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GM1 Gangliosidosis: Review of Clinical, Molecular, and Therapeutic Aspects

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GM1 Gangliosidosis: Review of Clinical, Molecular, and Therapeutic Aspects Molecular Genetics and Metabolism 94 (2008) 391–396 Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme Minireview GM1 gangliosidosis: Review of clinical, molecular, and therapeutic aspects Nicola Brunetti-Pierri a, Fernando Scaglia a,b,* a Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA b Texas Children’s Hospital, Houston, TX 77030, USA article info abstract Article history: GM1 gangliosidosis is a lysosomal storage disorder due to deficiency of the b-galactosidase enzyme. This Received 16 February 2008 deficiency results in accumulation of GM1 gangliosides and related glycoconjugates in the lysosomes Received in revised form 12 April 2008 leading to lysosomal swelling, cellular damage, and organ dysfunction. The disease is lethal in the infan- Accepted 12 April 2008 tile and juvenile forms. To date, up to 102 mutations distributed along the b-galactosidase gene (GLB1) Available online 3 June 2008 have been reported. This review gives an overview of the clinical and molecular findings in patients with GM1 gangliosidosis. Furthermore, it describes therapeutic approaches which are currently under investi- Keywords: gation in animal models of the disease. GM gangliosidosis 1 Ó 2008 Elsevier Inc. All rights reserved. GLB1 Lysosomal storage disorders b-galactosidase GM1 gangliosidosis (MIM# 230500) is a lysosomal storage and Morquio B can be often obscured as in patients displaying disorder due to deficiency of the b-galactosidase enzyme (E.C. mental regression and the skeletal abnormalities of Morquio B. 3.2.1.23) which hydrolyzes the terminal b-galactosyl residues from The deficiency of b-galactosidase enzymatic activity, but in GM1 ganglioside, glycoproteins, and glycosaminoglycans [1] combination with neuraminidase deficiency, is also present in a (Fig. 1). The incidence of GM1 gangliosidosis has been estimated different disorder, galactosialidosis (MIM# 256540) [10,11] due to be 1 in 100,000–200,0000 live births [2]. Although the disorder to a defect in the protective protein/cathepsin A (PPCA) [12] stabi- is panethnic, an increased prevalence has been found in Brazil lizing the b-galactosidase/neuraminidase complex [13]. The clini- (1:17,000) [3,4], in the Roma population (1:10,000) [2,5], in the cal presentation of galactosialidosis partially overlaps with GM1 Maltese Islands (1:3700) [6], and in a Cypriot population [7]. gangliosidosis. However, the predominant clinical manifestations GM1 gangliosidosis can be classified into three types based on of galactosialidosis are attributed to the severe neuraminidase the clinical phenotype: (1) type 1 or infantile form with onset deficiency rather than the partial deficiency of the b-galactosidase between birth and 6 months, rapidly progressive with hypotonia, enzyme. severe central nervous system (CNS) degeneration and death by 1–2 years of age; (2) type 2 late infantile or juvenile with onset Disease pathogenesis between 7 months and 3 years, lag in motor and cognitive develop- ment, and slower progression; and (3) type 3 adult or chronic The clinical manifestations of GM1 gangliosidosis result from variant with late onset (3–30 years), a progressive extrapyramidal the massive storage of GM1 ganglioside and related glycoconju- disorder due to local deposition of glycosphingolipid in the caudate gates in different tissues and particularly in the CNS (Figs. 1–3). nucleus [8]. Adult patients have been mostly reported in the Japa- However, the molecular mechanisms leading to the disease patho- nese population. The severity of each type is inversely related to genesis are still incompletely understood. Neuronal cell death and the residual activity of the mutant b-galactosidase enzyme [9]. demyelination accompanied by astrogliosis and microgliosis are b-galactosidase deficiency is also responsible for Morquio disease usually observed in areas of severe neuronal vacuolation. Neuronal type B (MIM# 253010) characterized by marked skeletal abnor- apoptosis, endoplasmic reticulum (ER) stress response [14,15], malities, corneal clouding, cardiac involvement, increased urinary abnormal axoplasmic transport resulting in myelin deficiency excretion of keratan sulfate but no clinical signs of storage in neu- [16], and disturbed neuronal–oligodendroglial interactions ral tissues. However, the demarcation between GM1 gangliosidosis [17,18] have been proposed as possible pathomechanisms involved in GM1 gangliosidosis. Furthermore, inflammatory responses are considered to contribute to the pathogenesis and/or disease pro- gression [19]. More recently, an activation of autophagy leading * Corresponding author. Address: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Fax: +1 832 825 4294. to mitochondrial dysfunction in b-galactosidase deficient mouse E-mail address: [email protected] (F. Scaglia). brains has been implicated in the disease pathogenesis [20]. 