Colorado Care Network

Lysosomal storage disorders

Patient cohortTreatable monogenic diseaseSeeking a lead#cohort-lysosomal-storagePDF (members)

The anchor question: is a lysosomal storage disorder behind this adult's limb-girdle weakness, big spleen with low platelets, burning extremity pain with proteinuria, or stiff joints with no synovitis? Every disorder in this cohort has a disease-specific therapy, and every diagnosis starts with an enzyme assay or a gene test that primary care can order.

Who this cohort covers

Adults with the presentations these six disorders produce. Late-onset Pompe disease: progressive proximal weakness, mostly in the legs, with respiratory insufficiency that drives morbidity and mortality.1 Gaucher disease type 1: hepatosplenomegaly, anemia, thrombocytopenia and bone disease (osteopenia, lytic or sclerotic lesions, osteonecrosis), with no primary CNS disease.2 Fabry disease: acroparesthesia, angiokeratomas, hypohidrosis and proteinuria in the classic form; LVH, arrhythmia, kidney failure or stroke in the later-onset forms, the cardiac form usually in the sixth to eighth decade. Heterozygous women usually have milder, later disease; rarely, they are as severely affected as men.3 Chronic visceral ASMD (Niemann-Pick B): hepatosplenomegaly, slowly declining liver and lung function, osteopenia and an atherogenic lipid profile.4 Attenuated MPS I: progressive joint disease, valve disease, hearing loss, corneal clouding and carpal tunnel syndrome, sometimes with no neurologic involvement at all.5 Alpha-mannosidosis, mild type: recognized after age ten with myopathy and slow progression, alongside hearing loss, recurrent infections, lupus-like rheumatologic symptoms and psychiatric findings.6

The yield of looking is measured. Dried blood spot screening of 3,076 consecutive adults with hyperCKemia or limb-girdle weakness at seven German and British neuromuscular centers found late-onset Pompe disease in 2.4%.7 A reanalysis of 63 Fabry screening studies in high-risk clinics found pathogenic GLA variants in 0.94% of men and 0.90% of women screened in cardiac clinics, and in 0.15 to 0.21% of hemodialysis patients. The same reanalysis found benign variants in 47.9% of the men and 74.1% of the women originally reported with a GLA variant.8 A variant is not a diagnosis.

Care map

RoleYear 1, EstablishYear 2, TreatYear 3, Sustain
AnchorRecognize the pattern and order the first test. Three-generation pedigree, drawn for X-linked transmission when Fabry is possible3 and for consanguinity. Problem list across systems.Coordinate the therapy start. In the trials below, enzyme replacement ran as an infusion every one or two weeks,9 10 11 so the infusion site, home infusion and the coverage or cash-price conversation are anchor work.Annual review against the disease-specific surveillance calendar below. Re-screen the therapy choice each year as approvals change.
GeneticsEnzyme activity in leukocytes or dried blood spot, matched to the phenotype, then molecular confirmation. A low dried-blood-spot activity is a screen: in the Pompe cohort above, 232 low results yielded 74 molecular diagnoses.7 For Fabry in women, GLA sequencing, because a heterozygous pathogenic variant is what establishes the diagnosis in a woman.3 Check every GLA variant against current classification.8Cascade testing: at-risk siblings for the recessive disorders;1 2 for Fabry, both sexes along the X-linked pedigree, since an affected man passes the variant to every daughter.3 CYP2D6 genotype before eliglustat.12 Amenability testing of the GLA variant before migalastat.13Recheck GLA classifications: one reanalysis retired 20 variants once counted as disease-causing.8 Reclassification check on any other variant of uncertain significance.
SpecialistsBiochemical genetics or a lysosomal disease center to confirm and stage; a multidisciplinary treatment center where one exists.2 14 Neuromuscular medicine and pulmonology for Pompe, hematology for Gaucher and ASMD, nephrology and cardiology for Fabry.Disease-specific therapy through the treating center. Pompe: alglucosidase alfa, an estimated 28 m on the 6-minute walk and 3.4 points of FVC in its favor at 78 weeks;9 avalglucosidase alfa was noninferior to it.15 Gaucher type 1: ERT, or oral eliglustat, which shrank the spleen 28% (placebo, a 2% rise) and raised platelets 41% relative to placebo in nine months.16 Fabry: ERT as early as possible in all men and in women with manifestations,3 or migalastat for amenable variants.13 ASMD: olipudase alfa, a 22% gain in percent-predicted DLCO (placebo, 3%) and a 39% fall in spleen volume at one year.10 Attenuated MPS I: laronidase, which improves joint range of motion and mobility and slows respiratory disease.5 Alpha-mannosidosis: velmanase alfa, now standard treatment;6 in its phase III trial, the stair-climb end point showed no difference from placebo at 52 weeks.11Follow-up per organ involvement, at the interval the treating center sets.
DiagnosticsCBC with platelets, CK, creatinine, urinalysis, lipid panel, liver tests. Pompe: pulmonary function tests, ECG, echocardiogram including the ascending aorta.1 Gaucher: liver and spleen volume imaging, with skeletal MRI and DXA as needed.2 Fabry: ECG, echocardiogram, brain MRI, and renal function with urinalysis.3 ASMD: pulmonary function tests, lipid profile, liver tests and platelets.4 Attenuated MPS: echocardiogram, audiology, pulmonary function and median nerve conduction.5Track the trial endpoints: FVC and 6-minute walk in Pompe;9 spleen volume, hemoglobin and platelets in Gaucher;16 eGFR and LV mass index in Fabry;13 DLCO and spleen volume in ASMD;10 plasma oligosaccharides in alpha-mannosidosis.6Keep each chapter's calendar: Gaucher clinical review at least every six months and organ volumes every one to two years;2 Fabry renal function yearly and brain MRI every two to three years;3 Pompe pulmonary function, echocardiogram, ECG, DXA and audiology at least yearly.1
TherapiesPhysical therapy baseline for Pompe and alpha-mannosidosis: strength, endurance, gait.6 Noninvasive ventilation when Pompe respiratory insufficiency appears.1Ongoing PT. Orthopedic care and early carpal tunnel release, guided by nerve conduction, in MPS.5 Hearing aids for Fabry and alpha-mannosidosis.3 6Maintenance program; equipment review.
Behavioral health and nutritionScreen for depression and pain burden. Fabry neuropathic pain: gabapentin, carbamazepine or phenytoin; psychological assessment yearly from age 18.3Pain psychology. Feeding therapy and nutrition support in Pompe when swallowing or intake is a problem.1As needed.
CommunityDisease-specific patient organizations and registries.Trial referral where approved therapy does not fit.

Visit one

The map above is the evidence. This is what to do with the patient in the room. Each line comes from the Year 1 column and carries the same citations.

AskTrouble with stairs or rising from a chair, breathlessness;1 early satiety, bruising, bone pain;2 episodes of burning pain in the hands and feet, reduced sweating;3 joint stiffness, hand numbness, hearing loss;5 recurrent infections.6 Family: kidney failure, stroke or cardiomyopathy along an X-linked line;3 consanguinity; siblings with the same picture.
ExamineProximal leg strength;1 liver and spleen;2 4 angiokeratomas;3 joint range of motion and contractures;5 hearing.5 6
OrderCBC with platelets, CK, creatinine, urinalysis, lipid panel, liver tests. Enzyme activity in leukocytes or dried blood spot for the disorders the phenotype points to, with molecular confirmation of any low result;7 GLA sequencing for a woman with suspected Fabry.3 Alpha-L-iduronidase with urine glycosaminoglycans when MPS is on the list.5 ECG and echocardiogram.1 3
ReferBiochemical genetics or a lysosomal disease center with the enzyme result in hand; the organ specialist by phenotype.2 14 Pulmonary function tests for suspected Pompe or ASMD.1 4 Where: the esoteric assays, clinical expertise, procedural studies and specialist rosters.
Tell the patientThat each of these disorders has a specific treatment; that a low enzyme screen needs confirming before it is a diagnosis; that a confirmed result matters for siblings and, in Fabry, for children and the X-linked line.
DocumentThe phenotype that prompted testing, the pedigree, enzyme results with the reference range, the variant and its classification, and the referral question.

Roster for this cohort

Drawn from the esoteric assays roster (enzyme activity, dried blood spot testing, lysosomal gene panels), the clinical expertise roster (biochemical genetics consults), the empiric therapies roster (infusion centers and home infusion for enzyme replacement), the procedural studies roster (pulmonary function, echocardiography, nerve conduction), the advanced imaging roster (liver and spleen volumetry, skeletal and brain MRI), the specialist roster (neuromuscular medicine, hematology, nephrology, cardiology), and the therapists and counselor rosters. The roster is forming; members propose and vet entries in the cohort's Slack channel.

Readings

References

  1. Sperry E, Leslie N, Berry L, Pena L. Pompe disease. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1261
  2. Hughes DA, Pastores GM. Gaucher disease. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1269
  3. Mehta A, Hughes DA. Fabry disease. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1292
  4. Wasserstein MP, Schuchman EH. Acid sphingomyelinase deficiency. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1370
  5. Clarke LA. Mucopolysaccharidosis type I. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1162
  6. Ficicioglu C, Stepien KM. Alpha-mannosidosis. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1396
  7. Lukacs Z, Nieves Cobos P, Wenninger S, et al. Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness. Neurology. 2016;87(3):295-298. doi:10.1212/WNL.0000000000002758
  8. Doheny D, Srinivasan R, Pagant S, et al. Fabry disease: prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995-2017. J Med Genet. 2018;55(4):261-268. doi:10.1136/jmedgenet-2017-105080
  9. van der Ploeg AT, Clemens PR, Corzo D, et al. A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med. 2010;362(15):1396-1406. doi:10.1056/NEJMoa0909859
  10. Wasserstein M, Lachmann R, Hollak C, et al. A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: one-year results. Genet Med. 2022;24(7):1425-1436. doi:10.1016/j.gim.2022.03.021
  11. Borgwardt L, Guffon N, Amraoui Y, et al. Efficacy and safety of velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial. J Inherit Metab Dis. 2018;41(6):1215-1223. doi:10.1007/s10545-018-0185-0
  12. Kane M, Dean L. Eliglustat therapy and CYP2D6 genotype. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. NBK565950
  13. Germain DP, Hughes DA, Nicholls K, et al. Treatment of Fabry's disease with the pharmacologic chaperone migalastat. N Engl J Med. 2016;375(6):545-555. doi:10.1056/NEJMoa1510198
  14. Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416-427. doi:10.1016/j.ymgme.2018.02.014
  15. Diaz-Manera J, Kishnani PS, Kushlaf H, et al. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. Lancet Neurol. 2021;20(12):1012-1026. doi:10.1016/S1474-4422(21)00241-6
  16. Mistry PK, Lukina E, Ben Turkia H, et al. Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. JAMA. 2015;313(7):695-706. doi:10.1001/jama.2015.459

References retrieved from PubMed on 2026-10-30. Care maps are peer-authored clinical frameworks for network members, not individualized medical advice, and are reviewed at each yearly cycle.

Discuss this cohort in Slack

Colorado Care Network. Lysosomal storage disorders. Version 2026-10-30.