Clinical, Imaging, Genetic, and Disease Course Characteristics in Patients With GM2 Gangliosidosis: Beyond Age of Onset

BACKGROUND AND OBJECTIVES: GM2 gangliosidoses, a group of autosomal-recessive neurodegenerative lysosomal storage disorders, result from ß-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.

Clinical and imaging predictors of late-onset GM2 gangliosidosis: A scoping review.

OBJECTIVE: Late-onset GM2 gangliosidosis (LOGG) subtypes late-onset Tay-Sachs (LOTS) and Sandhoff disease (LOSD) are ultra-rare neurodegenerative lysosomal storage disorders presenting with weakness, ataxia, and neuropsychiatric symptoms. Previous studies considered LOTS and LOSD clinically indistinguishable; recent studies have challenged this. We performed a scoping review to ascertain whether imaging and clinical features may differentiate these diseases. METHODS: We examined MEDLINE/non-MEDLINE databases up to May 2022. Articles reporting brain imaging findings in genetically/enzymatically confirmed LOGG, symptom onset at age ≥ 10 years (or evaluated at least once ≥18 years) were included, yielding 170 LOGG patients (LOTS = 127, LOSD = 43) across 68 papers. We compared LOTS versus LOSD and performed regression analyses. Results were corrected for multiple comparisons. RESULTS: Age of onset was lower in LOTS versus LOSD (17.9 ± 8.2 vs. 23.9 ± 14.4 years, p = 0.017), although disease duration was similar (p = 0.34). LOTS more commonly had psychosis/bipolar symptoms (35.0% vs. 9.30%, p = 0.011) but less frequent swallowing problems (4.10% vs. 18.60%, p = 0.041). Cerebellar atrophy was more common in LOTS (89.0%) versus LOSD (60.5%), p < 0.0001, with more severe atrophy in LOTS (p = 0.0005). Brainstem atrophy was documented only in LOTS (14.2%). Independent predictors of LOTS versus LOSD (odds ratio [95% confidence interval]) included the presence of psychosis/bipolar symptoms (4.95 [1.59-19.52], p = 0.011), no swallowing symptoms (0.16 [0.036-0.64], p = 0.011), and cerebellar atrophy (5.81 [2.10-17.08], p = 0.0009). Lower age of onset (0.96 [0.93-1.00], p = 0.075) and tremor (2.50 [0.94-7.43], p = 0.078) were marginally statistically significant but felt relevant to include in the model. INTERPRETATION: These data suggest significant differences in symptomatology, disease course, and imaging findings between LOTS and LOSD.

Magnetic resonance imaging and spectroscopy in late-onset GM2-gangliosidosis.

OBJECTIVE: Our study aimed to quantify structural changes in relation to metabolic abnormalities in the cerebellum, thalamus, and parietal cortex of patients with late-onset GM2-gangliosidosis (LOGG), which encompasses late-onset Tay-Sachs disease (LOTS) and Sandhoff disease (LOSD). METHODS: We enrolled 10 patients with LOGG (7 LOTS, 3 LOSD) who underwent a neurological assessment battery and 7 age-matched controls. Structural MRI and MRS were performed on a 3 T scanner. Structural volumes were obtained from FreeSurfer and normalized by total intracranial volume. Quantified metabolites included N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), and combined glutamate-glutamine (Glx). Metabolic concentrations were corrected for partial volume effects. RESULTS: Structural analyses revealed significant cerebellar atrophy in the LOGG cohort, which was primarily driven by LOTS patients. NAA was lower and mI higher in LOGG, but this was also significantly driven by the LOTS patients. Clinical ataxia deficits (via the Scale for the Assessment and Rating of Ataxia) were associated with neuronal injury (via NAA), neuroinflammation (via mI), and volumetric atrophy in the cerebellum. INTERPRETATION: The decrease of NAA in the cerebellum suggests that, in addition to cerebellar atrophy, there is ongoing impaired neuronal function and/or loss, while an increase in mI indicates possible neuroinflammation in LOGG (more so within the LOTS subvariant). Quantifying cerebellar atrophy in relation to neurometabolic differences in LOGG may lead to improvements in assessing disease severity, progression, and pharmacological efficacy. Lastly, additional neuroimaging studies in LOGG are required to contrast LOTS and LOSD more accurately.

