Clinical Approach to Diagnosis of Lysosomal Storage Diseases

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1 Clinical Approach to Diagnosis of Lysosomal Storage Diseases M. Rohrbach, MD, PhD FMH Pädiatrie und FMH Medizinische Genetik Abteilung Stoffwechsel Universitätskinderklinik Zürich

2 Lysosomal storage disorders 45>; expanding number Individually rare as a group 1: high risk of recurrence (AR and XR) highly variable some are treatable diagnostically challenging 1 Prevalence of lysosomal disorders, JAMA, 1999, Vol 281;3;

3 A Substrate accumulation B D C Enzyme deficiency (Gene mutation) X Y Substrate accumulation

4 Glycosaminoglycans Mucopolysaccharidoses Glycoproteins Oligosaccharidoses Glycolipids Sphingolipidoses Lipids Classification Niemann-Pick C, Wolman Multi-enzyme; Trafficking; Complex

5 Metabolic studies for LSD Analysis of metabolites Analysis of gene product Molecular genetic analysis Blood: Chitotriosidase Blood: Enzyme activity Urine: Glycosaminoglycans qn/ql Toluidin Thin layer chromatography Blood/tissue: Mutation screening

6 Metabolite 1: Chitotriosidase (ChT) Fully active chitinase expressed by activated macrophages Elevation in Gaucher disease and in various lysosomal disorders, malaria, thalassaemia, atherosclerosis, etc Anti-fungal

7 Chitotriosidase in LSD Yufeng G et al J. Inher. Metab.Dis. 18 (1995)

8 ChT activity deficiency L. Malaguarnera Cell. Mol. Life Sci. 63 (2006)

9 Metabolite 2: Berry spot test, semiquantitative Glycosaminoglycan analysis P. Mabe et al. / Clinica Chimica Acta 345 (2004)

10 Metabolite 3: Urinary Glycosaminoglycans qn Whitley et al Molecular Genetics and Metabolism 75, (2002)

11 Metabolite 4: GAG electrophoresis Electrophoresis of GAGs followed by toluidin staining mix CS DS HS MPS III mix + CS DS HS

12 Metabolite 5: Thin layer Chromatography Oligosaccharides Sialic Acid Monosaccharide (fructose) Disaccharide (sucrose) Disaccharide (lactose) Trisaccharide (raffinose) 1: sugar marker 2: neonate, healthy 3: mannosidosis patient : sialic acid (marker) 2: Galactosialidosis patient 3: Galactosialidosis patient; acidic hydrolysis 4: control 5: control ; acidic hydrolysis

13 LSDs detected by metabolites Meatbolite testing for lysosomal disoders 75% Chitotriosidase Glycosaminoglycans TLC: Oligosaccharides TLC: Sialic acid Rest

14 Prevalence of LSDs α-mannosidosis 2% β-mannosidosis 2% Schindler 1% Fucosidosis 2% Sandoff 2% Gm1 Gangliosidosis 2% Mucolipidosis type II/III 2% Gaucher 14% Niemann Pick A/B 3% Maroteaux-Lamy 3% Hurler-Scheie 9% Niemann Pick C 4% Sanfilippo B 4% Tay-Sachs 4% Metachromatic Leukodystrophy 8% Cystinosis 4% Sanfilippo A 7% Morquio 5% > 50 Hydrolases Pompe 5% Krabbe 5% Hunter 6% Fabry 7% For Australia ; JAMA 281 p249 '99

15 Frequency of the disorder Metabolite testing for lysosomal disorders 33% Chitotriosidase Glycosaminoglycans TLC: Oligosaccharides TLC: Sialic acid Rest

16 Enzyme assay = Gene product Clinical features overlapping > 50 enzymes involved Exceptions: specific clinic Pompe disease Fabry disease Gaucher disease adults

17 Enzyme assay challenges: X- chromosomal: Fabry disease Infantile versus adult onset: Pompe disease Enzyme Activity for Determination of Presence of Fabry Disease in Women Results in 40% False-Negative Results Journal of the American College of Cardiology Vol. 51, No. 21, 2008 The Lancet. Vol 372 October 11, 2008

18 Confirmation Challenges: Mutation analysis nature of mutation, new mutations X linked disorders, carrier detection special problems reagents: unique reaction conditions allelic heterogeneity polymorphisms pseudogenes

19 Stepwise approach Suspicion Clinical Class diagnosis Screening metabolites Definitive diagnosis Enzyme DNA

20 Clinical approach based on the time of suspicion prenatal neonatal childhood adulthood Non-immune hydrops fetalis

21 Hydrops fetalis Glycosaminoglycans childhood Oligosaccharides Enzyme assay in cultured amniocytes Clinica Chimica Acta 371 (2006)

