Clinical, Imaging, Genetic, and Disease Course Characteristics in Patients With GM2 Gangliosidosis

Abstract

Background and Objectives

GM2 gangliosidoses, a group of autosomal-recessive neurodegenerative lysosomal storage disorders, result from β-hexosaminidase (HEX) deficiency with GM2 ganglioside as its main substrate. Historically, GM2 gangliosidoses have been classified into infantile, juvenile, and late-onset forms. With disease-modifying treatment trials now on the horizon, a more fine-grained understanding of the disease course is needed.

Methods

We aimed to map and stratify the clinical course of GM2 gangliosidoses in a multicenter cohort of pediatric and adult patients. Patients were stratified according to age at onset and age at diagnosis. The 2 resulting GM2 disease clusters were characterized in-depth for respective disease features (detailed standardized clinical, laboratory, and MRI assessments) and disease evolution.

Results

In 21 patients with GM2 gangliosidosis (17 Tay-Sachs, 2 GM2 activator deficiency, 2 Sandhoff disease), 2 disease clusters were discriminated: an early-onset and early diagnosis cluster (type I; n = 8, including activator deficiency and Sandhoff disease) and a cluster with very variable onset and long interval until diagnosis (type II; n = 13 patients). In type I, rapid onset of developmental stagnation and regression, spasticity, and seizures dominated the clinical picture. Cherry red spot, startle reactions, and elevated AST were only seen in this cluster. In type II, problems with balance or gait, muscle weakness, dysarthria, and psychiatric symptoms were specific and frequent symptoms. Ocular signs were common, including supranuclear vertical gaze palsy in 30%. MRI involvement of basal ganglia and peritrigonal hyperintensity was seen only in type I, whereas predominant infratentorial atrophy (or normal MRI) was characteristic in type II. These types were, at least in part, associated with certain genetic variants.

Discussion

Age at onset alone seems not sufficient to adequately predict different disease courses in GM2 gangliosidosis, as required for upcoming trial planning. We propose an alternative classification based on age at disease onset and dynamics, predicted by clinical features and biomarkers, into type I—an early-onset, rapid progression cluster—and type II—a variable onset, slow progression cluster. Specific diagnostic workup, including GM2 gangliosidosis, should be performed in patients with combined ataxia plus lower motor neuron weakness to identify type II patients.

Introduction

GM2 gangliosidoses are a group of autosomal-recessive neurodegenerative lysosomal storage disorders, resulting from a deficiency of lysosomal enzyme β-hexosaminidase (HEX) with accumulation of GM2 gangliosides predominantly in neurons resulting in a broad spectrum of neurologic signs and dysfunctions.^1,2

Historically, GM2 gangliosidoses have been classified into infantile, juvenile and late-onset (or adult) forms.^3-9 The infantile form has been reported to be characterized by developmental arrest, abnormal startle response, reduced muscle tone, seizures, rapid progression, and death in early childhood.^3,7,8 The later onset forms are described with slower progression and clinical features of spasticity and ataxia, dysarthria, and dysphagia, which may be followed by cognitive and/or psychiatric symptoms.^5,7,8 Predominant lower limb weakness due to anterior horn involvement and psychiatric symptoms has been reported to be characteristic of the late-onset forms.^6-8,10

However, not all evidence indicates that age at onset is strongly related to clinical characteristics and dynamics of the disease. In so-called “late-onset Tay-Sachs” disease, some patients were reported as “clumsy.”^6,11 or with “neurodevelopmental symptoms” already in childhood (poor motor skills, clumsiness, dysarthria, stuttering, learning difficulties).^8,10 Thus, there might be a group of GM2 patients with early-onset, but nevertheless slow disease course.

In addition, there have been differing views about the common age of symptom onset for the juvenile gangliosidosis phenotypes.^5,7,8,12 Further adding to the problems of this classification, some case reports have described—in addition to an infantile onset form—a “late-infantile onset” of GM2 gangliosidosis,^5,9 altogether pointing to variable and partly imprecise and inconsistent methods for distinguishing GM2 phenotypes.

