Novel CLN3 mutation causing autophagic vacuolar myopathy.
OBJECTIVE
To identify the genetic cause of a complex syndrome characterized by autophagic vacuolar myopathy (AVM), hypertrophic cardiomyopathy, pigmentary retinal degeneration, and epilepsy.


METHODS
Clinical, pathologic, and genetic study.


RESULTS
Two brothers presented with visual failure, seizures, and prominent cardiac involvement, but only mild cognitive impairment and no motor deterioration after 40 years of disease duration. Muscle biopsy revealed the presence of widespread alterations suggestive of AVM with autophagic vacuoles with sarcolemmal features. Through combined homozygosity mapping and exome sequencing, we identified a novel p.Gly165Glu mutation in CLN3.


CONCLUSIONS
This study expands the clinical phenotype of CLN3 disease. Genetic testing for CLN3 should be considered in AVM with autophagic vacuoles with sarcolemmal features.
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy. andrea.cortese@mondino.it.
Andrea
A
Cortese
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Arianna
A
Tucci
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Giovanni
G
Piccolo
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Carlo A
CA
Galimberti
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Pietro
P
Fratta
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Enrico
E
Marchioni
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Gianpiero
G
Grampa
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Cristina
C
Cereda
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Gaetano
G
Grieco
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Ivana
I
Ricca
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Alan
A
Pittman
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Patrizia
P
Ciscato
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Laura
L
Napoli
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Valeria
V
Lucchini
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Michela
M
Ripolone
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Raffaella
R
Violano
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Gigliola
G
Fagiolari
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Sara E
SE
Mole
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
John
J
Hardy
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Arrigo
A
Moglia
From the IRCCS National Institute of Neurology C. Mondino Foundation (A.C., G.P., C.A.G., E.M., C.C., G. Grieco, I.R., A.M.), Pavia, Italy; Department of Molecular Neuroscience, Reta Lila Weston Research Laboratories and MRC Centre for Neuromuscular Diseases (A.T., A.P., J.H.), and Department of Neurodegenerative Disease (P.F.), UCL Institute of Neurology, London, UK; Neuromuscular Unit (P.C., L.N., V.L., M.R., R.V., G.F., M.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Dino Ferrari Centre, Università di Milano, Italy; Neurology Unit (G. Grampa), Saronno Hospital, Italy; MRC Laboratory for Molecular Cell Biology (S.E.M.), Department of Genetics, Evolution and Environment, and UCL Institute of Child Health, University College London, UK; and Department of Neurological Sciences (A.M.), University of Pavia, Italy.
Maurizio
M
Moggio
D000328:Adult; D001343:Autophagy / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000235:genetics / Q000473:pathology*; D004827:Epilepsy / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology; D014617:Vacuoles / Q000235:genetics / Q000473:pathology
C105199:CLN3 protein, human; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones