Klaus Harzer - Academia.edu (original) (raw)

Papers by Klaus Harzer

Research paper thumbnail of Angiokeratoma corporis diffusum with severe acroparesthesia, an endothelial abnormality, and inconspicuous genetic findings

Angiokeratoma corporis diffusum (ACD) was long thought to be a specific dermal sign of Fabry dise... more Angiokeratoma corporis diffusum (ACD) was long thought to be a specific dermal sign of Fabry disease (FD, X-linked alpha-galactosidase A [GLA] deficiency). However, other lysosomal storage diseases (LSDs) have also been identified as triggers of ACD. Generalized vasculopathy is an important pathogenetic factor in FD and may also lead to the acroparesthesia (AP) often predominant in FD. We report on an 85-yearold woman with ACD present since her youth and associated with severe AP. Ultrastructure of the dermal lesion showed no lysosomal involvement, but the absence of the basement membrane of the endothelial cells of the capillary vessels was noteworthy. Repeated analyses of the GLA gene revealed no evidence of FD. Whole-exome sequencing was negative for FD and other LSDs, and allowed us to also study FD-related intronic regions of the GLA gene. This is the first report of a patient with FD-like ACD with an endothelial abnormality, otherwise unexplained vasculopathy and severe AP, which are not due to FD or another LSD. Based on family history, another genetic, yet unidentified, defect may cause the disease in this patient. In unexplained ACD, extended genetic analysis is required to exclude particular pathogenic variants of the GLA gene and other genes.

Research paper thumbnail of Challenges in Biochemical Diagnosis of Krabbe and Gaucher Disease

Abstracts of the 46th Annual Meeting of the Society for Neuropediatrics, 2021

Research paper thumbnail of Original Papers

The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-de®ci... more The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-de®cient Farber disease cells

Research paper thumbnail of Comparative Analysis of Cerebral Magnetic Resonance Imaging Changes in Nontreated Infantile, Juvenile and Adult Patients with Niemann-Pick Disease Type C

Neuropediatrics, 2019

Aim The study aims to describe cerebral MRI in different onset forms of Niemann-Pick type C (NPC)... more Aim The study aims to describe cerebral MRI in different onset forms of Niemann-Pick type C (NPC). Systematic MRI analyses in this rare lysosomal storage disease are lacking in the infantile and juvenile onset forms. Methods Thirty-two cerebral MRI scans from 19 patients with NPC were assessed using a newly established and validated scoring system which addresses white matter changes and supratentorial versus infratentorial atrophy. Results Seven scans were from six NPC patients with early infantile onset (<2 years of age), six scans were from three patients with late infantile onset (2–6 years), six scans from four with juvenile onset (6–15 years), and 13 from six with adult onset (>15 years). While supratentorial atrophy was the leading sign in the infantile groups, the juvenile and adult forms were characterized by both, infra- and supratentorial atrophy. White matter changes were found in nearly every patient; they increased with the disease duration in the earlier forms a...

Research paper thumbnail of Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra‐rare disease

Journal of Inherited Metabolic Disease, 2020

Multiple sulfatase deficiency (MSD) is an ultra‐rare neurodegenerative disorder caused by pathoge... more Multiple sulfatase deficiency (MSD) is an ultra‐rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine‐generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X‐linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype‐phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes. Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design.

Research paper thumbnail of Niemann-Pick C1 Disease: Correlations between NPC1 Mutations, Levels of NPC1 Protein, and Phenotypes Emphasize the Functional Significance of the Putative Sterol-Sensing Domain and of the Cysteine-Rich Luminal Loop

The American Journal of Human Genetics, 2001

Research paper thumbnail of Assay of β-glucosidase 2 (GBA2) activity using lithocholic acid β-3-O-glucoside substrate for cultured fibroblasts and glucosylceramide for brain tissue

Biological Chemistry

Beta-glucosidase 2 (GBA2) is deficient in a form of human spastic paraplegia due to defects in th... more Beta-glucosidase 2 (GBA2) is deficient in a form of human spastic paraplegia due to defects in the GBA2 (SPG46) gene. GBA2 was proposed as a modifier of Gaucher disease (lysosomal storage disease by deficient β-glucosidase 1; GBA1). Described assays of GBA2 activity mostly used artificial substrates incompletely modelling the situation with natural substrates in vivo. We studied GBA2 activities in vitro, using lithocholic acid β-glucoside or glucosylceramide as natural β-glucosidase substrates in tissues or cultured fibroblasts from murine and human individuals with the pathologic genotypes: Gba1-/-; Gba2-/-; GBA1-/- ; GBA2+/- and found expected and unexpected deviations from normal controls.

