Dataset Information

Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.

ABSTRACT:

Background

Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype.

Objective

The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST.

Methods

This study used a systematic cross-sectional analysis of clinical and molecular features.

Results

We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2-27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation).

Conclusions

These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP-SPAST. Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.

SUBMITTER: Mo A

PROVIDER: S-EPMC10062395 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.

Mo Alisa A Saffari Afshin A Kellner Melanie M Döbler-Neumann Marion M Jordan Catherine C Srivastava Siddharth S Zhang Bo B Sahin Mustafa M Fink John K JK Smith Linsley L Posey Jennifer E JE Alter Katharine E KE Toro Camilo C Blackstone Craig C Soldatos Ariane G AG Christie Michelle M Schüle Rebecca R Ebrahimi-Fakhari Darius D

Movement disorders : official journal of the Movement Disorder Society 20220914 12

<h4>Background</h4>Familial hereditary spastic paraplegia (HSP)-SPAST (SPG4) typically presents with a pure HSP phenotype.<h4>Objective</h4>The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP-SPAST.<h4>Methods</h4>This study used a systematic cross-sectional analysis of clinical and molecular features.<h4>Results</h4>We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: ...[more]

PMID: 36103453

Similar Datasets

Project description:BackgroundThe serine active site-containing protein 1 (SERAC1) biallelic variant usually causes MEGDEL syndrome, clinically characterized by increased excretion of 3-methylglutaconic in the urine, muscle hypotonia, sensorineural deafness, and Leigh-like lesions on brain MRI scans. In this study, we present a case from a Chinese family with disordered metabolism and dystonia owing to SERAC1 variants; the clinical phenotypes of the proband were different from those of MEGDEL syndrome but were similar to those juvenile-onset complicated hereditary spastic paraplegia. Thus, in this study, we aimed to confirm the relationship between SERAC1 variants and complicated hereditary spastic paraplegia.MethodsMRI and laboratory tests, including gas chromatography/mass spectrometry (GC/MS), were carried out for the proband. Whole-exome sequencing was used to detect the candidate SERAC1 variants. Variants were verified using Sanger sequencing. Various software programs (PolyPhen-2, MutationTaster, PROVEAN, and SIFT) were used to predict the pathogenicity of novel variants.ResultsBrain MRI scans showed a symmetric flake abnormal signal shadow in the bilateral basal ganglia in T2-weighted image (T2WI) and fluid-attenuated inversion recovery (FLAIR) analyses. The excretion of 3-methylglutaconic acid was found to be increased in our GC/MS analysis. Whole-exome sequencing showed novel compound heterozygous variants, including a novel c.1495A>G (p.Met499Val) variant in exon 14 of SERAC1 inherited from the father and a novel c.721_722delAG (p.Leu242fs) variant in exon 8 inherited from the mother. The pathogenicity prediction results showed that these two variants were deleterious.ConclusionsThis study presented a patient with complicated hereditary spastic paraplegia caused by SERAC1 variants. These findings expand the number of known SERAC1 variants and the phenotypic spectrum associated with SERAC1 deficiency. This study may contribute to counseling and prevention of hereditary diseases through prenatal.

Dataset Information

Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.

Background

Objective

Methods

Results

Conclusions

Publications

Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.

Similar Datasets

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