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PubMed1977

The deficiency of a lysosomal acid hydrolase in two clones derived from the human lymphoblastoid line F137 after mutagen treatment.

Two clones (out of a total of 181 clones tested) derived from the human lymphoblastoid (lymphoid) line F137 after mutagen treatment were found to be deficient in a lysosomal acid hydrolase. The clone N32 derived from EMS-treated F137 is deficient in N-acetyl hexosaminidase A and B but contains normal levels of N-acetyl hexosaminidase C and low levels of an enzyme resembling N-acetyl hexosaminidase S. Thus the enzyme deficiency in this clone appears to resemble the so-called Sandhoff variant of Tay-Sachs disease, a disease inherited as an autosomal recessive condition. The clone G3 derived from MNNG treated F137 is deficient in alpha-galactosidase A. This clone resembles the situation in X-linked Fabry's disease. Karyotype analysis of the clones failed to reveal any chromosome rearrangement or losses of chromosomal material that might have accounted for the mutations and it is suggested that a single point mutation might in each case account for the loss of enzyme activity. No storage of the natural substrates of the two enzymes could be demonstrated in the clones.

Cell Line↗
PubMed2005

Defective calcium homeostasis in the cerebellum in a mouse model of Niemann-Pick A disease.

We recently demonstrated that calcium homeostasis is altered in mouse models of two sphingolipid storage diseases, Gaucher and Sandhoff diseases, owing to modulation of the activities of a calcium-release channel (the ryanodine receptor) and of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) respectively, by the accumulating sphingolipids. We now demonstrate that calcium homeostasis is also altered in a mouse model of Niemann-Pick A disease, the acid sphingomyelinase (A-SMase)-deficient mouse (ASM-/-), with reduced rates of calcium uptake via SERCA in the cerebellum of 6-7-month-old mice. However, the mechanism responsible for defective calcium homeostasis is completely different from that observed in the other two disease models. Thus, levels of SERCA expression are significantly reduced in the ASM-/- cerebellum by 6-7 months of age, immediately before death of the mice, as are levels of the inositol 1,4,5-triphosphate receptor (IP3R), the major calcium-release channel in the cerebellum. Systematic analyses of the time course of loss of SERCA and IP3R expression revealed that loss of the IP3R preceeded that of SERCA, with essentially no IP3R remaining by 4 months of age, whereas SERCA was still present even after 6 months. Expression of zebrin II (aldolase C), a protein found in about half of the Purkinje cells in the adult mouse cerebellum, was essentially unchanged during development. We discuss possible pathological mechanisms related to calcium dysfunction that may cause Purkinje cell degeneration, and as a result, the onset of neuropathology in Niemann-Pick A disease.

Aging↗
PubMed2006

Lipocalin-type prostaglandin D synthase is up-regulated in oligodendrocytes in lysosomal storage diseases and binds gangliosides.

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is a dually functional protein, acting both as a PGD2-synthesizing enzyme and as an extracellular transporter of various lipophilic small molecules. L-PGDS is expressed in oligodendrocytes (OLs) in the central nervous system and is up-regulated in OLs of the twitcher mouse, a model of globoid cell leukodystrophy (Krabbe's disease). We investigated whether up-regulation of L-PGDS is either unique to Krabbe's disease or is a more generalized phenomenon in lysosomal storage disorders (LSDs), using LSD mouse models of Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis and Niemann-Pick type C1 disease. Quantitative RT-PCR revealed that L-PGDS mRNA was up-regulated in the brains of all these mouse models. In addition, strong L-PGDS immunoreactivity was observed in OLs, but not in either astrocytes or microglia in these models. Thus, up-regulation of L-PGDS appears to be a common response of OLs in LSDs. Moreover, surface plasmon resonance analyses revealed that L-PGDS binds GM1 and GM2 gangliosides, accumulated in neurons in the course of LSD, with high affinities (KD = 65 and 210 nm, respectively). This suggests that L-PGDS may play a role in scavenging harmful lipophilic substrates in LSD.

Animals↗
PubMed1973

N-acetyl-beta-hexosaminidase: role in the degradation of glycosaminoglycans.

Extracts of cultured normal human skin fibroblasts released radioactivity from a (14)C-labeled heptasaccharide prepared by addition of [(14)C]N-acetylgalactosamine to the nonreducing terminus of a hexasaccharide derived from chondroitin 4-sulfate whereas fibroblast extracts from patients with Tay-Sachs and Sandhoff-Jatzkewitz diseases did not. The results suggest that N-acetyl-beta-hexosaminidase A is responsible for degradation of the oligosaccharide substrate.

