Late-onset GM2 Gangliosidosis Research Articles

Fine-motor functioning and its relevance to activities of daily living in adults with late-onset GM2 gangliosidosis: Analysis of baseline data of AMETHIST trial

Fine-motor functioning and its relevance to activities of daily living in adults with late-onset GM2 gangliosidosis: Analysis of baseline data of AMETHIST trial

GM2-gangliosidosis patient journey: Results from interviews with late-onset GM2-gangliosidosis patients and frontline treaters show that the lack of disease awareness significantly delays diagnosis

GM2-gangliosidosis patient journey: Results from interviews with late-onset GM2-gangliosidosis patients and frontline treaters show that the lack of disease awareness significantly delays diagnosis

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

ObjectiveOur 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). MethodsWe 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. ResultsStructural 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. InterpretationThe 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.

A feasibility study of mHealth and wearable technology in late onset GM2 gangliosidosis (Tay-Sachs and Sandhoff Disease)

BackgroundAs part of a late onset GM2 gangliosidosis natural history study, digital health technology was utilized to monitor a group of patients remotely between hospital visits. This approach was explored as a means of capturing continuous data and moving away from focusing only on episodic data captured in traditional study designs. A strong emphasis was placed on real-time capture of symptoms and mobile Patient Reported Outcomes (mPROs) to identify the disease impact important to the patients themselves; an impact that may not always correlate with the measured clinical outcomes assessed during patient visits. This was supported by passive, continuous data capture from a wearable device.ResultsAdherence rate for wearing the device and completing the mPROs was 84 and 91%, respectively, resulting in a rich multidimensional dataset. As expected for a six-month proof-of-concept study in a disease that progresses slowly, statistically significant changes were not expected or observed in the clinical, mPROs, or wearable device data.ConclusionsThe study demonstrated that patients were very enthusiastic and motivated to engage with the technology as demonstrated by excellent compliance. The combination of mPROs and wearables generates feature-rich datasets that could be a useful and feasible way to capture remote, real-time insight into disease burden.

Patient and caregiver perspectives on burden of disease manifestations in late-onset Tay-Sachs and Sandhoff diseases

BackgroundThe GM2 gangliosidoses (GM2), Tay-Sachs and Sandhoff diseases, are rare, autosomal recessive genetic disorders caused by mutations in the lysosomal enzyme β-hexosaminidase A (HEXA) or β-hexosaminidase B (HEXB) genes, respectively. A minority of patients have a late-onset form of disease that presents from late-childhood to adulthood and has a slowly progressive course with prolonged survival.Little research has been published documenting patient experiences with late-onset Tay-Sachs and Sandhoff diseases and how the disease impacts their daily lives and functioning. This study explored the most frequent symptoms and functional impacts experienced by patients with late-onset GM2 gangliosidosis through interviews with patients and caregivers.MethodsA qualitative research study design was employed, using three focus groups and 18 one-on-one interviews with patients who were recruited at the National Tay-Sachs and Allied Diseases Annual Family Conference. Transcripts were generated from the discussions, and patient quotes were analyzed using a content analysis approach. Concepts were aggregated into symptom and functional impacts, and the frequency of mention in the focus groups and individual interviews was calculated.Key findingsMany of the frequently described symptoms [muscle weakness (n = 19, 95%), “clumsy” gait (n = 12, 60%), fatigue (n = 10, 50%)] and impacts [difficulty walking (n = 19, 95%), falling (n = 17, 85%), and climbing stairs (n = 16, 80%)] disclosed by patients and caregivers were similar to those previously reported in the literature. However, less frequently described symptoms such as gastrointestinal issues (n = 4, 20%) and coughing fits (n = 5, 25%) have been expanded upon. This study evaluated the immediate impact of these symptoms on the patients’ lives to highlight the burden of these symptoms and the functional limitations on daily living activities, independence, and emotional well-being. The findings were used to develop a conceptual disease model that could serve as a foundation for patient-centered outcomes in clinical trials and provide insights to the medical community that may benefit patient care.ConclusionsThis study contributes to the current understanding of symptoms associated with late-onset GM2 gangliosidosis, and further identifies the many consequences and impacts of the disease. These symptoms and impacts could be measured in clinical trials to examine the effects of novel treatments from the patient perspective.