1096-7192/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2008.04.012 392 N. Brunetti-Pierri, F. Scaglia / Molecular Genetics and Metabolism 94 (2008) 391–396 ysis. A total of 209 patients met our selection criteria; 130 were infantile, 23 juvenile, and 56 adult GM1 gangliosidosis. Data were analyzed for clinical features and molecular findings. The main clinical features are listed in Table 1. As expected, we found that signs and symptoms of the CNS involvement were invariably pres- ent in all cases. In the infantile form, although present with high prevalence, the classic features seen in storage disorders such as coarse facial features (87%), cherry-red macula (59%), hepatosplen- omegaly (85%), skeletal dysostosis (82%) were not constantly pres- ent, at least at the time of the diagnosis. Macular cherry-red spot, hepatosplenomegaly, and skeletal involvement had higher preva- lence in the infantile form compared to the juvenile form (Table 1). Cardiomyopathy has been reported in patients with all three forms and it is overall present in about one third of the cases. About 6% of the infantile cases presented at birth with hydrops Fig. 1. Biochemical defect in GM1 gangliosidosis. b-galactosidase enzyme fetalis and there have been very few case reports of extensive Mon- hydrolyzes the terminal b-galactosyl residues from GM1 ganglioside. Lack of golian spot [21–24] or angiokeratoma [25]. b-galactosidase leads to massive accumulation of GM1 ganglioside. Abbreviations: Glc, glucose; Gal, galactose; GalNAc, N-acetylgalactosamine; NANA, N-acetyl neu- raminic acid. Biochemical defect b-galactosidase is synthesized as an 85-kDa precursor that is Clinical features post-translationally glycosylated to an 88 kDa form and processed into the mature 64 kDa lysosomal enzyme [13]. The enzyme in The clinical suspicion of GM gangliosidosis is usually based on 1 lysosomes is complexed with two other hydrolases: PPCA and the presence of signs of storage such as coarse facial features, gin- neuraminidase. In white blood cells and fibroblasts, b-galactosi- gival hypertrophy, corneal clouding, cherry-red macula, hepato- dase enzyme activity is deficient in both GM gangliosidosis and splenomegaly, vacuolated lymphocytes, and skeletal dysostosis in 1 galactosialidosis. Nevertheless, galactosialidosis can be distin- addition to a history of psychomotor regression. In the absence guished biochemically from GM gangliosidosis because it presents of these findings the diagnosis is more elusive. To determine the 1 with normal b-galactosidase activity in serum or plasma while en- prevalence of the ‘‘cardinal features” in GM gangliosidosis, we 1 zyme activity is deficient in GM gangliosidosis [26]. However, a have searched the Medline database and analyzed the published 1 definitive diagnosis is based on measurement of neuraminidase cases of infantile, juvenile, and adult or chronic variant GM gangli- 1 activity. Due to its instability, neuraminidase is not measured in osidosis. The search was performed with the key words ‘‘GM gan- 1 leukocytes [27] and its activity has to be determined in fibroblasts. gliosidosis” and ‘‘beta-galactosidase deficiency”. The reference lists Alternatively, the diagnosis of GM gangliosidosis can be confirmed of the reports thus retrieved were also scrutinized. We analyzed 1 by b-galactosidase gene (GLB1) molecular testing. published cases with sufficient clinical data, and with a diagnosis Residual b-galactosidase activity in fibroblasts from patients, of GM gangliosidosis confirmed by either biochemical assay of 1 measured using the artificial 4-methylumbelliferyl b-galactopy- b-galactosidase and neuraminidase and/or by GLB1 molecular anal- ranoside substrate, varies from 0.07–1.3% of control values in infantile patients to 0.3–4.8% in the juvenile form and up to 9% in adults. Residual b-galactosidase activities in Morquio B disease fibroblasts range between 1.3 and 7% of the normal [28]. GLB1 mutations in GM1 gangliosidosis GLB1 maps to the short arm of chromosome 3 and contains 16 exons. It gives rise to two alternatively spliced mRNAs: a transcript of 2.5 kb encoding the lysosomal enzyme and a transcript of 2.0 kb, encoding the elastin binding protein (EBP), a major component of the nonintegrin cell surface elastin receptor complex localized on the cell surface [29,30]. In the 2 kb transcript, exons 3, 4, and 6 are missing, and exon 5 has a different reading frame giving rise to a unique stretch of 32 amino acids that allows EBP to bind trop- oelastin [31,32]. Although
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