New HSP gene discovered

SERAC1 deficiency causing complex HSP

 

The SERAC1 gene has been associated previously with a severe neurodegenerative condition of infants, and complex HSP now expands the range of diseases associated with mutations in it.

 

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.

 

SOURCE: J Med Genet. 2017 Sep 15. pii: jmedgenet-2017-104622. doi: 10.1136/jmedgenet-2017-104622. [Epub ahead of print] PMID: 28916646

 

SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family.

 

Roeben B1,2, Schüle R1,2, Ruf S3, Bender B4, Alhaddad B5, Benkert T6, Meitinger T5,7, Reich S1, Böhringer J3, Langhans CD8, Vaz FM9, Wortmann SB5,7,10, Marquardt T11, Haack TB5,7, Krägeloh-Mann I3, Schöls L1,2, Synofzik M1,2.

 

1 Department of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), University of Tübingen, Tübingen, Baden-Württemberg, Germany.

2 German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

3 Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital Tübingen, Tübingen, Germany.

4 Department of Neuroradiology, University of Tübingen, Tübingen, Baden-Württemberg, Germany.

5 Institute of Human Genetics, Technische Universität München, Munich, Germany.

6 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

7 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

8 Division of Neuropediatrics and Pediatric Metabolic Medicine, University Children’s Hospital Heidelberg, Heidelberg, Germany.

9 Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, Noord Holland, The Netherlands.

10 Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.

11 Department of Pediatrics, University Hospital of Muenster, Muenster, Germany.