Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Saputra, Lydia; Kumar, Kishore R.

doi:10.1007/s11910-021-01099-x

Cited by 24 publications

(21 citation statements)

References 112 publications

(131 reference statements)

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“…Gait disturbance was the most common initial symptom in both the patients with HSPs and patients with SCAs. The results were in line with previous studies and reviews showing that the clinical characteristics of SCAs and SPGs were overlapped ( 7 , 10 , 11 , 15 , 16 ). Pyramidal signs and spasticity could be the first neurological sign before the appearance of cerebellar signs in SCAs and even some cases of SCAs could manifest as the phenotype of pure form of HSPs ( 10 , 12 ).…”

Section: Discussionsupporting

confidence: 92%

“…A variety of hereditary diseases overlap the neurological phenotypes or even share genes with HSPs such as hereditary cerebellar ataxia, spastic ataxia, inherited neuropathies, leukodystrophies, hereditary amyotrophic lateral sclerosis, monogenic Parkinson's disease, and some hereditary metabolic disorders ( 7 , 8 ). The majority of these diseases can be differentiated from HSPs by clinical presentations, MRI of the brain and/or spinal cord, or laboratory tests of blood, urine, and/or cerebrospinal fluid ( 8 , 9 ); others should be differentiated and diagnosed by genetic testing.…”

Section: Introductionmentioning

confidence: 99%

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Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia

et al. 2022

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Background and PurposeA variety of hereditary diseases overlap with neurological phenotypes or even share genes with hereditary spastic paraplegia (HSP). The aim of this study was to determine the clinical features and genetic spectrum of patients with clinically suspected HSPs.MethodsA total of 52 patients with clinically suspected HSPs were enrolled in this study. All the patients underwent next-generation sequencing (NGS) and triplet repeat primed PCR to screen for the dynamic mutations typical of spinocerebellar ataxia (SCA). Multiplex ligation-dependent probe amplification (MLPA) was further conducted in patients with no causative genetic mutations detected to examine for large deletions and duplications in genes of SPAST, ATL1, REEP1, PGN, and SPG11. Clinical characteristics and findings of brain MRI were analyzed in patients with definite diagnoses.ResultsThe mean age of the patients studied was 36.90 ± 14.57 years. 75% (39/52) of patients manifested a phenotype of complex form of HSPs. A genetic diagnosis was made in 51.9% (27/52) of patients, of whom 40.3% (21/52) of patients had mutations in HSPs genes (SPG4/SPG6/SPG8/SPG11/SPG15/SPG78/SPG5A) and 11.5% (6/52) of patients had mutations in SCAs genes (SCA3/SCA17/SCA28). SPG4 and SPG11 were the most common cause of pure form of HSPs (5/6, 83.3%) and complex form of HSPs (5/15, 33.3%), respectively. Gait disturbance was the most common initial symptom in both the patients with HSPs (15/21) and in patients with SCAs (5/6). Dysarthria and cerebellar ataxia were detected in 28.5% (6/21) and 23.8% (5/21) of patients with HSPs, respectively, and were the most common symptoms in addition to progressive weakness and spasticity of the lower limbs. Cerebellar atrophy was seen on the brain MRI of patients with SPG5A, SCA3, and SCA28.ConclusionCausative genetic mutations were identified in 51.9% of patients with clinically suspected HSPs by NGS and triplet repeat primed PCR. A final diagnosis of HSPs or SCAs was made in 40.3% and 11.5% of patients, respectively. The clinical manifestations and neuroimaging findings overlapped between patients with HSPs and patients with SCAs. Dynamic mutations should be screened in patients with clinically suspected HSPs, especially in those with phenotypes of complex form of HSPs.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia

et al. 2022

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“…Through a WES approach followed by in silico targeted gene analysis, the present study describes the first identification of a pathogenic variant in the SPG7 gene in the Cypriot population. The successful efficacy of this approach in the study of HCAs and HSPs has been well documented ( Coutelier et al, 2018 ; Sahin and Saat, 2021 ; Saputra and Kumar, 2021 ). Compared to other diagnostic approaches such as the classic Sanger sequencing based on phenotype-oriented gene prioritization, or even the NGS gene targeted panel sequencing, the exome targeted capture has several advantages.…”