With now a growing number of therapeutic approaches for GM2 gangliosidoses on the horizon (e.g., 2 gene therapy trials [NCT04669535 and NCT04798235]),^7,8,13-16 an accurate stratification of disease course and phenotypic progression clusters is now no longer only a conceptual effort but indeed a prerequisite to identify the window of opportunity for therapies and to inform promising trial designs. The lack of clarity and consistence in classification of GM2 gangliosidoses interferes with both efficient trial designs and appropriate selection of patients for clinical trial cohorts, particularly as early start of treatment is the key for clinical efficacy of disease-modifying therapies in neurometabolic diseases.¹⁷

The problems and controversies of the current classification scheme, as well as the need for a more accurate stratification approach, stimulated the following systematic natural history study in patients with GM2 gangliosidoses. In a multicenter cohort from 6 German centers, we aimed to map and stratify the clinical course and typical MRI patterns of GM2 gangliosidoses by disease onset and dynamics, cutting across—and thus overcoming—classic disease classifications that are based only on age groups (e.g., infantile/juvenile/adult) or clinical eponyms (e.g., Tay-Sachs, Sandhoff). Specifically, we investigated whether it is exclusively age at onset or rather the dynamics of the disease—also independent from age at onset—that distinguish between severe and moderate disease courses in GM2 gangliosidosis.

Methods

Patients and Clinical Assessment

Clinical and neuroimaging data of patients with GM2 gangliosidosis were retrospectively collected in 6 rare disease expert centers in Germany with specific focus on diagnosing and treating these disorders. Inclusion criteria were proven enzyme deficiency of β-hexosaminidase A (Tay-Sachs disease) or β-hexosaminidase A+B (Sandhoff disease) or pathogenic variation in any of the GM2 genes (HEXA, HEXB, GMA2).

Patients were diagnosed between January 2012 and July 2018. Clinical data were systematically assessed by the center's disease expert physicians according to a standardized data sheet. It covered parameters, including demographics, genotype, enzyme activity, developmental milestones, neurologic and clinical features (such as spasticity, ataxia, and acoustic startle with respect to onset and on follow-up), psychiatric involvement (psychosis, depression, and other conditions), MRI results (including systematic reanalysis of original MRI images, if available), additional laboratory results, and neurophysiology (see data sheet in supplement).

Neuroimaging

As a first step, a systematic literature search was performed on PubMed without restrictions on year of publication (search terms: MRI AND one of the following terms: GM2, Gangliosidoses, Tay-Sachs, Sandhoff) reviewing and collecting typical MRI features in GM2 gangliosidosis. As step 2, a standardized data sheet was developed, covering all these features and allowing to document any additional changes previously not noted for GM2 gangliosidosis (eTable 1, links.lww.com/WNL/D258). In a third step, MRI images were analyzed by 2 independent investigators for all subjects where MRI images were available, with one of them (I.K-M) blinded for the clinical data (eTable 2).

Enzyme Activity

Biochemical analysis of enzyme activity was performed for all patients where samples were available (17/21 patients) in the certified neurometabolic laboratory of the Children Hospital Tübingen, with a proven long-standing experience in diagnostic hexosaminidase analysis. β-Hexosaminidase A and whole β-hexosaminidase activities were measured in leukocyte samples isolated from EDTA blood using p-nitrophenyl-6-sulfo-2-acetamido-2-deoxy-d-glucopyranoside or p-nitrophenyl-N-acetyl-β-d-glucosaminide as substrate. A detailed description of methods has been published previously.¹⁸

Statistics

During recruitment of patients for this study, it became obvious that there are 2 clusters of patients with GM2. Descriptive statistics were used to describe age at onset, age at diagnosis, and time from onset to diagnosis, and statistical comparison of the 2 groups was performed using Mann-Whitney U test, due to the small cohorts, with non-normal distribution.

Standard Protocol Approvals, Registrations, and Patient Consents

Ethics approval for this study in its present form was obtained from the local ethics committee in Tübingen according to local regulations (Nr. 664/2019BO2). The need for informed consent was waived because of the historical nature of the data, all collected within the context of regular medical care.

Data Availability

All relevant data are within the article. Individual participant's values from the whole patient cohort may be made available on reasonable request to the corresponding author, pending the approval of the Institutional Review Board of the University of Tübingen, Germany.

Results

Patient Cohort

Twenty-one patients were included. 17 patients were diagnosed with Tay-Sachs disease (16 enzymatically through β-hexosaminidase A deficiency, confirmed genetically; 1 only genetically [age: 1.7–52 years]). Two of these patients have been published previously,¹⁹ 2 patients with Sandhoff disease (both enzymatically with β-hexosaminidase A+B deficiency, 1 also tested genetically [age: 8 years]) and 2 patients with GM2 activator deficiency with normal enzyme activities (diagnosis made genetically [age: 5 years]). These 2 patients have been published previously.²⁰ Time of disease onset in 2 patients, where it had been reported as “early infancy” and “kindergarten,” respectively, was estimated as age 3 years; and in one patient, where it had been reported as “in the first year,” was estimated as age 6 months.

