Is NIPA1-associated hereditary spastic paraplegia always ‘pure’? Further evidence of motor neurone disease and epilepsy as rare manifestations

Tanti, Matthew; Cairns, Diane; Mirza, Nasir; McCann, Emma; Young, Carolyn A

doi:10.1007/s10048-020-00619-0

Cited by 9 publications

(12 citation statements)

References 16 publications

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“…The pathogenic nonsense variants of the NIPA1 gene associated with HSP are c.316G>A p. (Gly106Arg), c.316G>C p. (Gly106Arg), c.134C>G p. (Tyr45Arg), c.298G>A p, (Ala100Thr), and c.731A>G p (Gln244Arg) (7,8). The case described here had the most common variant, c.316G>A p. (Gly106Arg).…”

Section: Discussionmentioning

confidence: 72%

“…The SPG6 variant, identified in the patient described in this report, is caused by mutations in the NIPA1 gene, located at 15q11.2, and accounts for 1% of all autosomal dominant HSP cases (7); it encodes a magnesium transporter involved in neuronal development and maintenance. Long-term endoplasmic reticulum stress in this variant has been associated with several neurodegenerative disorders, such as Parkinson's disease or amyotrophic lateral sclerosis (ALS) (7).…”

Section: Discussionmentioning

confidence: 86%

“…Although SPG6 phenotypes associated with epilepsy have been described in the literature, their pathophysiological relationship is still unclear (12)(13)(14). Tanti et al (7), by describing the case of a 32-year-old patient with HSP, epilepsy and ALS, reported the first case of a family with NIPA1 pathogenic variants and ALS segregation; they concluded that NIPA1 pathogenic variants, particularly c.316G>A p.(Gly106Arg), are associated with pure and complex HSP.…”

Section: Discussionmentioning

confidence: 99%

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Hereditary spastic paraplegia due to NIPA1 gene mutation: Case report

Parra-Párraga

Espinosa

2022

Case reports

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Introduction: Hereditary spastic paraplegia (HSP) is the term for a group of neurological disorders characterized by progressive spasticity and muscle weakness in the lower limbs. Its etiology is genetic and has been associated with mutations in more than 60 genes. HSP is rare and may be useful in the differential diagnosis of cerebral palsy. Case presentation: 16-year-old male with a diagnosis of HSP due to mutation of the NIPA1 gene:c.316G>A (p. Gly106arg), which corresponds to HSP type 6 (SPG6). The patient presented with clinical signs of progressive upper motor neuron syndrome in the lower limbs, such as spasticity, hyperreflexia and paraparesis, associated with focal onset seizures diagnosed at age 11 and successfully treated with valproic acid. Spasticity treatment was complex and included oral baclofen, intraoperative botulinum toxin, physical therapy, and multilevel orthopedic surgery for the management of musculoskeletal deformities. Conclusion: This is a rare case of complex HSP, associated with epilepsy, due to the mutation of the NIPA1 gene (SPG6), the most common pathogenic variant within this type of mutation. The present case demonstrates the importance of making an early diagnosis of GSP6 to perform timely interventions in these patients, prevent complications, and avoid a higher level of disability.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Hereditary spastic paraplegia due to NIPA1 gene mutation: Case report

Parra-Párraga

Espinosa

2022

Case reports

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“…SPG6 is known as a generally pure form of HSP; however, more cases with a complicated phenotype have also been reported. The comorbidities included idiopathic generalized epilepsy (Svenstrup et al, 2011), polyneuropathy (Liu et al, 2008;Du et al, 2011), cognitive impairment (Martinez-Lage et al, 2012), ataxia (Kim et al, 2019), postural tremor (Svenstrup et al, 2011;Lu et al, 2018) and amyotrophic lateral sclerosis (ALS) (Tanti et al, 2020). Until now, epilepsy has been described in eight families with SPG6 (Reed et al, 2005;Svenstrup et al, 2011;Arkadir et al, 2014;Lu et al, 2018;Tanti et al, 2020;Fabbro et al, 2021;Spagnoli et al, 2021), including the first index patient in our study, who presented with a complicated form of HSP.…”

Section: Discussionmentioning

confidence: 78%

“…To date, less than 30 SPG6 families have been reported in different ethnic populations (Chen et al, 2005;Bien-Willner et al, 2006;Kaneko et al, 2006;Munhoz et al, 2006;Klebe et al, 2007;Kim et al, 2019). The phenotype was often pure form; however, complicated forms have also been described with polyneuropathy (Du et al, 2011), idiopathic generalized epilepsy (Svenstrup et al, 2011), cognitive impairment (Martinez-Lage et al, 2012), ataxia (Kim et al, 2019), or amyotrophic lateral sclerosis (ALS) (Tanti et al, 2020). The mutational spectrum of NIPA1 is quite limited with only seven mutations reported previously, and most of the SPG6 patients harbored a hotspot mutation c.316G > A (p.G106R) (Hedera, 2013).…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6

Jun

et al. 2022

Front. Genet.

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Background: Mutations in the NIPA1 gene cause hereditary spastic paraplegia (HSP) type 6 (SPG6), which is a rare type of HSP with a frequency of less than 1% in Europe. To date, less than 30 SPG6 families and limited NIPA1 mutations have been reported in different ethnic regions. The clinical features are variable.Methods: We screened for NIPA1 mutations by whole exome sequencing or next generation sequencing in 35 unrelated Chinese families with HSP. The clinical manifestations were evaluated.Results: Two variants of NIPA1 were identified in three index patients (3/35, 8.6%), two of whom carried a previously reported common variant c.316G > A (p.G106R), and the third patient harbored a novel likely pathogenic variant c.126C > G (p.N42K). Both variants were de novo in the three index patients. The phenotype was pure HSP in two patients and complicated HSP with epilepsy in the third one.Conclusion:NIPA1-related HSP is more common in China than it in Europe. Both pure and complicated form of HSP can be found. The variant c.316G > A is a hotspot mutation, and the novel variant c.126C > G expands the mutational spectrum. The phenomenon of de novo mutations in NIPA1 emphasizes the need to consider autosomal dominant HSP-related genes in sporadic patients.

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Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia

Fang

Chou

Hsu

et al. 2023

Ann Clin Transl Neurol

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Objective NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort. Methods We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene‐based splicing assay, RT‐PCR analysis on the patients' RNA, and cell‐based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression. Results Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3′ end of NIPA1 exon 3 near the exon–intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression. Interpretation SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent‐onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy.

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Is NIPA1-associated hereditary spastic paraplegia always ‘pure’? Further evidence of motor neurone disease and epilepsy as rare manifestations

Cited by 9 publications

References 16 publications

Hereditary spastic paraplegia due to NIPA1 gene mutation: Case report

Hereditary spastic paraplegia due to NIPA1 gene mutation: Case report

Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6

Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia

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