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.

Original languageEnglish
JournalJournal of Neurology
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Hereditary Spastic Paraplegia
Mutation
Brain
Magnetic Resonance Imaging
Phenotype
Cerebellar Ataxia
Corpus Callosum
Dyskinesias
Eye Movements
Multicenter Studies
Differential Diagnosis
Magnetic Resonance Spectroscopy
Retrospective Studies
Genotype
Lipids

Keywords

  • Hereditary spastic paraparesis
  • HSP
  • Leukodystrophy
  • SPG54
  • Thin corpus callosum

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

@article{848f913a72534285b8ae8f7f3bd83881,
title = "Defining the clinical-genetic and neuroradiological features in SPG54: description of eight additional cases and nine novel DDHD2 variants",
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 = "Hereditary spastic paraparesis, HSP, Leukodystrophy, SPG54, Thin corpus callosum",
author = "Francesco Nicita and Fabrizia Stregapede and Alessandra Tessa and Bassi, {Maria Teresa} and Aleksandra Jezela-Stanek and Guido Primiano and Antonio Pizzuti and Melissa Barghigiani and Marta Nardella and Ginevra Zanni and Serenella Servidei and Guja Astrea and Elena Panzeri and Cristina Maghini and Luciana Losito and Rafal Ploski and Piotr Gasperowicz and Santorelli, {Filippo Maria} and Enrico Bertini and Lorena Travaglini",
year = "2019",
month = "1",
day = "1",
doi = "10.1007/s00415-019-09466-y",
language = "English",
journal = "Journal of Neurology",
issn = "0340-5354",
publisher = "Dr. Dietrich Steinkopff Verlag GmbH and Co. KG",

}

TY - JOUR

T1 - Defining the clinical-genetic and neuroradiological features in SPG54

T2 - description of eight additional cases and nine novel DDHD2 variants

AU - Nicita, Francesco

AU - Stregapede, Fabrizia

AU - Tessa, Alessandra

AU - Bassi, Maria Teresa

AU - Jezela-Stanek, Aleksandra

AU - Primiano, Guido

AU - Pizzuti, Antonio

AU - Barghigiani, Melissa

AU - Nardella, Marta

AU - Zanni, Ginevra

AU - Servidei, Serenella

AU - Astrea, Guja

AU - Panzeri, Elena

AU - Maghini, Cristina

AU - Losito, Luciana

AU - Ploski, Rafal

AU - Gasperowicz, Piotr

AU - Santorelli, Filippo Maria

AU - Bertini, Enrico

AU - Travaglini, Lorena

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Hereditary spastic paraparesis

KW - HSP

KW - Leukodystrophy

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KW - Thin corpus callosum

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