Disease Clusters by Time to Diagnosis and Disease Progression

Analyses of age at onset of first symptoms and age at diagnosis revealed 2 clusters of patients based on differences in disease progression (see Figure 1): a first cluster (8 patients; identifier numbers 1–8 in Figure 1) with early onset (first symptoms occurred between 0.3 and 2.1 years [median 0.7 years]) and also early diagnosis (between 0.8 and 3.4 years [median: 1.6 years]). Early disease onset and rapid disease progression consecutively resulted in a shorter time span from onset to diagnosis (0.2 up to 2.4 years [median 0.7 years]). Patients with GM2 activator deficiency and Sandhoff disease were only found in this first group.

Figure 1. GM2 Clusters Based on Differences in Disease Progression.

Tay-Sachs (patients 3, 5, 6, 8–21), activator deficiency (patients 4, 7), and Sandhoff disease (patients 1, 2) according to age at diagnosis (end point of the bar) and onset of first symptoms, as well as age at first MRI (magnetic resonance imaging) indicating 2 disease clusters (type I patients 1–8; type II patients 9–21).

A second cluster (13 patients; identifier numbers 9–21, Figure 1) was characterized by very variable and later symptom onset (median: 14 years, range from birth to 35 years) and a longer interval from symptom onset until diagnosis was established (median 16 years, range 10–47 years), indicating a slower disease course, characterized for a long period by unspecific “prodromal” signs. Age at diagnosis ranged from 15 to 53 years (median 28 years).

Comparison of age at onset, age at diagnosis, and time from onset to diagnosis each differed statistically significant between cluster 1 and cluster 2 (p < 0.001).

Clinical Features

We next analyzed the disease features and disease dynamics of the GM2 gangliosidosis disease spectrum, particularly testing whether they would characterize discriminate between the 2 disease clusters, respectively (Table 1).

Table 1.

Genotype-Phenotype Correlation

Patients	Type	Gene	Variant 1	Variant 2	Regression/Stagnation	Spasticity	Seizure	Balance and gait	Fine motor skills	Dysarthria	Dysphagia	Psychiatric	Weakness
21	II	HEXA	c.805G>A	c.805G>A	-	-	-	-	-	-	-	-	++
20	II	HEXA	c.805G>A	c.1274_1277dupTATC	-	-	-	++	+	+	+	-	+
19	II	HEXA	c.805G>A	c.1274_1277dupTATC	n.a.	+	-	++	+	+	+	-	+
18	II	HEXA	c.805 G>A	c.1274_1277dupTATC	n.a.	+	-	+	++	+	+	+	n.a.
17	II	HEXA	c.1073+1G>A	c.805G>A	n.a.	-	-	++	+	+	-	+	+
16	II	HEXA	c.805G>A	c.915_917delCTT	-	-	-	++	+	+	+	+	+
15	II	HEXA	c.1510C>T	c.1561T>C	-	-	-	+	-	+	-	++	+
14	II	HEXA	c.805G>A	c.779C>G	-	-	-	++	-	+	-	-	++
13	II	HEXA	c.805G>A	c.947dupA	n.a.	-	-	++	+	+	+	-	++
12	II	HEXA	c.611A>G	c.805G>A	-	-	-	++	+	+	+	+	+
11	II	HEXA	c.1510C>T	c.1561T>C	+	-	-	++	-	++	+	+	+
10	II	HEXA	c.805G>A	c.1274_1277dupTATC	+	-	-	+	+	+	+	+	-
9	II	HEXA	c.1302C>G	c.459+5G>A	+	-	-	++	+	-	-	-	-
8	I	HEXA	c.346+1G>C	c.533G>A	+	+	+	++	+	+	+	-	n.a.
7	I	GM2A	c.262_264delAAG	c.262_264delAAG	++	+	+	n.a.	++	+	+	n.a.	n.a.
6	I	HEXA	c.409C>T	c.409C>T	+	+	+	n.a.	+	n.a.	+	-	n.a.
5	I	HEXA	c.409C>T	c.1274_1277dupTATC	++	+	-	n.a.	+	n.a.	+	-	n.a.
4	I	GM2A	c.369_371delinsATTAA	c.369_371delinsATTAA	++	+	+	n.a.	+	n.a.	+	-	n.a.
3	I	HEXA	c.570+1G>A	c.570+1G>A	++	+	+	n.a.	+	n.a.	+	-	n.a.
2	I	HEXB	c.875C>T	Deletion Exon 1 und 2 Hex B	++	+	-	+	+	n.a.	+	-	n.a.
1	I	HEXB	n.a.	n.a.	++	+	+	n.a.	+	n.a.	+	-	n.a.

++: initial symptom; +: during disease course; -: patient without this symptom; n. a.: not applicable.

Stagnation and regression were the dominant features of disease dynamics in cluster 1, present in 100% of patients (as an initial symptom in 6/8 patients and later in the disease course in all 8 patients), concerning all developmental aspects (i.e., cognitive and motor). Stagnation and regression were never reported at disease onset in cluster 2; in 3 patients (33%), it was reported during the course of the disease.

Problems with balance and gait were characteristic symptoms in cluster 2 (12/13 patients, 92%), being the initial symptom in 9/13 patients. As 6 patients in cluster 1 did not reach the milestone “independent walking,” this variable was not applicable for this group.

Muscle weakness and atrophy were reported in 10 of 12 patients (83%) of cluster 2 (with no data available for 1 patient), predominantly involving the lower proximal limbs (10 patients had proximal and 3 patients had distal weakness of the lower limb, 4 patients had proximal weakness of the upper limb, and 6 patients had muscle atrophy of the lower limb). It was an initial symptom in 3 of 12 patients (25%). In young children, muscle weakness is clinically difficult to distinguish from hypotonia; therefore, we did not characterize it in cluster 1.

Symptoms characterizing the further disease course—rather than disease onset—were spasticity in cluster 1, which was reported in all 8/8 patients of cluster 1 but only in 2 of 13 patients of cluster 2. Seizures, although not initially, were a characteristic symptom in cluster 1 (6/8 subjects, 75%) but absent (0%) in patients of cluster 2.

Psychiatric disorders were only reported in cluster 2, again as a very frequent feature (7/13, 54%, as initial symptom in 1/13 patients). Psychiatric features included particularly the psychotic-affective spectrum: psychosis, bipolar depression, paranoid schizophrenia, and mixed schizoaffective disorder.

Features frequently occurring in both clusters (mostly during follow-up) were

• Dysphagia: 8 of 13 patients (62%) in cluster 2 and 8 of 8 (100%) in cluster 1.

• Dysarthria: 11 of 13 patients (84%) in cluster 2 (as initial symptom in one patient) and 2 of 2 patients (100%) of cluster 1 where the item dysarthria was applicable (it was not applicable in the other 6/8 subjects of cluster 1 who never learned to speak).

• Problems with fine motor skills: 8 of 8 patients (100%) in cluster 1 (as initial symptom in one patient) and 9 of 13 patients (69%) in cluster 2 (as initial symptom in one patient).

Five of 13 patients (38%) in cluster 2 developed cognitive impairment, yet this variable was not assessed systematically, thus likely underreported.

Startle reflex was reported in all 8 patients of cluster 1 (100%), but in none of the patients from cluster 2 (0%). Cherry red spot was also present only in cluster 1 (6/8 patients; missing data from the 8th patient), but not in cluster 2. Hepatosplenomegaly is an overall rather rare feature in GM2 gangliosidoses, reported in 2 of 8 patients (25%) from cluster 1, but in none of cluster 2.

Several ocular abnormalities, such as slowing of saccades (5/13, 38%), saccadic smooth pursuit eye movement (3/13, 23%), or vertical gaze palsy (4/13, 31%), were only observed in cluster 2 (total 11/13 patients), but not in cluster 1. By contrast, nystagmus was seen in 50% of cluster 1 patients (4/8), while only in 1 patient (1/13, 8%) of cluster 2.

β-Hexosaminidase Activity Levels

Figure 2 illustrates the β-hexosaminidase A activity in the 2 clusters (including GM2 activator deficiency and Sandhoff disease). Activity was largely reduced in patients with Tay-Sachs disease, varying from no detectable activity to 1.7 nmol/h/10⁶ cells and not discriminating between the 2 clusters. In Sandhoff disease subjects, β-hexosaminidase A activity was reduced (whole hexosaminidase assay data not shown). As expected, in patients with GM2 activator deficiency, β-hexosaminidase A activity was in the normal range.

