Advertisement

Defining the clinical-genetic and neuroradiological features in SPG54: description of eight additional cases and nine novel DDHD2 variants

  • Francesco NicitaEmail author
  • Fabrizia Stregapede
  • Alessandra Tessa
  • Maria Teresa Bassi
  • Aleksandra Jezela-Stanek
  • Guido Primiano
  • Antonio Pizzuti
  • Melissa Barghigiani
  • Marta Nardella
  • Ginevra Zanni
  • Serenella Servidei
  • Guja Astrea
  • Elena Panzeri
  • Cristina Maghini
  • Luciana Losito
  • Rafal Ploski
  • Piotr Gasperowicz
  • Filippo Maria Santorelli
  • Enrico Bertini
  • Lorena Travaglini
Original Communication

Abstract

Recessive mutations in DDHD2 cause SPG54, a complex hereditary spastic paraplegia (HSP) with less than forty patients reported worldwide. In this retrospective, multicenter study we describe eight additional SPG54 cases harboring homozygous or compound heterozygous DDHD2 variants. Finally, we reviewed literature data on SPG54, with the aim to better define the phenotype and the brain magnetic resonance imaging (MRI) pattern as well as genotype–phenotype correlations. SPG54 is typically characterized by early-onset (i.e., congenital or, more frequently, infantile) delay in motor and cognitive milestones, coupled or followed by appearance of spasticity. Cognitive impairment is absent in adult-onset cases. Spasticity progresses over time. Abnormal eye movement, found in about 50% of cases, is the feature most frequently associated with spasticity and developmental delay. Cerebellar ataxia is a prominent sign in several patients, including one adult of this study, suggesting to include SPG54 in the differential diagnosis of spastic-ataxia syndromes. Brain MRI shows thin corpus callosum and non-specific periventricular white matter lesions in about 90% and 70% of cases, respectively. Brain MR spectroscopy reveals abnormal lipid peak in 90% of investigated patients. Twenty-one pathogenic changes have been reported so far, many of which are nonsense or small deletion/duplication. Most mutations appear to be private, with only two mutations recurring in three (i.e., R287*) or more families (i.e., D660H). The identification of nine novel variants expands the molecular spectrum of DDHD2-related HSP and corroborates the notion of a quite homogeneous clinical and neuroradiological phenotype in spite of different genotypes.

Keywords

HSP SPG54 Leukodystrophy Hereditary spastic paraparesis Thin corpus callosum 

Notes

Acknowledgements

The work of Dr. Bassi MT was supported by the Italian Ministry of Health, Grant no. RC 2017–2018–2019 and 5XMille; EB, FS and FN were supported by Ricerca Corrente of the Italian Ministry of Health.

Compliance with ethical standards

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standards

All procedures performed in this paper were in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments and have been approved by the appropriate local ethics committees.

Supplementary material

415_2019_9466_MOESM1_ESM.docx (22 kb)
Supplementary file1 (DOCX 21 kb)
415_2019_9466_MOESM2_ESM.docx (25 kb)
Supplementary file2 (DOCX 24 kb)