Natural History of Adult Patients with GM2 Gangliosidosis.

OBJECTIVE: GM2 gangliosidoses are lysosomal diseases due to biallelic mutations in the HEXA (Tay-Sachs disease [TS]) or HEXB (Sandhoff disease [SD]) genes, with subsequent low hexosaminidase(s) activity. Most patients have childhood onset, but some experience the first symptoms during adolescence/adulthood. This study aims to clarify the natural history of adult patients with GM2 gangliosidosis. METHODS: We retrospectively described 12 patients from a French cohort and 45 patients from the literature. RESULTS: We observed 4 typical presentations: (1) lower motoneuron disorder responsible for proximal lower limb weakness that subsequently expanded to the upper limbs, (2) cerebellar ataxia, (3) psychosis and/or severe mood disorder (only in the TS patients), and (4) a complex phenotype mixing the above 3 manifestations. The psoas was the first and most affected muscle in the lower limbs, whereas the triceps and interosseous were predominantly involved in the upper limbs. A longitudinal study of compound motor action potentials showed a progressive decrease in all nerves, with different kinetics. Sensory potentials were sometimes abnormally low, mainly in the SD patients. The main brain magnetic resonance imaging feature was cerebellar atrophy, even in patients without cerebellar symptoms. The prognosis was mainly related to gait disorder, as we showed that beyond 20 years of disease evolution, half of the patients were wheelchair users. INTERPRETATION: Improved knowledge of GM2 gangliosidosis in adults will help clinicians achieve correct diagnoses and better inform patients on the evolution and prognosis. It may also contribute to defining proper outcome measures when testing emerging therapies. ANN NEUROL 2020;87:609-617.

Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study.

BACKGROUND: GM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease) are unrelenting heritable neurodegenerative conditions of lysosomal ganglioside accumulation. Although progressive brain atrophy is characteristic, longitudinal quantification of specific brain structures has not been systematically studied. OBJECTIVES: The goal of this longitudinal study has been to quantify and track brain MRI volume changes, including specific structure volume changes, at different times in disease progression of childhood gangliosidoses, and to explore quantitative brain MRI volumetry (qMRI) as a non-invasive marker of disease progression for future treatment trials. METHODS: Brain qMRI studies were performed in 14 patients with gangliosidoses (9 infantile, 5 juvenile) yearly. Cerebellar cortex and white matter, caudate, putamen, corpus callosum, ventricles, total brain, and intracranial volumes were measured, as well as total brain volume. Age-matched controls were available for the patients with the juvenile phenotype. RESULTS: The infantile phenotype of all gangliosidoses showed a consistent pattern of macrocephaly and rapidly increasing intracranial MRI volume with both (a) brain tissue volume (cerebral cortex and other smaller structures) and (b) ventricular volume (P<0.01 for all). In contrast to apparent enlargement of the total brain volume, and chiefly the enlarged cerebral cortex, a subset of smaller brain substructures generally decreased in size: the corpus callosum, caudate and putamen became smaller with time. The volume of cerebellar cortex also decreased in patients with infantile GM1-gangliosidosis and juvenile GM1- and GM2-gangliosidosis; however, infantile GM2-gangliosidosis cerebellar cortex was the exception, increasing in size. Elevated intracranial pressure (estimated by lumbar spinal pressure) was a common finding in infantile disease and showed continued increases as the disease progressed, yet lacked MRI signs of hydrocephalus except for increasing ventricular size. Notably, in patients with juvenile gangliosidosis, macrocephaly and elevated intracranial pressure were absent and total brain volume decreased with time compared to controls (P=0.004). CONCLUSIONS: The disease course of infantile versus juvenile gangliosidoses is clearly distinguished by the rate of brain disease progression as characterized by qMRI. Assessments by qMRI represent a robust non-invasive method for monitoring CNS changes in the clinical course of gangliosidoses and is ideally suited to monitor effects of novel CNS-directed therapies in future clinical trials.

