The initial approach to diagnosis is based on clinical features e.g. hepatosplenomegaly, dysmorphic features, psychomotor regression, ocular abnormalities (e.g., corneal clouding).
Storage disorders are manifestations of lysosomal dysfunction usually as a consequence of defective single genes encoding for a single enzyme required for the metabolism of lipids, glycoproteins, or the mucopolysaccharides. Estimates indicate that approximately one in every 25,000 babies born in the United States will have some form of the mucopolysaccharidoses (see factsheet), a group of congenital disorders conferring with it inability to breakdown glycosaminoglycans. These diseases are grouped into the broader lysosomal storage disease classification. Lysosomal storage diseases are autosomal recessive conditions occasioning deficient metabolic enzymic activity that manifest from accumulation of high molecular weight metabolic complexes– such as these mucopolysaccharides–in tissue. Diagnosis (antenatal genetics are now also available) is traditionally via specific enzyme assay of biopsied tissue fibroblast.
presenting features;
- coarse facial features
- dark eyebrows, broad fleshy nose
- thick lips, ear lobes, skin
- cloudy cornea
- broad hands and feet with stiff joints
- protuberant abdomen (hepatosplenomegaly)
- progressive mental retardation:
- Hurler syndrome (MPS – I / MPS – IH)
- Hunter syndrome (MPS – II): X-linked, with clear corneas
- Sanfilippo syndrome (MPS – III)
- skeletal problems, normal mentation
- Maroteaux-Lamy (MPS – IV)
The mucopolysaccharidoses, as they are known, have a variable prognosis.
Hurler syndrome is associated with a decline in growth and developmental delay. Hematopoietic cell transplantation (HCT) in MPS IH reduces mortality from cardiac and pulmonary disease while preserving central nervous system (CNS) function such that treated children with MPS IH are living beyond the second decade and into adulthood.¹ In lipid storage disorders (mucolipidoses), by contrast, the facies are generally not as striking, there is earlier (early) brain involvement, and reticuloendothelial storage sites predominate.
- Gaucher disease
- Niemann-Pick disease
- Fabry disease
- Farber’s disease
- Gangliosidosis
- Krabbe disease
- Metachromatic leukodystrophy
- Wolman’s disease
All these disorders, along with the glycogen storage disorders (GSD; glycogenosis) and others, might be classified under the broader term inborn errors of metabolism. Although episodes of hypoglycemia and enlargement of the liver are the main findings in all hepatic GSD, heterogeneity of presentation is considerable. The inherited metabolic diseases were traditionally classified as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. But with the advent of molecular technologies, hundreds of new inherited disorders of metabolism have been discovered.
Reference
Polgreen, L.E., Lund, T.C., Braunlin, E. et al. “Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.” Pediatr Res 87, 104–111 (2020). https://doi.org/10.1038/s41390-019-0541-2.