Biochemical and mutational analyses of HEXA in a cohort of Egyptian patients with infantile Tay-Sachs disease. Expansion of the mutation spectrum.

BACKGROUND: Tay-Sachs disease (TSD), an autosomal recessively inherited neurodegenerative lysosomal storage disease, reported worldwide with a high incidence among population of Eastern European and Ashkenazi Jewish descent. Mutations in the alpha subunit of HEXA that encodes for the ß-hexosaminidase-A lead to deficient enzyme activity and TSD phenotype. This study is the first to highlight the HEXA sequence variations spectrum in a cohort of Egyptian patients with infantile TSD. RESULTS: This study involved 13 Egyptian infant/children patients presented with the infantile form of TSD, ten of the 13 patients were born to consanguineous marriages. ß-hexosaminidase-A enzyme activity was markedly reduced in the 13 patients with a mean activity of 3 µmol/L/h ± 1.56. Sanger sequencing of the HEXA' coding regions and splicing junctions enabled a detection rate of ~ 62% (8/13) in our patients revealing the molecular defects in eight patients; six homozygous-mutant children (five of them were the product of consanguineous marriages) and two patients showed their mutant alleles in heterozygous genotypes, while no disease-causing mutation was identified in the remaining patients. Regulatory intragenic mutations or del/dup may underlie the molecular defect in those patients showing no relevant pathogenic sequencing variants or in the two patients with a heterozygous genotype of the mutant allele. This research identified three novel, likely pathogenic variants in association with the TSD phenotype; two missense, c.920A > C (E307A) and c.952C > G (H318D) in exon 8, and a single base deletion c.484delG causing a frameshift E162Rfs*37 (p.Glu162ArgfsTer37) in exon 5. Three recurrent disease-causing missense mutations; c.1495C > T (R499C), c.1511G > A(R504H), and c.1510C > T(R504C) in exon 13 were identified in five of the eight patients. None of the variants was detected in 50 healthy Egyptians' DNA. Five variants, likely benign or of uncertain significance, S3T, I436V, E506E, and T2T, in exons 1, 11,13, & 1 were detected in our study. CONCLUSIONS: For the proper diagnostics, genetic counseling, and primary prevention, our study stresses the important role of Next Generation Sequencing approaches in delineating the molecular defect in TSD-candidate patients that showed negative Sanger sequencing or a heterozygous mutant allele in their genetic testing results. Interestingly, the three recurrent TSD associated mutations were clustered on chromosome 13 and accounted for 38% of the HEXA mutations detected in this study. This suggested exon 13 as the first candidate for sequencing screening in Egyptian patients with infantile TSD. Larger studies involving our regional population are recommended, hence unique disease associated pathogenic variations could be identified.

Doença de Tay-Sachs: relato de caso / Tay-Sachs disease: a case report

RESUMO A doença de Tay-Sachs é um distúrbio neurodegenerativo autossômico recessivo, o qual envolve o metabolismo dos lipídios, levando ao acúmulo de gangliosídeos nos tecidos, devido à deficiência da enzima hexosaminidase A. Esse depósito progressivo resulta em perda da função neurológica e, quando acomete as células ganglionares da mácula, causa o achado típico da doença, a "mácula em cereja". A patologia é diagnosticada por meio dos níveis de hexosaminidase A e hexosaminidase total no soro, além análise do DNA do gene HEXA. Este caso relata uma criança com doença de Tay-Sachs cujo diagnóstico foi suspeitado por conta dos achados oftalmológicos.

ABSTRACT Tay-Sachs Disease is an autosomal recessive neurodegenerative disorder, which involves the metabolism of lipids, leading to the accumulation of gangliosides in the tissues, due to the deficiency of the enzyme Hexosaminidase A. This progressive deposit results in loss of neurological function and, when it affects macula ganglion cells, it causes the typical disease finding, the "cherry red spot". The pathology is diagnosed through the levels of Hex A and total Hexosaminidase in the serum, in addition to the analysis of the DNA of the HEXA gene. This case reports a child with Tay-Sachs disease with a suspected diagnosis was through ophthalmologic findings.

[Clinical characteristics and genetic analysis of a child with infantile Sandhoff disease and eosinophilia].

