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PubMed1975

The gangliosidoses.

The gangliosidoses are hereditary diseases with a recessive mode of inheritance and are caused by a genetically induced enzymatic block, which results in the accumulation of gangliosides in various tissues of the body, mainly in the brain. Although Tay-Sachs disease, the most commonly occurring of the gangliosidoses, has been known for nearly 100 years, additional variants of ganglioside "storage" disorders have been discovered during the past 15 years. Considerable progress in the knowledge of these disorders has been made with the advent of electron microscopy and with the elaboration of new biochemical and enzyme-chemical techniques. At the present the gangliosidoses are not amenable to therapy. Therefore the foreseeable future the pragmatic approach involves identification of the high-risk pregnancy and antenatal diagnosis.

Axons↗
PubMed1977

N-Acetyl-beta-hexosaminidase isoenzymes of amniotic fluid and maternal serum. Their relevance to prenatal diagnosis of the GM2 gangliosidoses.

The isoenzymes of N-acetyl-beta-hexosaminidase were quantitated in 30 amniotic fluid and 13 maternal serum samples collected between 11 and 40 weeks of gestation using DEAE-Sephadex A-25 chromatography. Isoenzymes A and B consitituted the major components of most amniotic fluids but seven samples characterized by high N-acetyl-beta-hexosaminidase activities contained high proportion of an isoenzyme apparently identical to isoenzyme P of maternal serum. This passage of maternal serum N-acetyl-beta-hexosaminidase into the amniotic cavity could lead to false negative diagnosis of type B and type O GM2 gangliosidoses if the diagnosis rely solely upon isoenzyme analysis in amniotic fluid. However, the release of maternal enzyme into amniotic fluid seems to be restricted to the third trimester of gestation and should not interfere with prenatal diagnosis of the GM2 gangliosidoses ususally performed at an earlier stage of gestation.

Amniotic Fluid↗
PubMed1979

The gangliosidoses: comparative features and research applications.

Ganglioside storage diseases are inherited defects of lysosomal hydrolases that result in intralysosomal accumulation of gangliosides and other complex metabolites. Gangliosidoses occur in man, cats, cattle, dogs and swine. In all species, these diseases are characterized clinically by relentlessly progressive neurological deterioration. Lysosomal hypertrophy with characteristic ultrastructural inclusions occur in neurons, endothelial and other cells. Definitive diagnosis requires biochemical identification of the storage product and enzyme deficiency. Gangliosidoses in animals are important models of human lysosomal diseases and may be a significant complication in the maintenance of certain purebred stocks of domestic animals.

Animals↗
PubMed1979

Biochemistry and genetics of gangliosidoses.

The gangliosidoses comprise an-ever increasing number of biochemically and phenotypically variant diseases. In most of them an autosomal recessive inherited deficiency of a lysosomal hydrolase results in the fatal accumulation of glucolipids (predominantly in the nervous tissue) and of oligosaccharides. The structure, substrate specificity, immunological properties of and genetic studies on the relevant glycosidases, ganglioside GM1 beta-galactosidase and beta-hexosaminidase isoenzymes, are reviewed in this paper. Contrary to general expectation, only a poor correlation is observed between the severity of the disease and residual activity of the defective enzyme when measured with synthetic or natural substrates in the presence of detergents. For the understanding of variant diseases and for their pre- and postnatal diagnosis, the necessity of studying the substrate specificity of normal and mutated enzymes under conditions similar to the in vivo situation, e.g., with natural substrates in the presence of appropriate activator proteins, is stressed. The possibility that detergents may have adverse affects on the substrate specificity of the enzymes is discussed for the beta-hexosaminidases. The significance of activator proteins for the proper interaction of lipid substrates and water-soluble hydrolases is illustrated by the fatal glycolipid storage resulting from an activator protein deficiency in the AB variant of GM2-gangliosidosis. Recent somatic complementation studies have revealed the existence of a presumably post-translational modification factor necessary for the expression of ganglioside GM1 beta-galactosidase activity. This factor is deficient in a group of variants of GM1-glangliosidosis. Among the possible reasons for the variability of enzyme activity levels in heterozygotes and patients, allelic mutations, formation of hybrid enzymes, and the existence of patients as compound heterozygotes are discussed. All these may result in the production of mutant enzymes with an altered specificity for a variety of natural substrates.