Figure 2. β-Hexosaminidase A Activity in nmol/h/10⁶ Cells.

GM2 disease cluster 1 included patients with Sandhoff disease (SD) and activator deficiency (AD). Minimal permissible value for β-hexosaminidase A assay was set as 6.48 nmol/h/10⁶ cells (dashed line).

Aspartate Transaminase Lactate Dehydrogenase Blood Levels

Aspartate transaminase (AST) levels (available in 19 patients) were elevated in all patients of cluster 1 (8/8, 100%) (ranging from 153 U/L to 240 U/L), but in none of the patients of cluster 2 (0/11; 0%). Lactate dehydrogenase (LDH) levels were also elevated in all patients (6/6, 100%) of cluster 1 (ranging from 613 to 990 U/L), but only in 2 of 7 patients of cluster 2, and only to a much lower level (maximal 325 U/L); for details, see eTable 3 (links.lww.com/WNL/D258).

Genotype Associations of the GM2 Disease Clusters

The HEXA variant c.805G>A was highly prevalent in cluster 2 (10/13, one patient was homozygous), but absent in cluster 1, thus indicating a possible genotype-phenotype association, at least for this HEXA variant. Variant c.1274_1277dupTATC was also more frequently observed in cluster 2 (3 times) than in cluster 1 (1 time). By contrast, c.409C>T was observed only in cluster 1 patients (3 times, one patient homozygous). For all genetic findings, see eTable 4 (links.lww.com/WNL/D258).

MRI Imaging

The following MRI features were identified in patients with GM2 gangliosidosis^20-24 and operationally defined in the study CRF data sheet:

• Delayed myelination: normal myelination pattern on T1w and T2w images, but delayed for age.

• Peritrigonal signal hyperintensity on T2w images also covering the optic radiation

• Atrophy of supratentorial or infratentorial structures (according to Gburek²⁵).

• Abnormalities of the basal ganglia: swollen appearance with mild hyperintensity on T2w and difficulties in distinguishing the capsula interna from surrounding parenchyma.

• Hypomyelination, for example, insufficient myelination without progression and a discrepancy between T1-weighted and T2-weighted images (T1w > T2w).

Brain MRI information was available for 19 of 21 patients: in 16 patients, MRI image data sets were directly available (all included T2w or FLAIR images) and in 3 patients, there were only written reports. Two patients for whom no brain MRI information was available had Tay-Sachs disease.

Abnormal findings were classified into the following patterns (see Figures 3 and 4).

Figure 3. MRI Findings (Multiple Answers Possible).

GM2 disease cluster 1 shown in dark blue [I], in total 8 patients. GM2 disease cluster 2 shown in light blue [II], in total 13 patients.

Figure 4. MRI Findings in GM2.

MRI T2w sagittal (A) and coronal (B), in a patient with Tay-Sachs disease, aged 40 years, showing infratentorial atrophy with enlarged spaces between the foliae of the cerebellar hemispheres and the vermis (arrow). By contrast, supratentorial structures appear normal. MRI T2w in a patient (C) with Tay-Sachs disease at age 26 months and patient (D) also with Tay-Sachs disease at age 13 months showing peritrigonal signal hyperintensity (thick arrow) also affecting the optic radiation, basal ganglia appear mildly hyperintense and swollen, and the anterior capsula interna is difficult to distinguish (thin arrow). MRI T2w axial (E) and coronal (F), in a patient with Sandhoff disease, aged 24 months, showing hypomyelination. The entire cerebellar and cerebral white matter is hyperintense; signal hypointensity appears only in the corpus callosum (arrow) and as a stripe in the external capsule. Basal ganglia appear mildly hyperintense and swollen.

Atrophy, predominantly infratentorial, without abnormalities of basal ganglia or white matter, was found in 8 of 16 patients, all belonging to cluster 2 (8/11; 73%), and 2 also showed additional supratentorial atrophy.

Basal ganglia abnormalities and abnormal myelination of optic radiation were found in 7 of 8 patients of cluster 1. Global myelination was slightly delayed in 2 patients with this pattern.

Hypomyelination was found in one patient with Sandhoff disease. Signal indicating myelin was only observed in the splenium and the pedunculi cerebelli. Both on T1w and T2w, there was no progression of myelination with age (MRI at 10 months and 2 years). Basal ganglia appeared swollen and mildly T2w hyperintense; in addition, there was mild infratentorial atrophy.