OBJECTIVE: To explore the genetic basis for a girl featuring epilepsy, developmental delay and regression. METHODS: Clinical data of the patient was collected. Activities of hexosaminidase A (Hex A) and hexosaminidase A&B (Hex A&B) in blood leukocytes were determined by using a fluorometric assay. Peripheral blood samples were collected from the proband and six members from her pedigree. Following extraction of genomic DNA, whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing. RESULTS: Enzymatic studies of the proband have shown reduced plasma Hex A and Hex A&B activities. Genetic testing revealed that she has carried c.1260_1263del and c.1601G>C heterozygous compound variants of the HEXB gene. Her mother, brother and sister were heterozygous carriers of c.1260_1263del, while her father, mother, three brothers and sister did not carry the c.1601G>C variant, suggesting that it has a de novo origin. Increased eosinophils were discovered upon cytological examination of peripheral blood and bone marrow samples. CONCLUSION: The compound heterozygous variants of c.1260_1263del and c.1601G>C of the HEXB gene probably underlay the Sandhoff disease in this child. Eosinophilia may be noted in infantile Sandhoff disease.

sp2-Iminosugars targeting human lysosomal ß-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease.

The late-onset form of Tay-Sachs disease displays when the activity levels of human ß-hexosaminidase A (HexA) fall below 10% of normal, due to mutations that destabilise the native folded form of the enzyme and impair its trafficking to the lysosome. Competitive inhibitors of HexA can rescue disease-causative mutant HexA, bearing potential as pharmacological chaperones, but often also inhibit the enzyme O-glucosaminidase (GlcNAcase; OGA), a serious drawback for translation into the clinic. We have designed sp2-iminosugar glycomimetics related to GalNAc that feature a neutral piperidine-derived thiourea or a basic piperidine-thiazolidine bicyclic core and behave as selective nanomolar competitive inhibitors of human Hex A at pH 7 with a ten-fold lower inhibitory potency at pH 5, a good indication for pharmacological chaperoning. They increased the levels of lysosomal HexA activity in Tay-Sachs patient fibroblasts having the G269S mutation, the highest prevalent in late-onset Tay-Sachs disease.

Sandhoff disease in the elderly: a case study.

Sandhoff disease is an infrequent, genetically caused disorder with a recessive autosomal inheritance pattern. It belongs to the gangliosidosis GM2 group and is produced by mutations in gen HEXB leading to reduction in enzymatic activity of enzymes ß-hexosaminidase A and B. Adult-onset GM2 gangliosidosis is rare. Here we report a white male who presented at age 69 with a fast-progression, motor neuron disease, mimicking amyotrophic lateral sclerosis (ALS), combined with autonomic dysfunction, sensory ataxia, and exaggerated startle to noise. Enzymatic assays demonstrated deficiency of both Hexosaminidases A and B leading to the diagnosis of Sandhoff disease.

Atypical presentation of late-onset Sandhoff disease: a case report.

BACKGROUND AND PURPOSE: Sandhoff disease is a rare type of hereditary (autosomal recessive) GM2-gangliosidosis, which is caused by mutation of the HEXB gene. Disruption of the ß subunit of the hexosaminidase (Hex) enzyme affects the function of both the Hex-A and Hex-B isoforms. The severity and the age of onset of the disease (infantile or classic; juvenile; adult) depends on the residual activity of the enzyme. The late-onset form is characterized by diverse symptomatology, comprising motor neuron disease, ataxia, tremor, dystonia, psychiatric symptoms and neuropathy. METHODS: A 36-year-old female patient has been presenting progressive, symmetrical lower limb weakness for 9 years. Detailed neurological examination revealed mild symmetrical weakness in the hip flexors without the involvement of other muscle groups. The patellar reflex was decreased on both sides. Laboratory tests showed no relevant alteration and routine electroencephalography and brain MRI were normal. Nerve conduction studies and electromyography revealed alterations corresponding to sensory neuropathy. Muscle biopsy demonstrated signs of mild neurogenic lesion. Her younger brother (32-year-old) was observed with similar symptoms. RESULTS: Detailed genetic study detected a known pathogenic missense mutation and a 15,088 base pair long known pathogenic deletion in the HEXB gene (NM_000521.4:c.1417G>A; NM_000521:c.-376-5836_669+1473del; double heterozygous state). Segregation analysis and hexosaminidase enzyme assay of the family further confirmed the diagnosis of late-onset Sandhoff disease. CONCLUSION: The purpose of this case report is to draw attention to the significance of late-onset Sandhoff disease amongst disorders presenting with proximal predominant symmetric lower limb muscle weakness in adulthood.

Hexosaminidase A (HEXA) regulates hepatic sphingolipid and lipoprotein metabolism in mice.