Adolescent↗
PubMedDate not supplied

[Clinical and electrophysiological aspects of the gangliosidoses (author's transl)].

The gangliosidoses belong to the family of diseases known as the lipidoses and are due to an excess of ganglioside I (GM1) or II (GM2). The illness described by Landing belongs to Group I, whilst Tay-Sachs and Sandhoff's disease are type 2. This study was particularly concerned with the electro-clinical aspects of group 2, and 4 stages have been differentiated: --the first occurs between 4-10 months: the child is apathetic, hypotonic and has occasional audiogenic seizures; fundoscopy revealing the classical cherry red spot on the macula. The diagnosis can be confirmed by biopsy. The EEG is irregular but abnormalities are minor. --the second stage (10 months-2 years) the child spastic and amaurotic, often unresponsive is suffering from frequent seizures. The EEG is of high voltage, with slow and sharp waves. Auditory stimulation does not produce EEG changes. --in the third and 4th stages (after 2 years) the child is in a vegetative state with a progressive reduction in EEG voltage and sharp waves until death aged 3 or 4. Although there is a good correlation between clinical signs and EEG this is of no diagnostic value.

Brain↗
PubMedDate not supplied

The lipidoses: morphologic changes in the nervous system in Gaucher's disease, GM2 gangliosidoses and Niemann-Pick disease.

The present paper presents, in tabular form, most of the inborn errors of lipid metabolism (exclusive of the hyperlipoproteinemias); some may, with further studies, be removed from this category. Three of the lipidoses and their subtypes which are associated with severe neurologic disorders are discussed, i.e., infantile Gaucher's disease, Niemann-Pick disease and the GM2 gangliosidoses. Particular emphasis is placed on the importance of careful biochemical and enzymatic studies of either surgical or autopsy material of any patient suspected of having one of the lipidoses. Only by such studies can an exact diagnosis of virtually all of these inborn errors of lipid metabolism be established. Such a diagnosis is important, since in many instances an antenatal diagnosis is possible by demonstration of the enzymatic defect in cell grown in tissue culture from the amniotic fluid.

Brain↗
PubMed1978

The abnormalities of beta-galactosidase in GM1-gangliosidoses.

The activity of GM1 beta-galactosidase in the brain and liver of patients with GM1-gangliosidosis was assayed using GM1-ganglioside tritiated in the terminal galactose. In the cases of GM1-gangliosidosis Types 1 and 2A the activity was less than 0.5% of the control. In the liver of GM1-gangliosidosis Type 2B the activity was observed to be much higher than that of Types 1 and 2A. On Sephadex G-150 gel filtration, three active fractions (I, II and III) for 4-methylumbelliferyl beta-galactopyranoside (4MU) and two active fractions (I and II) for GM1-ganglioside were obtained in the control liver. There was no active fraction for GM1-ganglioside in spite of the preserved fraction I for 4MU in the liver of GM1-gangliosidosis Type 1 or Type 2A. In any of the three cases fraction II for both 4MU and G71-ganglioside was not detected.

Brain↗
PubMed1977

Quantitation of the enzymically deficient cross reacting material in GM1 gangliosidoses.

Normal quantities of GM1 beta-galactosidase cross reacting material (CRM) (0.31-0.47 microgram/mg protein) were detected by a sensitive radial immunodiffusion assay in skin fibroblasts from patients with GM1 gangliosidosis type 1 and adult variants, whereas elevated levels were found in GM1 gangliosidosis type 2 (0.41-0.72 microgram/mg protein). The specific activity of the immunologically CRM towards GM1 ganglioside of normal fibroblasts was about 500 times that of type 1, 100 times that of type 2, and 30 times that of the adult variants.