Natural history of late-onset GM2 gangliosidosis: Four years of data collected at NTSAD annual conferences

Intramuscular fat infiltration is a dynamic process, in response to exercise and muscle health, which can be quantified by estimating fat fraction (FF) from Dixon MRI. Healthy hip abductor muscles are a good indicator of a healthy hip and an active lifestyle as they have a fundamental role in walking. The automated measurement of the abductors' FF requires the challenging task of segmenting them. We aimed to design, develop and evaluate a multi-atlas based method for automated measurement of fat fraction in the main hip abductor muscles: gluteus maximus (GMAX), gluteus medius (GMED), gluteus minimus (GMIN) and tensor fasciae latae (TFL).We collected and manually segmented Dixon MR images of 10 healthy individuals and 7 patients who underwent MRI for hip problems. Twelve of them were selected to build an atlas library used to implement the automated multi-atlas segmentation method. We compared the FF in the hip abductor muscles for the automated and manual segmentations for both healthy and patients groups. Measures of average and spread were reported for FF for both methods. We used the root mean square error (RMSE) to quantify the method accuracy. A linear regression model was used to explain the relationship between FF for automated and manual segmentations.The automated median (IQR) FF was 20.0(16.0–26.4) %, 14.3(10.9–16.5) %, 15.5(13.9–18.6) % and 16.2(13.5–25.6) % for GMAX, GMED, GMIN and TFL respectively, with a FF RMSE of 1.6%, 0.8%, 2.1%, 2.7%. A strong linear correlation (R2 = 0.93, p < .001, m = 0.99) was found between the FF from automated and manual segmentations. The mean FF was higher in patients than in healthy subjects.The automated measurement of FF of hip abductor muscles from Dixon MRI had good agreement with FF measurements from manually segmented images. The method was accurate for both healthy and patients groups.

Quantitative oculomotor and nonmotor assessments in late-onset GM2 gangliosidosis.

A cross-sectional study was performed to evaluate whether quantitative oculomotor measures correlate with disease severity in late-onset GM2 gangliosidosis (LOGG) and assess cognition and sleep as potential early nonmotor features. Ten patients with LOGG underwent quantitative oculomotor recordings, including measurements of the angular vestibulo-ocular reflex (VOR), with results compared to age- and sex-matched controls. Disease severity was assessed by ataxia rating scales. Cognitive/neuropsychiatric features were assessed by the cerebellar cognitive affective syndrome (CCAS) scale, Cerebellar Neuropsychiatric Rating Scale, and sleep quality evaluated using subjective sleep scales. Oculomotor abnormalities were found in all participants, including 3/10 with clinically normal eye movements. Abnormalities involved impaired saccadic accuracy (5/10), abnormal vertical (8/10) and horizontal (4/10) pursuit, reduced optokinetic nystagmus (OKN) responses (7/10), low VOR gain (10/10), and impaired VOR cancellation (2/10). Compared to controls, the LOGG group showed significant differences in saccade, VOR, OKN, and visually enhanced VOR gains. Severity of saccadic dysmetria, OKN, and VOR fixation-suppression impairments correlated with ataxia scales (p < 0.05). Nine out of ten patients with LOGG had evidence of the CCAS (5/10 definite, 2/10 probable, 2/10 possible). Excessive daytime sleepiness was present in 4/10 and 8/10 had poor subjective sleep quality. Cerebellar oculomotor abnormalities were present in all patients with LOGG, including those with normal clinical oculomotor examinations. Saccade accuracy (dorsal cerebellar vermis localization), fixation suppression, and OKN gain (cerebellar flocculus/paraflocculus localization) correlated with disease severity, suggesting that quantitative oculomotor measurements could be used to track disease progression. We found evidence of the CCAS, suggesting that cerebellar dysfunction may explain the cognitive disorder in LOGG. Sleep impairments were prevalent and require further study.