Hexosaminidase A (HexA), a heterodimer consisting of HEXA and HEXB, converts the ganglioside sphingolipid GM2 to GM3 by removing a terminal N-acetyl-d-galactosamine. HexA enzyme deficiency in humans leads to GM2 accumulation in cells, particularly in neurons, and is associated with neurodegeneration. While HexA and sphingolipid metabolism have been extensively investigated in the context of neuronal lipid metabolism, little is known about the metabolic impact of HexA and ganglioside degradation in other tissues. Here, we focussed on the role of HexA in the liver, which is a major regulator of systemic lipid metabolism. We find that hepatic Hexa expression is induced by lipid availability and increased in the presence of hepatic steatosis, which is associated with increased hepatic GM3 content. To assess the impact of HEXA on hepatic lipid metabolism, we used an adeno-associated virus to overexpress HEXA in the livers of high-fat diet fed mice. HEXA overexpression was associated with increased hepatic GM3 content and increased expression of enzymes involved in the degradation of glycated sphingolipids, ultimately driving sphingomyelin accumulation in the liver. In addition, HEXA overexpression led to substantial proteome remodeling in cell surface lipid rafts, which was associated with increased VLDL processing and secretion, hypertriglyceridemia and ectopic lipid accumulation in peripheral tissues. This study established an important role of HEXA in modulating hepatic sphingolipid and lipoprotein metabolism.

A pathogenic HEXA missense variant in wild boars with Tay-Sachs disease.

Gangliosidoses are inherited lysosomal storage disorders caused by reduced or absent activity of either a lysosomal enzyme involved in ganglioside catabolism, or an activator protein required for the proper activity of a ganglioside hydrolase, which results in the intra-lysosomal accumulation of undegraded metabolites. We hereby describe morphological, ultrastructural, biochemical and genetic features of GM2 gangliosidosis in three captive bred wild boar littermates. The piglets were kept in a partially-free range farm and presented progressive neurological signs, starting at 6 months of age. Animals were euthanized at approximately one year of age due to their poor conditions. Neuropathogens were excluded as a possible cause of the signs. Gross examination showed a reduction of cerebral and cerebellar consistency. Central (CNS) and peripheral (PNS) nervous system neurons were enlarged and foamy, with severe and diffuse cytoplasmic vacuolization. Transmission electron microscopy (TEM) of CNS neurons demonstrated numerous lysosomes, filled by parallel or concentric layers of membranous electron-dense material, defined as membranous cytoplasmic bodies (MCB). Biochemical composition of gangliosides analysis from CNS revealed accumulation of GM2 ganglioside; furthermore, Hex A enzyme activity was less than 1% compared to control animals. These data confirmed the diagnosis of GM2 gangliosidosis. Genetic analysis identified, at a homozygous level, the presence of a missense nucleotide variant c.1495C > T (p Arg499Cys) in the hexosaminidase subunit alpha gene (HEXA), located within the GH20 hexosaminidase superfamily domain of the encoded protein. This specific HEXA variant is known to be pathogenic and associated with Tay-Sachs disease in humans, but has never been identified in other animal species. This is the first report of a HEXA gene associated Tay-Sachs disease in wild boars and provides a comprehensive description of a novel spontaneous animal model for this lysosomal storage disease.

Tay-Sachs Disease: Two Novel Rare HEXA Mutations from Pakistan and Morocco.

BACKGROUND: Tay-Sachs disease (TSD) is a rare autosomalrecessive genetic disorder characterized by progressive destruction of nerve cells in the brain and spinal cord. It is caused by genetic variations in the HEXA gene leading to a deficiency of ß hexosaminidase A (HEXA) isoenzyme activity. This study aimed to identify causative gene variants in 3 unrelated consanguineous families presented with TSD from Pakistan and Morocco. METHODS: Detailed clinical investigations were carried out on probands in 3 unrelated consanguineous families of Pakistani and Moroccan origin. Targeted gene sequencing and Whole Exome Sequencing (WES) were performed for variant identification. Candidate variants were checked for co-segregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP and the 1,000 Genome Project were searched to determine frequencies of the alleles. Conservation of the missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. RESULTS: We report on 3 children presented with Tay-Sachs Disease. The ß hexosaminidaseA enzyme activity was reduced in the Pakistani patient in one of the pedigrees. Genetic testing revealed 2 novel homozygous variants (p.Asp386Alafs*13 and p.Trp266Gly) in the gene HEXA in Pakistani and Moroccan patients respectively.The third family of Pakistani origin revealed a previously reported variant (p.Tyr427Ilefs*5) in HEXA. p.Tyr427Ilefs*5 is the most commonly occurring pathogenic variationin Ashkenazi but was not reported in Pakistani population. CONCLUSION: Our study further expands the ethnic and mutational spectrum of Tay-Sachs disease emphasizing the usefulness of WES as a powerful diagnostic tool where enzymatic activity is not performed for Tay-Sachs disease. The study recommends targeted screening for these mutations (p.Tyr427Ilefs5) for cost effective testing of TSD patients. Further, the study would assist in carrier testing and prenatal diagnosis of the affected families.