In 3 patients, cerebral MRI was normal (no signs of atrophy, normal myelination, and no involvement of basal ganglia or white matter). All belonged to cluster 2 (patients numbers 9, 11, and 15).

Discussion

The GM2 gangliosidoses used to be classified by age at onset into: (1) an infantile form, with onset in infancy and death before 4 years³; (2) a juvenile form, with onset in early to midchildhood or adolescence (1.5–15 years,⁵ respectively, 2–5 years^7,8); and (3) an adult or late-onset form with onset in late childhood or much later (8–36 years,⁶ respectively, 10–42 years¹⁰). Our analysis of 21 patients with GM2 gangliosidosis shows that this classification—while intuitively appealing—might not correspond to actually meaningful disease clusters. For example, patients with an early childhood onset may have a rather mild disease course, resulting in a clinical diagnosis not before late childhood or adulthood, and a clinical, imaging, and genetic profile much more similar to “late-onset” than other “early-onset” cases. Meaningful GM2 disease clusters should reflect not only age at onset, but rather differences in clinical, imaging, genetic, and disease course characteristics.

Using “time to diagnosis” as an assistive methodologic tool to uncover so far potentially hidden GM2 disease stratifications, we indeed identified 2 GM2 disease clusters which—beyond and independent from simply age at onset—differed in their clinical, imaging, and genetic profile. To discover these 2 clusters, we went beyond classical age at onset classifications (infantile/juvenile/adult) or clinical eponyms (Tay-Sachs, Sandhoff, activator deficiency disease), pooled together all GM2 patients without such prior conjectures, and stratified them by the temporal delay between onset of symptoms and diagnosis. In cluster 1, there was little delay until the diagnosis was established (median 0.7 years), whereas delay was significantly longer in cluster 2 (10–47 years, median 16 years).

The 2 clusters did show a difference in age at onset with patients in cluster 1 showing symptoms on average earlier than patients in cluster 2 with a certain overlap. Age at onset alone did not sufficiently differentiate between the 2 disease clusters. Age at onset rather was only one variable among a larger cluster of clinical, neuroimaging, laboratory, and genetic features and biomarkers that were different between the 2 groups.

In fact, a classification fully based on classical age at onset (infantile/juvenile/adult) was even impedimental, as the clusters found using this stratification did not provide evidence for a meaningful difference in clinical, imaging, and genetic profiles between a juvenile and an adult-onset form, and patients with very late diagnosis could have onset of symptoms already in infancy and early childhood.

The use of “time to diagnosis” as described here as a first classifier is certainly only a proxy surrogate, that is, an assistive methodologic tool to uncover true underlying clinical, biological, and trial relevant differences. This variable is certainly, at least in general, influenced by a variety of factors, for example, access to diagnostic capacities (rare disease expert centers, MRI, genetic tests, and analysis of enzyme activity) or experience of the treating physician with an awareness of rare lysosomal diseases. However, the important difference in time to diagnosis between the 2 groups cannot be explained by such “disease extrinsic” factors alone. Given the extreme difference in time to diagnosis between the 2 clusters—and the wide range difference in manifold clinical, imaging, laboratory, and genetic features corresponding to each cluster—a difference in disease dynamics, type of features, and severity of features is much more likely to explain why diagnosis was achieved rather early or late.

In the following, we describe the characteristic features of these 2 clusters with an emphasis on differentiating features. These features cover clinical, MRI imaging, laboratory, and genetic findings.

GM2 Gangliosidosis Cluster With Early Age at Onset and Rapid Disease Progression: Type I

This cluster comprised 8 patients with an onset between 0.3 and 2.1 years. All patients with activator deficiency or Sandhoff disease (4/8) belonged to this group. Developmental stagnation and regression were the presenting and dominant features, spasticity developed in all, and seizures characterized the further disease course in all but 2 patients. A startle reflex was present in all patients and a cherry red spot in 6 patients. These features discriminated this group clearly from disease cluster type 2, where none of these features was reported in any patient. Our findings thus highlight that these features are indicative of a rapid progression cluster of GM2 patients.

Elevated AST levels were discriminative for this rapidly progressive cluster against the slower progressive cluster, being elevated in all patients of cluster 1, but none of cluster 2. Elevated AST levels in early-onset GM2 patients have been described previously,²⁶ and a differential analysis in GM2 patients with variable age at onset has not been performed to our knowledge. The elevated AST level does not only distinguish cluster 1 from cluster 2 GM2 patients but also GM2 patients from other lysosomal storage diseases. Specifically, to our knowledge, AST is not elevated in other infantile forms of lysosomal storage diseases, for example, metachromatic leukodystrophy or Krabbe disease (own experience).