References

  1. 1.
    Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A (2014) Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms. Exp Neurol 261:518–539CrossRefGoogle Scholar
  2. 2.
    Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ et al (2012) Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet 91(6):1073–1081CrossRefGoogle Scholar
  3. 3.
    Travaglini L, Aiello C, Stregapede F et al (2018) The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype–phenotype correlations for rare HSP-related genes. Neurogenetics 19(2):111–121CrossRefGoogle Scholar
  4. 4.
    Gonzalez M, Nampoothiri S, Kornblum C et al (2013) Mutations in phospholipase DDHD2 cause autosomal recessive hereditary spastic paraplegia (SPG54). Eur J Hum Genet 21(11):1214–1218CrossRefGoogle Scholar
  5. 5.
    Citterio A, Arnoldi A, Panzeri E et al (2014) Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis. J Neurol 261(2):373–381CrossRefGoogle Scholar
  6. 6.
    Magariello A, Citrigno L, Zuchner S et al (2014) Further evidence that DDHD2 gene mutations cause autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Eur J Neurol 21(3):e25–26CrossRefGoogle Scholar
  7. 7.
    Doi H, Ushiyama M, Baba T et al (2014) Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation. Sci Rep 4:7132CrossRefGoogle Scholar
  8. 8.
    Novarino G, Fenstermaker AG, Zaki MS et al (2014) Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343(6170):506–511CrossRefGoogle Scholar
  9. 9.
    Alrayes N, Mohamoud HS, Jelani M et al (2015) Truncating mutation in intracellular phospholipase A1 gene (DDHD2) in hereditary spastic paraplegia with intellectual disability (SPG54). BMC Res Notes 8:271CrossRefGoogle Scholar
  10. 10.
    Kumar KR, Wali GM, Kamate M et al (2016) Defining the genetic basis of early onset hereditary spastic paraplegia using whole genome sequencing. Neurogenetics 17(4):265–270CrossRefGoogle Scholar
  11. 11.
    Thabet F, Tlili-Graiess K, Tabarki B (2019) Distinct neuroimaging features of DDHD2 gene-related spastic paraplegia, a mimicker of cerebral palsy. Arch Dis Child.  https://doi.org/10.1136/archdischild-2018-316484 Google Scholar
  12. 12.
    Schuurs-Hoeijmakers JH, Vulto-van Silfhout AT, Vissers LE et al (2013) Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing. J Med Genet 50(12):802–811CrossRefGoogle Scholar
  13. 13.
    D'Amore A, Tessa A, Casali C et al (2018) Next generation molecular diagnosis of hereditary spastic paraplegias: an Italian cross-sectional study. Front Neurol 9:981CrossRefGoogle Scholar
  14. 14.
    Hensiek A, Kirker S, Reid E (2015) Diagnosis, investigation and management of hereditary spastic paraplegias in the era of next-generation sequencing. J Neurol 262(7):1601–1612CrossRefGoogle Scholar
  15. 15.
    Pascual B, de Bot ST, Daniels MR et al (2019) "Ears of the Lynx" MRI sign is associated with SPG11 and SPG15 hereditary spastic paraplegia. AJNR Am J Neuroradiol 40(1):199–203CrossRefGoogle Scholar
  16. 16.
    Liguori R, Giannoccaro MP, Arnoldi A et al (2014) Impairment of brain and muscle energy metabolism detected by magnetic resonance spectroscopy in hereditary spastic paraparesis type 28 patients with DDHD1 mutations. J Neurol 261(9):1789–1793CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Francesco Nicita
    • 1
    Email author
  • Fabrizia Stregapede
    • 1
  • Alessandra Tessa
    • 2
  • Maria Teresa Bassi
    • 3
  • Aleksandra Jezela-Stanek
    • 4
  • Guido Primiano
    • 5
  • Antonio Pizzuti
    • 6
  • Melissa Barghigiani
    • 2
  • Marta Nardella
    • 1
  • Ginevra Zanni
    • 1
  • Serenella Servidei
    • 5
  • Guja Astrea
    • 2
  • Elena Panzeri
    • 3
  • Cristina Maghini
    • 7
  • Luciana Losito
    • 8
  • Rafal Ploski
    • 9
  • Piotr Gasperowicz
    • 9
  • Filippo Maria Santorelli
    • 2
  • Enrico Bertini
    • 1
  • Lorena Travaglini
    • 1
  1. 1.Unit of Neuromuscular and Neurodegenerative Disorders, Department of NeurosciencesIRCCS, Bambino Gesù Research HospitalRomeItaly
  2. 2.Molecular MedicineIRCCS Fondazione Stella MarisPisaItaly
  3. 3.Laboratory of Molecular BiologyScientific Institute IRCCS E. MedeaBosisio PariniItaly
  4. 4.Department of Genetics and Clinical ImmunologyNational Institute of Tuberculosis and Lung DiseasesWarsawPoland
  5. 5.UOC Neurofisiopatologia Fondazione Policlinico Universitario A. Gemelli IRCCS, Istituto Di Neurologia Università Cattolica del Sacro CuoreRomeItaly
  6. 6.Department of Experimental MedicineSapienza University, Umberto I Polyclinic HospitalRomeItaly
  7. 7.Neuromuscular Disorders UnitScientific Institute IRCCS E. MedeaBosisio PariniItaly
  8. 8.Unit for Severe Disabilities in Developmental Age and Young Adults (Developmental Neurology and Neurorehabilitation)Scientific Institute IRCCS E. MedeaBrindisiItaly
  9. 9.Department of Medical GeneticsMedical University of WarsawWarsawPoland

Personalised recommendations