Carbohydrate Metabolism, Inborn Errors↗
PubMed1975

Variability of acid hydrolase activities in cultured skin fibroblasts and amniotic fluid cells.

The specific activities of lysosomal hydrolases in cultured skin fibroblasts and amniotic fluid cells showed wide and unpredictable variations between cultures, which may lead to difficulty in differentiating normal, heterozygous, and homozygous cells. However, the variability for a given culture was similar for all enzymes assayed, so that a clearer differentiation of a relative deficiency of a given enzyme could be obtained by expressing its activity in ratio to that of another enzyme. Activity ratios were particularly useful in the evaluation of enzyme levels in cultured amniotic fluid cells. Results of their application to tests of pregnancies at risk for metachromatic leucodystrophy, Krabbe's leucodystrophy, GM1-gangliosidosis, and GM2-gangliosidosis (Sandhoff variant) are presented.

Amniotic Fluid↗
PubMed1977

Fine structure of cutaneous nerves in ganglioside storage disease.

Skin punch biopsies of six children suffering from infantile or late onset Tay-Sachs disease, juvenile Sandhoff disease, or GM gangliosidosis type I, contained axons which, when viewed with the electron microscope, were distended by large amorphous black deposits. These are nonspecific residual bodies. Their large numbers indicate severe disturbance of the nerve cell and may be part of the dying back process. The three cases with Tay-Sachs disease had also axonal zebra or complex membranous bodies which appeared to be specific. Cytoplasmic vacuolation of other cells was a feature in the patient with GM1 gangliosidosis. Biopsies of three parents were negative.

Axons↗
PubMed2002

Cerebral lipidoses in patients with progressive neurodegeneration: a study from south India.

OBJECTIVE: To study the prevalence and clinical profile of cerebral lipidoses in patients with progressive neurodegeneration. SUBJECTS AND METHODS: A total of 771 patients clinically diagnosed with a progressive neurodegenerative disease were investigated for lipidoses. Specific enzyme assays in serum and leucocytes and other relevant investigations, including histopathology, neuroimaging and neurophysiological studies were conducted when indicated. RESULTS: Fifty-four cases of sphingolipidoses and 1 case of sialidosis type 1 were diagnosed. The sphingolipidoses consisted of 30 cases of metachromatic leukodystrophy, 13 cases of Tay-Sachs disease and its variants, 11 cases of Sandhoff disease, and 1 case each of Niemann-Pick disease and multiple sulphatase deficiency. The clinical features were similar to earlier reports. Parental consanguinity was present in 63.6% of patients. CONCLUSIONS: In south India, where consanguineous marriages are strongly favoured, inherited diseases such as the cerebral lipidoses should be considered when evaluating a patient with progressive neurodegeneration. The establishment of specialised referral centres would provide a helpful approach to the prevention and management of these fatal disorders.

Journal Article↗
PubMed1986

Development of serum hexosaminidase activity in infants.

Serum activity of hexosaminidases A and B has been measured to identify patients with Tay-Sachs and Sandhoff diseases, and may also be influenced by other clinical conditions including neonatal necrotizing enterocolitis. We have characterized the normal developmental pattern of hexosaminidase activity in serum by measuring this enzyme activity in 61 neonates of 27-40 weeks gestation who were followed from birth to age 4-8 weeks. Total serum hexosaminidase activity significantly increased with postnatal and gestational age, and with initiation of enteral feeding. We conclude that serum hexosaminidase activity in infants with clinical conditions that may influence serum activity of this enzyme must be compared to that in normal infants of similar gestational and postnatal ages.

Aging↗
PubMed2004

Cerebral glycolipidoses: clinical characteristics of 41 pediatric patients.

