Porphyria-associated leukoencephalopathy (LENCEP) is an autosomal recessive disorder characterized by the onset of variable and slowly progressive neurologic abnormalities in childhood or adolescence with survival to late adulthood. Features include spastic paraparesis, cerebellar ataxia, peripheral axonal neuropathy, ocular abnormalities, and leukoencephalopathy affecting the deep cerebral white matter on brain imaging. Some individuals have more severe manifestations, such as optic atrophy with progressive visual loss, loss of ambulation, and mild cognitive decline. Laboratory studies show variably increased plasma and urinary levels of delta-aminolevulinic acid (ALA), porphobilinogen (PBG), and uroporphyrin due to decreased HMBS enzyme activity. The severity of the disorder appears to depend on the particular genotype and the variant effects on HMBS enzymatic activity; intrafamilial variability is often observed. The clinical discrepancies may be particularly apparent in individuals with compound heterozygous HMBS variants that have different effects on enzyme function (Stutterd et al., 2021). [from OMIM]

Etiology