Aldolase A deficiency

December 31, 2014

Synonyms

Overview

Aldolase A deficiency is an autosomal recessive metabolic disorder resulting in a deficiency of the enzyme aldolase A, which is found predominantly in muscle and red blood cells. It may lead to myopathy, exercise intolerance and rhabdomyolysis associated with hemolytic anaemia.

Symptoms

Convulsions
Excessive sleepiness
Irritability
Poor feeding as a baby
Problems after eating fruits and fructose/sucrose-containing foods
Vomiting
Myopathy
Exercise intolerance
Rhabdomyolysis
Hemolytic anemia
Premature muscle fatigue
Muscle weakness
Jaundice
Reduced muscle mass
Reduced muscle tone
Enlarged liver
Enlarged spleen

Causes

Characterised as a recessive disorder, symptomatic presentation requires the inheritance of aldolase A mutations from both parents. This conclusion is substantiated through the continuum type presentation witnessed, wherein heterozygous parents have intermediate enzyme activity. Structural instability has been indicated in four of the patients, with particular sensitivity to increased temperature according to direct enzymatic testing. This is exemplified in the early diagnosis of hereditary pyropoikilocytosis in the Sicilian girl. Deterioration with fever is likewise congruent. However, this direct relation has been disputed due to the increased overall metabolism and oxygen consumption also accompanying such maladies.

Sequence analysis has been conducted for three of the patients each revealing a distinct alteration at regions of typically high conservation. The conversion of the 128th aspartic acid to glycine causes conformational change according to CD spectral analysis and thermal lability in mutagenic analysis. Similarly the charge disruption created through the exchange of the negatively charged glutamic acid for positively charged lysine (at residue 209 of the E helix) disrupts interface interaction of the protein's subunits and therein destabilises its native tetrahedral configuration. The final case is unique in its non-homozygosity. A comparable maternal missense mutation wherein tyrosine is replaced by cysteine alters the carboxy-terminus due to its proximity to a crucial hinge structure. However, the paternal nonsense mutation at arginine 303 truncates the peptide. It is notable that Arg303 is required for enzymatic activity.

The initial 1973 case is atypical, in that no indication of aldolase A structural abnormality was found in isoelectric focusing, heat stabilization, electrophoresis or enzyme kinetics. It was concluded that either disordered regulation or a basic defect creating more rapid tetrameric inactivation were the most probable causes.

Diagnosis

Diagnosis is suggested clinically and supported by elevated galactose levels and the presence of reducing substances other than glucose (eg, galactose, galactose 1-phosphate) in the urine; it is confirmed by enzyme analysis of RBCs, hepatic tissue, or both.

Prognosis

Hereditary fructose intolerance may be relatively mild or a very severe disease. Complete avoidance of fructose and sucrose produces good results in most children with this condition. A few children will go on to develop severe liver disease. In the severe form, even eliminating fructose and sucrose from the diet may not prevent severe liver disease.

Treatment

Treatment is elimination of all sources of galactose in the diet, most notably lactose, which is a source of galactose present in all dairy products, including milk-based infant formulas and a sweetener used in many foods. A lactose-free diet prevents acute toxicity and reverses some manifestations but may not prevent neurocognitive deficits