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Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48)
Jennifer Hirst1, Marianna Madeo1, Katrien Smets1
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.
Objective:
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.
Methods:
We performed clinical, radiologic, and pathologic studies in 6 patients with biallelic mutations in AP5Z1.
Results:
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.
Conclusions:
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.
Insights
Mutations in the AP5Z1 gene cause hereditary spastic paraplegia (HSP) and related neurodegenerative disorders. This study details genotype-phenotype correlations and reveals overlap with lysosomal storage diseases.
Area of Science:
- Genetics
- Neuroscience
- Cell Biology
Background:
- Biallelic mutations in AP5Z1 gene are linked to hereditary spastic paraplegia (HSP), specifically SPG48.
- The AP-5 zeta (ζ) subunit, encoded by AP5Z1, plays a role in cellular transport and function.
Purpose of the Study:
- To establish genotype-phenotype correlations in patients with homozygous or compound heterozygous AP5Z1 variants.
- To expand the understanding of AP5Z1-associated neurodegenerative disorders.
Main Methods:
- Clinical, radiologic, and pathologic evaluations of 6 patients with biallelic AP5Z1 mutations.
- Analysis of AP-5 ζ protein levels in patient-derived cells.
- Histopathological and ultrastructural examination of skin fibroblasts.
Main Results:
- Four out of six patients showed complete loss of AP-5 ζ protein.
- Clinical presentations included spastic paraparesis, neuropathy, ataxia, dystonia, myoclonus, and parkinsonism.
- Fibroblasts exhibited storage material, indicating lysosomal dysfunction.
Conclusions:
- AP5Z1 mutations are associated with a broader spectrum of neurodegenerative disorders than previously recognized.
- There is a significant clinical and pathophysiologic overlap between autosomal recessive HSP and lysosomal storage disorders.
- These findings highlight the importance of AP-5 ζ in neuronal health and lysosomal function.
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