The juvenile gangliosidoses: A timeline of clinical change

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Abstract

Background

The gangliosidoses are rare inherited diseases that result in pathologic accumulation of gangliosides in the central nervous system and other tissues, leading to severe and progressive neurological impairment and early death in the childhood forms. No treatments are currently approved for the gangliosidoses, and development of treatments is impaired by limited understanding of the natural history of these diseases.

Objective

The objective of this study is to improve understanding of the juvenile gangliosidoses phenotypes and the late-infantile phenotypic subtype.

Methods

Through a prospective natural history study of subjects with juvenile GM1- and GM2-gangliosidosis, a timeline of clinical changes was developed for the classic juvenile phenotypes and the late-infantile phenotypes and results of serial neurodevelopmental testing was analyzed.

Results

Several candidate ‘outcome measures’ were identified: changes in ambulation and verbalization skills, the communication domain from neurodevelopmental testing and the caregiver-reported socialization domain.

Conclusions

The most common symptoms leading caregivers to seek a genetic diagnosis were changes in ambulation and verbalization.

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Most cited references 22

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Natural history of infantile G(M2) gangliosidosis.

C P Tifft, Florian S Eichler, Ourania A Giannikopoulos … (2011)

G(M2) gangliosidoses are caused by an inherited deficiency of lysosomal β-hexosaminidase and result in ganglioside accumulation in the brain. Onset during infancy leads to rapid neurodegeneration and death before 4 years of age. We set out to quantify the rate of functional decline in infantile G(M2) gangliosidosis on the basis of patient surveys and a comprehensive review of existing literature. Patients with infantile G(M2) gangliosidosis (N = 237) were surveyed via questionnaire by the National Tay Sachs & Allied Diseases Association (NTSAD). These data were supplemented by survival data from the NTSAD database and a literature survey. Detailed retrospective surveys from 97 patients were available. Five patients who had received hematopoietic stem cell transplantation were evaluated separately. The mortality rate of the remaining 92 patients was comparable to that of the 103 patients from the NTSAD database and 121 patients reported in the literature. Common symptoms at onset were developmental arrest (83%), startling (65%), and hypotonia (60%). All 55 patients who had learned to sit without support lost that ability within 1 year. Individual functional measures correlated with each other but not with survival. Gastric tube placement was associated with prolonged survival. Tay Sachs and Sandhoff variants did not differ. Hematopoietic stem cell transplantation was not associated with prolonged survival. We studied the timing of regression in 97 cases of infantile G(M2) gangliosidosis and conclude that clinical disease progression does not correlate with survival, likely because of the impact of improved supportive care over time. However, functional measures are quantifiable and can inform power calculations and study design of future interventions.

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The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported.

Susan Blaser, Tracy Stockley, Gustavo Maegawa … (2006)

Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal beta-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients. A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, beta-hexosaminidase enzyme activity, and mutation analysis was collected. In our cohort of patients, the mean (+/-SD) age of onset of symptoms was 5.3 +/- 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 +/- 5.6 years. The mean time for progression to becoming wheelchair-bound was 6.2 +/- 5.5 years. The mean age of onset of speech problems was 7.0 +/- 5.6 years, with a mean time of progression to anarthria of 5.6 +/- 5.3 years. Muscle wasting (10.6 +/- 7.4 years), proximal weakness (11.1 +/- 7.7 years), and incontinence of sphincters (14.6 +/- 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the Tay-Sachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence of R178H and R499H mutations was predictive of an early onset and rapidly progressive course. The presence of either G269S or W474C mutations was associated with a later onset of symptoms along with a more slowly progressive disease course. Juvenile GM2 gangliosidosis is clinically heterogeneous, not only in terms of age of onset and clinical features but also with regard to the course of the disease. In general, the earlier the onset of symptoms, the more rapidly the disease progresses. The Tay-Sachs and Sandhoff variants differed somewhat in the frequency of specific clinical characteristics. Speech deterioration progressed more rapidly than gait abnormalities in both the Tay-Sachs variant and Sandhoff variant groups. Among patients with the Tay-Sachs variant, the HEXA genotype showed a significant correlation with the clinical course.