Functional performance in late-onset GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases), longitudinal data over 3 consecutive years

Anatomically, the normal state in the human adult is an esophagus that is entirely tubular and has a sharp transition to the saccular stomach where it forms an acute angle of His. Histologically, the normal esophagus is lined entirely by stratified squamous epithelium, transitioning at the gastroesophageal junction to gastric oxyntic epithelium, which lines the entire proximal stomach. Cardiac epithelium is normally absent. Its presence indicates the abnormal state of the dilated distal esophagus that results from damage to the abdominal segment of the lower esophageal sphincter. It is the early stage of gastroesophageal reflux disease (GERD) that is presently ignored and mistaken as normal proximal stomach. This normal state is not recognized at present time by the myth that 1–4 mm of cardiac epithelium normally exists between the distal end of the squamous epithelium and the proximal limit of gastric oxyntic epithelium. Evidence that eradicates this myth includes the facts: (1) The cardiac epithelium is absent in some people. (2) The presence of cardiac epithelium in the dilated distal esophagus is associated with the presence of submucosal esophageal glands. (3) Its extent varies from 0 to <15 mm in persons without GERD and increases up to 30 mm in patients with GERD. (4) The presence of any cardiac epithelium is associated with abnormal acid exposure, reflux esophagitis, and manometric abnormalities in the lower esophageal sphincter. (5) Cardiac epithelium extends into the thoracic esophagus as visible columnar-lined esophagus (CLE) in patients with severe GERD associated with severe lower esophageal sphincter damage. (6) The morphologic, immunohistochemical, and molecular features of cardiac epithelium in the dilated distal esophagus and visible CLE are identical and different than those of distal gastric epithelium. Eradication of the myth that cardiac epithelium is normally absent is essential to the understanding of the pathologic changes associated with the earliest stage of GERD. Existence of the myth at present prevents this understanding.

Diagnostic Approach to Childhood-Onset Cerebellar Atrophy

Hereditary ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. Selection of appropriate clinical and genetic tests for patients with cerebellar atrophy poses a diagnostic challenge. Neuroimaging is a crucial initial investigation in the diagnostic evaluation of ataxia in childhood, and the presence of cerebellar atrophy helps guide further investigations. We performed a detailed review of 300 patients with confirmed cerebellar atrophy on magnetic resonance imaging over a 10-year period. A diagnosis was established in 47% of patients: Mitochondrial disorders were most common, followed by neuronal ceroid lipofuscinosis, ataxia telangiectasia, and late-onset GM2 gangliosidosis. We review the common causes of cerebellar atrophy in childhood and propose a diagnostic approach based on correlating specific neuroimaging patterns with clinical and genetic diagnoses.

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay–Sachs or Sandhoff variants)

Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ß-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay–Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the α or β subunit of Hex A can be partially rescued, i.e. enhanced levels of both enzyme protein and activity in lysosomes, following the growth of patient cells in the presence of the drug, pyrimethamine. The objectives of the present clinical trial were to establish the tolerability and efficacy of the treatment of late-onset GM2 gangliosidosis patients with escalating doses of pyrimethamine, to a maximum of 100 mg per day, administered orally in a single daily dose, over a 16-week period . The primary objective, tolerability, was assessed by regular clinical examinations, along with a panel of hematologic and biochemical studies. Although clinical efficacy could not be assessed in this short trial, treatment efficacy was evaluated by repeated measurements of leukocyte Hex A activity, expressed relative to the activity of lysosomal ß-glucuronidase. A total of 11 patients were enrolled, 8 males and 3 females, aged 23 to 50 years. One subject failed the initial screen, another was omitted from analysis because of the large number of protocol violations, and a third was withdrawn very early as a result of adverse events which were not drug-related. For the remaining 8 subjects, up to a 4-fold enhancement of Hex A activity at doses of 50 mg per day or less was observed. Additionally marked individual variations in the pharmacokinetics of the drug among the patients were noted. However, the study also found that significant side effects were experienced by most patients at or above 75 mg pyrimethamine per day. We concluded that pyrimethamine treatment enhances leukocyte Hex A activity in patients with late-onset GM2 gangliosidosis at doses lower than those associated with unacceptable side effects. Further plans are underway to extend these trials and to develop methods to assess clinical efficacy.