Canine GM2-Gangliosidosis Sandhoff Disease Associated with a 3-Base Pair Deletion in the HEXB Gene.

BACKGROUND: GM2-gangliosidosis is a fatal neurodegenerative lysosomal storage disease (LSD) caused by deficiency of either ß-hexosaminidase A (Hex-A) and ß-hexosaminidase B (Hex-B) together, or the GM2 activator protein. Clinical signs can be variable and are not pathognomonic for the specific, causal deficiency. OBJECTIVES: To characterize the phenotype and genotype of GM2-gangliosidosis disease in an affected dog. ANIMALS: One affected Shiba Inu and a clinically healthy dog. METHODS: Clinical and neurologic evaluation, brain magnetic resonance imaging (MRI), assays of lysosomal enzyme activities, and sequencing of all coding regions of HEXA, HEXB, and GM2A genes. RESULTS: A 14-month-old, female Shiba Inu presented with clinical signs resembling GM2-gangliosidosis in humans and GM1-gangliosidosis in the Shiba Inu. Magnetic resonance imaging (MRI) of the dog's brain indicated neurodegenerative disease, and evaluation of cerebrospinal fluid (CSF) identified storage granules in leukocytes. Lysosomal enzyme assays of plasma and leukocytes showed deficiencies of Hex-A and Hex-B activities in both tissues. Genetic analysis identified a homozygous, 3-base pair deletion in the HEXB gene (c.618-620delCCT). CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical, biochemical, and molecular features are characterized in a Shiba Inu with GM2-gangliosidosis. The deletion of 3 adjacent base pairs in HEXB predicts the loss of a leucine residue at amino acid position 207 (p.Leu207del) supporting the hypothesis that GM2-gangliosidosis seen in this dog is the Sandhoff type. Because GM1-gangliosidosis also exists in this breed with almost identical clinical signs, genetic testing for both GM1- and GM2-gangliosidosis should be considered to make a definitive diagnosis.

Rare Variant of GM2 Gangliosidosis through Activator-Protein Deficiency.

GM2 gangliosidosis, AB variant, is a very rare form of GM2 gangliosidosis due to a deficiency of GM2 activator protein. We report on two patients with typical clinical features suggestive of GM2 gangliosidosis, but normal results for hexosaminidase A and hexosaminidase B as well as their corresponding genes. Genetic analysis of the gene encoding the activator protein, the GM2A gene, elucidated the cause of the disease, adding a novel mutation to the spectrum of GM2 AB variant. This report points out that in typical clinical constellations with normal enzyme results, genetic diagnostic for activator protein defects should be performed.

[Clinical characteristics of early juvenile GM2 gangliosidosis: a case report].

We describe the case of a 15-year-old male with early juvenile type GM2 gangliosidosis. He first manifested with progressive clumsiness in his extremities at the age of 1.5 years, followed by motor regression. Intellectual disability became evident as late as age 6 years. This discrepancy along with rapid motor deterioration after varicella infection, lack of startle response or macrocephaly, and paucity of myoclonus were thought to be characteristic of juvenile GM2 gangliosidosis. In contrast to the cerebellar atrophy as the initial finding in usual juvenile GM2 gangliosidosis, magnetic resonance imaging revealed initially cerebral, and subsequently cerebellar, progressive atrophy. Autistic behavioral problems, including phonophobia, during intellectual regression in this patient was also unusual in juvenile GM2 gangliosidosis. Thus, recognition of these features would prompt proper diagnosis and insights into the pathomechanisms of GM2 gangliosidosis.

Protease-resistant modified human ß-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model.

