Late Onset Tay-Sachs Disease in a Non-Jewish Patient: Case Report

AbstractTay-Sachs disease (TSD) is a rare, inherited, autosomal rececessive lysosomal storage disease. The late-onset form is an uncommon condition among non-Jewish population.We present the case of a 32 years old male patient without Jewish origins, in whom the disease began in adolescence and was initially diagnosed with spinal muscular atrophy. He developed progressively protean neurological symptomatology, including tetraparesis, cerebellar and extrapyramidal syndromes. The diagnosis was based on the cerebral MRI, showing severe cerebellar atrophy and the determination of the Hexosaminidase A activity, revealing low level.In patients showing signs of lower motor neuron involvement, cerebellar and pyramidal signs and marked cerebellar atrophy the late-onset TSD should be suspected, and the first step in establishing the diagnosis should be to determine the serum activity of Hexosaminidase A.

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Neuropsychiatry in Late Onset Tay-Sachs Disease

Advances in Medical Technologies and Clinical Practice - Communicating Rare Diseases and Disorders in the Digital Age ◽

10.4018/978-1-7998-2088-8.ch009 ◽

2020 ◽

pp. 274-291

Author(s):

Natan Gadoth

Keyword(s):

Late Onset ◽

Cerebellar Atrophy ◽

Cerebellar Degeneration ◽

Adult Onset ◽

Delay In Diagnosis ◽

Clinical Onset ◽

Tay Sachs Disease ◽

Hexosaminidase A ◽

Disease Understanding ◽

Symptoms And Signs

The neuropsychiatric adult onset Tay-Sachs disease is relatively unknown. Although clinical features and mode of presentation are variable, there are common symptoms and signs of, for example, spinocerebellar atrophy, motor neuron disease, psychiatric disorder, and neuroimaging features of cerebellar atrophy. This chapter reviews the neuropsychiatric features of Late Onset Tay-Sachs disease, discussing possible interconnections between psychosis and the cerebellum in this disease. Understanding this interlink offers some important insights into the rarity of the disease that together with the diverse clinical onset and manifestations are responsible for a marked delay in diagnosis and even misdiagnosis. Genetic testing for the activity of Hexosaminidase A, prompted by the presence of cerebellar atrophy will establish the diagnosis. In all, the combination of cerebellar degeneration together with atypical psychiatric features is in line with the ongoing assumption that the cerebellum and its thalamo-cortical outflow are responsible for psychosis, and in particular, schizophrenia.

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Automated Determination of Serum Hexosaminidase A by pH Inactivation for Detection of Tay-Sachs Disease Heterozygotes

Clinical Chemistry ◽

10.1093/clinchem/20.5.538 ◽

1974 ◽

Vol 20 (5) ◽

pp. 538-543 ◽

Cited By ~ 17

Author(s):

Abraham Saifer ◽

Guta Perle

Keyword(s):

Automated System ◽

Ashkenazi Jewish Population ◽

Tay Sachs Disease ◽

Hexosaminidase A ◽

Ph Inactivation ◽

The Mean ◽

Manual Test ◽

Normal Adults ◽

Automated Determination

Abstract We have automated a manual test for detection of heterozygotes of Tay-Sachs disease by assay of hexosaminidase A in serum, based on pH inactivation [Clin. Chim. Acta 43, 417 (1973)]. The same manifold is used both for the total hexosaminidase and pH-inactivation (hexosaminidase B) procedures. Automation expedites mass screening of the Ashkenazi Jewish population for carriers of the Tay-Sachs gene (prevalence rate, 1:30), because 100 or more tests can be performed daily. The mean percentage value and range (±2 SD) of hexosaminidase A for normal adults is 68.6 (58-79) and for carriers is 48.8 (39-59) with the automated pH-inactivation procedure. "Presumed carriers" (<53% hexosaminidase A) and individuals in the uncertain range (53 to 58%) should be retested by using leukocytes, to avoid the effect of certain physical ailments, before being labeled as carriers. The same automated system used for this assay can also be used to detect carriers of at least seven other sphingolipidoses for which artificial fluorogenic substrates are available.

