Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations

Chloe A. Stutterd*, Alexa Kidd, Chris Florkowski, Edward Janus, Miriam Fanjul, Anthony Raizis, Teddy Y. Wu, John Archer, Richard J. Leventer, David J. Amor, Vesna Lukic, Melanie Bahlo, Paul Gow, Paul J. Lockhart, Marjo S. van der Knaap, Martin B. Delatycki

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Pathogenic heterozygous variants in HMBS encoding the enzyme hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase, cause acute intermittent porphyria (AIP). Biallelic variants in HMBS have been reported in a small number of children with severe progressive neurological disease and in three adult siblings with a more slowly, progressive neurological disease and distinct leukoencephalopathy. We report three further adult individuals who share a distinct pattern of white matter abnormality on brain MRI in association with biallelic variants in HMBS, two individuals with homozygous variants, and one with compound-heterozygous variants. We present their clinical and radiological features and compare these with the three adult siblings previously described with leukoencephalopathy and biallelic HMBS variants. All six affected individuals presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. This recognizable pattern of MRI abnormalities is seen in all six adults described here. Biallelic variants in HMBS cause a phenotype that is distinct from AIP. It is not known whether AIP treatments benefit individuals with HMBS-related leukoencephalopathy. One individual reported here had improved neurological function for 12 months following liver transplantation followed by decline and progression of disease.

Original languageEnglish
Pages (from-to)2941-2950
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Volume185
Issue number10
DOIs
Publication statusPublished - Oct 2021

Bibliographical note

Funding Information:
We thank the individuals and their families for their participation in this research. Chloe A Stutterd was supported by the Royal Children's Hospital/Murdoch Children's Research Institute Flora Suttie Neurogenetics Fellowship made possible by the Suttie Family and their supporters, the Thyne-Reid Foundation and the Macquarie Foundation. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors. Melanie Bahlo was supported by the Australian Government National Health and Medical Research Council (NHMRC) with a Program Grant (1054618) and a Senior Research Fellowship (1102971). Additional funding was provided by the Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program. Richard J. Leventer is supported by a Melbourne Children's Clinician Scientist Fellowship. Paul J Lockhart is supported by the Vincent Chiodo Foundation.

Funding Information:
Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program; Melbourne Children's Clinician Scientist Fellowship; National Health and Medical Research Council, Grant/Award Numbers: 1054618, 1102971; Royal Children's Hospital/Murdoch Children's Research Institute Flora Suttie Neurogenetics Fellowship; Vincent Chiodo Foundation Funding information

Funding Information:
We thank the individuals and their families for their participation in this research. Chloe A Stutterd was supported by the Royal Children's Hospital/Murdoch Children's Research Institute Flora Suttie Neurogenetics Fellowship made possible by the Suttie Family and their supporters, the Thyne‐Reid Foundation and the Macquarie Foundation. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors. Melanie Bahlo was supported by the Australian Government National Health and Medical Research Council (NHMRC) with a Program Grant (1054618) and a Senior Research Fellowship (1102971). Additional funding was provided by the Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program. Richard J. Leventer is supported by a Melbourne Children's Clinician Scientist Fellowship. Paul J Lockhart is supported by the Vincent Chiodo Foundation.

Publisher Copyright:
© 2021 Wiley Periodicals LLC

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • acute intermittent porphyria
  • homozygous dominant acute intermittent porphyria
  • hydroxymethylbilane synthase
  • porphobilinogen deaminase

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