arylsulfatase A deficiency (metachromatic leukodystrophy, MLD) 1
  • Developmental regression in early childhood
  • Spasticity w/preserved cognitive function
MRI: involvement of deep WM primarily w/sparing of subcortical WM early in disease course; enhancement of cranial nerves; tigroid pattern (stripes/spots of spared perivascular WM) w/o abnormal periventricular WM
ASPA Canavan disease 1
  • Hypotonia, head lag, macrocephaly, & difficulties w/suck & swallow
  • DD ± regression
  • MRI: involvement of subcortical WM & globus pallidus & thalami
  • Elevation in N-acetylcysteine on MR spectroscopy
  • MRI: diffuse WM changes w/o frontal predominance; sparing of putamen
GALC Krabbe disease 1
  • Early feeding difficulties, hypotonia, & irritability
  • Developmental regression & seizures
  • MRI: involvement of thalami & cerebellar WM
  • Macrocephaly not present
  • MRI: involvement of deep WM primarily w/sparing of subcortical WM until later in disease course; thickening/enhancement of optic nerves & peripheral nerves
GCDH Glutaric acidemia type 1 1
  • Macrocephaly, DD, extrapyramidal signs (often preceded by an acute encephalopathy during infancy)
  • MRI: involvement of basal ganglia
MRI: lack of enhancement of affected structures; widening of sylvian fissures & expansion of CSF spaces
HEPACAM
MLC1 		Megalencephalic leukoencephalopathy w/subcortical cysts 1 & 2A 1
  • Megalencephaly during infancy, DD, seizures
  • MRI: involvement of subcortical WM
MRI: subcortical cysts, relative sparing of cerebellar WM, sparing of basal ganglia
L2HGDH L-2-hydroxyglutaric aciduria (OMIM 236792) 1
  • DD, seizures, dysarthria, ataxia (often w/insidious progression)
  • MRI: involvement of subcortical, WM & basal ganglia; anterior to posterior involvement of WM
MRI: sparing of brain stem & cerebellum; no enhancement
PEX1
PEX6
PEX12
(13 assoc genes) 2		Zellweger spectrum disorder (ZSD)
  • Neonatal-infantile onset: hypotonia, feeding difficulties, & seizures
  • Childhood onset: hypotonia, DD, regression, & diffuse involvement of WM incl cerebrum, brain stem, & cerebellum
  • Adolescent-adult onset: variable ID, pyramidal signs, & ataxia
  • May be assoc w/liver, heart, kidney, & skeletal system dysfunction; distinct facial features
  • Neonatal-infantile onset of ZSD MRI findings: cortical dysplasia, generalized ↓ in WM volume, delayed myelination, & ventricular dilatation
  • Childhood onset of ZSD MRI findings: involvement of parietooccipital WM progressing to entire cerebral WM

CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; WM = white matter

1.

Mode of inheritance is autosomal recessive.

2.

Biallelic pathogenic variants in PEX1, PEX6, PEX12 account for 60.5%, 14.5%, and 7.6% of Zellweger spectrum disorder (ZSD), respectively. ZSD is also known to be caused by biallelic pathogenic variants in PEX2, PEX3, PEX10, PEX5, PEX11β, PEX13, PEX14, PEX16, PEX19, or PEX26. ZSD is typically inherited in an autosomal recessive manner. One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state.

From: Alexander Disease

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