A retrospective clinical and biochemical analysis of 41 pediatric patients with cerebral lipidoses seen between 1995 to 2003 was performed at a tertiary referral center for neurologic disorders in southern India. Enzyme assays in serum and leukocytes, including histopathology, neuroimaging, and neurophysiology studies, were performed. There were 20 cases of metachromatic leukodystrophy (infantile,14; juvenile, 6), 12 cases of Tay-Sachs disease (infantile, 9; late G(M2-M3) gangliosidoses, 3), 8 cases of Sandhoff's disease, and 1 male case with multiple sulfatase deficiency. Consanguinity was present in 51.2% of cases. The male-to-female ratio was 23:17. Similar illness in the families was noted in 24.4%. The prominent clinical features in sulfatide lipidoses were regression of motor and mental milestones, seizures, and speech impairment, and in G(M2) gangliosidoses, the features were delayed milestones, startle myoclonus, seizures, and the presence of cherry-red spots. The case with multiple sulfatase deficiency had low levels of arylsulfatase A and B. This study indicates that these autosomal recessive inherited disorders are indeed prevalent in India.

Adolescent↗
PubMed1992

Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre.

Of 910 children under the age of 12 years referred to the national center, we were able to assign an etiology to 473 (52%). This group consisted of lysosomal storage diseases (32%), amino acid disorders (14%), organic acid disorders (16%), various chromosome abnormalities and syndromes with dysmorphia or brain dysgenesis (26%), and various other metabolic diseases (12%). While such amino acidemias as branched-chain amino acidemia (MSUD) in classic and intermediate forms (44%) and hyperphenylalaninemia (PKU) due to 6-pyruvoyltetrahydropterin synthase deficiency (6PTSD) (19%) were common, classic PKU was rare (16%). Methylmalonic acidemia (31%), 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (16%), and propionic acidemia (12%) were encountered more frequently than other types of organic acidemias. When compared to the number of referred Down's syndrome patients, the results suggested the birth of at least one infant with neurometabolic disease per 50 births. Five tribes of Saudi Arabia constituted 26% of the diagnosable neurometabolic diseases. Diseases such as MSUD, 6 PTSD, Sanfilippo syndrome type B, methylmalonic acidemia, homocystinuria, GM2 gangliosidosis Sandhoff variant, infantile central nervous system spongy degeneration (Canavan disease), and neuraminidase deficiency showed definite tribal occurrence. In addition, 32% to 42% of the definitely diagnosed, and 25% to 87% of patients with probable neurometabolic disease but without a definable etiology, had more than one sibling affected. It is concluded that the many rare autosomal diseases of Saudi Arabia are due to "founder effect" created by marriages occurring within tribal and extended family boundaries.

Brain Diseases, Metabolic↗
PubMed1992

GM1 gangliosidosis type 2 in two siblings.

A sister and brother, now aged 7 and 9 years, presented with developmental arrest, gait disturbance, dementia, and a progressive myoclonic epilepsy syndrome with hyperacusis in the second year of life. Then, spastic quadriparesis led to a decerebrate state. In the absence of macular or retinal degeneration, organomegaly, and somatic-facial features suggesting mucopolysaccharidosis, the presence of hyperacusis together with sea-blue histiocytes in bone marrow biopsies and deficient beta-galactosidase activity but normal glucosidase, hexosaminidase, and neuraminidase activity on lysosomal enzyme assays constitutes the clinical-pathologic-biochemical profile of GM1 gangliosidosis type 2. This is a rare, late infantile onset, progressive gray-matter disease in which beta-galactosidase deficiency is largely localized to the brain, though it can be demonstrated in leukocytes and cultured skin fibroblasts. It must be distinguished from the Jansky-Bielschowsky presentation of neuronal ceroid lipofuscinosis, mitochondrial encephalopathy, lactic acidosis, strokelike episodes (MELAS) and myoclonic epilepsy with ragged-red fibers (MERRF) syndromes, atypical presentations of GM2 gangliosidoses (Tay-Sachs and Sandhoff's diseases), primary sialidosis (neuraminidase deficiency), galactosialidosis, and Alpers' disease.

Biopsy↗
PubMed2004

Increased concentration of GM1-ganglioside in cerebrospinal fluid in dogs with GM1- and GM2-gangliosidoses and its clinical application for diagnosis.

