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NeuroMolecular Medicine

, Volume 18, Issue 1, pp 81–90 | Cite as

The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy

  • Saranya Suriyanarayanan
  • Mari Auranen
  • Jussi Toppila
  • Anders Paetau
  • Maria Shcherbii
  • Eino Palin
  • Yu Wei
  • Tarja Lohioja
  • Beate Schlotter-Weigel
  • Ulrike Schön
  • Angela Abicht
  • Bernd Rautenstrauss
  • Henna Tyynismaa
  • Maggie C. Walter
  • Thorsten Hornemann
  • Emil YlikallioEmail author
Original Paper

Abstract

Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme’s substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.547C>T, p.(Arg183Trp). The variant changed a conserved amino acid and was not found in public variant databases. All patients had a relatively mild progressive distal sensory impairment, with onset after age 50. Small fibers were affected early, leading to abnormalities on quantitative sensory testing. Sural biopsy revealed a severe chronic axonal neuropathy with subtotal loss of myelinated axons, relatively preserved number of non-myelinated fibers and no signs for regeneration. Skin biopsy with PGP9.5 labeling showed lack of intraepidermal nerve endings early in the disease. Motor manifestations developed later in the disease course, but there was no evidence of autonomic involvement. Patients had elevated serum 1-deoxysphingolipids, and the variant protein produced elevated amounts of 1-deoxysphingolipids in vitro, which proved the pathogenicity of the variant. Our results expand the genetic spectrum of HSAN1C and provide further detail about the clinical characteristics. Sequencing of SPTLC2 should be considered in all patients presenting with mild late-onset sensory-predominant small or large fiber neuropathy.

Keywords

Neuropathy Hereditary sensory autonomic neuropathy Serine palmitoyl-CoA transferase Sphingolipid 

Abbreviations

1-deoxySL

1-Deoxysphingolipid

DML

Distal motor latency

ENMG

Electroneuromyography

HbA1C

Glycated hemoglobin

HSAN

Hereditary sensory and autonomic neuropathy

NCV

Nerve conduction velocity

QST

Quantitative sensory testing

SA

Sphinganine

SISu

Sequencing Initiative Suomi

SO

Sphingosine

SPT

Serine palmitoyl-CoA transferase

Notes

Acknowledgments

In memoriam to B.R. a dear colleague and friend who unexpectedly passed away too premature. We thank Riitta Lehtinen for technical assistance. The authors wish to thank the following funding sources for support: Hospital District of Helsinki and Uusimaa (for M.A. and E.Y.), Sigrid Jusélius Foundation (for H.T.), University of Helsinki (for H.T.), the Academy of Finland (for H.T. and E.Y.), The 7th Framework Program of the European Commission (“RESOLVE”, Project Number 305707) for S.S. Furthermore, T.H. and S.S are grateful to the Hurka Foundation, the Novartis Foundation, and the Rare Disease Initiative Zurich (“radiz”, Clinical Research Priority Program for Rare Diseases, University of Zurich).

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

12017_2015_8379_MOESM1_ESM.pdf (6 kb)
Supplementary material 1 (PDF 5 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Saranya Suriyanarayanan
    • 1
    • 2
  • Mari Auranen
    • 3
    • 4
  • Jussi Toppila
    • 5
  • Anders Paetau
    • 6
  • Maria Shcherbii
    • 3
  • Eino Palin
    • 3
  • Yu Wei
    • 1
  • Tarja Lohioja
    • 7
  • Beate Schlotter-Weigel
    • 8
  • Ulrike Schön
    • 9
  • Angela Abicht
    • 9
  • Bernd Rautenstrauss
    • 9
  • Henna Tyynismaa
    • 3
  • Maggie C. Walter
    • 8
  • Thorsten Hornemann
    • 1
    • 2
  • Emil Ylikallio
    • 3
    Email author
  1. 1.Institute for Clinical Chemistry, University Hospital ZurichUniversity of ZurichZurichSwitzerland
  2. 2.Competence Center for Personalized Medicine (CC-PM)ZurichSwitzerland
  3. 3.Research Programs Unit, Molecular Neurology, Biomedicum HelsinkiUniversity of HelsinkiHelsinkiFinland
  4. 4.Clinical Neurosciences, NeurologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  5. 5.Department of Clinical Neurophysiology, Medical Imaging CenterHelsinki University Central HospitalHelsinkiFinland
  6. 6.Department of Pathology, HUSLABUniversity of HelsinkiHelsinkiFinland
  7. 7.NeurocenterKuopio University HospitalKuopioFinland
  8. 8.Friedrich-Baur-Institute, Department of NeurologyLudwig-Maximilians-University of MunichMunichGermany
  9. 9.Medical Genetics CentreMunichGermany

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