What is the management of lysosomal storage disorders?

Management of Lysosomal Storage Disorders

The management of lysosomal storage disorders requires a multidisciplinary team approach led by a biochemical geneticist experienced in treating LSDs, combining disease-specific therapy with symptom-specific measures to reduce morbidity, mortality, and improve quality of life. 1

Diagnostic Confirmation

• Diagnosis must be established through specific enzyme assays and mutational analysis, as clinical presentations can vary widely 1
• Urinary mucopolysaccharides and oligosaccharides may be useful for screening but can be normal or nonspecifically elevated in healthy neonates 1
• Presymptomatic individuals may be identified through newborn screening, family-based testing after proband identification, carrier screening, or prenatal testing 1

Treatment Approaches

Enzyme Replacement Therapy (ERT)

• Most widely used treatment for LSDs, supplying the missing enzyme through repeated intravenous infusions 1
• Available for several LSDs including Fabry disease, Gaucher disease, Pompe disease, and certain mucopolysaccharidoses 1
• Decision to initiate ERT should be made according to clinical judgment of the managing metabolic physician in conjunction with the patient's family 1
• For Fabry disease, baseline diagnostic studies (ECG, echocardiogram, ophthalmologic examination, renal function tests) should be obtained before starting therapy 1

Hematopoietic Stem Cell Transplantation (HSCT)

• Used successfully in management of some LSDs 1
• Reconstituted hematopoietic system from a healthy donor provides stem cells that produce the missing enzyme 1
• Advantage: cells can integrate into many tissues, including the CNS 1
• Disadvantages: high morbidity and mortality, low level of correction, time required for cell integration 1

Substrate Reduction Therapy

• Miglustat (OPFOLDA) is approved for use in combination with enzyme replacement for certain LSDs, such as late-onset Pompe disease in adults weighing ≥40 kg who are not improving on current ERT 2
• Works by stabilizing misfolded but functional enzymes as they are synthesized in the endoplasmic reticulum 1

Emerging Therapies

• Gene therapy approaches are being evaluated in clinical trials with potential to become new standard of care treatments 3
• Small molecule therapies including chaperone therapies are approved for some LSDs 4

Disease-Specific Management

Fabry Disease

• Baseline diagnostic studies should include ECG, echocardiogram, ophthalmologic examination, renal function tests, and plasma/urine GL-3 1
• Follow-up with metabolic specialist at 6-month intervals to monitor for onset of symptoms 1
• Detailed pedigree should be constructed to identify at-risk family members 1

Gaucher Disease

• Classified into three main variants: type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic) 1
• Management approach varies based on disease type and severity 1

Follow-up and Monitoring

• Comprehensive management requires ongoing multidisciplinary team approach 1
• Team should include relevant medical specialists familiar with LSDs 1
• Regular monitoring for disease progression and treatment efficacy is essential 1
• Genetic counseling is essential to provide understanding of inheritance patterns and identify at-risk family members 1

Special Considerations

• Early intervention is critical as most treatments are more effective before significant organ damage has occurred 5
• Patient and parent support groups provide valuable emotional support and practical advice 1
• For women with X-linked LSDs like Fabry disease, disease manifestations may be determined by the degree of X-chromosomal inactivation 1
• Carrier screening programs have been effective in reducing incidence of certain LSDs, particularly Tay-Sachs disease in Ashkenazi Jewish populations 1