GM1- and GM2-gangliosidoses are lethal lysosomal diseases that are caused by a defect of acid hydrolases, resulting in the intralysosomal accumulation of the specific physiological substrates, GM1- and GM2-gangliosides, respectively. In the present study a method for the diagnosis of canine GM1-gangliosidosis was established using canine cerebrospinal fluid (CSF). The concentration of GM1-ganglioside in CSF was determined by thin-layer chromatography-enzyme immunostaining using biotin-conjugated cholera toxin B, which specifically binds with GM1-ganglioside. The concentration of CSF GM1-ganglioside was increased in Shiba dogs with GM1-gangliosidosis, and the increased level was approximately proportional to the age of the dogs. The concentration was high in the affected dog even at 5 months of age, when Shiba dogs with GM1-gangliosidosis first manifest neurologic signs. In addition, the concentration of CSF GM1-ganglioside in a dog with the GM2-gangliosidosis 0 variant (Sandhoff disease) was also 7 times the normal level. From these results it was concluded that this laboratory technique enables a definitive and early diagnosis of canine GM1-gangliosidosis even if tissues and organs cannot be obtained. However, because GM1-ganglioside can also be elevated in cases of GM2-gangliosidosis, it is necessary to assay for specific enzyme deficiencies to definitively separate GM1- from GM2-gangliosidosis.

Animals↗
PubMed2006

Substrate reduction therapy in the infantile form of Tay-Sachs disease.

Substrate reduction therapy (SRT) with miglustat has been proposed for treatment of some lysosomal storage disorders. Based on the positive experience in Gaucher disease and experimental data in Tay-Sachs (TSD) and Sandhoff animal models, the authors investigated the clinical efficacy of SRT in two patients with infantile TSD. SRT could not arrest the patients' neurologic deterioration. However, a significant drug concentration in CSF as well as macrocephaly prevention were observed.

1-Deoxynojirimycin↗
PubMed1977

A new juvenile hexosaminidase deficiency disease presenting as cerebellar ataxia. Clinical and biochemical studies.

A boy with mild hand tremor since age 2 1/2 was found at 4 to have cherry-red spots and mild trucal ataxia without seizures or dementia. Biochemically, he had striking hexosaminidase deficiency (serum: 4.6 percent of normal, 88.9 percent heat-labile; leukocyte: 2.2 percent of normal, 84.6 percent heat-labile; fibroblast 12.8 percent normal, 93.1 percent heat-labile). The residual hexosaminidase activity migrated electrophoretically in two bands. The major band comigrated with hexosaminidase A, the minor with hexosaminidase S. Hexosaminidase B was totally absent. The parents had partially reduced hexosaminidase with a decreased heat-stabile fraction. This disorder may result from a new mutation closely related to that causing Sandhoff-Jatzkewitz disease.

Cerebellar Ataxia↗
PubMed2004

Newborn screening for lysosomal storage disorders: clinical evaluation of a two-tier strategy.

OBJECTIVE: To evaluate the use of protein markers using immune-quantification assays and of metabolite markers using tandem mass spectrometry for the identification, at birth, of individuals who have a lysosomal storage disorder. METHODS: A retrospective analysis was conducted of Guthrie cards that were collected from newborns in Denmark during the period 1982-1997. Patients whose lysosomal storage disorder (LSD; 47 representing 12 disorders) was diagnosed in Denmark during the period 1982-1997 were selected, and their Guthrie cards were retrieved from storage. Control cards (227) were retrieved from the same period. Additional control cards (273) were collected from the South Australian Screening Centre (Australia). RESULTS: From 2 protein and 94 metabolite markers, 15 were selected and evaluated for their use in the identification of LSDs. Glycosphingolipid and oligosaccharide markers showed 100% sensitivity and specificity for the identification of Fabry disease, alpha-mannosidosis, mucopolysaccharidosis (MPS) IVA, MPS IIIA, Tay-Sachs disease, and I-cell disease. Lower sensitivities were observed for Gaucher disease and sialidosis. No useful markers were identified for Krabbe disease, MPS II, Pompe disease, and Sandhoff disease. The protein markers LAMP-1 and saposin C were not able to differentiate individuals who had an LSD from the control population. CONCLUSIONS: Newborn screening for selected LSDs is possible with current technology. However, additional development is required to provide a broad coverage of disorders in a single, viable program.

Antibodies, Monoclonal↗
PubMed1999

Biogenesis of lysosomes by endocytic flow of plasma membrane.

