Publications about genetic testing for metabolic disorders
  1. Lysosomal storage diseases (LSD) panel

Lysosomal storage diseases (LSD) panel

May 30, 2018

Disease summary:

Lysosomal storage diseases (LSD) are a heterogeneous group of inherited disorders characterized by the accumulation of partially digested or undigested macromolecules in cells, due to the absence of different lysosomal enzymes, which ultimately results in cellular dysfunction and clinical abnormalities 1, 2. To date >50 different LSDs have been described.  They affect the central nervous system, skeleton, skin, heart and/or other organs, resulting in specific phenotypic profiles. Based on the type of accumulated substrate, LSDs are classified into different subtypes (Table 1).

Autosomal recessive, X-linked recessive

1/7,100-7,700 (combined for all LSDs) 1, 2, 3

Major clinical symptoms depend on the LSD subtype but in general include the following 1, 2:

  • Developmental delay and/or regression
  • Progressive neurological features (hypotonia, weakness, seizures, movement disorders, muscle weakness and other)
  • Organomegaly (enlarged spleen and liver)
  • Pulmonary and cardiac issues
  • Dysmorphic features
  • Skeletal abnormalities (dysostosis multiplex)
  • Visual and/or hearing loss
  • Presence of the specific clinical features for each LSD subtype
  • Presence of specific accumulated products in serum/ urine
  • Absent or reduced e activity of the specific enzyme
  • Positive family history of LSD
  • Identification of a pathogenic variant in one of the associated genes: AGA, AP3B1, ARSA, ARSB, ASAH1, CLN6, CLN8, CTNS, CTSA, CTSK, FUCA1, GAA, GALC, GALNS, GBA, GLA, GLB1, GM2A, GNPTAB, GNPTG, GNS, GUSB, HEXA, HEXB, HGSNAT, HYAL1, IDS, IDUA, LAMP2, LIPA, LYST, MAN2B1, MANBA, MCOLN1, MLPH, MYO5A, NAGA, NAGLU, NEU1, NPC1, NPC2, NPR2, PPT1, PSAP, RAB27A, SGSH, SLC17A5, SMPD1, SUMF1, TPP1.

Enzyme replacement therapy is available for some LSDs and presents the best therapeutic option when available.

Bone marrow transplantation is a possible option for some LSDs.

Symptomatic treatment can relieve symptoms1, 2:

  • Treatment for seizures, cardiac, respiratory and other abnormalities
  • Physical/occupational therapy
  • Special nutrition/diet depending on the LSD subtype
  • Liver transplantation
  • Visual, hearing aids, speech therapy, psychotherapy and others
  • Urea cycle disorders
  • Fatty acid oxidation disorders
  • Mitochondrial diseases, CADASIL (Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), Leigh syndrome and others
  • Zellweger syndrome, peroxisome biogenesis disorders
  • Congenital muscular dystrophies
  • Charcot-Marie-Tooth disease

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • CentoLSD: LSD comprehensive enzyme panel (21 enzymes) with option to reflex to specific genetic testing if an enzyme deficiency is identified
  • Lysosomal storage disease NGS Panel Plus: sequencing of the genes AGA, AP3B1, ARSA, ARSB, ASAH1, CLN6, CLN8, CTNS, CTSA, CTSK, FUCA1, GAA, GALC, GALNS, GBA, GLA, GLB1, GM2A, GNPTAB, GNPTG, GNS, GUSB, HEXA, HEXB, HGSNAT, HYAL1, IDS, IDUA, LAMP2, LIPA, LYST, MAN2B1, MANBA, MCOLN1, MLPH, MYO5A, NAGA, NAGLU, NEU1, NPC1, NPC2, NPR2, PPT1, PSAP, RAB27A, SGSH, SLC17A5, SMPD1, SUMF1, TPP1.
  • Lysosomal storage disease NGS Panel Plus + CNV: sequencing and additionally detection of large deletions and duplications from the NGS data
  • Lysosomal storage disease NGS Panel Genomic:

    • Step 1: whole genome sequencing with analysis of only panel genes for sequencing (exonic and intronic) and deletion/duplication variants
    • Step 2: if no variant is detected, reflex to bioinformatics analysis of whole genome based on phenotype.