Late-onset hexosaminidase A deficiency mimicking primary lateral sclerosis

The GM2 gangliosidosis are a group of metabolic disorders in which deficiency of a lysosomal enzyme, hexosaminidase A (Hex A), leads to an abnormal intracellular accumulation of lipids in neurons and glia. Total deficiency is responsible for a fatal infantile disorder, Tay-Sachs disease, characterized by involution in motor abilities, hypotonia, seizures and cortical blindness, with death around 5 or 6 years-old. Partial deficiency of enzyme activity is associated with a variety of late-onset (teenagers and young adults) neurological phenotypes, characterized by upper and lower motor neuron signs, cerebellar disturbances, parkinsonism, and psychosis or dementia in different combinations. Macular cherry red spots, which are typical for Tay-Sachs, are not apparent in these patients. All of the GM2 gangliosidosis subtypes are inherited in an autosomal recessive fashion and the differences in age at onset and disease course may be partly attributed to the underlying Hex A gene defect. Patients with infantile onset tend to be homozygous or compound heterozygote for severe, deleterious (“null”) alleles, whereas patients with late-onset disease have a combination of one severe and another allele associated with residual Hex A activity. Late onset GM2 gangliosidosis (LOGM2) is commonly included in the differential diagnosis of amyotrophic lateral sclerosis (ALS), due to the involvement of anterior horn cell, causing weakness, atrophy, cramps and fasciculations. We report a patient with unusual clinical features of isolated upper motor neuron (UMN) involvement, resembling primary lateral sclerosis (PLS).

Neuropathology of chronic GM2 gangliosidosis due to hexosaminidase A deficiency

Autopsy studies of late-onset GM2 gangliosidosis are sparse and only one adult case is on record. The case of partial Hex A deficiency presented here started in childhood as spinal muscular atrophy which progressed slowly over 4 decades. Cognitive function remained intact throughout the entire course, but during the last few years of life allodynia supervened. The patient died at 44 years of age. In good correlation with clinical observations the autopsy findings showed the most severe accumulation of lipid and consequent regressive change in the anterior horns of the spinal cord. Extensive but less severe storage was found in other spinal cord neurons, brain stem and selected basal ganglia. Cerebral cortex was virtually spared by storage but was the site of excessive formation of lipofuscin which was also present in many other neurons in the CNS. Marked storage and ganglionic loss was also found in the dorsal root ganglia, and the fasciculus gracilis was severely depleted of myelinated fibers. Electron microscopy showed accumulated gangliosides almost exclusively in the form of single and coalescing zebra bodies. In conclusion, the pathology in this case of chronic GM2 gangliosidosis, though in part conforming with previous observations, differed in several aspects. First, the cerebral cortex was--with only a few exceptions--free of ganglioside storage. Also spared was the cerebellum. In addition, homogeneous accumulation of zebra bodies contrasted with heterogeneity of neuronal inclusions found in other chronic cases. Finally, the involvement of sensory neurons was prominent and potentially related to allodynia. Molecular study of HEXA gene in this patient showed an TATC1278/? genotype.

