SPG48 HSP studied in depth

Multiple associated complications


An in-depth study of SPG48 HSP found a range of associated complications on top of the spastic paraplegia. A lysosomal storage disorder was also found.



Biallelic mutations in the AP5Z1 gene encoding the AP-5 ζ subunit have been described in a small number of patients with hereditary spastic paraplegia (HSP) (SPG48); we sought to define genotype-phenotype correlations in patients with homozygous or compound heterozygous sequence variants predicted to be deleterious.



We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1.



In 4 of the 6 patients, there was complete loss of AP-5 ζ protein. Clinical features encompassed, not only prominent spastic paraparesis, but also sensory and motor neuropathy, ataxia, dystonia, myoclonus, and parkinsonism. Skin fibroblasts from affected patients tested positive for periodic acid Schiff and autofluorescent storage material, while electron microscopic analysis demonstrated lamellar storage material consistent with abnormal storage of lysosomal material.



Our findings expand the spectrum of AP5Z1-associated neurodegenerative disorders and point to clinical and pathophysiologic overlap between autosomal recessive forms of HSP and lysosomal storage disorders.


SOURCE: Neurol Genet. 2016 Aug 25;2(5):e98. doi: 10.1212/NXG.0000000000000098. eCollection 2016. PMID: 27606357 PMCID: PMC5001803 DOI: 10.1212/NXG.0000000000000098


Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48).


Hirst J1, Madeo M1, Smets K1, Edgar JR1, Schols L1, Li J1, Yarrow A1, Deconinck T1, Baets J1, Van Aken E1, De Bleecker J1, Datiles MB 3rd1, Roda RH1, Liepert J1, Züchner S1, Mariotti C1, De Jonghe P1, Blackstone C1, Kruer MC1.


1Cambridge Institute for Medical Research (J.H., J.R.E.), University of Cambridge, Addenbrooke’s Hospital, UK; Children’s Health Research Center (M.M., A.Y.), Cancer Biology Research Center, Sanford Research, Sioux Falls; Neurogenetics Group (K.S., T.D., J.B., P.D.J.), Department of Molecular Genetics VIB, Antwerp, Belgium; Department of Neurology (K.S., J.B., P.D.J.), Antwerp University Hospital, Belgium; Laboratories of Neurogenetics and Neuropathology (K.S., T.D., J.B., P.D.J.), Institute Born-Bunge, University of Antwerp, Belgium; Department of Neurology (L.S., J. Liepert), Hertie Institute for Clinical Brain Research, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE) (L.S.), Tübingen, Germany; Department of Neurology (J. Li), Vanderbilt University, Nashville, TN; Department of Ophthalmology (E.V.A.), Department of Neurology (J.D.B.), Ghent University Hospital, Belgium; National Eye Institute (M.B.D.), National Institutes of Health, Bethesda, MD; Cell Biology Section (R.H.R., C.B.), Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Department of Neurology (R.H.R.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurorehabilitation (J. Liepert), Kliniken Schmieder, Allensbach, Germany; Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL; Genetics of Neurodegenerative and Metabolic Diseases Unit (C.M.), IRCCS-Fondazione Istituto Neurologico Carlo Besta, Milan, Italy; Departments of Child Health, Neurology & Genetics (M.C.K.), University of Arizona College of Medicine, Phoenix; Program in Neuroscience (M.C.K.), Arizona State University, Tempe; and Pediatric Movement Disorders Program and Neurogenetics Research Program (M.C.K.), Barrow Neurological Institute, Phoenix Children’s Hospital, AZ.

Your email address will not be published. Required fields are marked *