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Rapid Nonradioactive Tracer Method for Detecting Carriers of the Major Ashkenazi Jewish Tay-Sachs Disease Mutations

Clinical Chemistry ◽

10.1093/clinchem/38.11.2249 ◽

1992 ◽

Vol 38 (11) ◽

pp. 2249-2255 ◽

Cited By ~ 4

Author(s):

P M Strasberg ◽

J T Clarke

Keyword(s):

Mutation Analysis ◽

Restriction Analysis ◽

Type I ◽

Ashkenazi Jewish ◽

Lysosomal Storage ◽

Ashkenazi Jews ◽

Dot Blot ◽

Chain Reactions ◽

Tay Sachs Disease ◽

Hexosaminidase A

Abstract Tay-Sachs disease (TSD, GM2 gangliosidosis, Type I) is an autosomal recessive lysosomal storage disease caused by deficiency of beta-hexosaminidase A (Hex A) resulting from mutations in the gene (HEXA) encoding the alpha-subunit of the enzyme. Three mutations, in exons 7 and 11 and at the exon 12-intron 12 junction, account for > 90% of alleles identified in obligate Ashkenazi Jewish carriers. Mutation analysis requires amplification of available DNA by separate polymerase chain reactions (PCRs) and either restriction digestion and gel electrophoresis or 32P-labeled allele-specific oligonucleotide (ASO) probes. We developed a simple, nonradioisotopic method for rapidly identifying TSD carriers by a triplex PCR reaction followed by dot-blot analysis, using three wild-type and three mutant ASOs end-labeled with digoxigenin-dUTP (dig-ASO). Hybridization was demonstrated immunologically by reaction with an anti-digoxigenin-alkaline phosphatase conjugate followed by colorimetric demonstration of phosphatase activity. The results of analyses by the dig-ASO method of 65 carriers identified by serum enzyme activity and of 6 high-risk fetuses in prenatal testing were the same as those obtained by more conventional restriction analysis. Dig-ASO testing correctly reclassified 10 individuals who had tested inconclusively on analysis for leukocyte beta-hexosaminidase A activity; 3 were identified as carriers and 7 as noncarriers. The simplicity of the assay and the avoidance of the radioisotopes make this a potentially useful method for TSD carrier detection by mutation analysis in Ashkenazi Jews from populations in whom the identity and frequencies of the common TSD mutations are known.

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Liquid Chromatography–Tandem Mass Spectrometry Assay of Leukocyte Acid α-Glucosidase for Post-Newborn Screening Evaluation of Pompe Disease

Clinical Chemistry ◽

10.1373/clinchem.2016.259036 ◽

2017 ◽

Vol 63 (4) ◽

pp. 842-851 ◽

Cited By ~ 10

Author(s):

Na Lin ◽

Jingyu Huang ◽

Sara Violante ◽

Joseph J Orsini ◽

Michele Caggana ◽

...

Keyword(s):

Newborn Screening ◽

Pompe Disease ◽

Late Onset ◽

Treatment Options ◽

Internal Standard ◽

Lysosomal Storage ◽

Blood Samples ◽

Liquid Chromatography Tandem Mass ◽

Progressive Weakness

Abstract BACKGROUND Pompe disease (PD) is the first lysosomal storage disorder to be added to the Recommended Uniform Screening Panel for newborn screening. This condition has a broad phenotypic spectrum, ranging from an infantile form (IOPD), with severe morbidity and mortality in infancy, to a late-onset form (LOPD) with variable onset and progressive weakness and respiratory failure. Because the prognosis and treatment options are different for IOPD and LOPD, it is important to accurately determine an individual's phenotype. To date, no enzyme assay of acid α-glucosidase (GAA) has been described that can differentiate IOPD vs LOPD using blood samples. METHODS We incubated 10 μL leukocyte lysate and 25 μL GAA substrate and internal standard (IS) assay cocktail for 1 h. The reaction was purified by a liquid–liquid extraction. The extracts were evaporated and reconstituted in 200 μL methanol and analyzed by LC-MS/MS for GAA activity. RESULTS A 700-fold higher analytical range was observed with the LC-MS/MS assay compared to the fluorometric method. When GAA-null and GAA-containing fibroblast lysates were mixed, GAA activity could be measured accurately even in the range of 0%–1% of normal. The leukocyte GAA activity in IOPD (n = 4) and LOPD (n = 19) was 0.44–1.75 nmol · h−1 · mg−1 and 2.0–6.5 nmol · h−1 · mg−1, respectively, with no overlap. The GAA activity of pseudodeficiency patients ranged from 3.0–28.1 nmol · h−1 · mg−1, showing substantial but incomplete separation from the LOPD group. CONCLUSIONS This assay allows determination of low residual GAA activity in leukocytes. IOPD, LOPD, and pseudodeficiency patients can be partially differentiated by measuring GAA using blood samples.