Pyrimethamine as a Potential Pharmacological Chaperone for Late-onset Forms of GM2 Gangliosidosis

Late-onset GM2 gangliosidosis is composed of two related, autosomal recessive, neurodegenerative diseases, both resulting from deficiency of lysosomal, heterodimeric beta-hexosaminidase A (Hex A, alphabeta). Pharmacological chaperones (PC) are small molecules that can stabilize the conformation of a mutant protein, allowing it to pass the quality control system of the endoplasmic reticulum. To date all successful PCs have also been competitive inhibitors. Screening for Hex A inhibitors in a library of 1040 Food Drug Administration-approved compounds identified pyrimethamine (PYR (2,4-diamino 5-(4-chlorophenyl)-6-ethylpyrimidine)) as the most potent inhibitor. Cell lines from 10 late-onset Tay-Sachs (11 alpha-mutations, 2 novel) and 7 Sandhoff (9 beta-mutations, 4 novel) disease patients, were cultured with PYR at concentrations corresponding to therapeutic doses. Cells carrying the most common late-onset mutation, alphaG269S, showed significant increases in residual Hex A activity, as did all 7 of the beta-mutants tested. Cells responding to PC treatment included those carrying mutants resulting in reduced Hex heat stability and partial splice junction mutations of the inherently less stable alpha-subunit. PYR, which binds to the active site in domain II, was able to function as PC even to domain I beta-mutants. We concluded that PYR functions as a mutation-specific PC, variably enhancing residual lysosomal Hex A levels in late-onset GM2 gangliosidosis patient cells.

The Natural History of Cognitive Dysfunction in Late-Onset GM2 Gangliosidosis

Late-onset GM2 gangliosidosis (LGG) is a rare disease that is often considered in the differential diagnosis of adolescents and young adults who present with multiple realms of neurologic dysfunction. Cognitive disturbances are common but have not been systematically studied. To determine the natural history of cognitive dysfunction in patients with LGG. Case series and literature review. Urban tertiary referral clinic. Individuals with hexosaminidase A deficiency as the origin of LGG. Cognitive dysfunction, psychiatric symptoms, and cerebellar, upper motor neuron, lower motor neuron, or extrapyramidal symptoms and signs. Historical and examination data from 62 patients were found. Forty-four percent of LGG patients had some degree of cognitive dysfunction. Cognitive dysfunction was associated with a greater number of other elemental neurologic deficits. In 21 patients with acceptable longitudinal information, 8 (38%) had a static cognitive disorder, whereas progressive dementia was evident in 13 patients (62%), including 2 of our cases with serial neuropsychological testing. Neuroimaging often showed nonspecific cerebellar and/or cerebral atrophy. Cognitive dysfunction is a frequent manifestation of LGG. Patients who experience cognitive dysfunction are more likely to have a greater number of other neurologic manifestations of the disease. Cognitive dysfunction may take the form of static encephalopathy, but progressive dementia is more often encountered. The pathogenesis of cognitive dysfunction in this disease is unknown, highlighting the need for further study.

Neuropsychological assessment of patients with late onset GM2 gangliosidosis.

To characterize cognitive status in a sample of individuals with late-onset GM2 gangliosidosis (commonly referred to as late-onset Tay-Sachs disease). Seventeen subjects (13 men, 4 women) diagnosed with GM2 gangliosidosis were evaluated. Subjects ranged in age from 18 to 56 years and were in various stages of disease progression. Subjects underwent comprehensive neuropsychological assessment. Impairment was defined as performance more than 1.6 SD below the normative mean. Group mean performance was within the denoted normal range on all measures except on a task assessing visual sequencing and set shifting. Approximately one-half of the sample scored in the impaired range on measures of processing speed, visual sequencing, and set shifting. One-third of the sample also scored in the impaired range on measures of delayed verbal recall. Impairment tended to be restricted to a subset of the sample, as 5 of the 14 subjects able to undergo formal testing accounted for 70% of the total number of impaired scores. If the three subjects unable to participate in formal testing are also considered impaired, 47% of the current sample exhibited significant cognitive impairment in at least one cognitive domain. In late-onset GM2 gangliosidosis, there is a risk of impairment in executive functioning and memory as well as cerebellar dysfunction. Dementia was not present in any subjects in the current sample.