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Infantile gangliosidoses: Mapping a timeline of clinical changes

Jeanine R. Jarnes Utz, Sarah Kim, Kelly King … (2017)

Background Infantile gangliosidoses include GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease). To date, natural history studies in infantile GM2 (iGM2) have been retrospective and conducted through surveys. Compared to iGM2, there is even less natural history information available on infantile GM1 disease (iGM1). There are no approved treatments for infantile gangliosidoses. Substrate reduction therapy using miglustat has been tried, but is limited by gastrointestinal side effects. Development of effective treatments will require identification of meaningful outcomes in the setting of rapidly progressive and fatal diseases. Objectives This study aimed to establish a timeline of clinical changes occurring in infantile gangliosidoses, prospectively, to: 1) characterize the natural history of these diseases; 2) improve planning of clinical care; and 3) identify meaningful future treatment outcome measures. Methods Patients were evaluated prospectively through ongoing clinical care. Results Twenty-three patients were evaluated: 8 infantile GM1, 9 infantile Tay-Sachs disease, 6 infantile Sandhoff disease. Common patterns of clinical change included: hypotonia before 6 months of age; severe motor skill impairment within first year of life; seizures; dysphagia and feeding-tube placement before 18 months of age. Neurodevelopmental testing scores reached the floor of the testing scale by 20 to 28 months of age. Vertebral beaking, kyphosis, and scoliosis were unique to patients with infantile GM1. Chest physiotherapy was associated with increased survival in iGM1 (p=0.0056). Miglustat combined with a low-carbohydrate ketogenic diet (the Syner-G regimen) in patients who received a feeding-tube was associated with increased survival in infantile GM1 (p=0.025). Conclusions This is the first prospective study of the natural history of infantile gangliosidoses and the very first natural history of infantile GM1. The homogeneity of the infantile gangliosidoses phenotype as demonstrated by the clinical events timeline in this study provides promising secondary outcome measure candidates. This study indicates that overall survival is a meaningful primary outcome measure for future clinical trials due to reliable timing and early occurrence of this event. Combination therapy approaches, instead of monotherapy approaches, will likely be the best way to optimize clinical outcomes. Combination therapy approaches include palliative therapies (e.g., chest physiotherapy) along with treatments that address the underlying disease pathology (e.g. miglustat or future gene therapies).

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Author and article information

Contributors

Kelly E. King

Sarah Kim

Chester B. Whitley

Jeanine R. Jarnes-Utz

Journal

Journal ID (nlm-ta): Mol Genet Metab Rep

Journal ID (iso-abbrev): Mol Genet Metab Rep

Title: Molecular Genetics and Metabolism Reports

Publisher: Elsevier

ISSN (Electronic): 2214-4269

Publication date PMC-release: 14 November 2020

Publication date Collection: December 2020

Publication date (Electronic): 14 November 2020

Volume: 25

Electronic Location Identifier: 100676

Affiliations

[a ]Department of Pediatrics, University of Minnesota, 2450 Riverside Avenue, Minneapolis, MN 55454-1450, USA

[b ]Gene Therapy Center, University of Minnesota, 420 Delaware St SE, MMC 391, Minneapolis, MN 55455-0341, USA

[c ]Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 420 Delaware St SE, MMC 446, Minneapolis, MN 55455-0341, USA

[d ]Advanced Therapies Program, University of Minnesota (UMMC) and Fairview Hospitals, Minneapolis, MN 55454, USA

Author notes

[* ]Corresponding author at: Department of Pediatrics, University of Minnesota, 2450 Riverside Avenue, Minneapolis, MN 55454-1450, USA. utzx0002@ 123456umn.edu

Article

Publisher Item ID: S2214-4269(20)30122-1 Publisher ID: 100676

DOI: 10.1016/j.ymgmr.2020.100676

PMC ID: 7674119

SO-VID: 54e066ae-f9e2-40d6-beba-d3029ce1781a

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 2 November 2020

Date accepted : 2 November 2020

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The juvenile gangliosidoses: A timeline of clinical change

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Abstract

Background

Objective

Methods

Results

Conclusions

Related collections

Language change

Most cited references 22

Natural history of infantile G(M2) gangliosidosis.

The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported.

Infantile gangliosidoses: Mapping a timeline of clinical changes

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Cited by 7

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