The natural history of Type 1 infantile GM1 gangliosidosis: A literature-based meta-analysis

Abstract

Introduction

Type 1 GM1 gangliosidosis is an ultra-rare, rapidly fatal lysosomal storage disorder, with life expectancy of <3 years of age. To date, only one prospective natural history study of limited size has been reported. Thus, there is a need for additional research to provide a better understanding of the progression of this disease. We have leveraged the past two decades of medical literature to conduct the first comprehensive retrospective study characterizing the natural history of Type 1 GM1 gangliosidosis.

Objectives

The objectives of this study were to establish a large sample of patients from the literature in order to identify: 1) clinically distinguishing factors between Type 1 and Type 2 GM1 gangliosidosis, 2) age at first symptom onset, first hospital admission, diagnosis, and death, 3) time to onset of common clinical findings, and 4) timing of developmental milestone loss.

Methods

PubMed was searched with the keyword “GM1 Gangliosidosis” and for articles from the year 2000 onwards. A preliminary review of these results was conducted to establish subtype classification criteria for inclusion of only Type 1 patients, resulting in 44 articles being selected to generate the literature dataset of 154 Type 1 GM1 gangliosidosis patients. Key clinical events of these patient cases were recorded from the articles.

Results

Comprehensive subtyping criteria for Type 1 GM1 gangliosidosis were created, and clinical events, including onset, diagnosis, death, and symptomology, were mapped over time. In this dataset, average age of diagnosis was 8.7 months, and average age of death was 18.9 months.

Discussion

This analysis demonstrates the predictable clinical course of this disease, as almost all patients experienced significant multi-organ system dysfunction and neurodevelopmental regression, particularly in the 6- to 18-month age range. Patients were diagnosed at a late age relative to disease progression, indicating the need for improved public awareness and screening.

Conclusion

This study highlights the significant burden of illness in this disease and provides critical natural history data to drive earlier diagnosis, inform clinical trial design, and facilitate family counseling.

Introduction

GM1 gangliosidosis (MIM# 230500) is a neuronopathic lysosomal storage disorder caused by a deficiency in the enzyme β-galactosidase (βgal, E.C. 3.2.1.23) due to biallelic mutations in the GLB1 gene. The ubiquitous lysosomal enzyme βgal is responsible for the degradation of GM1 ganglioside, oligosaccharides, and keratan sulfate, all of which perform many cellular signaling and structural roles [27]. Deficiency of βgal results in toxic lysosomal storage of these substrates, leading to cellular apoptosis. GM1 ganglioside buildup occurs primarily in the central nervous system (CNS), the predominant area of ganglioside synthesis, and causes severe progressive neurological deficits. Systemic disease manifestations are also common due to keratan sulfate and oligosaccharide buildup in peripheral organs, such as the heart, bone, liver, and spleen [8].

The incidence of GM1 gangliosidosis has been reported to be 1 in 100,000–200,000 live births per year [34], with increased incidence in certain populations due to founder mutations [14,16,23,29,31]. There are currently no FDA-approved treatments for this disease, and management of these patients is limited to symptomatic supportive care.

Three clinical forms of GM1 gangliosidosis have been described based on age of first symptom onset and severity of disease progression. The Type 1 infantile form is the most severe, with death often before 3 years of age. This subtype has traditionally been characterized by an age of first symptom onset between birth and 6 months, with clinical findings of hypotonia and developmental delay in almost all patients [8]. Several cases of perinatal onset have been reported, including intrauterine growth retardation, hydrops fetalis, and placental vacuolization [33]. In addition to CNS symptoms, infants frequently have accompanying hepatosplenomegaly, skeletal dysplasia, cherry-red maculae, cardiomyopathy, and coarse facial features [8].

The Type 2 form has been subdivided into the late infantile (Type 2a) and juvenile (Type 2b) subtypes. Late infantile patients often have symptom onset between 7 months and 2 years of age, while juvenile patients typically develop symptoms between 2 and 3 years of age. Type 2 patients exhibit similar symptoms to Type 1 patients, including psychomotor regression and eye and bone abnormalities, but have an attenuated progression [27]. Lastly, the Type 3 variant (chronic or adult) is characterized by later symptom onset (between 3 and 30 years of age) and progressive extrapyramidal symptoms, including dystonia and gait disturbance [37].

Disease severity is associated with the residual activity of the mutant βgal enzyme, with activity nearly absent in Type 1-associated mutations and a small amount of residual activity in Type 2 and 3 patients [8,36,40]. Over 165 mutations have been reported in the GLB1 gene (ClinVar Database), and several genotype-phenotype analyses have been published [8]. Common pathogenic mutations associated with Type 1 disease, including p.R59H and c.1622-1627insG, have been identified in patients from specific geographic regions, such as Brazil [3,30,32], Spain, and among the Roma [29,30,34]. Type 2 and 3 patients are usually compound heterozygotes, with one null allele producing a nonfunctional βgal enzyme and the other often a missense allele resulting in impaired but residual enzyme production [10,13]. p.I51H, p.T82M, and p.R201H are GLB1 mutations reported to cause low βgal activity and have been identified in multiple slower-progressing Type 2 or 3 patients [13,18,21,27,41].

The ultra-rare and rapidly fatal nature of Type 1 disease presents significant challenges in understanding the natural history of this subtype. In this context, results from two clinical studies (NCT00668187, NCT02030015) have been published [20,24,38]. NCT00668187 is the first prospective study in Type 1 GM1 gangliosidosis, and NCT02030015 is an interventional trial studying the Syner-G regimen (miglustat + ketogenic diet) in infantile gangliosidosis subjects. Both studies were conducted by one academic group at a single clinical site. Jarnes Utz et al. reported pooled results from both studies, characterizing clinical changes over time and overall survival in eight Type 1 GM1 gangliosidosis patients [20]. Three out of eight of these patients were given the experimental Syner-G regimen, which may have confounded the reported observations of disease progression [20]. Furthermore, two other longitudinal analyses derived from the prospective natural history study (NCT00668187) have been published, but their scope was limited to tracking only biomarker and brain MRI changes over time [24,38]. Brunetti-Pierri and Scaglia published a GM1 gangliosidosis literature review over a decade ago, identifying a retrospective literature cohort of 130 infantile patients. However, although symptom prevalence was reported, timing of symptom onset or disease progression were not discussed [8]. Taken together, there is a paucity of natural history data around this subtype. Given that multiple interventional clinical trials in Type 1 GM1 gangliosidosis are planned to begin in 2020, there is a need to further characterize disease progression to inform future research study design, identify clinical endpoints, and facilitate family counseling.

This literature-based meta-analysis of Type 1 GM1 gangliosidosis is the first comprehensive retrospective study analyzing the time course of this disease. The analysis was conducted using data aggregated from the last two decades of published reports, with the goal of contributing to the current body of available natural history data. We have established an improved classification for the Type 1 subtype and a mapping of clinical findings as the disease progresses.