Objective To demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding SERAC1 to the increasing number of complex lipid cHSP genes.
Methods Combined genomic and functional validation studies (whole-exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family.
Results 5 of 6 affected subjects shared cHSP as a common disease phenotype. Three subjects presented with juvenile-onset oligosystemic cHSP, still able to walk several miles at age >10–20 years. This benign phenotypic cluster and disease progression is strikingly divergent to the severe infantile phenotype of all SERAC1 cases reported so far. Two family members showed a more multisystemic juvenile-onset cHSP, indicating an intermediate phenotype between the benign oligosystemic cHSP and the classic infantile SERAC1 cluster. The homozygous splice mutation led to loss of the full-length SERAC1 protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling. These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype.
Conclusions Our findings add SERAC1 to the increasing list of complex lipid cHSP genes. At the same time they redefine the phenotypic spectrum of SERAC1 deficiency. It is associated not only with the severe infantile-onset ‘Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like’ syndrome (MEGDEL syndrome), but also with oligosystemic juvenile-onset cHSP as part of the now unfolding SERAC1 deficiency spectrum.
- hereditary spastic paraplegia
- 3-methylglutaconic aciduria
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Contributors Collection and analysis of data: BR, SuR, BB, TBH, SeR, RS and MS. Drafting of the manuscript: BR and MS. Critical review of the manuscript: BR, SuR, BB, BA, TB, TM, C-DL, TBH, SeR, RS, IK-M, LS and MS.
Funding This research was supported by the European Union within the 7th European Community Framework Programme through funding for the E-RARE-3 Joint Transnational Call grant ’Preparing therapies for autosomal recessive ataxias' (PREPARE) (BMBF, 01GM1607 to MS), the e-Rare Network NEUROLIPID (BMBF, 01GM1408B to RS) and a Marie Curie International Outgoing Fellowship (grant PIOF-GA-2012-326681 to RS), and the Else Kröner-Fresenius-Stiftung (to MS). It was further supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R01NS072248 (RS). We thank the participants and their family for participating in this study. This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (to TBH; grant #01ZX1405C).
Disclaimer Dr BR has received travel expenses from Actelion Pharmaceuticals Ltd., unrelated to this manuscript and research. Dr BB has received travel expenses from Bayer Vital. Drs TMa and MS have received travel expenses and presentation honoraria from Actelion Pharmaceuticals Ltd, unrelated to this manuscript and research. All other authors report no disclosures.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics committee of the Medical Faculty of the University of Tübingen.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it was published Online First. The name of Saskia B Wortmann has been updated.