title: Mitochondrial dysfunction in hereditary spastic paraparesis with mutations in DDHD1/SPG28.
abstract: 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.
authors.affiliation: Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mignarri
authors.affiliation: Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rubegni
authors.affiliation: Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tessa
authors.affiliation: Unit of Neurology, Nuovo Ospedale San Giovanni Battista, Foligno, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Stefanucci
authors.affiliation: Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Malandrini
authors.affiliation: Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cardaioli
authors.affiliation: Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Meschini
authors.affiliation: Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Stromillo
authors.affiliation: Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Doccini
authors.affiliation: Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
authors.affiliation: Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy. Electronic address: filippo3364@gmail.com.
authors.forename: Filippo Maria
authors.initials: FM
authors.lastname: Santorelli
authors.affiliation: Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Dotti
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D004252:DNA Mutational Analysis; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000209:etiology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D054512:Phospholipases A2, Calcium-Independent / Q000235:genetics* / Q000378:metabolism; D035781:Siblings; D015419:Spastic Paraplegia, Hereditary / Q000150:complications* / Q000235:genetics*
chemical_list: D000255:Adenosine Triphosphate; D054512:Phospholipases A2, Calcium-Independent
keywords: DDHD1; Hereditary spastic paraplegia; Mitochondrial disease; SPG28