Abstract:Hereditary spastic paraplegia (HSP) is a heterogeneous condition
characterized by progressive spasticity and weakness in the lower limbs. It is
divided into two major groups, complicated and uncomplicated, based on the
presence of additional features such as intellectual disability, ataxia,
seizures, peripheral neuropathy and visual problems. SPG56 is an autosomal
recessive form of HSP with complicated and uncomplicated manifestations,
complicated being more common. CYP2U1 gene mutations have been
identified a… Show more
“…Up to now, 17 variants have been reported in SPG56 families (Table and Figure ) including those described in this work (Citterio et al., ; Iodice et al., ; Kariminejad et al., ; Kumar et al., ; Leonardi et al., ; Masciullo et al., ; Tesson et al., ). Nine of them predict protein truncation and are therefore classified as deleterious according to sequence variant classification and interpretation guidelines (VUS class 5) (Plon et al., ; Richards et al., ).…”
Section: Resultssupporting
confidence: 51%
“…Both patients manifested typical early onset complex HSP with severe functional impairment associated with ID and brain MRI abnormalities suggestive of white matter changes and initially interpreted as delayed myelination due to perinatal insults. The clinical spectrum of SPG56 is wide and pure and complex forms of HSP have been described (Citterio et al, 2014;Iodice et al, 2017;Kariminejad et al, 2016;Kumar et al, 2016;Leonardi et al, 2016;Masciullo et al, 2016;Tesson et al, 2012). Cognitive impairment, brain MRI abnormalities, dystonia, and peripheral neuropathy are among the most frequently associated features in complex forms, including SPG56 (Kariminejad et al, 2016).…”
Section: Discussionmentioning
confidence: 99%
“…To date, 11 families have been reported having variants in CYP2U1 (Citterio et al, 2014;Iodice et al, 2017;Kariminejad et al, 2016;Kumar et al, 2016;Leonardi et al, 2016;Masciullo et al, 2016;Tesson et al, 2012). Among them, truncating and missense variants have been observed either at homozygous or compound heterozygous state.…”
Hereditary spastic paraplegia (HSP) is an inherited disorder of the central nervous system mainly characterized by gradual spasticity and weakness of the lower limbs. SPG56 is a rare autosomal recessive early onset complicated form of HSP caused by mutations in CYP2U1. The CYP2U1 enzyme was shown to catalyze the hydroxylation of arachidonic acid. Here, we report two further SPG56 families carrying three novel CYP2U1 missense variants and the development of an in vitro biochemical assay to determine the pathogenicity of missense variants of uncertain clinical significance. We compared spectroscopic, enzymatic, and structural (from a 3D model) characteristics of the over expressed wild-type or mutated CYP2U1 in HEK293T cells. Our findings demonstrated that most of the tested missense variants in CYP2U1 were functionally inactive because of a loss of proper heme binding or destabilization of the protein structure. We also showed that functional data do not necessarily correlate with in silico predictions of variants pathogenicity, using different bioinformatic phenotype prediction tools. Our results therefore highlight the importance to use biological tools, such as the enzymatic test set up in this study, to evaluate the effects of newly identified variants in clinical settings.
“…Up to now, 17 variants have been reported in SPG56 families (Table and Figure ) including those described in this work (Citterio et al., ; Iodice et al., ; Kariminejad et al., ; Kumar et al., ; Leonardi et al., ; Masciullo et al., ; Tesson et al., ). Nine of them predict protein truncation and are therefore classified as deleterious according to sequence variant classification and interpretation guidelines (VUS class 5) (Plon et al., ; Richards et al., ).…”
Section: Resultssupporting
confidence: 51%
“…Both patients manifested typical early onset complex HSP with severe functional impairment associated with ID and brain MRI abnormalities suggestive of white matter changes and initially interpreted as delayed myelination due to perinatal insults. The clinical spectrum of SPG56 is wide and pure and complex forms of HSP have been described (Citterio et al, 2014;Iodice et al, 2017;Kariminejad et al, 2016;Kumar et al, 2016;Leonardi et al, 2016;Masciullo et al, 2016;Tesson et al, 2012). Cognitive impairment, brain MRI abnormalities, dystonia, and peripheral neuropathy are among the most frequently associated features in complex forms, including SPG56 (Kariminejad et al, 2016).…”
Section: Discussionmentioning
confidence: 99%
“…To date, 11 families have been reported having variants in CYP2U1 (Citterio et al, 2014;Iodice et al, 2017;Kariminejad et al, 2016;Kumar et al, 2016;Leonardi et al, 2016;Masciullo et al, 2016;Tesson et al, 2012). Among them, truncating and missense variants have been observed either at homozygous or compound heterozygous state.…”
Hereditary spastic paraplegia (HSP) is an inherited disorder of the central nervous system mainly characterized by gradual spasticity and weakness of the lower limbs. SPG56 is a rare autosomal recessive early onset complicated form of HSP caused by mutations in CYP2U1. The CYP2U1 enzyme was shown to catalyze the hydroxylation of arachidonic acid. Here, we report two further SPG56 families carrying three novel CYP2U1 missense variants and the development of an in vitro biochemical assay to determine the pathogenicity of missense variants of uncertain clinical significance. We compared spectroscopic, enzymatic, and structural (from a 3D model) characteristics of the over expressed wild-type or mutated CYP2U1 in HEK293T cells. Our findings demonstrated that most of the tested missense variants in CYP2U1 were functionally inactive because of a loss of proper heme binding or destabilization of the protein structure. We also showed that functional data do not necessarily correlate with in silico predictions of variants pathogenicity, using different bioinformatic phenotype prediction tools. Our results therefore highlight the importance to use biological tools, such as the enzymatic test set up in this study, to evaluate the effects of newly identified variants in clinical settings.
“…5 ) which has never been reported in CYP2U1 –related condition so far. Given the complex clinical and radiological picture of this and other reported patients [ 19 ] we propose to consider CYP2U1 mutations as the cause of a broader phenotypic spectrum ranging from pure spastic paraparesis (SPG56) to a veritable encephalopathy with cerebral calcification. Fig.…”
BackgroundWe present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses.MethodsWe collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification.ResultsWe collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two.ConclusionsGenetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.
“…Currently known physiological substrates of CYP2U1 are unsaturated fatty acids such as arachidonic acid and N-arachidonoyl serotonin, suggesting its possible role in lipid metabolism [9]. To date, a total of 17 families including 31 patients have been reported [10][11][12][13][14][15][16][17][18][19][20][21]. SPG56 patients present complicated form of HSP: lower limb spasticity and weakness frequently associated with other neurological or systemic abnormalities.…”
Purpose. Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene (s) to solve the ABCC6-negative patients.Methods. First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients.Results. 6.4% of ABCC6-negative PXE patients (n = 3) harboured biallelic pathogenic variants in Claire Pujol and Christelle M. Durand contributed equally to this work.
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