The objective of this review is to examine the biogenesis of lysosomes during the endocytic flow of plasma membrane. Two models have been proposed to explain the formation of lysosomes by this process: the "maturational" and the "stationary" models. According to the former, pinocytotic vesicles fuse among themselves to yield endosomes, which in turn, transform first into multivesicular bodies (MVB) and then into mature lysosomes. Therefore, endosomes and lysosomes would be transient organelles. On the other hand, the "stationary" model proposes that the endocytic pathway is formed by functionally and physically distinct compartments. Cultured cells exposed to ammonium chloride (NH4Cl) and leupeptin after a pulse of cationic ferritin were recently used to freeze endosomes and lysosomes. NH4Cl produced a retention of cationic ferritin in endosomes, indicating that this agent interfered with the endosomal/lysosomal progression. Leupeptin did not affect this process. The number of lysosomes increased in cells treated with both lysosomotropic agents. Thus, NH4Cl affected the endosomal and lysosomal compartments, whereas leupeptin had a preferential effect on lysosomes. Mice mutants with defects of plasma membrane degradation, including a Tay-Sachs model, a Sandhoff disease model, as well as, mice with the inactivated prosaposin gene were used to analyze the biogenesis of lysosomes. Thin sections of mutant cells were examined under the electron microscope, and the analysis revealed a selective accumulation of MVBs and the disappearance of lysosomes, suggesting that the formation of MVBs is a required step in lysosomal maturation and that the intravesicular content of MVBs is necessary for the digestion of plasma membrane components. Taken together, these data indicate that endosomes and MVBs are preceding steps in lysosomal biogenesis and that endosomes, MVBs, and lysosomes are transient organelles.

Animals↗
PubMed2001

Acute necrotizing encephalopathy of childhood.

Symmetric change of the entire area of the bilateral thalami, as with panthalamic lesions, plus involvement of other regions in the brain rarely occurs to previously healthy children. The term, acute necrotizing encephalopathy of childhood, has recently been proposed. Its clinical, radiological, and pathological features are described. This disease predominantly affects infants and young children living in Taiwan and Japan, and manifests itself as acute encephalopathy following 2 to 4 days of fever and minor symptoms of the respiratory and/or gastrointestinal systems. The hallmark of this encephalopathy consists of multifocal, symmetric brain lesions affecting the bilateral thalami, and/or cerebral periventricular white matter, brainstem tegmentum, or cerebellar medulla, which can be documented by ultrasonography, computed tomography, and magnetic resonance imaging of the brain. The prognosis is usually poor. Less than 10% of patients recover completely. Cases with good outcome were reported to have reversible imaging changes. Focal neurologic deficits are common sequelae. The pathogenesis of acute necrotizing encephalopathy of childhood is still not known. Some diseases, such as Reye's syndrome, vascular occlusion, tumor, hemorrhage of the thalamus, Sandhoff disease, or Leigh and Wernicke encephalopathies must be differentiated clinically, radiologically, or pathologically. By excluding other disease entities, acute necrotizing encephalopathy of childhood can be diagnosed.

Acute Disease↗
PubMed1999

Inherited metabolic disorders in Thailand--Siriraj experience.

The incidence of inborn errors of metabolism (IEM) in Thailand is yet unknown. However, by estimation it is generally accepted to be 1 in 5,000. From a survey in 7 medical schools from different parts of the country and a large pediatric hospital in Bangkok, we found numerous cases of IEM nationwidc. Thesc were amino acid disorders, carbohydrate disorders, urea cycle defects, peroxisomal, lysosomal storage disorders, and many others. Since Thais are quite homogeneous in their genetic make-up; it is, therefore, very likely that IEM is much more prevalent than we realized. With the exception of thalassemias, IFAM is probably very common in Thailand and other countries in the Asia-Pacific region. IEM identified were amino acid disorders eg phenylketonuria, maple syrup urine disease: urea cycle disorders eg ornithine transcarbamylase deficincy (OTC), argininosuccinic lyase deficiency (ALD), argininosuccinic acid synthetasc deficiency (ASD); glycogen storage disorders eg Pompe's discase, Von Gierkc's; organic acid disorders eg, isovaleric acidemia, methylmalonic acidemia. Lysosmal storagc disorders identified were GM1 gangliosidosis, mucolipidosis II, Hurler, Hunter, Maroteaux-Lamy, Sialidosis (neuraminidase deficicncy), Sly, Scheie, Gaucher, Niemann-Pick, Sandhoff and many other neurodegeneraative disorders identified were rhizomelic chondrodysplasia punctata (RCDP) and Zellweger. Recently fatty acid oxidation disorders: MCAD, translocase deficiency and multiple carbosxylase deficiency 9biotinidase deficiency) were also identified.

Child↗