title: Acute intermittent porphyria-related leukoencephalopathy.
abstract: 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.
authors: From 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.
authors: Sietske H
authors: SH
authors: Kevelam
authors: From 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.
authors: Rochus A
authors: RA
authors: Neeleman
authors: From 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.
authors: Quinten
authors: Q
authors: Waisfisz
authors: From 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.
authors: Edith C H
authors: EC
authors: Friesema
authors: From 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.
authors: Janneke G
authors: JG
authors: Langendonk
authors: From 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. ms.vanderknaap@vumc.nl.
authors: Marjo S
authors: MS
authors: van der Knaap
mesh_terms: D001921:Brain / Q000000981:diagnostic imaging*; D005190:Family; D005260:Female; D014644:Genetic Variation; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D056784:Leukoencephalopathies / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017118:Porphyria, Acute Intermittent / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics; D012189:Retrospective Studies
chemical_list: D011163:Hydroxymethylbilane Synthase