The enzyme deficiencies of α-aminoadipic
semialdehyde dehydrogenase and the saccharopine dehydrogenases have been
associated with increased serum levels of l-lysine. The clinical
presentation is very variable and may include developmental delay,
hypotonia, lethargy recurrent emesis, and diarrhea.
Alpha-Aminoadipic Semialdehyde Synthase Deficiency;
Lysine Intolerance; Lysine:Alpha-Ketoglutarate Reductase Deficiency; l-Lysine:NAD-Oxido-Reductase Deficiency.
Inherited in a autosomal recessive way.
Parental consanguinity has been reported in some cases and is considered a
risk factor. The defect has been related to a mutation in the α-aminoadipic semialdehyde synthase (AASS) gene, which maps to gene locus
The enzyme AASS has both lysine ketoglutarate
reductase and saccharopine dehydrogenase activity and therefore is
bifunctional. It is involved in the first two steps of the lysine
degradation pathway in humans. Lysine-ketoglutarate reductase catalyzes the
metabolism of l-lysine to saccharopine, which is cleaved to α-aminoadipic semialdehyde and glutamic acid by saccharopine dehydrogenase.
A defect either in one or both of these enzymes results in familial
hyperlysinemia, lysinuria, and saccharopinuria of variable degree. An
alternative metabolism, the so-called “pipecolic acid pathway,” functions
only as an overflow pathway and is not suited to handle the relatively large
amounts of l-lysine from oral intake.
Most often, the disease is diagnosed by a general
screening for metabolic disease initiated by clinical signs. The enzyme AASS
is present in almost all body cells, with the highest concentration found in
the liver. However, skin fibroblast can be used to perform the standard test
(incubation of the fibroblast with radioactive/labeled l-lysine and
measurement of the carbon dioxide production) and confirm the diagnosis. In
most cases, the enzyme activity is less than 10% of normal.
Clinical manifestation is highly variable. The
descriptions range from symptom-free to severe developmental delay, spastic
diplegia, seizures, rigidity, coma, episodic vomiting, and diarrhea. In one
case, coma and hyperammonia resolved with a low-protein diet. However, it
now seems that hyperlysinemia is not associated with an ill effect in the
majority of cases. A special diet seems not indicated, but some physicians
prefer to limit protein intake in their patients.
Evaluate antiseizure medication,
frequency of emesis, and diarrhea. Electrolyte and volume status should be
watched carefully in the presence of vomiting and diarrhea. Patients with
mental retardation may benefit from sedative and anxiolytic premedication
and/or presence of the primary caregiver during induction of anesthesia.
With a history of vomiting,
rapid-sequence induction and endotracheal intubation are recommended. Check
blood gases and electrolytes at least once intraoperatively (or better
preoperatively) in association with recent or ongoing vomiting/diarrhea.
Patients on chronic antiseizure
medication may show altered hepatic drug metabolism.
Hyperlysinemia can also be
found in the following disorders:
Pyruvate Carboxylase Deficiency: Mitochondrial disease impairing
synthetic pathways and leading to hypoglycemia and severe lactic acidosis.
D-2-Hydroxyglutaric Aciduria: Metabolic disease resulting ...