Mitochondrial dysfunction in hereditary spastic paraparesis with mutations in DDHD1/SPG28

Andrea Mignarri, Anna Rubegni, Alessandra Tessa, Stefano Stefanucci, Alessandro Malandrini, Elena Cardaioli, Maria Chiara Meschini, Maria Laura Stromillo, Stefano Doccini, Antonio Federico, Filippo Maria Santorelli, Maria Teresa Dotti

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Mutations in DDHD1 cause the SPG28 subtype of hereditary spastic paraplegia (HSP). Recent studies suggested that mitochondrial dysfunction occurs in SPG28. Here we describe two siblings with SPG28, and report evidence of mitochondrial impairment in skeletal muscle and skin fibroblasts. Patient 1 (Pt1) was a 35-year-old man with spastic paraparesis and urinary incontinence, while his 25-year-old brother (Pt2) had gait spasticity and motor axonal neuropathy. In these patients we identified the novel homozygous c.1429C > T/p.R477∗mutation in DDHD1, using a next-generation sequencing (NGS) approach. Histochemical analyses in muscle showed mitochondrial alterations, and multiple mitochondrial DNA (mtDNA) deletions were evident. In Pt1, respiratory chain enzyme activities were altered in skeletal muscle, mitochondrial ATP levels reduced, and analysis of skin fibroblasts revealed mitochondrial fragmentation. It seems possible that the novel nonsense mutation identified abolishes DDHD1 protein function thus altering oxidative metabolism. Qualitative alterations of mtDNA could have a pathogenetic significance. We suggest to perform DDHD1 analysis in patients with multiple mtDNA deletions.

Original languageEnglish
Pages (from-to)287-291
Number of pages5
JournalJournal of the Neurological Sciences
Publication statusPublished - Mar 15 2016


  • DDHD1
  • Hereditary spastic paraplegia
  • Mitochondrial disease
  • SPG28

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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