Table 2.

Other Disorders Affecting the White Matter Diffusely During Childhood to Consider in the Differential Diagnosis of CACH/VWM

DisorderGene(s)MOIDistinguishing MRI findings
AARS2-related ovarioleukodystrophy AARS2 AR
  • Extensive or diffuse cerebral WM changes
  • Involvement of the corpus callosum connecting lesions on both sides
  • Involvement of long descending tracts
Childhood cerebral form of X-linked adrenoleukodystrophy ABCD1 XLExtensive or diffuse cerebral WM changes but, as a rule, no cystic degeneration
Arylsulfatase A deficiency (metachromatic leukodystrophy) ARSA AR
Krabbe disease GALC AR
Canavan disease ASPA AR
Alexander disease GFAP AD
  • WM signal changes have a frontal predominance.
  • The cystic degeneration may affect the subcortical or deep WM.
  • Basal ganglia & thalamic abnormalities are frequently present.
  • Contrast enhancement of characteristic structures often facilitates diagnosis.
Megalencephalic leukoencephalopathy with subcortical cysts HEPACAM
MLC1 		AR
AD 1
  • Diffusely abnormal & mildly swollen cerebral hemispheric WM that does not show signs of diffuse rarefaction or cystic degeneration
  • Subcortical cysts are almost always present in the anterior temporal area & often in other regions.
  • Cysts are best seen on proton density & FLAIR.
Mitochondrial leukoencephalopathies See footnote 2.AD
AR
mt
  • MRI abnormalities may be similar to those seen in CACH/VWM, but WM cysts are typically well delineated (in contrast to CACH/VWM).
  • Prominent & diffuse WM rarefaction & cystic degeneration may be seen in mitochondrial disorders.
PLP1-related disorders
(Pelizaeus Merzbacher disease & X-linked spastic paraplegia 2)		 PLP1 XL
  • Diffuse hyperintensity of WM on T2-weighted images is also observed in leukodystrophies w/primary hypomyelination (e.g., PLP1-related disorders), but these disorders have a normal or nearly normal WM signal on T1-weighted images & CT scan.
  • There is no WM rarefaction of cystic degeneration.
  • In addition, central nerve conduction evaluated w/evoked potentials is always severely affected even at an early stage of the disease.
CADASIL NOTCH3 ADConsider these disorders in those w/adult-onset CACH/VWM; however, the early constant diffuse symmetric alteration of WM on MRI in eIF2B-related disorders is distinctive.
Autosomal dominant leukodystrophy with autonomic disease LMNB1 AD
Acquired white matter disorders such as multiple sclerosisSee footnote 3.See footnote 4.

AD = autosomal dominant; AR = autosomal recessive; CACH/VWM = childhood ataxia with central nervous system / hypomyelination / vanishing white matter; MOI = mode of inheritance; mt = mitochondrial; WM = white matter; XL = X-linked

1.

Biallelic pathogenic variants in MLC1 or HEPACAM are causative of classic megalencephalic leukoencephalopathy with subcortical cysts (MLC1 or MLC2A, respectively); heterozygous HEPACAM pathogenic variants are causative of MLC2B. MLC1 and MLC2A are inherited in an autosomal recessive manner. MLC2B is inherited in an autosomal dominant manner.

2.

Mitochondrial diseases are a clinically heterogeneous group of disorders that can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA).

3.

See Phenotypic Series: Multiple sclerosis, susceptibility to for a list of genes associated with this phenotype in OMIM.

4.

Available data suggest that multiple sclerosis is inherited as a complex multifactorial disorder that results from the interaction of genetic and environmental factors.

From: Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter

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