Analysis of the first MRI performed during disease course revealed a characteristic pattern in this cluster, not seen in the other. An involvement of the basal ganglia and peritrigonal signal hyperintensity also covering the optic radiation was the typical neuroimaging feature in all patients. Basal ganglia appeared swollen and mildly T2w hyperintense. Peritrigonal white matter, including the optic radiation, was abnormal with hyperintensity on T2w. Two patients showed additional slightly delayed global myelination. One patient with Sandhoff disease showed severe hypomyelination in addition to the described basal ganglia abnormalities and mild infratentorial atrophy.

In early-onset GM2 forms, the characteristic swollen MRI aspect of the diencephalon, especially the basal ganglia, has been well described previously,^21-23 while peritrigonal signal hyperintensity also covering the optic radiation to our knowledge has only been reported by us before in 2 children with GM2 gangliosidosis due to activator deficiency.²⁰ Early-onset GM2 gangliosidosis has been described as a brain hypomyelination disorder.^23,27 However, in our cohort of GM2 patients, we identified hypomyelination only in one patient with Sandhoff disease. Thus, our results do not support hypomyelination as a typical feature of early-onset GM2 gangliosidosis. In contrast to previous MRI reports on GM2 disease, we did not observe extensive T2 signal increase in cerebral white matter. This might be explained by the fact that the MRIs analyzed here were mostly acquired early in the disease course, while demyelination represents a feature of later disease progression.^4,21,22

The disease course in this GM2 disease cluster might—at least in part—be associated with certain genetic variants. The HEXA missense variant c.409C>T was observed only in this cluster (with one patient being homozygous for this variant), indicating that this variant is associated with a more severe phenotype, compared with the variants observed in group 2.

GM2 Gangliosidosis Cluster With Variable Age at Onset and Slow Disease Progression: Type II

This cluster comprised 13 patients. Age at onset was very variable and ranged from early infancy up to 35 years. Presenting symptoms were mostly problems with balance or gait (69%), which became a general feature of almost all cluster 2 subjects in the course of the disease. Muscle weakness and atrophy were frequent, in 25% already at disease onset, in more than 80% during the course of the disease, predominantly involving the proximal lower limbs. This feature has so far been reported as a characteristic finding in patients with the later onset forms of Tay-Sachs disease.^6,10

Typical features different from cluster 1 and characterizing the disease course were psychiatric symptoms, which were seen in more than 50% of patients, and comprised severe symptoms within the psychotic-affective disease spectrum, such as psychosis, bipolar disorder, paranoid schizophrenia, and mixed schizoaffective disorders. These features have been described by Masingue et al.¹⁰ in a similar distribution in late-onset forms of Tay-Sachs disease. With a prevalence of >80%, oculomotor impairments were also frequent features in this cluster during disease course. This corroborates and extends earlier findings on saccade abnormalities in late-onset Tay-Sachs disease.²⁸ Although vertical gaze palsy has been reported before in single patients with Tay-Sachs disease,^29-31 we here provide systematic evidence that this feature is a frequent oculomotor finding, observed in 30% of cluster 2 GM2 patients.

First MRI in cluster 2 patients was characterized by atrophy (seen in 73%) or was normal. Atrophy was predominantly infratentorial; in 2 patients, it was also supratentorial. Basal ganglia or white matter was not involved. These findings were in agreement with previous studies in later onset patients.^6,10,32

Cluster 2 represents a challenge for early and specific diagnosis. Our data illustrate an important diagnostic delay, with a large “delta diagnosis”—not only of years but of decades—indicating the need for raising awareness for this group. Obviously, an insidious onset and a very slow disease progression with symptoms considered unspecific do not raise suspicion of a neurodegenerative metabolic disease. The ‘red flag’ for pediatric neurologists and neurologists is to be aware of early signs of ataxia and (lower motor) weakness and not to interpret them merely as unspecific “clumsiness,“but initiate a diagnostic workup, including GM2 gangliosidosis. This is especially important as MRI findings in this group may not raise suspicion as they may be normal or comprise only mild cerebellar atrophy, which may be missed when interpreting the MRI.

