Partitioning of the cell into organellar compartments offers the advantage and vulnerability of specialized function. Genetic mutations that alter the structure or targeting of organellar proteins may disrupt the entire organelle and produce multiple metabolic abnormalities. Examples of generalized organellar dysfunction include alterations of the mannose-6-phosphate targeting in lysosomes (e.g., I-cell disease), deletions of mitochondrial DNA (e.g., Kearns–Sayre syndrome), and mutations in peroxisomal membrane proteins (e.g., Zellweger syndrome). Other genetic mutations affect only one organellar protein, producing a more limited and specific phenotype (e.g., Fabry disease, Leber hereditary optic neuropathy, or adrenoleukodystrophy).
The dietary manipulations that are effective for the “small”-molecule disorders have limited use for organellar disorders. Deficiencies of lysosomal enzymes often lead to “storage” diseases, with the accumulation of “large” molecules that are internally synthesized and independent of dietary sources. Other lysosomal diseases, as well as disorders affecting the structure of mitochondria or peroxisomes, may involve an excess or deficiency of molecules within cellular compartments; these molecules are less accessible to manipulation by diet.
Many organellar disorders are progressive, involving a phase of normal development until the accumulation of metabolites interferes with organ function. Often several organs are affected, particularly the brain, eye, heart, liver, and skeleton. Most of the disorders exhibit insidious loss of previously acquired developmental milestones, followed by neurodegeneration and death. The age at which the deceleration of development occurs and the rate of progression vary widely.