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Acute intermittent porphyria-related leukoencephalopathy
Sietske H Kevelam1, Rochus A Neeleman1, Quinten Waisfisz1
1From the Department of Child Neurology, Amsterdam Neuroscience (S.H.K., M.S.v.d.K.), and Department of Clinical Genetics (Q.W.), VU University Medical Center, Amsterdam; Department of Internal Medicine (R.A.N., J.G.L.), and Netherlands Porphyria Center, Center for Lysosomal and Metabolic Diseases, Department of Internal Medicine (E.C.H.F., J.G.L.), Erasmus MC, Rotterdam; and Department of Functional Genomics (M.S.v.d.K.), Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.
Genetic variants in the HMBS gene cause a rare, slowly progressive leukoencephalopathy. This study identifies a novel phenotype of this condition with childhood onset and long life expectancy.
Area of Science:
- Genetics
- Neurology
- Biochemistry
Background:
- Leukoencephalopathies are a group of white matter disorders of the brain.
- Autosomal recessive inheritance patterns suggest a single gene etiology.
- Acute intermittent porphyria (AIP) is typically an autosomal dominant disorder caused by HMBS variants.
Observation:
- A family presented with a distinct leukoencephalopathy characterized by specific MRI findings including white matter abnormalities and cerebellar atrophy.
- Clinical manifestations included progressive spastic paraparesis, ataxia, neuropathy, and visual/oculomotor deficits.
- Affected individuals exhibited biochemical evidence of impaired heme synthesis pathway function.
Findings:
- Whole-exome sequencing identified compound heterozygous missense variants in the hydroxymethylbilane synthase (HMBS) gene.
- These HMBS variants, typically associated with autosomal dominant AIP, segregated with the leukoencephalopathy phenotype in this family.
- Patients showed elevated porphobilinogen and 5'-aminolevulinic acid levels with reduced HMBS enzyme activity.
Implications:
- This study expands the phenotypic spectrum of bi-allelic HMBS variants beyond severe, early-fatal encephalopathy.
- It describes a novel leukoencephalopathy with childhood onset, slow progression, and prolonged survival.
- The findings highlight the importance of considering HMBS gene variants in unexplained inherited leukoencephalopathies.
