A new phenotype associated with homozygous <i><scp>GRN</scp></i> mutations: complicated spastic paraplegia

Faber, Ingrid; Prota, Joana Rosa Marques; Martínez, Alberto; Lopes-Cendes, Íscia; França, Marcondes C.

doi:10.1111/ene.13194

Cited by 23 publications

(19 citation statements)

References 5 publications

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“…First, we confirmed that homozygous GRN mutations are involved in CLN11, as only four families have been reported until now (Smith et al, 2012;Canafoglia et al, 2014;Almeida et al, 2016;Faber et al, 2017;Kamate et al, 2019). All mutations identified here have been previously detected in the heterozygous state in FTD patients (Benussi et al, 2009;Almeida et al, 2014;Perry et al, 2013;Pottier et al, 2018) and one, p.(Gln257Profs*27), in the homozygous state in another CLN11 patient (Faber et al, 2017).…”

Section: Discussionsupporting

confidence: 86%

Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms

Huin

Barbier

Bottani

et al. 2019

Brain

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Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.

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Section: Discussionsupporting

confidence: 86%

Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms

Huin

Barbier

Bottani

et al. 2019

Brain

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“…In eleven families Sanger sequencing was the primary diagnostic method, whereas WES was performed in six ( França Jr et al, 2012 ; Faber et al, 2017 ). Of the 16 families in our cohort, seven had at least one allele with a previously described nonsense mutation affecting SPG11 gene (c.118C>T), with four homozygous and three compound heterozygous kindreds.…”

Section: Resultsmentioning

confidence: 99%

SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage

Faber

Martinez

Rezende

et al. 2018

NeuroImage: Clinical

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SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

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“…They may not be comprehensively covered by some next-generation sequencing panels and include the spinocerebellar ataxias, autosomal recessive ataxias, spastic ataxias, demyelinating and hypomyelinating leukodystrophies, and other rare metabolic and neurodegenerative disorders (table 2). [46][47][48][49][50][51][52][53] Several of the diseases in these groups, such as SCA1 (ATXN1), SCA3 (ATXN3), and Friedreich's ataxia (FXN) are triplet repeat disorders and may not therefore be covered by gene panels, even if they are extended to include wider groups of monogenic diseases associated with spasticity. [54][55][56] Particular attention should however be given to atypical presentations of treatable diseases in which lower limb spasticity occurs, often in the context of other clinical features, in the absence of T2-weighted imaging abnormalities in the spinal cord.…”

Section: Genetic Testingmentioning

confidence: 99%

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Shribman

Reid

Crosby

et al. 2019

The Lancet Neurology

200

207

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Hereditary spastic paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative diseases characterised by progressive spasticity of the lower limbs. The pathogenic mechanism, associated clinical features and imaging abnormalities vary significantly according to the affected gene. Here, we describe the clinical and imaging characteristics of the more common forms of HSP. We discuss how to approach the diagnosis and management of a suspected case of HSP in the era of next generation sequencing, before discussing treatment and the potential of emerging therapeutic options for specific causes of HSP based on their underlying molecular mechanism.

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A new phenotype associated with homozygous GRN mutations: complicated spastic paraplegia

Cited by 23 publications

References 5 publications

Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms

Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms

SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

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