  • Individuals with a positive family history of a LSD
  • Individuals with symptoms suggestive of a LSD (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of Lysosomal storage disease can allow for genetic counseling and may direct medical management.


Table 1. Overview of the genes in CENTOGENE´s Lysosomal storage disease panel

DiseaseOMIM disease Protein Gene OMIM Main storage material
Mucopolysaccharidoses (MPSs)
MPS I (Hurler, Scheie, Hurler/Scheie) 607014 607015 607016

α-Iduronidase 

IDUA
252800
Dermatan sulphate, heparan sulphate
MPS II (Hunter) 309900 Iduronate sulphatase IDS
309900
Dermatan sulphate, heparan sulphate
MPS III A (Sanfilippo A) 252900 Heparan sulphamidase SGSH
605270
Heparan sulphate
MPS III B (Sanfilippo B) 252920 Acetyl α-glucosaminidase

NAGLU 609701

Heparan sulphate
MPS III C (Sanfilippo C) 252930 α-glucosaminide N-acetyltransferase HGSNAT
610453
Heparan sulphate
MPS III D (Sanfilippo D) 252940 N-acetyl glucosamine-6-sulphatase GNS
607664
Heparan sulphate
MPS IVA (Morquio A) 253000 Acetyl galactosamine-6-sulphatase GALNS
612222
Keratan sulphate, chondroitin 6-sulphate
MPS IV B (Morquio B) 253010 β-Galactosidase GLB1
611458
Keratan sulphate
MPS VI (Maroteaux-Lamy) 253200 Arylsulphatase B ARSB
611542
Dermatan sulphate
MPS VII (Sly) 253220 β-Glucuronidase GUSB
611499
Dermatan sulphate, heparan sulphate, chondroitin 6-sulphate
MPS IX (Natowicz) 601492 Hyaluronidase HYAL1
607071
Hyaluronan
DiseaseOMIM disease Protein Gene OMIM Main storage material
Sphingolipidoses
Fabry disease 301500 α-Galactosidase A GLA
300644
Globotriaoslyceramide (Gb3) and related glycosphingolipids 
Farber disease 228000 Acid ceramidase ASAH1
613468
Ceramide
Gangliosidosis GM1 (Types I, II, III) 230500, 230600, 230650 GM1-β-galactosidase GLB1
611458
GM1 ganglioside, keratan sulphate, glycolipids
Gangliosidosis GM2, Tay-Sachs 272800 β-Hexosaminidase A HEXA
606869
GM2 ganglioside, oligosaccharides, glycolipids
Gangliosidosis GM2, Sandhoff 268800 β-Hexosaminidase AB HEXAB
606873
GM2 ganglioside, oligosaccharides
Gaucher disease (Types I, II, III) 230800, 230900, 231000 Glucosylceramidase GBA
606463
Glucosylceramide
Krabbe disease 245200 β-Galactosylceramidase GALC
606890
Galactosylceramide
Metachromatic leukodystrophy 250100 Arylsulphatase A ARSA
607574
Sulphatides
Niemann-Pick (type A, type B) 257200, 607616 Sphingomyelinase SMPD1
607608
Sphingomyelin
DiseaseOMIM disease Protein Gene OMIM Main storage material
Oligosaccharidoses (glycoproteinoses)
Aspartylglycosaminuria 208400 Glycosylasparaginase AGA
613228
Aspartylglucosamine
Fucosidosis 230000 α-Fucosidase FUCA1
612280
Glycoproteins, glycolipids
α-Mannosidosis 248500 α-Mannosidase MAN2B1
609458
Mannose-rich oligos
β-Mannosidosis 248510 β-Mannosidase MANBA
609489
Man(β1 → 4)GlnNAc
Schindler disease 609241 N-acetylgalactosaminidase NAGA
104170
Sialylated/asialoglycopeptides, glycolipids
Sialidosis 256550 Neuraminidase NEU1
608272
Oligos, glycopeptides