Section: Discussionmentioning

confidence: 99%

“…However, it might be more expensive than a targeted panel analysis with a relatively lower coverage provided. The major limitation of both the targeted panel and WES compared to the WGS approach, which provides longer reads, has been their inability to detect repeat expansions, deep intronic variants or CNVs ( Coutelier et al, 2018 ; Krygier and Mazurkiewicz-Bełdzińska, 2021 ; Saputra and Kumar, 2021 ). Therefore, for undiagnosed patients excluded from small scale variants through gene panel analysis or WES, the use of WGS could be a promising option.…”

Section: Discussionmentioning

confidence: 99%

A Novel SPG7 Gene Pathogenic Variant in a Cypriot Family With Autosomal Recessive Spastic Ataxia

et al. 2022

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The SPG7 gene encodes the paraplegin protein, an inner mitochondrial membrane—localized protease. It was initially linked to pure and complicated hereditary spastic paraplegia with cerebellar atrophy, and now represents a frequent cause of undiagnosed cerebellar ataxia and spastic ataxia. We hereby report the molecular characterization and the clinical features of a large Cypriot family with five affected individuals presenting with spastic ataxia in an autosomal recessive transmission mode, due to a novel SPG7 homozygous missense variant. Detailed clinical histories of the patients were obtained, followed by neurological and neurophysiological examinations. Whole exome sequencing (WES) of the proband, in silico gene panel analysis, variant filtering and family segregation analysis of the candidate variants with Sanger sequencing were performed. RNA and protein expression as well as in vitro protein localization studies and mitochondria morphology evaluation were carried out towards functional characterization of the identified variant. The patients presented with typical spastic ataxia features while some intrafamilial phenotypic variation was noted. WES analysis revealed a novel homozygous missense variant in the SPG7 gene (c.1763C > T, p. Thr588Met), characterized as pathogenic by more than 20 in silico prediction tools. Functional studies showed that the variant does not affect neither the RNA or protein expression, nor the protein localization. However, aberrant mitochondrial morphology has been observed thus indicating mitochondrial dysfunction and further demonstrating the pathogenicity of the identified variant. Our study is the first report of an SPG7 pathogenic variant in the Cypriot population and broadens the spectrum of SPG7 pathogenic variants.

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“…1,2 In some cases, nonmotor symptoms precede the onset of motor symptoms and signs of corticospinal tract dysfunction can be subtle initially. Next-generation sequencing has enabled an early diagnosis of many forms of HSP 3 ; however, interpretation of novel missense variants remains challenging. Functional studies in patient-derived cells assist the interpretation of molecular findings and can support a diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early‐onset psychosis

Alecu

Saffari

Jumo

et al. 2022

Ann Clin Transl Neurol

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CAPN1‐associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogenous syndrome due to loss of calpain‐1 function. Here we illustrate a translational approach to the case of an 18‐year‐old patient who first presented with psychiatric symptoms followed by spastic gait, intention tremor, and neurogenic bladder dysfunction, consistent with a complex form of HSP. Exome sequencing showed compound‐heterozygous missense variants in CAPN1 (NM_001198868.2: c.1712A>G (p.Asn571Ser)/c.1991C>T (p.Ser664Leu)) and a previously reported heterozygous stop‐gain variant in RCL1. In silico analyses of the CAPN1 variants predicted a deleterious effect and in vitro functional studies confirmed reduced calpain‐1 activity and dysregulated downstream signaling. These findings support a diagnosis of SPG76 and highlight that the psychiatric symptoms can precede the motor symptoms in HSP. Our results also suggest that multiple genes can potentially contribute to complex neuropsychiatric diseases.

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Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Cited by 24 publications

References 112 publications

Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia

Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia

A Novel SPG7 Gene Pathogenic Variant in a Cypriot Family With Autosomal Recessive Spastic Ataxia

Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early‐onset psychosis

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