GM2 gangliosidoses, including Tay-Sachs and Sandhoff diseases, are neurodegenerative lysosomal storage diseases that are caused by deficiency of ß-hexosaminidase A, which comprises an αß heterodimer. There are no effective treatments for these diseases; however, various strategies aimed at restoring ß-hexosaminidase A have been explored. Here, we produced a modified human hexosaminidase subunit ß (HexB), which we have termed mod2B, composed of homodimeric ß subunits that contain amino acid sequences from the α subunit that confer GM2 ganglioside-degrading activity and protease resistance. We also developed fluorescent probes that allow visualization of endocytosis of mod2B via mannose 6-phosphate receptors and delivery of mod2B to lysosomes in GM2 gangliosidosis models. In addition, we applied imaging mass spectrometry to monitor efficacy of this approach in Sandhoff disease model mice. Following i.c.v. administration, mod2B was widely distributed and reduced accumulation of GM2, asialo-GM2, and bis(monoacylglycero)phosphate in brain regions including the hypothalamus, hippocampus, and cerebellum. Moreover, mod2B administration markedly improved motor dysfunction and a prolonged lifespan in Sandhoff disease mice. Together, the results of our study indicate that mod2B has potential for intracerebrospinal fluid enzyme replacement therapy and should be further explored as a gene therapy for GM2 gangliosidoses.

Newly observed thalamic involvement and mutations of the HEXA gene in a Korean patient with juvenile GM2 gangliosidosis.

Neuroimaging studies of patients with GM2 gangliosidosis are rare. The thalamus and basal ganglia are principally involved in patients affected by the infantile form of GM2 gangliosidosis. Unlike in the infantile form, in juvenile or adult type GM2 gangliosidosis, progressive cortical and cerebellar atrophy is the main abnormality seen on conventional magnetic resonance imaging (MRI); no basal ganglial or thalamic impairment were observed. This report is of a Korean girl with subacute onset, severe deficiency of hexosaminidase A activity and mutations (Arg137Term, Ala246Thr) of the HEXA gene. A 3.5-year-old girl who was previously in good health was evaluated for hypotonia and ataxia 3 months ago and showed progressive developmental deterioration, including cognitive decline. Serial brain MRI showed progressive overall volume decrease of the entire brain and thalamic atrophy. Fluorine-18 FDG PET scan showed severe decreased uptake in bilateral thalamus and diffuse cerebral cortex. We suggest, through our experience, that the thalamic involvement in MR imaging and FDG-PET can be observed in the juvenile form of GM2 gangliosidosis, and we suspect the association of mutations in the HEXA gene.

GM2 gangliosidosis variant B1 neuroradiological findings.

Variant B1 is a rare type of GM2 gangliosidosis. Clinically, it shows a wide spectrum of forms ranging from infantile to juvenile. We report the first magnetic resonance imaging (MRI) findings from three patients affected by GM2 gangliosidosis variant B1, two presenting with the infantile form and one with the juvenile form. The MRI appearances of the two patients with the infantile form disease are congruent with those reported for the early-onset type of both Tay-Sachs and Sandhoff diseases, and are characterized by early involvement of the basal ganglia and thalamus with cortical atrophy appearing later. In contrast, the patient with the juvenile form of variant B1 showed progressive cortical and white-matter atrophy of the supratentorial structures and, to a lesser extent, the infratentorial structures. No basal ganglia or thalamic anomalies were observed. Because in the adult forms of both Tay-Sachs and Sandhoff diseases a progressive cerebellar atrophy represents the only abnormality detectable, it appears that an MRI pattern peculiar to GM2 gangliosidosis can be defined. This pattern ranges from the basal ganglia injury associated with the early and severe demyelination process noted in the infantile form of the disease, to cerebellar atrophy with no supratentorial anomalies in the adult form. An "intermediate" MRI picture, with cortical atrophy and mild cerebellar atrophy, but without basal ganglia impairment, can be observed in the juvenile form. In addition, our investigations suggest that MRI abnormalities in GM2 gangliosidosis correlate with the clinical form of the disease rather than with the biochemical variant of the enzymatic defect.