DiseaseOMIM disease Protein Gene OMIM Main storage material
Glycogenoses
Glycogenosis II/Pompe disease 232300 α1,4-glucosidase GAA
606800
Glycogen
DiseaseOMIM disease Protein Gene OMIM Main storage material
Lipidoses
Wolman disease/CESD 278000 Acid lipase LIPA
613497
Cholesterol esters
DiseaseOMIM disease Protein Gene OMIM Main storage material
Non-enzymatic lysosomal protein defect
Gangliosidosis 2, GM2 AB variant 272750 GM2 activator protein GM2A
613109
GM2 ganglioside, glycolipids
Combined SAP deificency 611721 Prosaposin PSAP
176801
Glucosylceramides, galactosylceramides, sulphatides
Metachromatic leukodystrophy due to SAP-b deficiency 249900 Sulphatides
Krabbe disease, atypical 611722 Galactosylceramide
Gaucher disease, atypical 610539 XGlucosylceramide
DiseaseOMIM disease Protein Gene OMIM Main storage material
Transmembrane protein defect: defects in transporter proteins
Sialic acid storage disease 269920, 604369 Sialin SLC17A5
604322
Sialic acid
Cystinosis 219800 Cystinosin CTNS
606272
Cystine
Niemann-Pick Type C1 257220 Niemann-Pick type 1 (NPC1) NPC1
607623
Cholesterol, sphingolipids
Niemann-Pick, Type C2 607625 Niemann-Pick type 2 (NPC2) NPC2
601015
Cholesterol, sphingolipids
DiseaseOMIM disease Protein Gene OMIM Main storage material
Transmembrane protein defect: defect in structural proteins
Danon disease 300257 Lysosome-associated membrane protein 2 LAMP2
309060
Cytoplasmatic debris, glycogen
Mucolipidosis IV 252650 Mucolipin MCOLN1
605248
Lipids
DiseaseOMIM disease Protein Gene OMIM Main storage material
Transmembrane protein defect: defect in lysosomal enzymes
Multiple sulfatase deficiency 272200 Sulfatase-modifying factor 1 SUMF1
607939
Glycosaminoglycans
Galactosialidosis 256540 Protective protein cathepsin A CTSA
613111
Sialyloligosaccharides
Mucolipidosis IIα/β, IIIα/β 252500, 252600 GlcNAc-1-P transferase GNPTAB
607840
Oligosaccharidea, glycosaminoglycans, lipids
Mucolipidosis IIIγ 232605 GlcNAc-1-P transferase GNPTG
607838
Oligosaccharidea, glycosaminoglycans, lipids
DiseaseOMIM disease Protein Gene OMIM Main storage material
Neuronal ceroid lipofuscinoses (NCLs)
NCL 1 256730 Palmitoyl protein thioesterase PPT1
600722
Autofluorescent lipopigment : Saposins A and D
NCL 2 204500 Tripeptidyl peptidase 1 TPP1
607998
Autofluorescent lipopigment , subunit c of ATP synthase
NCL 3 204200 CLN3, lysosomal protein CLN3
607042
Autofluorescent lipopigment , subunit c of ATP synthase
NCL 5 256731 CLN5, soluble lysosomal protein CLN5
608102
Autofluorescent lipopigment , subunit c of ATP synthase
NCL 6 601780 CLN6, transmembrane protein CLN6
606725
Autofluorescent lipopigment , subunit c of ATP synthase
NCL 7 601780 CLC7, lysosomal chloride channel MFSD8
611124
Autofluorescent lipopigment , subunit c of ATP synthase
NCL 8 600143 CLN8, transmembrane protein CLN8
607837
Autofluorescent lipopigment , subunit c of ATP synthase
NCL 10 610127 Cathepsin D CTSD
116840
Autofluorescent lipopigment : Saposins A and D