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                <title level="j">Brain - A Journal of Neurology </title>
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                <term xml:lang="en">Progranulin</term>
                <term xml:lang="en">GRN</term>
                <term xml:lang="en">Cerebellar ataxia</term>
                <term xml:lang="en">Neuronal ceroid lipofuscinosis</term>
                <term xml:lang="en">Frontotemporal dementia</term>
                <term xml:lang="en">frontotemporal lobar degeneration</term>
                <term xml:lang="en">TDP-43</term>
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              <classCode scheme="mesh">Adolescent</classCode>
              <classCode scheme="mesh">Adult</classCode>
              <classCode scheme="mesh">Frontotemporal Dementia / diagnostic imaging</classCode>
              <classCode scheme="mesh">Heterozygote</classCode>
              <classCode scheme="mesh">RNA Splicing / genetics</classCode>
              <classCode scheme="mesh">Homozygote</classCode>
              <classCode scheme="mesh">Humans</classCode>
              <classCode scheme="mesh">Middle Aged</classCode>
              <classCode scheme="mesh">Neuronal Ceroid-Lipofuscinoses / physiopathology</classCode>
              <classCode scheme="mesh">Mutation</classCode>
              <classCode scheme="mesh">Neuronal Ceroid-Lipofuscinoses / diagnostic imaging</classCode>
              <classCode scheme="mesh">Age of Onset</classCode>
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              <classCode scheme="mesh">Parkinsonian Disorders / physiopathology</classCode>
              <classCode scheme="mesh">Rare Diseases</classCode>
              <classCode scheme="mesh">Progranulins / genetics*</classCode>
              <classCode scheme="mesh">Progranulins / metabolism</classCode>
              <classCode scheme="mesh">Frontotemporal Dementia / genetics*</classCode>
              <classCode scheme="mesh">Retinitis Pigmentosa / genetics</classCode>
              <classCode scheme="mesh">TDP-43 Proteinopathies / diagnostic imaging</classCode>
              <classCode scheme="mesh">TDP-43 Proteinopathies / genetics</classCode>
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              <classCode scheme="mesh">Cerebellar Ataxia / genetics</classCode>
              <classCode scheme="mesh">TDP-43 Proteinopathies / physiopathology</classCode>
              <classCode scheme="mesh">Neuronal Ceroid-Lipofuscinoses / genetics*</classCode>
              <classCode scheme="mesh">Cognitive Dysfunction / genetics</classCode>
              <classCode scheme="mesh">Epilepsy / genetics</classCode>
              <classCode scheme="mesh">Female</classCode>
              <classCode scheme="mesh">Frontotemporal Dementia / physiopathology</classCode>
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              <classCode scheme="halDomain" n="sdv.neu">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]</classCode>
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              <p>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 counseling 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.</p>
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