Research paper thumbnail of Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells

Human Mutation

Metachromatic leukodystrophy (MLD) is an autosomal-recessive lysosomal storage disease caused by ... more Metachromatic leukodystrophy (MLD) is an autosomal-recessive lysosomal storage disease caused by mutations in the ARSA gene leading to arylsulfatase A (ARSA) deficiency and causing sulfatide accumulation. Main symptoms of the disease are progressive demyelination, neurological dysfunction, and reduced life expectancy. To date, more than 200 different ARSA variants have been reported in MLD patients. Here, we report the biochemical characterization of seven novel pathogenic variants (c.98T &amp;amp;amp;amp;gt; C, c.195delC, c.229G &amp;amp;amp;amp;gt; C, c.545C &amp;amp;amp;amp;gt; G, c.674A &amp;amp;amp;amp;gt; G, c.852T &amp;amp;amp;amp;gt; A, and c.1274A &amp;amp;amp;amp;gt; G), which were found when sequencing a cohort of 31 German MLD families. For that purpose, the ARSA cDNAs carrying the respective mutations inserted by site-directed mutagenesis were cloned into a MigR1 (MSCV, IRES, GFP, retrovirus-1) vector. The constructs were overexpressed using retroviral gene transfer in immortalized, human multipotent mesenchymal stromal cells prepared from a patient deficient in ARSA activity (late infantile MLD). In this novel ARSAcell system, the seven ARSA mutants showed ARSA activity of less than 10% when compared with wild type, which is evidence for the pathogenicity of all seven variants. In conclusion, the system of ARSA-immortalized MSC turned out to be a helpful novel tool for the biochemical characterization of ARSA variants.

Research paper thumbnail of Lysosomale Speicherkrankheiten

Der Pathologe, 2015

A considerable number of lysosomal storage diseases (LSD), which can occur at any age in life, sh... more A considerable number of lysosomal storage diseases (LSD), which can occur at any age in life, should be included in the differential diagnosis of histiocytic diseases. To what extent can pathologists contribute to the diagnostics of LSD? In material collected from LSD, morphological storage phenomena in some disease forms, particularly in histiocytic cells from bone marrow smears and some tissues are highlighted, presented and described. Due to the multitude and heterogeneity of LSDs this list is by no means exhaustive. In Gaucher disease, the forms of Niemann-Pick disease, cholesteryl ester storage disease (CESD), GM1 gangliosidosis and other LSDs, the histiocytic storage cells seen, for example, in bone marrow smears can be finely and ultrastructurally differentiated. Thereby, not only the presence of an LSD in general but also some individual types of LSD can be identified, even though preliminarily. To confirm the diagnosis the genetic and sometimes biochemical analysis of blood samples or fibroblast cultures from patients is usually required. The pathologist may be the first to suspect LSD and this applies to LSDs that show storage histiocytes or one of a number of other LSDs in which only minor or absent storage is seen in histiocytes but marked storage phenomena are found in other cell systems. Some of the numerous, extremely heterogeneous LSDs may, however, be overlooked as detailed knowledge of the generally rare LSDs is the domain of LSD specialists. Clinicians, pathologists, geneticists and biochemists should cooperate in solving the diagnostic problems.

Research paper thumbnail of The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement

Journal of Inherited Metabolic Disease, 2016

Research paper thumbnail of Analytische isoelektrische Fraktionierung der N-Acetyl-�-d-hexosaminidasen

Fresenius J Anal Chem, 1970

ABSTRACT

Research paper thumbnail of Analytical isoelectric fractionation of the N-acetyl-?-d-hexosaminidases

Research paper thumbnail of Bone marrow cytological storage phenomena in lipidoses

European Journal of Pediatrics, May 1, 1994

The bone marrow cytological storage phenomena in generalized lysosomal lipid storage disorders (G... more The bone marrow cytological storage phenomena in generalized lysosomal lipid storage disorders (Gaucher disease, Niemann-Pick disease, GM1-gangliosidosis, cholesterol ester storage diseases) are reviewed. The value of bone marrow cytology as a pre-screening method in the diagnostic strategy for the different diseases depends on the disease type suspected and the availability of biochemical screening methods. While cytological screening is not necessary in certain patients with typical clinical pictures, it may prove undispensable in others.