Antigens↗
PubMed2025

Similarities and Differences in the Late-Onset GM2 Gangliosidoses: Tay-Sachs and Sandhoff Diseases.

The two predominating subtypes of late-onset GM2 gangliosidosis are late-onset Tay-Sachs (LOTS) and late-onset Sandhoff disease (LOSD). Due to shared deficiencies of ß-hexosamindase A and significant clinical overlap, the two diseases have been considered indistinguishable. However, a growing body of evidence supports the notion of several distinctions between the two diseases. In this study, we highlight these distinctions through the cross-sectional evaluation of 27 late-onset GM2 gangliosidosis participants. Twenty-one participants with LOTS and 6 with LOSD were included in this study. We performed physical examinations alongside assessments for gait, balance, muscle strength, ataxia, nerve conduction velocities, and analyzed brain magnetic resonance imaging. Lower limb weakness (95% in LOTS, 100% in LOSD) and later development of upper limb weakness (90% in LOTS, 83% in LOSD) was highly prevalent in both cohorts. Accompanying gait disturbances, balance issues, and dysmetria (as assessed by the brief ataxia rating scale [BARS]) were also prevalent in both cohorts. Strength testing for the quadriceps and hamstrings demonstrated weakness in both cohorts, primarily impacting extensor muscles. Supratentorial gray and white matter volumes in both cohorts were similar to normative data. In contrast, BARS scores for dysarthria and oculomotor dysfunction were present and heterogenous in LOTS participants and absent in LOSD participants. 24% of LOTS participants and none of the LOSD participants had a history of neuropsychiatric symptoms. Cerebellar volume including lobules V and VI were lower in LOTS compared to LOSD and normative data. However, length dependent sensory neuropathy was present in all LOSD participants but absent in LOTS participants. Dysfunction of the posterior cerebellum (lobules VI, VII, and IX) has been shown to cause cerebellar cognitive affective syndrome (CCAS), that includes cognitive and behavioral disturbances. Furthermore, cerebellar dysfunction of lobules V and VI has been linked to dysarthric speech, and dysfunction of the posterior cerebellum has been linked to oculomotor symptoms. The finding of low cerebellar lobule volumes in LOTS, suggests the distinctive features of the LOTS phenotype are related to cerebellar dysfunction. However, the sensory symptoms unique to LOSD remains a mystery. The molecular and biochemical basis for the dichotomy between the LOTS and LOSD phenotypes requires further investigation.

GM2 Gangliosidosis↗
PubMed1977

The pathology of Sandhoff's disease.

We have presented the morbid anatomy of a case of Sandhoff's disease and have attempted to outline morphologic differences which distinguish this entity from other GM2 gangliosidoses. Yet, it may be well to maintain a sceptical eye. The anatomic differences among Tay-Sachs disease and its variants are more quantitative than qualitative and are overshadowed by the similarities. For these reasons, a definitive diagnosis must rest with the biochemist. Nevertheless, if many bizarre MCB's are encountered, the enzyme defect may be expected to differ from that of classical Tay-Sachs disease and, when seen in endothelial cells, they favour Sandhoff's disease. More importantly, if prominent visceral storage is found, and especially if it extends beyond the reticuloendothelial system to involve such selective sites as the kidneys and pancreas, Sandhoff's disease should immediately come to mind. For the pathologist, it is this latter point which more readily sets apart Sandhoff's disease from related GM2 gangliosidoses.

Brain↗
PubMed1979

Basic findings and current developments in sphingolipidoses.

Sphingolipidoses are caused by recessively inherited deficiencies of lysosomal hydrolases. The clinical backgrounds of and current biochemical and genetic approaches to the different forms and variants of gangliosidoses, trihexosylceramidosis (Fabry's disease), galactosylceramidosis (Krabbe's disease), sulfatidoses (metachromatic leukodystrophies), glucosylceramidosis (Gaucher's disease), sphingomyelinoses (Niemann-Pick disease) and ceramidosis (Farber's disease) are presented.