Late-Onset GM2 gangliosidosis presenting as burning dysesthesias

Two brothers with a painful neuropathy as a component of late-onset GM2 gangliosidosis of the Sandhoff type are presented. A dramatic response of the severe dysesthesias to amitriptyline and gabapentin is described. Symptomatic sensory neuropathy may be a component of late-onset GM2 gangliosidosis.

16. Late-onset GM2 gangliosidosis and other hexosaminidase mutations among Jews

Publisher Summary This chapter discusses the late-onset G M2 gangliosidosis and other Hexosaminidase mutation among Jews. Tay-Sachs Disease (TSD) is caused by absence of β-hexosaminidase (Hex) A, following which heat inactivation method (HIM) for quantifying Hex A using the synthetic substrate 4-MUG. The interaction between Hex A and G M2 ganglioside substrate is accomplished by a nonenzymatic protein, the G M2 activator. Hex A-deficient adults have residual Hex A activity that are significantly higher in TSD patients, but significantly lower than in TSD heterozygotes. AGG is a slowly progressing neurodegenerative disorder. The patients have very low Hex A activity and usually carry the Gly269Ser mutation in compound heterozygosity with an infantile TSD mutation. Homozygotes for the Gly269Ser mutation are only mildly affected. The enzyme β-hexosaminidase (Hex) B does not degrade the G M2 ganglioside in humans, and therefore has no direct involvement in TSD. However, it is a major participant in the routine enzymatic assay for identification of TSD genotypes because Hex B, like Hex A, hydrolyzes the synthetic substrate 4-MUG, and, unlike Hex A, it is heat stabile. It is estimated that 1 in 140 Moroccans is a TSD carrier, and seven different TSD mutations in this community have been identified.

P.3.052 - First episode schizophrenia: Treatment and outcome

This chapter discusses the late-onset GM2 gangliosidosis and other Hexosaminidase mutation among Jews. Tay-Sachs Disease (TSD) is caused by absence of β-hexosaminidase (Hex) A, following which heat inactivation method (HIM) for quantifying Hex A using the synthetic substrate 4-MUG. The interaction between Hex A and GM2 ganglioside substrate is accomplished by a nonenzymatic protein, the GM2 activator. Hex A-deficient adults have residual Hex A activity that are significantly higher in TSD patients, but significantly lower than in TSD heterozygotes. AGG is a slowly progressing neurodegenerative disorder. The patients have very low Hex A activity and usually carry the Gly269Ser mutation in compound heterozygosity with an infantile TSD mutation. Homozygotes for the Gly269Ser mutation are only mildly affected. The enzyme β-hexosaminidase (Hex) B does not degrade the GM2 ganglioside in humans, and therefore has no direct involvement in TSD. However, it is a major participant in the routine enzymatic assay for identification of TSD genotypes because Hex B, like Hex A, hydrolyzes the synthetic substrate 4-MUG, and, unlike Hex A, it is heat stabile. It is estimated that 1 in 140 Moroccans is a TSD carrier, and seven different TSD mutations in this community have been identified.

Late-onset GM2 gangliosidosis: Ashkenazi Jewish family with an exon 5 mutation (Tyr180-->His) in the Hex A alpha-chain gene.

Late-onset GM2 gangliosidosis is a variant form of Tay-Sachs disease characterized by onset of symptoms and signs in adolescence or in early adult life. The deficiency of beta-hexosaminidase A (Hex A) in this form of GM2 gangliosidosis has been invariably associated with the presence of the Gly269-->Ser substitution in the alpha-chain. We found two siblings of Ashkenazi Jewish descent diagnosed with late-onset GM2 gangliosidosis who were negative for the Gly269-->Ser mutation. Analysis of the HEXA gene showed that they were compound heterozygotes for the functionally silent 4-bp insertion in exon 11, typical of the infantile form of the disease and for a novel mutation, T538-->C, resulting in the missense Tyr180-->His. Expression studies in COS-7 cells suggested that the effect of this mutation was to decrease the stability of the alpha-chain at physiologic temperatures and therefore to indirectly affect the formation of mature Hex A.

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.