In silico analysis of the effects of disease-associated mutations of ß-hexosaminidase A in Tay-Sachs disease.

Tay-Sachs disease (TSD), a deficiency of b-hexosaminidase A (Hex A), is a rare but debilitating hereditary metabolic disorder. Symptoms include extensive neurodegeneration and often result in death in infancy. We report an in silico study of 42 Hex A variants associated with the disease. Variants were separated into three groups according to the age of onset: infantile (n=28), juvenile (n=9) and adult (n=5). Protein stability, aggregation potential and the degree of conservation of residues were predicted using a range of in silico tools. We explored the relationship between these properties and the age of onset of TSD. There was no significant relationship between proteinstability and disease severity or between protein aggregation and disease severity. Infantile TSD had a significantly higher mean conservation score than nondisease associated variants. This was not seen in either juvenile or adult TSD. This study has established that the degree of residue conservation may be predictive of infantile TSD. It is possible that these more highly conserved residues are involved in trafficking of the protein to the lysosome. In addition, we developed and validated software tools to automate the process of in silico analysis of proteins involved in inherited metabolic diseases. Further work is required to identify the function of well-conserved residues to establish an in silico predictive model of TSD severity.

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

BACKGROUND: The GM2 gangliosidoses (GM2), Tay-Sachs and Sandhoff diseases, are rare, autosomal recessive genetic disorders caused by mutations in the lysosomal enzyme ß-hexosaminidase A (HEXA) or ß-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. METHODS: A 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 FINDINGS: Many 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. CONCLUSIONS: This 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.

Patients' reactions and follow-up testing decisions related to Tay-Sachs (HEXA) variants of uncertain significance results.

JScreen is a national public health initiative based out of Emory University that provides reproductive carrier screening through an online portal and follow-up genetic counseling services. In 2014, JScreen began reporting to patients variants of uncertain significance (VUSs) in the gene that causes Tay-Sachs disease (HEXA). Genetic counseling was provided to discuss the VUS and patients were offered hexosaminidase A (HEXA) blood enzyme testing to assist with VUS reclassification. To identify patient reactions and factors influencing their follow-up testing decisions after receiving these results, we conducted a retrospective quantitative study by administering online surveys to 62 patients with HEXA VUSs. Participants who pursued enzyme testing and those who did not both experienced low levels of distress when receiving the VUS results. Perceptions of HEXA carrier status after genetic counseling, decisional conflict levels, plans to have children in the near future, time available to pursue enzyme testing, and eligibility for research were significant factors influencing decision-making to pursue or not pursue enzyme testing. Genetic counseling played an important role in helping patients understand the VUS and follow-up testing options. When discussing VUSs with patients, it would be beneficial for genetic counselors to focus on the patient's perception of the VUS, anxiety related to the uncertainty of their results, and follow-up options, when available.

Tay-Sachs disease: a novel mutation from India.

Lysosomal storage disorders or lipidoses are a wide spectrum of inherited diseases caused by deficiency of a specific lysosomal hydrolase. About 134 mutations have been described so far and this number is gradually increasing with newer mutations being reported. We report a 28-month-old child who presented to us with neurodevelopment regression, seizures and cherry red spot in both eyes. His hexosaminidase A enzyme activity was reduced and genetic testing revealed a homozygous novel variation in HEXA (hexosaminidase A) gene in the DNA sample of the patient.

Clinical presentation and outcome in infantile Sandhoff disease: a case series of 25 patients from Iranian neurometabolic bioregistry with five novel mutations.

