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Case Reports
. 2014 Jun 10;82(23):2072-6.
doi: 10.1212/WNL.0000000000000490. Epub 2014 May 14.

Novel CLN3 mutation causing autophagic vacuolar myopathy

Andrea Cortese  1 , Arianna Tucci  2 , Giovanni Piccolo  2 , Carlo A Galimberti  2 , Pietro Fratta  2 , Enrico Marchioni  2 , Gianpiero Grampa  2 , Cristina Cereda  2 , Gaetano Grieco  2 , Ivana Ricca  2 , Alan Pittman  2 , Patrizia Ciscato  2 , Laura Napoli  2 , Valeria Lucchini  2 , Michela Ripolone  2 , Raffaella Violano  2 , Gigliola Fagiolari  2 , Sara E Mole  2 , John Hardy  2 , Arrigo Moglia  2 , Maurizio Moggio  2
Affiliations
Case Reports

Novel CLN3 mutation causing autophagic vacuolar myopathy

Andrea Cortese et al. Neurology. .

Abstract

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.

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Figures

Figure 1
Figure 1. Family pedigree and genetic investigations
(A) Family pedigree and Sanger sequencing validation study of the c.494G>A mutation in the carrier mother (IV-1) and the 2 affected patients (V-1 and V-2). (B) T1-weighted brain MRI of V-1 performed at the age of 38 years showing mild cerebral and cerebellar atrophy. (C) Clustal Omega multiple alignment showing that glycine at position 165 (green highlighted) is conserved across very distant species and is part of a highly conserved small stretch of amino acids. (D) Schematic representation of CLN3 protein showing the relative position of the mutations in the second luminal loop of CLN3. The second luminal loop of CLN3 contains 12 pathogenic mutations, including 6 other missense mutations, suggesting that it is functionally or structurally important to CLN3 function. The transmembrane domains of CLN3 are shown as blue boxes and the cytosolic and lysosomal facing domains as lines. The mutations previously reported in the literature are shown in black. The novel p.Gly165Glu mutation reported here is shown in red.
Figure 2
Figure 2. Muscle biopsy of CLN3 disease presents alterations suggestive of autophagic vacuolar myopathy with autophagic vacuoles with sarcolemmal features
Representative light microscopy images of muscle biopsy from patients V-1 and V-2. (A) Gomori trichrome staining shows vacuoles with fuchsinophil rims. (B) All vacuoles show intense positive reaction for acid phosphatase. (C) Some vacuoles show acetylcholinesterase activity and a clear autofluorescence (data not shown). (D) LAMP-2 immunoreactivity is present at vacuole membrane level. (E) Vacuoles contain dystrophin-positive membrane debris; moreover, some vacuoles show dystrophin-positive membrane. (F) Positive staining for membrane attack complex (data not shown) and human leukocyte antigen class 1 (HLA1) is present in the cytoplasm of most muscle fibers; in addition, HLA1 is localized at membrane level. Original magnification: (A) 250×, (B) 100×, (C, E) 1,000×, (D, F) 400×.
Figure 3
Figure 3. Ultrastructural examination of muscle tissue and blood lymphocytes
Representative electron microscopy images of muscle biopsy from patients V-1 and V-2. (A, B) Large autophagic vacuoles containing myelin figures, cytoplasmic debris, and lysosomal glycogen sacs. (C, D) Intermyofibrillar and subsarcolemmal accumulations of electron-dense material that in some cases (D) are arranged to form structures similar to curvilinear bodies. (E) Blood lymphocyte containing multiple vacuoles of large size, some of which are empty, while other vacuoles contain osmiophilic material. (F) Vacuoles similar to those observed in blood lymphocytes have been recognized in some nuclei. Original magnification: (A) 4,000×, (C, E) 12,000×, (B, D, F) 20,000×.
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