Research paper thumbnail of Zum Tode von Professor Dr. med. J�rgen Peiffer

Research paper thumbnail of The two human lactosylceramidases and their respective enzyme activity deficiency diseases: Inhibition studies using p-nitrophenyl-?-D-galactoside

Hum Genet, 1978

Total lactosyl ceramide beta-galactosidase (LC) activity from normal and pathologic human leukocy... more Total lactosyl ceramide beta-galactosidase (LC) activity from normal and pathologic human leukocytes and tissues was subdivided into LC I (EC 3.2.1.46) and LC II (EC 3.2.1.23) activity by means of specific inhibition of LC II with 5 mM p-nitrophenyl-beta-D-galactoside (Ki = 1.5 mM). In globoid-cell leudodystrophy, inhibition of total LC was nearly complete (only LC II is active), whereas in GM1-gangliosidosis Type 1, very little inhibition was found (only LC I is actict). Total LC activity was not significantly low in either of the diseases, which have different genetic origins. The ratio of LC I to LC II activity may display remarkable genetic variation in normal probands.

Research paper thumbnail of The Two Human Lactosylceramidases and Their Respective Enzyme Activity Deficiency Diseases: Inhibition Studies Using p-Nitrophenyl-fl-D-Galactoside

Hum Genet, 1978

Total lactosyl ceramide beta-galactosidase (LC) activity from normal and pathologic human leukocy... more Total lactosyl ceramide beta-galactosidase (LC) activity from normal and pathologic human leukocytes and tissues was subdivided into LC I (EC 3.2.1.46) and LC II (EC 3.2.1.23) activity by means of specific inhibition of LC II with 5 mM p-nitrophenyl-beta-D-galactoside (Ki = 1.5 mM). In globoid-cell leudodystrophy, inhibition of total LC was nearly complete (only LC II is active), whereas in GM1-gangliosidosis Type 1, very little inhibition was found (only LC I is actict). Total LC activity was not significantly low in either of the diseases, which have different genetic origins. The ratio of LC I to LC II activity may display remarkable genetic variation in normal probands.

Research paper thumbnail of Genetic Variation of Hexosaminidase A and Arylsulfatase A Activity. Correlation Study in Amnio-Maternal Pairs of Cultured Cells

Hum Genet, 1981

Pairs of cultured amniotic cells and maternal fibroblasts (&quot;feto-maternal pairs&quot... more Pairs of cultured amniotic cells and maternal fibroblasts (&quot;feto-maternal pairs&quot;) were studied for hexosaminidase A (HXA) and arylsulfatase A (ASA) activity. These lysosomal enzyme activities are genetically deficient in Tay-Sachs disease and metachromatic leukodystrophy, respectively. After HXA was standardized by relating it to hexosaminidase B (HXB) activity, a feto-maternal correlation coefficient of r = 0.51 (n = 32; 95% confidence limits 0.197-0.73) was found for the HXA/HXB activity quotients. This coefficient was near the 0.5 value theoretically valid for mother-child pairs, suggesting that the studied activities reflect essentially the genetic variability. The studies of ASA revealed a high variability of individual activities, which was reduced in two steps: (1) The ASA activity was related to the mean of two lysosomal reference enzyme activities, total hexosaminidase and acid beta-galactosidase. (2) Since the square root of ASA activity was found to follow more closely the variation of the reference activities, the square root of ASA activity over the mean reference activity was taken as a more standardized measure of ASA activity, and the quotient was treated statistically. Positive feto-maternal correlation of standardized ASA activity was obtained after the elimination of three pairs with extreme values. A correlation coefficient of 4 = 0.42 (n - 26; 95% confidence limits 0.039-0.695) resulted. The implications of these correlation studies for the problem of heterozygote identification by quantitative enzyme assays in families deficient in HXA and ASA activity were considered.

