Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families

Pashaei, Mahdieh; Davarzani, Atefeh; Hajati, Reza; Zamani, Babak; Nafissi, Shahriar; Larti, Farzaneh; Nilipour, Yalda; Rohani, Mohammad; Alavi, Afagh

doi:10.1080/01677063.2021.1895146

Cited by 12 publications

(21 citation statements)

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“…Several cases of SPG64 had clinical features and electrodiagnostic findings suggestive of combined upper and lower motor neuron dysfunction. 18 Here, we expand upon these preliminary observations, demonstrating additional cases with findings consistent with both upper and lower motor neuron dysfunction and neuropathy. Of the 25 cases for which details of reflex examination are available, 40% show a mixed picture, 36% hyporeflexia/areflexia, and 24% hyperreflexia.…”

Section: Mixed Upper and Lower Motor Neuron Findings In Entpd1-relate...supporting

confidence: 54%

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Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia

Calame

Herman

Maroofian

et al. 2022

Annals of Neurology

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ObjectiveHuman genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683).MethodsIndividuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed.ResultsA total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414‐2_414‐1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574‐6_574‐3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574‐6_574‐3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism.InterpretationThe ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1‐related neurological disease, (2) highlights the importance of genotype‐driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022;92:304–321

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Section: Mixed Upper and Lower Motor Neuron Findings In Entpd1-relate...supporting

confidence: 54%

“…ENTPD1 was first identified as a candidate disease gene for AR DD/ID 33 and subsequently linked to SPG64 (MIM # 615683) 6,16–18 . These individuals had overlapping features of spastic paraplegia and DD/ID, but were highly variable in other neurological symptoms (see Table S1).…”

Section: Discussionmentioning

confidence: 99%

Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia

Calame

Herman

Maroofian

et al. 2022

Annals of Neurology

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“…All these neuroimaging findings would be helpful in differentiating HSPs from SCAs, for cerebellar atrophy is the only prominent neuroimaging finding in SCAs ( 21 ). However, cerebellar atrophy can also be found in some subtypes of HSPs such as SPG5A ( 22 ), SPG7 ( 20 , 23 ), SPG11 ( 23 , 24 ), SPG15 ( 25 ), SPG20 ( 26 ), SPG30 ( 27 ), SPG39 ( 28 ), and SPG46 ( 29 ). Cerebellar atrophy could even be the only abnormal neuroimaging finding in some subtypes of HSPs mentioned above ( 22 , 27 , 29 ).…”

Section: Discussionmentioning

confidence: 99%

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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“…Patients with pure HSP present progressive paraparesis and spasticity of the lower limbs.Whereas complex HSP is characterized by extremity spasticity with additional neurological and extraneurological symptoms such as dementia, amyotrophy, ataxia, seizures, deafness, and orthopedic abnormalities [4][5][6] . The patterns of inheritance of HSP include autosomal dominant (AD), autosomal recessive (AR), X-linked, and mitochondrial, which the pure HSP is dominated by AD and the complicated HSP is dominated by AR [7][8] . As a rare genetic disease, HSP is rarely studied in epidemiology and the global incidence ranging from 3 to 10 per 100,000 [9] .…”

mentioning

confidence: 99%

“…As a rare genetic disease, HSP is rarely studied in epidemiology and the global incidence ranging from 3 to 10 per 100,000 [9] . At present, more than 80 genes have been identi ed in HSP patients and the number of disease-causing loci is approaching one hundred [6][7] . Among all HSP types, hereditary spastic paraplegia type 4 (SPG4) caused by SPAST gene mutation was the most common, accounting for about 30%, and loss of function or haploinsu ciency has been reported as molecular pathogenesis in SPG4 [10] .…”

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confidence: 99%

A SPAST gene-related hereditary spastic paraplegia type 4 family: Identification by a novel mutation

Zhang

wang

2022

Preprint

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Objective: The aim of this study was to confirm the disease causing of a family with hereditary spastic paraplegia. Methods: Detailed clinical characterization analysis was undertake in the HSP family, taking peripheral blood sample from the 9 subjects for the extraction of genomic DNA and the proband underwent next generation sequencing. Potentially causative variants were identified by Sanger sequencing and multiplex ligation-dependent probe amplification. Results: In this study, we obtained clinical and genetic findings in the family with HSP. There were four generations including 47 members, and ten affected members displayed pure HSP, they showed clinical phenotyping that varied in their severity. Gene sequencing suggested that the proband has carried a novel heterozygous variant c.1057_1058insCC in the SPAST gene, and the same mutation was identified in other affected family members.Conclusions: Here, we showed a family with pure autosomal dominant HSP type 4(SPG4). The novel mutation c.1057_1058insCC of SPAST is the causative variant in this HSP-SPG4 family. And the persent study expands the mutation spectrum of SPAST and provides an opportunity to study the genotype-phenotype correlation in SPG4.

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Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families

Cited by 12 publications

References 48 publications

Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia

Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia

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

A SPAST gene-related hereditary spastic paraplegia type 4 family: Identification by a novel mutation

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