Fabry Disease↗
PubMed1978

Meganeurites and other aberrant processes of neurons in feline GM1-gangliosidosis: a Golgi study.

Golgi studies were carried out on neurons in several forebrain structures of young adult mutant cats with inherited beta-galactosidase deficiency and neurobehavioral deterioration due to GM1-ganglioside storage disease. Meganeurites similar to those observed in several human gangliosidoses were present on small and medium pyramidal neurons, granule cells of the fascia dentata and spiny neurons of the caudate nucleus. Large and giant pyramidal cells of the motor cortex exhibited prominent somatic spines but lacked meganeurites. Cortical non-pyramidal neurons and aspiny caudate cells were relatively normal in appearance although they showed variable increases in cell body diameter. The range of morphological alterations in different types of cortical neurons in feline GM1-gangliosidosis was identical to that found in human ganglioside storage diseases. Neurite outgrowth from meganeurites was particularly prominent in the feline mutant. The extensive proliferation of neurites confined to meganeurites indicates that the latter have growth properties typical of embryonic neuronal elements. The demonstration of neurite outgrowth from meganeurites of mature cortical neurons in feline GM1-gangliosidosis suggests a possible role for gangliosides in neurite formation during neuronal differentiation and synaptogenesis.

Animals↗
PubMed1976

The cerebral lipidoses.

The disorders presented consist of those clinical entities in which a reasonably well defined lipid storage material accumulated within nervous tissue. Many other progressive, degenerative disorders are suspected of being storage disorders, but their chemical pathology remains unclear. Collectively this group could be designated the sphingolipidoses. In each case, the disease is a genetic disturbance and transmitted as an autosomal recessive. Sphingolipid storage in each disorder is associated with deficient activity of a specific degradative enzyme or enzyme system, and these deficient enzymes are all lysosomal hydrolases. Lysosomal hydrolases catalyze the breakdown of complex molecules in digestive vacuoles (phagocytic or autophagic) within the cells. Lysosomes show structural latency (requiring osmotic shock or freeze thawing in vitro); their enzymes show maximal activity at acidic pH ranges, and on electron microscopic examination they appear as small, electron-dense intracellular bodies. These hydrolytic enzymes seem to have some form of biological vulnerability in terms of their genetic expression, and this vulnerability underlies the sphingolipidoses. Diagnosis in each case is primarily a clinical problem. The presentation of these disorders, especially in intermediate or advanced forms, is sufficiently distinctive to permit a reasonably accurate diagnosis on the basis of history, physical examination, and routine laboratory data. Patients seen in early stages may be more difficult to recognize but follow-up evaluations usually clarify the problem. Specific enzyme assays are now available for confirmation of the diagnosis in these disorders. A frequent finding in this connection is an increase in the activities of noninvolved lysosomal hydrolases in the storage disorders. Once a case is clinically diagnosed, the clinician has the responsibility of ensuring that proper genetic counseling is made available to the affected families. Considerable supportive care is needed in each case. These patients can survive for prolonged periods, and great stress is placed on their families by these prolonged, hopeless illnesses. Since the disorders affect infants or young children, their parents are usually young adults in their early reproductive years. It is essential that they receive information concerning the risk of subsequent pregnancies. Specific diagnosis of the fetus in early pregnancy can be made now by amniocentesis and enzyme assays on cultured fibroblasts. If the fetus is a homozygote on the basis of enzyme assays, the option of therapeutic abortion should be discussed with the family. For many parents there will be considerable sensitivity to the ethical implications of this course and, if any doubt arises, ethical or pastoral consultation should be sought. Although there are no specific therapeutic approaches, a considerable degree of supportive care can and should be given. In the gangliosidoses and late in the course of the leukodystrophies, seizures will present management problems...

Adult↗