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.

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.

Abnormal epiphyseal development in a feline model of Sandhoff disease.

Sandhoff disease (SD) is caused by decreased function of the enzyme ß-N-acetylhexosaminidase, resulting in accumulation of GM2 ganglioside in tissues. Neural tissue is primarily affected and individuals with the infantile form of the disease generally do not survive beyond 4 years of age. Current treatments address neurometabolic deficits to improve lifespan, however, this extended lifespan allows clinical disease to become manifest in other tissues, including the musculoskeletal system. The impact of SD on bone and joint tissues has yet to be fully determined. In a feline model of infantile SD, animals were treated by intracranial injection of adeno-associated virus vectors to supply the central nervous system with corrective levels of hexosaminidase, resulting in a twofold to threefold increase in lifespan. As treated animals aged, signs of musculoskeletal disease were identified. The present study characterized bone and joint lesions from affected cats using micro-computed tomography and histology. All affected cats had similar lesions, whether or not they were treated. SD cats displayed a significant reduction in metaphyseal trabecular bone and markedly abnormal size and shape of epiphyses. Abnormalities increased in severity with age and appear to be due to alteration in the function of chondrocytes within epiphyseal cartilage, particularly the articular-epiphyseal complex. Older cats developed secondary osteoarthritic changes. The changes identified are similar to those seen in humans with mucopolysaccharidoses. Statement of clinical significance: the lesions identified will have significant implications on the quality of life of individuals whose lifespans are extended due to treatments for the primary neurological effects of SD.

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.

Two-Year Follow-Up Magnetic Resonance Imaging and Spectroscopy Findings and Cerebrospinal Fluid Analysis of a Dog with Sandhoff's Disease.

A 13-month-old female Toy Poodle was presented for progressive ataxia and intention tremors of head movement. The diagnosis of Sandhoff's disease (GM2 gangliosidosis) was confirmed by deficient ß-N-acetylhexosaminidase A and B activity in circulating leukocytes and identification of the homozygous mutation (HEXB: c.283delG). White matter in the cerebrum and cerebellum was hyperintense on T2-weighted and fluid-attenuated inversion recovery magnetic resonance images. Over the next 2 years, the white matter lesions expanded, and bilateral lesions appeared in the cerebellum and thalamus, associated with clinical deterioration. Magnetic resonance spectroscopy showed progressive decrease in brain N-acetylaspartate, and glycine-myo-inositol and lactate-alanine were increased in the terminal clinical stage. The concentrations of myelin basic protein and neuron specific enolase in cerebrospinal fluid were persistently increased. Imaging and spectroscopic appearance correlated with histopathological findings of severe myelin loss in cerebral and cerebellar white matter and destruction of the majority of cerebral and cerebellar neurons.

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.

Early cardiac involvement in an infantile Sandhoff disease case with novel mutations.

INTRODUCTION: Hepatosplenomegaly is often present in infantile Sanshoff disease. However, cardiac involvement is extremely uncommon. CASE REPORT: We describe a 14-month-old female baby who exhibited mitral regurgitation and cardiomegaly at the age of 2months, dilation of the left atrium and left ventricle at age of 6months, followed by regression of developmental milestones after an episode of minor infection at age of 14months. Brain magnetic resonance imaging revealed signal changes over the bilateral thalami, bilateral cerebral white matter and left putamen. An examination of the fundus showed presence of cherry-red spots in both macular areas. The lysosomal enzymatic activities showed a marked reduction of ß-hexosaminidase B (HEXB) activity. Two novel mutations of HEXB gene were identified. One of the mutations was a c.1538 T>C mutation, which predicted a p.L513P amino acid substitution of leucine to proline; the other was a c.299+5 G>A mutation, which was a splice site mutation. CONCLUSION: Cardiac involvement might occur prior to neurological symptoms in infantile Sandhoff disease, and it should be included in the differential diagnoses of metabolic cardiomyopathies in the infantile stage.

TSPO in a murine model of Sandhoff disease: presymptomatic marker of neurodegeneration and disease pathophysiology.

