Clinical and genetic analysis of <i>ATP13A2</i> in hereditary spastic paraplegia expands the phenotype

Estiar, Mehrdad Asghari; Léveillé, Etienne; Spiegelman, Dan; Dupré, Nicolas; Trempe, Jean‐François; Rouleau, Guy A.

doi:10.1002/mgg3.1052

Cited by 22 publications

(23 citation statements)

References 17 publications

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“…For instance, mutations in ATP13A2 cause Kufor‐Rakeb syndrome, 42 which is an atypical parkinsonism‐dystonia disorder. More recently, ATP13A2 has been reported to also be associated with HSP 43,44 . SPG7 is another example of a gene associated with HSP as well as parkinsonism 45,46 .…”

Section: Discussionmentioning

confidence: 98%

GCH1 mutations in hereditary spastic paraplegia

et al. 2021

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GCH1 mutations have been associated with dopa‐responsive dystonia (DRD), Parkinson's disease (PD) and tetrahydrobiopterin (BH4)‐deficient hyperphenylalaninemia B. Recently, GCH1 mutations have been reported in five patients with hereditary spastic paraplegia (HSP). Here, we analyzed a total of 400 HSP patients (291 families) from different centers across Canada by whole exome sequencing (WES). Three patients with heterozygous GCH1 variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant. The former variant is predicted to be likely pathogenic and the latter is pathogenic. The three patients presented with childhood‐onset lower limb spasticity, hyperreflexia and abnormal plantar responses. One of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, who responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares processes and pathways with other HSP‐associated genes, and structural analysis of the variants indicated a disruptive effect. In conclusion, GCH1 mutations may cause HSP; therefore, we suggest a levodopa trial in HSP patients and including GCH1 in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors, epigenetics, and stochasticity could play a role in the clinical presentation.

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Section: Discussionmentioning

confidence: 98%

GCH1 mutations in hereditary spastic paraplegia

et al. 2021

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“…Visual and auditory hallucinations have been reported in the original Chilean kindred, which led to the gene discovery underlying Kufor‐Rakeb disease 6 : 2 patients had (paranoid) auditory hallucinations under treatment with trihexylphenidate, and 1 patient had visual hallucinations without medication. Recent reports of ATP13A2 mutations manifesting as hereditary spastic paraplegia mentioned acoustic hallucinations, delusions, or paranoid ideation (without detailing their relation to medication) 3,7 . Visual hallucinations and psychosis occurring during treatment with levodopa were also noted in 2 other reports 8,9 …”

Section: Discussionmentioning

confidence: 99%

Psychiatric Manifestations of ATP13A2 Mutations

Balint

Damásio

Magrinelli

et al. 2020

Movement Disord Clin Pract

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Background Background: Biallelic mutations in ATP13A2 were identified as the cause of Kufor-Rakeb disease, a pallido-pyramidal syndrome characterized by young-onset dystonia-parkinsonism with vertical supranuclear gaze palsy, spasticity, and cognitive decline. The phenotypic spectrum has broadened since, but predominantly psychiatric or behavioral manifestations have not been highlighted. Cases Cases: Here we report the clinical, radiological, and genetic findings in 2 unrelated patients with ATP13A2 mutations. One patient had a prominent behavioral (autistic spectrum) presentation and the other a psychiatric (paranoid psychosis) presentation. Both had additional features, such as delayed milestones, ataxia, pyramidal signs, upgaze restriction, or impaired cognition to varying extent, but these were partly subtle or developed later in the disease course. Conclusion Conclusion: Prominent behavioral or psychiatric features can be the first or most prominent manifestation of ATP13A2-related disease. They may be a diagnostic clue in patients with ataxia, spasticity, or parkinsonism and may require an interdisciplinary neurological and psychiatric treatment approach.

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“…More recently, ATP13A2 has been reported to also be associated with HSP. 44,45 SPG7 is another example of a gene associated with HSP as well as parkinsonism. 46,47 In addition, SPG11 mutations have been reported in patients with parkinsonism 48 and DRD 49 in addition to HSP.…”

Section: Discussionmentioning

confidence: 99%

GCH1mutations in hereditary spastic paraplegia

Varghaei

Yoon

Estiar

et al. 2021

Preprint

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GCH1 mutations have been associated with dopa-responsive dystonia (DRD), Parkinson’s disease (PD) and tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia B. Recently, GCH1 mutations have also been reported in five patients with hereditary spastic paraplegia (HSP). In this study, a total of 400 HSP patients (291 families) from different centers across Canada were analyzed by whole exome sequencing (WES). Three patients with GCH1 variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant. Both variants were predicted to be likely pathogenic. The three patients presented with childhood-onset spasticity in the lower limbs, hyperreflexia and abnormal plantar responses. Only one of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, and they responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares similar processes and pathways with other HSP-associated genes, and structural analysis of the variants suggested a disruptive effect. In conclusion, GCH1 mutations may also cause HSP; therefore, we suggest including GCH1 in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors could play a role in the clinical presentation of the disease.

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Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype

Cited by 22 publications

References 17 publications

GCH1 mutations in hereditary spastic paraplegia

GCH1 mutations in hereditary spastic paraplegia

Psychiatric Manifestations of ATP13A2 Mutations

GCH1mutations in hereditary spastic paraplegia

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