Lysosomal Storage Disorders Diagnostic Algorithm, Part 1

Clinical information: ■ Developmental delay/Cognitive impairment ■ Coarse features/Organomegaly ■ Dysostosis multiplex ■ Neurodegeneration/Behavioral changes ■ Ichthyosis ■ Hearing defects/loss

LSDS / Lysosomal Storage Disorders Screen, Random, Urine Testing includes: ■ Mucopolysaccharides (MPS) ■ Dermatan sulfate (DS) ■ Heparan sulfate (HS) ■ Keratan sulfate (KS) ■ Chondroitin 6-sulfate (CS) ■ Oligosaccharides (OLIGO) ■ Ceramide trihexosides (CT) – Normal for all disorders on this algorithm ■ Sulfatides (S) – Normal for all disorders on this algorithm

Elevated KS ■ Elevated DS and HS ■ Elevated KS and CS ■ Elevated DS ■ Elevated DS, HS and CS ■ Elevated HS Normal results ■ OLIGO – may ■ OLIGO – MPS IVA profile ■ OLIGO – may ■ OLIGO – normal ■ OLIGO – normal suggest MPS profile suggest MPS profile

MPS I (Hurler syndrome) MPS IVA MPS VI MPS VII MPS III A, B, C, D STOP or MPS II (Hunter syndrome) TeSTing cOmPleTe

mPS i mPS ii Order: ANAS / Alpha-N- Acetylglucosaminidase, Serum Order: IDUAW / Order 1 of the following: Order: G6SW / Consider: MPS6Z / Consider 1 of the following: Alpha-L-Iduronidase, ■ I2SW / Iduronate-2- N-Acetylgalactosamine Mucopolysaccharidosis VI, ■ Beta-glucuronidase nOrmal deficienT Leukocytes Sulfatase, Whole Blood 6-Sulfatase,Leukocytes Full Gene Analysis, Varies enzyme analysis ■ I2SBS / Iduronate-2- ■ GUSB sequencing Sulfatase, Blood Spot Does not rule out MPS IIIB confirmed MPS III A, C, D

If deficient, MPS I confirmed If deficient, MPS II confirmed If deficient, MPS IVA confirmed

Consider: SFPAN / Consider: MP3BZ / Mucopolysaccharidosis III, Mucopolysaccharidosis IIIB, Consider: MPS1Z / Hurler Consider: MPS2Z / Hunter Consider: GALNS sequencing Multi-Gene Panel, Varies Full Gene Analysis, Varies Syndrome, Full Gene Syndrome, Full Gene Analysis, Varies Analysis, Varies

OLIGO – MPS IVB profile OLIGO – GM1 OLIGO – α-fucosidosis profile OLIGO – galactosialidosis profile gangliosidosis profile

α-Fucosidosis Galactosialidosis MPS IVB (Morquio syndrome type B) GM1 gangliosidosis

Order: FUCW / Alpha-Fucosidase, Leukocytes Consider: CTSA sequencing

Order 1 of the following: ■ BGA / Beta-Galactosidase, Leukocytes If deficient, α-fucosidosis confirmed ■ BGABS / Beta-Galactosidase, Blood Spot ■ BGAW / Beta-Galactosidase, Blood

Consider: FUCA1 sequencing

If deficient, perform GLB1 sequencing to distinguish between the disorders