Hereditary lysosomal storage disorders are a group of diverse inherited disorders that arise from deficiency of enzymes required for the breakdown of products of intermediary metabolism.
Diagnosis depends on a high index of suspicion, and is easily made by biochemical test or mutational analysis. Tissue biopsy is rarely required to make the diagnosis.
Many people present in early childhood with hepatosplenomegaly, neurodevelopmental delay, cardiorespiratory disease, joint contractures, and failure to thrive. Others present later in childhood with pain, organ enlargement, skin rash, sensory organ damage, musculoskeletal abnormalities, muscle weakness, and neurodevelopmental delay.
Early referral to a specialist center is strongly advised so that patients and families may be assessed by a multidisciplinary team familiar with the disease.
Significant advances in treatment have occurred in recent years such that the outlook for patients has substantially changed. Specific treatments limited to certain subtypes include enzyme replacement therapy, chaperone therapy, substrate reduction therapy, and stem cell transplantation.
Lysosomal storage diseases (LSDs) are due to the inherited deficiency of one of over 40 lysosomal enzymes, and lead to accumulation of undegraded substrate in a range of organs and tissues. They are multisystem and progressive disorders. Clinical manifestations are diverse; presentation may be in childhood or in adult life. New treatments, including replacement of the deficient enzyme, are changing the natural history of these diseases.
History and exam
Key diagnostic factors
- Family history
- onset in childhood (MPS, Pompe, Gaucher, Fabry, Niemann-Pick type A)
- onset in adolescence (Fabry, Pompe, Gaucher types 1, 3, mucopolysaccharidosis, Niemann-Pick types B, C)
- onset in adulthood (Fabry, Gaucher type 1, Pompe)
- hepatomegaly and/or splenomegaly
- history of renal failure
- skin rash/cutaneous lesions
- large head circumference
- macular "cherry red spot" on ophthalmoscopy
- optic atrophy or retinitis pigmentosa on ophthalmoscopy
- corneal clouding on ophthalmoscopy
Other diagnostic factors
- neurodevelopmental delay
- hearing impairment/sudden deafness
- cataract on ophthalmoscopy
- eye movement disorder
- progressive dementia and ataxia or gait disturbance
- failure to thrive
- joint contracture
- skeletal abnormalities including spinal gibbus
- history of recurrent respiratory tract infections
- movement disorders
- premature stroke/transient ischemic attack
- valvular cardiac disease
- male sex (mucopolysaccharidosis [MPS] II, Fabry disease)
- Ashkenazi ethnicity
1st investigations to order
- enzyme assay
- substrate assay
- DNA analysis
Investigations to consider
- pulmonary function tests
- bone marrow biopsy
- muscle biopsy
- CT/MRI of enlarged organ (Gaucher)
- echocardiogram/ultrasound/MRI (Fabry)
- CT/x-ray (mucopolysaccharidosis)
type 1 Gaucher disease
type 2 Gaucher disease
type 3 Gaucher disease
Atul B. Mehta, MA, MB BChir, MD, FRCP, FRCPath
Royal Free Hospital
Professor in Haematology
University College London
ABM has served on advisory boards, received travel grants, research grants, undertaken clinical trials in association with and provided support for educational activities for Takeda, Sanofi-Genzyme, Amicus, Biomarin, Pfizer/Protalix, Freeline therapeutics, Prevail/Lilly, and AvroBio. He is also an author of a number of references cited in this topic.
Gregory M. Pastores, MD
Departments of Neurology and Pediatrics
NYU School of Medicine
GMP declares that he has no competing interests.
Uma Ramaswami, MD, FRCPCH
Paediatric Metabolic Unit
Cambridge University Hospitals
UR has received travel grants, honoraria for lectures, and funding for clinical trials from Shire HGT, Genzyme, and Actelion.
Michael Beck, MD
Head of Department
University of Mainz
MB has been reimbursed by Shire, the manufacturer of Elaprase and Replagal, for attending several conferences, for running educational programs and for consulting. MB has received honoraria for speaking from Genzyme (the manufacturer of Myozyme, Fabrazyme, Aldurazyme, and Cerezyme) and Actelion (the manufacturer of Zavesca). MB is an author of a number of references cited in this topic.
Elmer V. Villanueva, MD, ScM, FRIPH
Associate Professor of Public Health
Director of Research
Gippsland Medical School
EVV declares that he has no competing interests.
- Langerhans cell histiocytosis (differential diagnosis of type 2 and 3 Gaucher disease)
- Rheumatic fever (differential diagnosis of Fabry)
- Bacterial endocarditis (differential diagnosis of Fabry)
- Elosulfase alfa for treating mucopolysaccharidosis type 4A
- Treatment of mucopolysaccharidosis type II (Hunter syndrome): a Delphi derived practice resource of the American College of Medical Genetics and Genomics (ACMG)
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