In addition, this GM2 disease cluster might—at least in part—be associated with certain genetic variants. The HEXA c.805G>A variant was found in 10 of 13 patients of this cluster (with one patient being homozygous for this variant), extending earlier genotype-phenotype suggestions that this variant might be typically associated with a slower Tay-Sachs disease course.^7,11,33 Four patients in this cluster were compound heterozygous for this missense variant together with a LoF variant (c.[805G>A]; [1274_1277dupTATC]).

For a quick overview, the features of the 2 different types are schematically illustrated with respect to age in Figure 5.

Figure 5. Schematic Illustration of Signs and Symptoms in GM2 Disease.

Symptoms characteristic for type I in dark blue and for type II in light blue. MRI type I (involvement of the basal ganglia and peritrigonal signal hyperintensity); MRI type II (predominant infratentorial atrophy or normal MRI). AST = aspartate transaminase; LDH = lactate dehydrogenase.

In sphingolipidoses, enzyme activity as measured in leukocytes has been shown to correlate with disease severity and progression.³⁴ We did not find evidence that the levels of β-hexosaminidase A reliably discriminate between the 2 clusters. Statistical power may be limited due to small patient numbers, and larger cohorts may be needed to further analyze a potential correlation between disease severity and residual enzyme activity. In addition, enzyme activity as measured in leukocytes may not reflect activity in other cell (particularly neuronal) types.

Our study is limited by the retrospective data collection and relatively small sample size due to the rareness of the disease. Some clinical features might be underrepresented as they were not assessed prospectively and systematically (e.g., psychiatric problems, cognitive decline, or developmental delay). In addition, some of these clinical items could have been missed in a regular assessment. Moreover, particularly in type I patients, rapidly developing motor and cognitive signs predominate and may overshadow behavioral changes so that they might remain underrecognized.

Age at onset alone does not adequately predict different disease courses in GM2 gangliosidoses and, alone, does not appear sufficient as criterium for planning upcoming clinical trials. In addition to age at disease onset, we suggest to include clinical features and biomarkers which predict dynamics of the disease and propose a classification into 2 types: type I—an early-onset, rapid progression cluster—is characterized by developmental stagnation and regression, spasticity and seizures, “cherry red spot,” startle reactions, and elevated AST levels; early MRI involves changes of basal ganglia and peritrigonal hyperintensity. By contrast, type II—a variable onset, slow progression cluster—is characterized by problems with balance or gait, muscle weakness, dysarthria, and psychiatric symptoms as well as ocular signs, including vertical gaze palsy; early MRI shows predominant infratentorial atrophy or may be normal. The insidious onset, with initially apparently unspecific signs and a near to or normal MRI in type II, represents a challenge for early diagnosis. Signs of ataxia and weakness, even if mild, should lead to a specific diagnostic workup, including GM2 gangliosidosis.

Glossary

AST

aspartate transaminase

LDH

lactate dehydrogenase

Appendix. Authors

Name	Location	Contribution
Jan Kern, MD	Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data
Judith Böhringer, Dr rer nat	Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design
Dagmar Timmann, MD	Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Regina Trollmann, MD	Department of Neuropediatrics, Friedrich-Alexander University of Erlangen-Nürnberg, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Claudia Stendel, MD	Department of Neurology, Friedrich-Baur-Institute, University Hospital LMU, Munich, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Cristoph Kamm, MD	Department of Neurology, University of Rostock, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Markus Röbl, MD	Department of Pediatrics, University of Göttingen, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Vidiyaah Santhanakumaran, MSc	Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Germany	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data
Samuel Groeschel, MD	Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Germany	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data
Stefanie Beck-Wödl, Dr rer nat	Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data
Sophia Göricke, MD	Institute of Diagnostic and Interventional Radiology and Neuroradiology, Essen University Hospital, University of Duisburg-Essen, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data
Ingeborg Krägeloh-Mann, MD	Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data
Matthis Synofzik, MD	Research Division Translational Genomics of Neurodegenerative Diseases, Center for Neurology & Hertie-Institute for Clinical Brain Research, University of Tübingen; German Center for Neurodegenerative Diseases, Germany	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data

Study Funding

The authors report no targeted funding.

Disclosure

M. Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra and Lilly, all unrelated to the present manuscript. J. Kern, J. Böhringer, D. Timmann, R. Trollmann, C. Stendel, C. Kamm, M. Röbl, V. Santhanakumaran, S. Groeschel, S. Beck-Wödl, S. Göricke, I. Krägeloh-Mann reports no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.