Acute intermittent porphyria-related leukoencephalopathy
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Published on: May 29, 2020
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.
Objective:
To identify the genetic etiology of a distinct leukoencephalopathy with autosomal recessive inheritance in a single family.
Methods:
We analyzed available MRIs and retrospectively reviewed clinical information and laboratory investigations. We performed whole-exome sequencing to find the causal gene variants.
Results:
We identified 3 family members with a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons. Cerebellar atrophy was noted in advanced disease stages. Clinical features were childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. Whole-exome sequencing revealed compound heterozygous missense variants in the HMBS gene, both associated with the autosomal dominant disorder acute intermittent porphyria. Sanger sequencing of 6 healthy siblings confirmed the bi-allelic location of the variants and segregation with the disease. Patients had a slight and moderate increase in urinary and plasma porphobilinogen and 5'-aminolevulinic acid, respectively, and a 50% to 66% decrease in hydroxymethylbilane synthase enzyme activity compared to normal.
Conclusions:
Bi-allelic HMBS variants have been reported before as cause of severe encephalopathy with early childhood fatality in acute intermittent porphyria. Our cases demonstrate childhood onset, but milder and slower disease progression in middle-aged patients. With this, a novel phenotype can be added to the disease spectrum associated with bi-allelic HMBS variants: a leukoencephalopathy with early onset, slowly progressive neurologic symptomatology, and long life expectancy.
Insights
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.
