TY - JOUR
T1 - Defining the clinical-genetic and neuroradiological features in SPG54: 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 Alessandro
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
Y1 - 2019
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 - HSP
KW - Hereditary spastic paraparesis
KW - Leukodystrophy
KW - SPG54
KW - Thin corpus callosum
KW - HSP
KW - Hereditary spastic paraparesis
KW - Leukodystrophy
KW - SPG54
KW - Thin corpus callosum
UR - http://hdl.handle.net/10807/148763
U2 - 10.1007/s00415-019-09466-y
DO - 10.1007/s00415-019-09466-y
M3 - Article
SN - 0340-5354
VL - 266
SP - 2657
EP - 2664
JO - Journal of Neurology
JF - Journal of Neurology
ER -