Familial Hyperlysinemia

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.

Extremely rare.

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 7q31.3.

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 in abnormal MRI findings and psychomotor retardation, hypotonia, and nonneurologic signs.

L-2-Hydroxyglutaric Aciduria: Inborn error of metabolism manifesting as progressive neurodegenerative disorder with psychomotor retardation.

Propionic Acidemia: Inborn error of metabolism affecting the mitochondrial catabolism of valine and isoleucine. Left untreated it results in ketoacidosis, lethargy, coma, and eventually death.