Research paper thumbnail of Prenatal enzymatic diagnosis of Krabbe disease (globoid-cell leukodystrophy) using chorionic villi: pitfalls in the use of uncultured villi

Human Genetics, 1989

Sixteen pregnancies in families with children enzymatically diagnosed as having Krabbe disease (K... more Sixteen pregnancies in families with children enzymatically diagnosed as having Krabbe disease (KD) were monitored for prenatal KD using the assay of galactosyl ceramide beta-galactosidase (GCG) in uncultured chorionic villi (CV), cultured CV, or cultured amniotic fluid cells (AFC). Prenatal KD diagnoses were made for 5 pregnancies on the basis of lower than 10% normal GCG activity in cultured CV or AFC. Uncultured CV were studied in 3 out of the 5 KD embryos, although the GCG activities of 14%-23% as compared with control villi were diagnostically inconclusive; the relatively high activities were considered to be caused by maternal GCG contamination of these very small villus samples. Although the villi from 6 of the other pregnancies yielded more conclusive results, the use of uncultured CV alone is not recommended for prenatal KD diagnosis, this material being subject to possible uncontrolled contamination with maternal enzyme.

Research paper thumbnail of Nachweis des Enzymdefekts und vorl~ufige Identifizierung der Heterozygoten in einer Familie mit M. Gaucher Typ 1

Journal of Molecular Medicine Jmm, 1974

Research paper thumbnail of Prenatal enzymatic diagnosis and exclusion of Krabbe's disease (globoid-cell leukodystrophy) using chorionic villi in five risk pregnancies

Hum Genet, 1987

Galactosyl ceramide beta-galactosidase activity was determined in chorionic villi (CV) samples ob... more Galactosyl ceramide beta-galactosidase activity was determined in chorionic villi (CV) samples obtained between the 9th and 11th weeks of gestation from 5 women with pregnancies at risk for Krabbe&#39;s disease (globoid-cell leukodystrophy, KD). These enzyme activities were compared with those in controls, as well as with those in cultured amniotic fluid cells (AFC) from one of the five at-risk pregnancies and from 29 KD-risk pregnancies studied previously. The results of these CV enzyme analyses were such that one case of fetal KD was clearly diagnosable, one fetal genotype heterozygous for KD was presumed, and three normal fetal genotypes were suggested. The use of both uncultured and cultered CV can be recommended for prenatal KD testing, but AFC may continue to play an important role, too. Of the 58 prenatal KD tests we have evaluated since 1974, a positive diagnosis of Krabbe&#39;s disease was made (and confirmed after termination of pregnancy when feasible) in 23 which is significantly more than 25% of 58.

Research paper thumbnail of Angiokeratoma corporis diffusum with severe acroparesthesia, an endothelial abnormality, and inconspicuous genetic findings

Angiokeratoma corporis diffusum (ACD) was long thought to be a specific dermal sign of Fabry dise... more Angiokeratoma corporis diffusum (ACD) was long thought to be a specific dermal sign of Fabry disease (FD, X-linked alpha-galactosidase A [GLA] deficiency). However, other lysosomal storage diseases (LSDs) have also been identified as triggers of ACD. Generalized vasculopathy is an important pathogenetic factor in FD and may also lead to the acroparesthesia (AP) often predominant in FD. We report on an 85-yearold woman with ACD present since her youth and associated with severe AP. Ultrastructure of the dermal lesion showed no lysosomal involvement, but the absence of the basement membrane of the endothelial cells of the capillary vessels was noteworthy. Repeated analyses of the GLA gene revealed no evidence of FD. Whole-exome sequencing was negative for FD and other LSDs, and allowed us to also study FD-related intronic regions of the GLA gene. This is the first report of a patient with FD-like ACD with an endothelial abnormality, otherwise unexplained vasculopathy and severe AP, which are not due to FD or another LSD. Based on family history, another genetic, yet unidentified, defect may cause the disease in this patient. In unexplained ACD, extended genetic analysis is required to exclude particular pathogenic variants of the GLA gene and other genes.

Research paper thumbnail of Challenges in Biochemical Diagnosis of Krabbe and Gaucher Disease

Abstracts of the 46th Annual Meeting of the Society for Neuropediatrics, 2021

Research paper thumbnail of Original Papers

The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-de®ci... more The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-de®cient Farber disease cells

Research paper thumbnail of Comparative Analysis of Cerebral Magnetic Resonance Imaging Changes in Nontreated Infantile, Juvenile and Adult Patients with Niemann-Pick Disease Type C

