•MPSsresultfromaccumulationofmucopolysaccharidesinmanytissuesincludingliver,spleen,heart,bloodvessels,brain,cornea,andjoints.Affectedpatientsinallformshavecoarsefacialfeatures.ManifestationsofHurlersyndromeincludecornealclouding,coronaryarterialandvalvulardeposits,anddeathinchildhood.Huntersyndromeisassociatedwithamilderclinicalcourse.
An inherited deficiency of any one of the enzymes involved in glycogen synthesis or degradation can result in excessive accumulation of glycogen or some abnormal form of glycogen in various tissues. The type of glycogen stored, its intracellular location, and the tissue distribution of the affected cells vary depending on the specific enzyme deficiency. Regardless of the tissue or cells affected, the glycogen most often is stored within the cytoplasm, or sometimes within nuclei. One variant, Pompe disease, is a form of lysosomal storage disease, because the missing enzyme is localized to lysosomes. Most glycogenoses are inherited as autosomal recessive diseases, as is common with “missing enzyme” syndromes.
Approximately a dozen forms of glycogenoses have been described in association with specific enzyme deficiencies. Based on pathophysiologic findings, they can be grouped into three categories (
Table 7.4
Hepatic type. Liver contains several enzymes that synthesize glycogen for storage and also break it down into free glucose. Hence, a deficiency of the hepatic enzymes involved in glycogen metabolism is associated with two major clinical effects: enlargement of the liver due to storage of glycogen and hypoglycemia due to a failure of glucose production (
Fig. 7.12 ). Von Gierke disease (type I glycogenosis), resulting from a lack of glucose-6phosphatase, is the most important example of the hepatic form of glycogenosis (
Table 7.4
Myopathic type. In striated muscle, glycogen is an important source of energy. Not surprisingly, most forms of glycogen storage disease affect muscles. When enzymes that are involved in glycolysis are deficient, glycogen storage occurs in muscles and there is an associated muscle weakness due to impaired energy production. Typically, the myopathic forms of glycogen storage diseases are marked by muscle cramps after exercise, myoglobinuria, and failure of exercise to induce an elevation in blood lactate levels because of a block in glycolysis. McArdle disease (type V glycogenosis), resulting from a deficiency of muscle phosphorylase, is the prototype of myopathic glycogenoses.
Type II glycogenosis (Pompe disease) is caused by a deficiency of lysosomal acid maltase and is associated with deposition of glycogen in virtually every organ, but cardiomegaly is most prominent. Most affected patients die within 2 years of onset of cardiorespiratory failure. Therapy with the missing enzyme (glucosidase) can reverse cardiac muscle damage and modestly increase longevity.
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Inheriteddeficiencyofenzymesinvolvedinglycogenmetabolismcanresultinstorageofnormalorabnormalformsofglycogen,predominantlyinliverormusclesorinalltissues.
Inthehepaticform(vonGierkedisease),livercellsstoreglycogenbecauseofalackofhepaticglucose-6-phosphatase.
Thereareseveralmyopathicforms,includingMcArdledisease,inwhichlackofmusclephosphorylasegivesrisetostorageinskeletalmusclesandcrampsafterexercise.
InPompediseasethereislackoflysosomalacidmaltase,andallorgansareaffected,butheartinvolvementispredominant.