22 Prenatal GAGs and Oligos 2: GM1-gangliosidosis 3: Normal amniotic fluid 4: Galactosialidosis Clinica Chimica Acta 371 (2006)

23 Clinical approach based on the time of suspicion prenatal neonatal childhood adulthood Hepatosplenomegaly Cardiomyopathy Neurology Gaucher Type 2 Niemann Pick C Wolman Sphingolipid storage disease: Farber, Gaucher 2, GM1, NP A/B, Krabbe Mucopolysaccharide storage disease: MPS I, MPS IV, MPS VII Glycogen storage disease: Pompe Glycoprotein storage disease Schindler, Sialidosis Complex storage disease Wolman Multienzyme Pompe storage Pompe disease Gaucher 2 Transport and trafficking disorders Krabbe Sialuria, Salla Gangliosidoses Pediatrics; Volume 123, April 2009,

24 Neonatal Hepatosplenomegaly Cardiomyopathy Neurology Gaucher Type 2 Niemann Pick C Wolman M: Chitotriosidase (Fillipin stain) (Cholesterol) Pompe E: α-glycosidase Pompe Gaucher Type 2 Krabbe Gangliosidoses M: Chitotriosidase TLC Oligos E: Galactocerebrosidase

25 Clinical approach based on the time of suspicion prenatal neonatal childhood adulthood

26 M. Beck, Hum Genet (2007) 121:1 22

27 Childhood prenatal neonatal childhood adulthood Skin Progressiv neurology and mental deterioration +/- Ataxia, +/- Hypotonia Coarse/ Hepatosplenomegaly Skeletal Ophthalmology Mucopolysaccharidoses Oligosaccharidoses α-fucosidosis Fabry M: Oligosaccharides E: α-galactosidase A and gene analysis M: Glycosaminoglycans TLC: Oligosaccharides

28 Ophthalmology Cataracts Sialidosis α-mannosidosis M: TLC Cherry red spot Galactosialidosis GM1, GM2 α-mannosidosis Sialidosis M: TLC Oligosaccharides E: β-hexosaminidase A/B Corneal Clouding MPS I/IV/VI α-mannosidosis M: GAG, TLC Oligos

29 Childhood Progressiv neurology and mental deterioration Skeletal Hepatosplenomegaly Ataxia or Hypotonia Psychic dysfunction Mannosidosis Fucosidosis Galactosialidosis Siladisosis Niemann Pick C GM1 GM2 Salla Sialic acid storage Niemann Pick C Schindler M: TLC E: Confirmation M: ChT Filippin staining G: Mutation M: TLC Oligosaccharides + Sialic acid E: Confirmation M: ChT (Filippin staining) TLC E: Confirmation

30 Clinical case 1 M 1 2 M 4.5 year old boy, recently arrived in this country, with restricted movement, hepatosplenomegaly CS and DS mild mental retardation. prenatal neonatal childhood adulthood HS Skin Progressiv neurology and mental deterioration +/- Ataxia Coarse/ Hepatosplenomegaly/ skeletal Ophthalmology M: GAG s qn elevated GAG electrophoresis MPS II

31 Clinical case 2 6 year old girl with prominent cerebellar ataxia and mild mental retardation and previous hypotonia. Only able to speak a few words. prenatal neonatal childhood adulthood Skin Progressiv neurology and mental deterioration +/- Ataxia +/- hypotonia Coarse/ Hepatosplenomegaly/ skeletal Ophthalmology M: TLC for Oligosaccharides/ Free Sialic Acid Salla disease

32 Adulthood prenatal neonatal childhood adulthood Renal/Cardiology Progressiv neurology Fabry Ataxia and Dementia Without mental deterioration E: in male M: in female MLD Late onset Krabbe GM1/GM2 Niemann Pick C Neuronal ceroid lipofuscinosis M: Oligosaccharides; CTh Fingerprints in biopsies E: Arylsulfatase A E: Galactocerebrosidase

33 Probable Impact Treatable LSD α-mannosidosis 2% β-mannosidosis 2% Schindler 1% Fucosidosis 2% Sandoff 2% Gm1 Gangliosidosis 2% Gaucher 14% Mucolipidosis type II/III 2% Niemann Pick A/B 3% Maroteaux-Lamy 3% Hurler-Scheie 9% Niemann Pick C 4% Sanfilippo B 4% Tay-Sachs 4% Metachromatic Leukodystrophy 8% Cystinosis 4% Sanfilippo A 7% Morquio 5% Pompe 5% Krabbe 5% Hunter 6% Fabry 7%

34 Conclusion Conclusion > 45 lysosomal storage disoders Specific diagnosis is challenging Critically important to patient management Some are treatable Clinical features Stepwise approach: Metabolite, Gene product, Mutation analysis

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