BACKGROUND: Infantile Sandhoff disease (ISD) is a GM2 gangliosidosis that is classified as a lysosomal storage disorder. The most common symptoms of affected individuals at presentation are neurologic involvement. Here we report clinical course and demographic features in a case series of infantile Sandhoff disease. Enzymatically and some genetically proven cases of ISD were extracted from the Iranian Neurometabolic Registry (INMR) in Children's Medical Center, Iran, Tehran from December 2010 to December 2016. RESULT: Twenty five cases of infantile SD (13 female, 12 male) were included in this study. The age range of patients was 9-24 months with a mean of 15.8 months. The consanguinity rate of parents affected families was about 80%. The mean age of patients at disease onset was 6.4 months and the mean age at diagnosis was 14 months. Patients were diagnosed with a mean delay of 7.8 months. Eleven of patients died due to aspiration pneumonia and intractable seizure. The most common features at presentation (92%) were developmental delay or regression in speech and cognitive domains. Cherry red spots were detected in 17 patients (68%). Organomegaly was detected only in two patients. Enzyme studies showed marked reductions of both Hexosaminidase A and B in all patients. HEXB gene mutation studies performed in eight patients identified 6 different mutations, which five of them were novel. CONCLUSION: Infantile SD should be considered for each child presented with neurologic symptoms such as developmental delay and regression and cherry red spots in ophthalmic examination. Organomegaly is not a frequent clinical finding in infantile SD. Additionally; there are a genetic heterogenisity among Iranian patients.

In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease.

The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation-π interaction with Trp460. Among them, DMDP amide (6) proved to be the most potent competitive inhibitor with a Ki value of 0.041 µM. We analyzed the dynamic properties of both DMDP amide (6) and DNJNAc (1) in aqueous solution using molecular dynamics (MD) calculations; the distance of the interaction between Asp322 and 3-OH and Glu323 and 6-OH was important for stable interactions with Hex A, reducing fluctuations in the plasticity of the active site. DMDP amide (6) dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43% of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15% of the wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide (6), therefore, represents a new promising pharmacological chaperone candidate for the treatment of Tay-Sachs disease.

Lysosomal Proteins as a Therapeutic Target in Neurodegeneration.

Several proteins that are mutated in lysosomal storage diseases are linked to neurodegenerative disease. This review focuses on some of these lysosomal enzymes and transporters, as well as current therapies that have emerged from the lysosomal storage disease field. Given the deeper genetic understanding of lysosomal defects in neurodegeneration, we explore why some of these orphan disease drug candidates are also attractive targets in subpopulations of individuals with neurodegenerative disease.

Tay-Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum-associated degradation.

Loss of function of the enzyme ß-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay-Sachs disease (TSD). It has been proposed that mutations in the α chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA α mutants, seeking to identify relevant cellular quality control mechanisms. The α mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared with wild-type α. E482K is more severely misfolded than G269S, as observed by its aggregation and inability to associate with the HexA ß chain. Importantly, both mutants are retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and are degraded by the proteasome, indicating that they are cleared via ER-associated degradation (ERAD). Leveraging these discoveries, we observed that manipulating the cellular folding environment or ERAD pathways can alter the kinetics of mutant α degradation. Additionally, growth of patient fibroblasts at a permissive temperature or with chemical chaperones increases cellular Hex activity by improving mutant α folding. Therefore modulation of the ER quality control systems may be a potential therapeutic route for improving some forms of TSD.

Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs: an open label, extended pilot study.

BACKGROUND: Late Onset Tay- Sachs disease (LOTS) is a rare neurodegenerative lysosomal storage disease which results from mutations in the gene encoding the α subunit (HEXA) of ß-hexosaminidase enzyme (HexA). At the present time, no effective treatment exists for LOTS and other neurodegenerative diseases involving the central nerve system (CNS). Pyrimethamine (PMT) was previously shown to act as a HexA chaperone in human fibroblasts in vitro carrying some (e.g., αG269S), but not all LOTS-related mutations. The present study assessed the effect of cyclic, low dose and long term pyrimethamine treatment on HexA in subjects with LOTS. METHODS: In an open label trial in 4 LOTS patients, PMT was initiated at an average daily dose of ~2.7 mg and administered cyclically guided by blood lymphocyte HexA activity for a mean duration of 82.8 (±22.5; SD) weeks (~1.5 year). RESULTS: HexA activity rose in all subjects, with a mean peak increase of 2.24 folds (±0.52; SD) over baseline activity (range 1.87-3). The mean treatment time required to attain this peak was of 15.7 (±4.8; SD) weeks. Following increase in activity, HexA gradually declined with the continued use of PMT, which was then stopped, resulting in the return of HexA activity to baseline. A second cycle of PMT treatment was then initiated, resulting again in an increase in HexA activity. Three of the patients experienced a measurable neuropsychiatric deterioration whereas one subject remained entirely stable. CONCLUSIONS: Cyclic low dose of PMT can increase HexA activity in LOTS patients. However, the observed increase is repeatedly transient and not associated with discernible beneficial neurological or psychiatric effects.

Late onset GM2 gangliosidosis mimicking spinal muscular atrophy.

A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally.