Module 4 · Inborn Errors of Metabolism
Lysosomal Storage Disorders
Genetic deficiency of any lysosomal hydrolase causes accumulation of that enzyme’s substrate in the lysosome, eventually producing organelle dysfunction and tissue-specific pathology. > 50 lysosomal storage disorders (LSDs) are recognised. Combined, they affect ~1 in 5 000 live births, making them one of the most clinically significant categories of inborn errors of metabolism.
1. The Major LSDs
| Disease | Enzyme | Substrate | Hallmark |
|---|---|---|---|
| Gaucher | GBA (glucocerebrosidase) | Glucocerebroside | Hepatosplenomegaly, Gaucher cells in marrow |
| Fabry | α-galactosidase A (GLA) | Globotriaosylceramide | X-linked; cardiac, renal, stroke |
| Pompe | α-glucosidase (GAA) | Glycogen | Cardiomyopathy, myopathy |
| Tay-Sachs | Hex A (HEXA) | GM2 ganglioside | CNS, cherry-red macular spot |
| Sandhoff | Hex A/B (HEXB) | GM2 + asialo | CNS + visceral |
| Niemann-Pick A/B | SMPD1 (sphingomyelinase) | Sphingomyelin | CNS (A), visceral (B) |
| Niemann-Pick C | NPC1/NPC2 | Cholesterol | CNS progressive; “juvenile Alzheimer’s” |
| Hurler (MPS I) | IDUA | Dermatan/heparan sulphate | Coarse facies, dysostosis, CNS |
| Hunter (MPS II) | IDS | Dermatan/heparan | X-linked |
| Krabbe | GALC | Galactocerebroside | Infantile CNS, psychosine toxicity |
| MLD | ARSA | Sulfatide | Demyelination, CNS |
2. Pathophysiology
Substrate accumulation per se is not the whole story. LSDs show a hierarchy of pathology:
- Direct substrate toxicity: bulk accumulation distorts lysosomal size and function.
- Secondary storage: the primary accumulation interferes with clearance of other substrates, producing an expanded “storage spectrum.”
- Autophagy block: swollen lysosomes cannot fuse with autophagosomes; autophagic cargo accumulates, stressing proteostasis.
- Inflammation & neurodegeneration: stored substrate acts as a DAMP, driving chronic microglial and macrophage activation.
Onset correlates inversely with residual enzyme activity: classical phenotypes have < 5% activity; attenuated phenotypes (Gaucher type I; late-onset Pompe) have 5–20%, often presenting only in adulthood.
3. Enzyme Replacement Therapy (ERT)
Recombinant human hydrolase is administered intravenously; the enzyme bears the M6P tag (produced in mammalian cells or tailored in E. coli with added M6P) and is taken up via the cation-independent M6P receptor at target cells. Approved ERTs:
- Imiglucerase, velaglucerase, taliglucerase for Gaucher (1991–2012).
- Agalsidase-α / -β for Fabry.
- Alglucosidase-α for Pompe.
- Laronidase, idursulfase, elosulfase for MPS I, II, IV-A.
- Sebelipase-α for LIPA deficiency.
Limitation: ERT does not cross the blood-brain barrier, so does not help CNS manifestations. This makes ERT effective for Gaucher type I (visceral only) but insufficient for Gaucher type II/III, Hurler, Krabbe. Intrathecal administration and BBB-penetrating enzyme fusions (e.g., transferrin-receptor-targeted laronidase) are being developed.
4. Substrate Reduction Therapy (SRT)
Alternative to ERT: small molecules that inhibit substrate synthesis, reducing load on the deficient enzyme. Miglustat(inhibits glucosylceramide synthase) for Gaucher, Niemann-Pick C. Eliglustat (more potent, more specific) for Gaucher. SRT is oral, BBB-crossing (important for neuronopathic forms), and usable in combination with ERT.
5. Gene Therapy & HSC Approaches
Durable enzyme supply is the goal for CNS-involving LSDs. HSC gene therapy: patient HSCs are lentivirally transduced with the missing enzyme, reinfused, and daughter microglia produce enzyme in the CNS. Approved: OTL-200 (Libmeldy, atidarsagene autotemcel) for metachromatic leukodystrophy, EU approval 2020. In trials for Hurler, Krabbe, Hunter. Advantage: single dose, lifelong supply, reaches CNS via microglial engraftment. AAV gene therapy: direct intrathecal or intravenous AAV delivery; trials for MPS, Pompe, Batten.
6. GBA and Parkinson’s Disease
Heterozygous GBA mutations — one wild-type, one mutant — do not cause Gaucher disease but confer ~5× lifetime risk of Parkinson’s disease. GBA is the strongest single genetic risk factor for PD identified to date. Mechanism: reduced glucocerebrosidase activity allows α-synuclein to aggregate (direct substrate-level; GlcCer promotes α-synuclein fibrillisation). GBA agonists (ambroxol, a cough medicine, repurposed) are in trials for GBA-PD. This link between a lysosomal hydrolase and neurodegeneration is one of the strongest bridges between Module 5 and Module 6 of this course.