Almost from birth, affected infants fail to thrive. Vomiting and diarrhea appear within a few days of milk ingestion. Jaundice and hepatomegaly usually become evident during the first week of life. Accumulation of galactose and galactose-1-phosphate in the kidney impairs amino acid transport, resulting in aminoaciduria. Fulminant Escherichia coli septicemia occurs with increased frequency. Newborn screening tests are widely utilized in the United States. They depend on fluorometric assay of GALT enzyme activity on a dried blood spot. A positive screening test must be confirmed by assay of GALT levels in RBC. Antenatal diagnosis is possible by assay of GALT activity in cultured amniotic fluid cells or determination of galactitol level in amniotic fluid supernatant.
Many of the clinical and morphologic changes of galactosemia can be prevented or ameliorated by removal of galactose from the diet for at least the first 2 years of life. If instituted soon after birth, this diet prevents cataracts and liver damage and permits almost normal development. Even with dietary restrictions, however, older patients frequently are affected by a speech disorder and gonadal failure (especially premature ovarian failure) and, less commonly, by an ataxic condition.
GalactosemiaisanautosomalrecessivedisordercausedbylackoftheGALTenzyme,leadingtotheaccumulationofgalactose-1-phosphateanditsmetabolitesintissues.
Clinicalfeaturesmayincludejaundice,liverdamage,cataracts,neuraldamage,vomitinganddiarrhea,andE. coli sepsis.Dietaryrestrictionofgalactosecanpreventatleastsomeofthemoreseverecomplications.
Lysosomes, the digestive system of the cells, contain a variety of hydrolytic enzymes that are involved in the breakdown of complex substrates, such as sphingolipids and mucopolysaccharides, into soluble end products. These large molecules may be derived from the turnover of intracellular organelles that enter the lysosomes by autophagy, or they may be acquired from outside the cell by phagocytosis. With an inherited lack of a lysosomal enzyme, catabolism of its substrate remains incomplete, leading to accumulation of the partially degraded insoluble metabolites within the lysosomes (
Fig. 7.8 ). This is called primary storage. Stuffed with incompletely digested macromolecules, lysosomes become large and numerous enough to interfere with normal cell functions. Because lysosomal function is also essential for autophagy, impaired autophagy gives rise to secondary storage of autophagic substrates such as polyubiquinated proteins and old and effete mitochondria. The absence of this quality-control mechanism causes accumulation of dysfunctional mitochondria, which can trigger the generation of free radicals and apoptosis.
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Approximately 60 lysosomal storage diseases have been identified. These may result from abnormalities of
Fig. 7.8 Pathogenesisoflysosomalstoragediseases.Inthisexample,acomplexsubstrateisnormallydegradedbyaseriesoflysosomalenzymesintosolubleendproducts(A,BandC).Ifthereisadeficiencyormalfunctionofoneoftheenzymes(e.g.,B),catabolismisincomplete,andinsolubleintermediatesaccumulateinthelysosomes.Inadditiontothisprimarystorage,secondarystorageandtoxiceffectsresultfromdefectiveautophagy.
lysosomal enzymes or proteins involved in substrate degradation, endosomal sorting, or lysosomal membrane integrity. Lysosomal storage disorders are divided into categories based on the biochemical nature of the substrates and the accumulated metabolites. (
Table 7.3 ). Within each group are several entities, each resulting from the deficiency of a specific enzyme.