Translocator protein (18 kDa), formerly known as the peripheral benzodiazepine receptor (PBR), has been extensively used as a biomarker of active brain disease and neuroinflammation. TSPO expression increases dramatically in glial cells, particularly in microglia and astrocytes, as a result of brain injury, and this phenomenon is a component of the hallmark response of the brain to injury. In this study, we used a mouse model of Sandhoff disease (SD) to assess the longitudinal expression of TSPO as a function of disease progression and its relationship to behavioral and neuropathological endpoints. Focusing on the presymptomatic period of the disease, we used ex vivo [(3)H]DPA-713 quantitative autoradiography and in vivo [(125)I]IodoDPA-713 small animal SPECT imaging to show that brain TSPO levels markedly increase prior to physical and behavioral manifestation of disease. We further show that TSPO upregulation coincides with early neuronal GM2 ganglioside aggregation and is associated with ongoing neurodegeneration and activation of both microglia and astrocytes. In brain regions with increased TSPO levels, there is a differential pattern of glial cell activation with astrocytes being activated earlier than microglia during the progression of disease. Immunofluorescent confocal imaging confirmed that TSPO colocalizes with both microglia and astrocyte markers, but the glial source of the TSPO response differs by brain region and age in SD mice. Notably, TSPO colocalization with the astrocyte marker GFAP was greater than with the microglia marker, Mac-1. Taken together, our findings have significant implications for understanding TSPO glial cell biology and for detecting neurodegeneration prior to clinical expression of disease.

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.

Neuroimaging findings of four patients with Sandhoff disease.

Sandhoff disease is a severe form of GM2 gangliosidosis that is caused by the deficiency of both hexosaminidase A and B. Startle reaction, hypotonia, psychomotor retardation, and blindness are the main clinical features. Presented are computed tomography and magnetic resonance imaging findings of four patients with Sandhoff disease diagnosed by enzymatic analyses. Bilateral homogeneous thalamic hyperdensity was evident on computed tomography. Magnetic resonance imaging scans revealed mild cortical atrophy, a thin corpus callosum, and abnormal signal intensities in the caudate nucleus, globus pallidum, putamen, cerebellum, and brainstem. No correlation was evident between the severity of the central nervous system imaging findings and the clinical pictures. In this article the neuroimaging findings of four patients with Sandhoff disease are discussed.

Muscle computed tomography features of motor neuron disease in late-onset GM2 gangliosidosis.

Late-onset GM2 gangliosidosis, a rare inherited neuronal storage disease, is characterized by a variety of clinical manifestations. The common clinical picture comprises neuromuscular, spinocerebellar, extrapyramidal, cognitive, and psychiatric abnormalities. Details of the extent of muscle involvement have never been reported. Eight patients with this syndrome were evaluated for the existence and extent of motor neuron disease using routine electrodiagnosis and systematic evaluation of skeletal musculature by computed tomography. Motor neuron disease was present in each and every patient regardless of the clinical manifestations and to a degree beyond that suspected on neurological examination. Muscle imaging disclosed a diffuse wasting and fatty replacement of muscles with predilection of pelvic and thigh muscles, and especially the quadriceps group. It seems that progressive motor disability in this syndrome is mainly due to motor neuron disease, as manifested by muscle atrophy, which can be easily demonstrated by muscle computed tomography.

Thalamic hyperdensity--is it a diagnostic marker for Sandhoff disease?

Sandhoff disease, also known as GM2-gangliosidoses variant 0, is caused by the deficient activity of both hexosaminidase A and hexosaminidase B. We report a 15-month-old boy diagnosed with Sandhoff disease by demonstrating the enzyme deficiency. The interesting finding was bilateral thalamic hyperdensity on the CT scan. The hyperdensity in all previously published cases was homogeneous and symmetric and limited to the thalamus; the cause still remains unknown. We suggest that the finding of dense thalami may be useful as a specific diagnostic criterion for the GM2-gangliosidoses and especially for Sandhoff disease.

[GM2 gangliosidosis, O variant (Sandhoff disease): suspected diagnosis of a storage disease by ultrasound]. / GM2-Gangliosidose, Variante O (M. Sandhoff): Verdachtsdiagnose einer Speicherkrankheit durch Ultraschall.

We report on a 3.6 year old boy who suffers from Sandhoff disease. The diagnosis was suspected because of striking ultrasound findings: Parts of the thalamus were more echogenic, the cortical gyri were sharp and accentuated. The CT- and MRI features were similar to the US-findings. The diagnosis was confirmed by demonstrating the typical enzyme deficiency in leucocytes.

Increased density of the thalamus on CT scans in patients with GM2 gangliosidoses.

In 13 patients, the GM2 gangliosidoses, Sandhoff disease and Tay-Sachs disease, were found to be constantly associated with homogeneously and symmetrically increased CT attenuation within the thalami. In the only patient examined with MR imaging, a T2-weighted sequence showed hypointense thalami. It is suggested that this finding is caused by an accumulation of calcium, associated with the intracellular storage of GM2 ganglioside. The finding of dense thalami may be useful as a specific diagnostic criterion for GM2 gangliosidoses. In a few patients with blocks in adjacent steps in the sphingolipid metabolism, this finding was not present.