TABLE 2.

Summary of the genetic defects, neuro-pathogenesis and benefits of Allo-HSCT in IEM with neurological involvement.

Disease	Genetic defect	Neuro-pathogenesis	Benefits of Allo-HSCT
HS	Loss of function variants of the IDUA gene (encoding alpha-L-iduronidase)	Glycosaminoglycan accumulation in meninges and arachnoid vili Ganglioside accumulation	Donor microglia induced cross-correction
MLD	Mutations in the ARSA gene (encoding arylsulfatase)	Accumulation of sulfatides in myelin sheaths leading to demyelination Inhibition of OP differentiation into myelin-producing cells Microglia dysfunction	Restored microglial dysfunction by donor-derived myeloid cells Clearance of myelin debris, digestion of extracellular sulfatides and induction of OP differentiation
KD	Mutations in the GALC gene (encoding galactocerebrosidase)	Accumulation of galactolipids in the central and peripheral nervous leading to demyelination	Donor microglia induced cross-correction
X-ALD	Mutation in the ABCD1 gene (encoding adrenoleukodystrophy protein)	Accumulation of VLCFA in myelin sheaths leading to demyelination Dysregulated oxidative phosphorylation and mitochondrial dysfunction in neuroaxons Microglial dysfunction Peripheral inflammatory response	Restored microglial dysfunction by donor-derived myeloid cells Pro-regenerative M2 phenotype, attenuation of neuro-inflammation, and improved phagocytic function

HS, Hurler Syndrome; MLD, Metachromatic Leukodystrophy; KD, Krabbe’s Disease; X-ALD, X-Linked Adrenoleukodystrophy; OP, oligodendrocyte precursor; VLCFA, very long chain fatty acids.