Neuropediatrics, 2019

Aim The study aims to describe cerebral MRI in different onset forms of Niemann-Pick type C (NPC)... more Aim The study aims to describe cerebral MRI in different onset forms of Niemann-Pick type C (NPC). Systematic MRI analyses in this rare lysosomal storage disease are lacking in the infantile and juvenile onset forms. Methods Thirty-two cerebral MRI scans from 19 patients with NPC were assessed using a newly established and validated scoring system which addresses white matter changes and supratentorial versus infratentorial atrophy. Results Seven scans were from six NPC patients with early infantile onset (<2 years of age), six scans were from three patients with late infantile onset (2–6 years), six scans from four with juvenile onset (6–15 years), and 13 from six with adult onset (>15 years). While supratentorial atrophy was the leading sign in the infantile groups, the juvenile and adult forms were characterized by both, infra- and supratentorial atrophy. White matter changes were found in nearly every patient; they increased with the disease duration in the earlier forms a...

Research paper thumbnail of Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra‐rare disease

Journal of Inherited Metabolic Disease, 2020

Multiple sulfatase deficiency (MSD) is an ultra‐rare neurodegenerative disorder caused by pathoge... more Multiple sulfatase deficiency (MSD) is an ultra‐rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine‐generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X‐linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype‐phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes. Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design.

Research paper thumbnail of Niemann-Pick C1 Disease: Correlations between NPC1 Mutations, Levels of NPC1 Protein, and Phenotypes Emphasize the Functional Significance of the Putative Sterol-Sensing Domain and of the Cysteine-Rich Luminal Loop

The American Journal of Human Genetics, 2001

Research paper thumbnail of Assay of β-glucosidase 2 (GBA2) activity using lithocholic acid β-3-O-glucoside substrate for cultured fibroblasts and glucosylceramide for brain tissue

Biological Chemistry

Beta-glucosidase 2 (GBA2) is deficient in a form of human spastic paraplegia due to defects in th... more Beta-glucosidase 2 (GBA2) is deficient in a form of human spastic paraplegia due to defects in the GBA2 (SPG46) gene. GBA2 was proposed as a modifier of Gaucher disease (lysosomal storage disease by deficient β-glucosidase 1; GBA1). Described assays of GBA2 activity mostly used artificial substrates incompletely modelling the situation with natural substrates in vivo. We studied GBA2 activities in vitro, using lithocholic acid β-glucoside or glucosylceramide as natural β-glucosidase substrates in tissues or cultured fibroblasts from murine and human individuals with the pathologic genotypes: Gba1-/-; Gba2-/-; GBA1-/- ; GBA2+/- and found expected and unexpected deviations from normal controls.

Research paper thumbnail of Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A-deficient immortalized mesenchymal stromal cells

Human Mutation

Metachromatic leukodystrophy (MLD) is an autosomal-recessive lysosomal storage disease caused by ... more Metachromatic leukodystrophy (MLD) is an autosomal-recessive lysosomal storage disease caused by mutations in the ARSA gene leading to arylsulfatase A (ARSA) deficiency and causing sulfatide accumulation. Main symptoms of the disease are progressive demyelination, neurological dysfunction, and reduced life expectancy. To date, more than 200 different ARSA variants have been reported in MLD patients. Here, we report the biochemical characterization of seven novel pathogenic variants (c.98T &amp;amp;amp;amp;gt; C, c.195delC, c.229G &amp;amp;amp;amp;gt; C, c.545C &amp;amp;amp;amp;gt; G, c.674A &amp;amp;amp;amp;gt; G, c.852T &amp;amp;amp;amp;gt; A, and c.1274A &amp;amp;amp;amp;gt; G), which were found when sequencing a cohort of 31 German MLD families. For that purpose, the ARSA cDNAs carrying the respective mutations inserted by site-directed mutagenesis were cloned into a MigR1 (MSCV, IRES, GFP, retrovirus-1) vector. The constructs were overexpressed using retroviral gene transfer in immortalized, human multipotent mesenchymal stromal cells prepared from a patient deficient in ARSA activity (late infantile MLD). In this novel ARSAcell system, the seven ARSA mutants showed ARSA activity of less than 10% when compared with wild type, which is evidence for the pathogenicity of all seven variants. In conclusion, the system of ARSA-immortalized MSC turned out to be a helpful novel tool for the biochemical characterization of ARSA variants.

