The low incidence of this syndrome is often related to aldolase A's essential glycolytic role along with its exclusive expression in blood and skeletal muscle. Early developmental reliance and constitutive function prevents severe mutation in successful embryos. Infrequent documentation thus prevents clear generalisation of symptoms and causes. However five cases have been well described. ALDOA deficiency is diagnosed through reduced aldoA enzymatic activity, however, both physiological response and fundamental causes vary. Ethnicity Mutation Consanguinity Primary Symptoms Canadian Jewish Unknown Yes Dysmorphic features, Hemolytic anemia, Elevated liver glycogen, Stunted growth and development Japanese Unknown Probable Hemolytic anemia, Neonatal hyperbilirubinemia, Hepatomegaly, Splenomegaly Japanese 386 A:G (Asp128Gly) Probable Hemolytic anemia, Hepatomegaly, Splenomegaly German 619 G:A (Glu206Lys) No Hemolytic anemia, Rhabdomyolysis, Hyperbilirubinemia, Stunted growth and development Sicilian 931 C:T (Arg303X),1037 G:A (Cys 338Tyr) No Hemolytic anemia, Pyropoikilocytosis, Hyperkalemia, Jaundice, Rhabdomyolysis, Frequent infection Anemia Blood-related pathology is seen in all patients. Typically diagnosed at birth, congenital nonspherocytic hemolytic anemia is characterised by premature destruction of red blood cells without apparent abnormality in shape. Erythrocyte dependency on anaerobic glycolysis for ATP homeostasis, causes perturbation of this pathway to result in disruption of cellular processes including electrostatic membrane gradients (typically maintained through transporters of high energetic demand) ultimately leading to membrane instability and lysis. Pathway summary: heme degradation to bilirubin This shortened erythrocyte life-span and increased destruction links to hyperbilirubinemia which often presents as jaundice in the accumulation of bilirubin through excessive hemoglobin breakdown. Another side effect of cellular rupture both in the form of hemolysis and rabdomyolysis is excessive plasma concentrations of electrolytes such as potassium. This can lead to hyperkalemia, potentially of great cardiac concern. Glycolysis also produces 2,3-diphosphoglycerate required to modulate hemoglobin's affinity for oxygen (2,3-Bisphosphoglycerate synthesis). Thus dysregulation of glycolysis is also implicated in the functional distribution of oxygen possibly leading to organ hypoxia. A complex pattern for this metabolite is suggested with discrepancy in findings. One Japanese patient had elevated levels, while the original Jewish Canadian boy had below average concentration. Glucose metabolism also links intrinsically to the pentose phosphate pathway in the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) necessary for synthetic processes and reduced glutathione involved in protecting red cells against oxidant damage. In particular increased fructose-1,6-bisphosphate accumulation can have inhibitory effects on glucose-6-phosphate dehydrogenase, an essential enzyme of this pathway. Lactate accumulation has also been noted in some patients, potentially linked to reciprocal stimulation of pyruvate kinase, a key enzyme in lactic acid fermentation. Myopathy In non-contiguous patients an aggravated form of adolase-a deficiency has been seen to manifest in muscular deterioration. This is often recognized initially through signs of muscle weakness and exercise intolerance, suggesting rapid muscular fatigue and damage, likely directly related to ATP depletion. This breakdown of muscular fibers or, rhabdomyolysis, can lead to detectable blood creatine phosphate level elevation and potentially exaggerated hyperkalemia. Other Delayed growth and development was noted in some patients, although not fully explained, this may be generally associated with the physiological difficulties implicit in errors of energy metabolism. In particular neurological impairment was conjecturally linked with the predominant role of aldolase A in the brain during development. However, this was not substantiated with direct enzymatic kinetic study. Elevated liver glycogen in one patent was rationalised through an accumulation of fructose-1,6-bisphosphate leading to impaired glucose metabolism and increased diversion of hexose sugars from peripheral tissues. Within the liver the aldolase C isoform is unaffected and therefore hepatic metabolism is assumed to be normally functioning and compensatory processes may be operating. Compromised immunity has also been indicated, relating to the predominance or exclusivity of aldolase A in leukocytes. This was correlated with recurrent infection in the Sicilian case. Focal disruption of vital energy metabolism has thus far prevented complete investigation of non-catalytic perturbation. However relation to membrane structural stability has been implicated in the concurrence of<unk>  and dominant (mild) hereditary elliptocytosis, speculatively also relating to ATP depletion.
Aldolase A deficiency
Transaldolase deficiency
Enolase deficiency
Ornithine aminotransferase deficiency
Glutaminase deficiency
Pyruvate kinase deficiency
D-glycerate dehydrogenase deficiency
3-Hydroxyisobutyryl-CoA deacylase deficiency