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Hexosaminidase a deficiency manifesting as spinal muscular atrophy of late onset

Annals of Neurology ◽

10.1002/ana.410240316 ◽

1988 ◽

Vol 24 (3) ◽

pp. 451-453 ◽

Cited By ~ 20

Author(s):

Avi Karni ◽

Ruth Navon ◽

Menachem Sadeh

Keyword(s):

Spinal Muscular Atrophy ◽

Late Onset ◽

Muscular Atrophy ◽

Hexosaminidase A

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801 DIAGNOSIS AND CARRIER DETECTION OF TAY-SACHS DISEASE USING SULFATED FLUOROGENIC SUBSTRATES: DIRECT DETERMINATION OF HEXOSAMINIDASE A IN SERUM DURING PREGNANCY AND IN THE PRESENCE OF HEREDITARY HEATLABILE HEXOSAMINIDASE B

Pediatric Research ◽

10.1203/00006450-198504000-00831 ◽

1985 ◽

Vol 19 (4) ◽

pp. 244A-244A

Author(s):

Yoav Ben-Yoseph ◽

Joanne E Reld ◽

Henry L Nadler

Keyword(s):

Direct Determination ◽

Carrier Detection ◽

Fluorogenic Substrates ◽

Tay Sachs Disease ◽

Hexosaminidase A

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

Molecular Biology of the Cell ◽

10.1091/mbc.e16-01-0012 ◽

2016 ◽

Vol 27 (24) ◽

pp. 3813-3827 ◽

Cited By ~ 18

Author(s):

Devin Dersh ◽

Yuichiro Iwamoto ◽

Yair Argon

Keyword(s):

Quality Control ◽

Endoplasmic Reticulum ◽

Control Mechanisms ◽

Permissive Temperature ◽

Lysosomal Storage ◽

Loss Of Function ◽

Er Quality Control ◽

Tay Sachs Disease ◽

Hexosaminidase A ◽

Α Chain

Loss of function of the enzyme β-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 β 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.

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Tay-Sachs disease

Revista de la Facultad de Medicina ◽

10.15446/revfacmed.v67n3.69742 ◽

2019 ◽

Vol 67 (3) ◽

pp. 323-329

Author(s):

Carlos Andrés Gualdrón-Frías ◽

Laura Tatiana Calderón-Nossa

Keyword(s):

Autosomal Recessive ◽

Neurodegenerative Disorder ◽

Clinical Manifestations ◽

Lysosomal Storage ◽

Adequate Treatment ◽

Autosomal Recessive Disorders ◽

Tay Sachs Disease ◽

Mesh Terms ◽

Hexosaminidase A ◽

Gm2 Gangliosidoses

Introduction: Lysosomal storage disease is caused by the deficiency of a single hydrolase (lysosomal enzymes). GM2 gangliosidoses are autosomal recessive disorders caused by deficiency of β-hexosaminidase and Tay-Sachs disease (TSD) is one of its three forms.Objective: To perform a review of the state of the art on TSD describing its definition, epidemiology, etiology, physiopathology, clinical manifestations and news in diagnosis and treatment.Materials and methods: A literature search was carried out in PubMed using the MeSH terms “Tay-Sachs Disease”.Results: 1 233 results were retrieved in total, of which 53 articles were selected. TSD is caused by the deficiency of the lysosomal enzyme β-hexosaminidase A (HexA), and is characterized by neurodevelopmental regression, hypotonia, hyperacusis and cherry-red spots in the macula. Research on molecular pathogenesis and the development of possible treatments has been limited, consequently there is no treatment established to date.Conclusion: TSD is an autosomal recessive neurodegenerative disorder. Death usually occurs before the age of five. More research and studies on this type of gangliosidosis are needed in order to find an adequate treatment.

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