Research paper thumbnail of Lysosomale Speicherkrankheiten

Der Pathologe, 2015

A considerable number of lysosomal storage diseases (LSD), which can occur at any age in life, sh... more A considerable number of lysosomal storage diseases (LSD), which can occur at any age in life, should be included in the differential diagnosis of histiocytic diseases. To what extent can pathologists contribute to the diagnostics of LSD? In material collected from LSD, morphological storage phenomena in some disease forms, particularly in histiocytic cells from bone marrow smears and some tissues are highlighted, presented and described. Due to the multitude and heterogeneity of LSDs this list is by no means exhaustive. In Gaucher disease, the forms of Niemann-Pick disease, cholesteryl ester storage disease (CESD), GM1 gangliosidosis and other LSDs, the histiocytic storage cells seen, for example, in bone marrow smears can be finely and ultrastructurally differentiated. Thereby, not only the presence of an LSD in general but also some individual types of LSD can be identified, even though preliminarily. To confirm the diagnosis the genetic and sometimes biochemical analysis of blood samples or fibroblast cultures from patients is usually required. The pathologist may be the first to suspect LSD and this applies to LSDs that show storage histiocytes or one of a number of other LSDs in which only minor or absent storage is seen in histiocytes but marked storage phenomena are found in other cell systems. Some of the numerous, extremely heterogeneous LSDs may, however, be overlooked as detailed knowledge of the generally rare LSDs is the domain of LSD specialists. Clinicians, pathologists, geneticists and biochemists should cooperate in solving the diagnostic problems.

Research paper thumbnail of The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement

Journal of Inherited Metabolic Disease, 2016

Research paper thumbnail of Analytische isoelektrische Fraktionierung der N-Acetyl-�-d-hexosaminidasen

Fresenius J Anal Chem, 1970

ABSTRACT

Research paper thumbnail of Analytical isoelectric fractionation of the N-acetyl-?-d-hexosaminidases

Research paper thumbnail of Bone marrow cytological storage phenomena in lipidoses

European Journal of Pediatrics, May 1, 1994

The bone marrow cytological storage phenomena in generalized lysosomal lipid storage disorders (G... more The bone marrow cytological storage phenomena in generalized lysosomal lipid storage disorders (Gaucher disease, Niemann-Pick disease, GM1-gangliosidosis, cholesterol ester storage diseases) are reviewed. The value of bone marrow cytology as a pre-screening method in the diagnostic strategy for the different diseases depends on the disease type suspected and the availability of biochemical screening methods. While cytological screening is not necessary in certain patients with typical clinical pictures, it may prove undispensable in others.

Research paper thumbnail of Zum Tode von Professor Dr. med. J�rgen Peiffer

Research paper thumbnail of The two human lactosylceramidases and their respective enzyme activity deficiency diseases: Inhibition studies using p-nitrophenyl-?-D-galactoside

Hum Genet, 1978

Total lactosyl ceramide beta-galactosidase (LC) activity from normal and pathologic human leukocy... more Total lactosyl ceramide beta-galactosidase (LC) activity from normal and pathologic human leukocytes and tissues was subdivided into LC I (EC 3.2.1.46) and LC II (EC 3.2.1.23) activity by means of specific inhibition of LC II with 5 mM p-nitrophenyl-beta-D-galactoside (Ki = 1.5 mM). In globoid-cell leudodystrophy, inhibition of total LC was nearly complete (only LC II is active), whereas in GM1-gangliosidosis Type 1, very little inhibition was found (only LC I is actict). Total LC activity was not significantly low in either of the diseases, which have different genetic origins. The ratio of LC I to LC II activity may display remarkable genetic variation in normal probands.

Research paper thumbnail of The Two Human Lactosylceramidases and Their Respective Enzyme Activity Deficiency Diseases: Inhibition Studies Using p-Nitrophenyl-fl-D-Galactoside

Hum Genet, 1978

Total lactosyl ceramide beta-galactosidase (LC) activity from normal and pathologic human leukocy... more Total lactosyl ceramide beta-galactosidase (LC) activity from normal and pathologic human leukocytes and tissues was subdivided into LC I (EC 3.2.1.46) and LC II (EC 3.2.1.23) activity by means of specific inhibition of LC II with 5 mM p-nitrophenyl-beta-D-galactoside (Ki = 1.5 mM). In globoid-cell leudodystrophy, inhibition of total LC was nearly complete (only LC II is active), whereas in GM1-gangliosidosis Type 1, very little inhibition was found (only LC I is actict). Total LC activity was not significantly low in either of the diseases, which have different genetic origins. The ratio of LC I to LC II activity may display remarkable genetic variation in normal probands.

Research paper thumbnail of Genetic Variation of Hexosaminidase A and Arylsulfatase A Activity. Correlation Study in Amnio-Maternal Pairs of Cultured Cells

Hum Genet, 1981

Pairs of cultured amniotic cells and maternal fibroblasts (&quot;feto-maternal pairs&quot... more Pairs of cultured amniotic cells and maternal fibroblasts (&quot;feto-maternal pairs&quot;) were studied for hexosaminidase A (HXA) and arylsulfatase A (ASA) activity. These lysosomal enzyme activities are genetically deficient in Tay-Sachs disease and metachromatic leukodystrophy, respectively. After HXA was standardized by relating it to hexosaminidase B (HXB) activity, a feto-maternal correlation coefficient of r = 0.51 (n = 32; 95% confidence limits 0.197-0.73) was found for the HXA/HXB activity quotients. This coefficient was near the 0.5 value theoretically valid for mother-child pairs, suggesting that the studied activities reflect essentially the genetic variability. The studies of ASA revealed a high variability of individual activities, which was reduced in two steps: (1) The ASA activity was related to the mean of two lysosomal reference enzyme activities, total hexosaminidase and acid beta-galactosidase. (2) Since the square root of ASA activity was found to follow more closely the variation of the reference activities, the square root of ASA activity over the mean reference activity was taken as a more standardized measure of ASA activity, and the quotient was treated statistically. Positive feto-maternal correlation of standardized ASA activity was obtained after the elimination of three pairs with extreme values. A correlation coefficient of 4 = 0.42 (n - 26; 95% confidence limits 0.039-0.695) resulted. The implications of these correlation studies for the problem of heterozygote identification by quantitative enzyme assays in families deficient in HXA and ASA activity were considered.

Research paper thumbnail of Prenatal enzymatic diagnosis of Krabbe disease (globoid-cell leukodystrophy) using chorionic villi: pitfalls in the use of uncultured villi

Human Genetics, 1989

Sixteen pregnancies in families with children enzymatically diagnosed as having Krabbe disease (K... more Sixteen pregnancies in families with children enzymatically diagnosed as having Krabbe disease (KD) were monitored for prenatal KD using the assay of galactosyl ceramide beta-galactosidase (GCG) in uncultured chorionic villi (CV), cultured CV, or cultured amniotic fluid cells (AFC). Prenatal KD diagnoses were made for 5 pregnancies on the basis of lower than 10% normal GCG activity in cultured CV or AFC. Uncultured CV were studied in 3 out of the 5 KD embryos, although the GCG activities of 14%-23% as compared with control villi were diagnostically inconclusive; the relatively high activities were considered to be caused by maternal GCG contamination of these very small villus samples. Although the villi from 6 of the other pregnancies yielded more conclusive results, the use of uncultured CV alone is not recommended for prenatal KD diagnosis, this material being subject to possible uncontrolled contamination with maternal enzyme.

Research paper thumbnail of Nachweis des Enzymdefekts und vorl~ufige Identifizierung der Heterozygoten in einer Familie mit M. Gaucher Typ 1

Journal of Molecular Medicine Jmm, 1974

Research paper thumbnail of Prenatal enzymatic diagnosis and exclusion of Krabbe's disease (globoid-cell leukodystrophy) using chorionic villi in five risk pregnancies

Hum Genet, 1987

Galactosyl ceramide beta-galactosidase activity was determined in chorionic villi (CV) samples ob... more Galactosyl ceramide beta-galactosidase activity was determined in chorionic villi (CV) samples obtained between the 9th and 11th weeks of gestation from 5 women with pregnancies at risk for Krabbe&#39;s disease (globoid-cell leukodystrophy, KD). These enzyme activities were compared with those in controls, as well as with those in cultured amniotic fluid cells (AFC) from one of the five at-risk pregnancies and from 29 KD-risk pregnancies studied previously. The results of these CV enzyme analyses were such that one case of fetal KD was clearly diagnosable, one fetal genotype heterozygous for KD was presumed, and three normal fetal genotypes were suggested. The use of both uncultured and cultered CV can be recommended for prenatal KD testing, but AFC may continue to play an important role, too. Of the 58 prenatal KD tests we have evaluated since 1974, a positive diagnosis of Krabbe&#39;s disease was made (and confirmed after termination of pregnancy when feasible) in 23 which is significantly more than 25% of 58.