Journal of Neurology

, Volume 264, Issue 9, pp 2021–2023 | Cite as

Exome sequencing reveals a novel homozygous mutation in ACP33 gene in the first Italian family with SPG21

  • Marina ScarlatoEmail author
  • Andrea Citterio
  • Alessandra Barbieri
  • Claudia Godi
  • Elena Panzeri
  • Maria Teresa Bassi
Letter to the Editors

Dear Sirs,

SPG21, also known as Mast Syndrome (MIM 248900), is an ultra-rare autosomal recessive complicated form of hereditary spastic paraparesis (HSP) characterized by slowly progressive spasticity with dementia, occurring with high frequency in the Old Order Amish [1]. After the first Amish family, a single Japanese family with two affected members was reported [2]. Here we describe an Italian family with a single affected member carrying a novel homozygous single base deletion in the acidic cluster protein 33, ACP33 gene (SPG21) and presenting with a phenotype characterized by cognitive decline prevailing on the spastic paraparesis component.

Difficulties at school and motor problems were noted in the patient since childhood. By the early 20s, mental function declined with progressive speech limitation, as well as evidence of clear executive dysfunctions and subtle personality disturbances. At neurological examination at 39 years of age, a spastic paraparesis was evident, with...



The Authors wish to thank the patient and his family for participating to the study. This work was supported by the Italian Ministry of health under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases Grant NEUROLIPID, by the 5XMille Funds and by Grant No. RC 2014-2017 to MTB.

Compliance with ethical standards

Conflicts of interest

All authors declare not to have any conflict of interest with the study and manuscript.

Ethical standard

The study was conducted according to the ethical standards stated in the declaration of Helsinki.

Informed consent

Patients and patient's family were informed about the intention to publish the study and provided a written informed consent.

Supplementary material

Supplementary material 1 (MP4 18361 kb)


  1. 1.
    Simpson MA, Cross H, Proukakis C, Pryde A, Hershberger R, Chatonnet A, Patton MA, Crosby AH (2003) Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am J Hum Genet 73:1147–1156CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ishiura H, Takahashi Y, Hayashi T, Saito K, Furuya H, Watanabe M, Murata M, Suzuki M, Sugiura A, Sawai S, Shibuya K, Ueda N, Ichikawa Y, Kanazawa I, Goto J, Tsuji S (2014) Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses. J Hum Genet 59:163–172. doi: 10.1038/jhg.2013.139 CrossRefPubMedGoogle Scholar
  3. 3.
    Zeitlmann L, Sirim P, Kremmer E, Kolanus W (2001) Cloning of ACP33 as a novel intracellular ligand of CD4. J Biol Chem 276:9123–9132 (PubMed PMID: 11113139) CrossRefPubMedGoogle Scholar
  4. 4.
    Hanna MC, Blackstone C (2009) Interaction of the SPG21 protein ACP33/maspardin with the aldehyde dehydrogenase ALDH16A1. Neurogenetics 10(3):217–228. doi: 10.1007/s10048-009-0172-6 (PubMed PMID: 19184135) CrossRefPubMedGoogle Scholar
  5. 5.
    Soderblom C, Stadler J, Jupille H, Blackstone C, Shupliakov O, Hanna MC (2010) Targeted disruption of the Mast syndrome gene SPG21 in mice impairs hind limb function and alters axon branching in cultured cortical neurons. Neurogenetics 11:369–378. doi: 10.1007/s10048-010-0252-7 CrossRefPubMedGoogle Scholar
  6. 6.
    Davenport A, Bivona A, Latson W, Lemanski LF, Cheriyath V (2016) Loss of maspardin attenuates the growth and maturation of mouse cortical neurons. Neurodegener Dis 16:260–272. doi: 10.1159/000443666 CrossRefPubMedGoogle Scholar
  7. 7.
    Panza E, Escamilla-Honrubia JM, Marco-Marín C, Gougeard N, De Michele G, Morra VB, Liguori R, Salviati L, Donati MA, Cusano R, Pippucci T, Ravazzolo R, Németh AH, Smithson S, Davies S, Hurst JA, Bordo D, Rubio V, Seri M (2016) ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism. Brain 139(Pt 1):e3. doi: 10.1093/brain/awv247 CrossRefPubMedGoogle Scholar
  8. 8.
    Coutelier M, Goizet C, Durr A, Habarou F, Morais S, Dionne-Laporte A, Tao F, Konop J, Stoll M, Charles P, Jacoupy M, Matusiak R, Alonso I, Tallaksen C, Mairey M, Kennerson M, Gaussen M, Schule R, Janin M, Morice-Picard F, Durand CM, Depienne C, Calvas P, Coutinho P, Saudubray JM, Rouleau G, Brice A, Nicholson G, Darios F, Loureiro JL, Zuchner S, Ottolenghi C, Mochel F, Stevanin G (2015) Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain 138(Pt 8):2191–2205. doi: 10.1093/brain/awv143 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Agosta F, Scarlato M, Spinelli EG, Canu E, Benedetti S, Bassi MT, Casali C, Sessa M, Copetti M, Pagani E, Comi G, Ferrari M, Falini A, Filippi M (2015) Hereditary spastic paraplegia: beyond clinical phenotypes toward a unified pattern of central nervous system damage. Radiology 276:207–218. doi: 10.1148/radiol.14141715 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Neurology Department & INSPEIRCCS San Raffaele Scientific InstituteMilanItaly
  2. 2.Laboratory of Molecular BiologyScientific Institute IRCCS E. MedeaLeccoItaly
  3. 3.Neurology Department, Psychology ServiceIRCCS San Raffaele Scientific InstituteMilanItaly
  4. 4.Neuroradiology DepartmentNeuroradiology Research Group and CERMAC, IRCCS San Raffaele Scientific InstituteMilanItaly

Personalised recommendations