Lysinuric Protein Intolerance

Lysinuric protein intolerance (LPI) is an autosomal recessive disorder of cationic amino acid transport due to biallelic variants in SLC7A7, with protein aversion, hyperammonaemia after protein meals, failure to thrive, hepatosplenomegaly, osteoporosis, and in some, pulmonary alveolar proteinosis and kidney disease. It is common in Finland and in southern Italy and Japan through founder variants.

Pathophysiology. SLC7A7 encodes y+LAT1, the basolateral transporter of lysine, arginine and ornithine in the intestine and renal tubule. Loss causes loss of these amino acids in urine and poor absorption, which depletes urea cycle intermediates and causes hyperammonaemia.

Macrophage dysfunction explains the immune and pulmonary complications.

Symptoms appear at weaning when protein intake rises.

• Normal growth during breast feeding, with vomiting, diarrhoea and failure to thrive after weaning
• Spontaneous protein aversion
• Hyperammonaemia with lethargy, vomiting and coma after protein loads
• Hepatosplenomegaly
• Short stature, sparse hair and osteoporosis with fractures
• Muscle hypotonia and weakness
• Pulmonary alveolar proteinosis, interstitial lung disease and respiratory failure
• Glomerular and tubular kidney disease
• Autoimmune and immune dysregulation: haemophagocytic lymphohistiocytosis, lupus like disease
• Hypertriglyceridaemia and anaemia
• Developmental delay, usually mild

• Plasma and urine amino acids: raised urinary lysine, arginine and ornithine, with low or normal plasma lysine, arginine and ornithine.
• Plasma ammonia (raised after protein), and urinary orotic acid (raised).
• SLC7A7 sequencing with deletion and duplication analysis.
• Ferritin, lactate dehydrogenase, triglycerides and blood count in patients with immune disease.
• Chest imaging and lung function for alveolar proteinosis.
• Renal assessment: urinalysis, protein excretion and creatinine.
• Bone density scan.

Differential diagnosis.

• Urea cycle disorders (ornithine transcarbamylase deficiency, citrullinaemia, argininosuccinic aciduria)
• Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome
• Cystinuria (the dibasic aminoaciduria of cystinuria lacks hyperammonaemia)
• Coeliac disease and other causes of failure to thrive

• Diet: protein restriction to 0.5 to 1.5 g/kg daily (adults about 0.5 to 0.8 g/kg) with adequate energy, spread across the day, and avoidance of large protein loads.
• Citrulline supplementation: citrulline 100 mg/kg daily in 2 to 3 divided doses (adults 3 to 8 g daily), which replenishes urea cycle intermediates and reduces ammonia, adjusted to ammonia and orotic acid levels. Avoid doses that cause gastrointestinal upset.
• Carnitine: levocarnitine 50 mg/kg daily if plasma free carnitine is low.
• Acute hyperammonaemia: stop protein, give 10% glucose intravenously with insulin as needed to prevent catabolism, and add sodium benzoate 250 mg/kg and sodium phenylbutyrate 250 mg/kg intravenously over 90 to 120 minutes as a loading dose followed by 250 mg/kg daily of each by infusion. Use haemodialysis for ammonia over 500 micromol/L or neurological deterioration.
• Pulmonary alveolar proteinosis: whole lung lavage for symptomatic disease, with systemic corticosteroids for interstitial lung disease (prednisolone 0.5 to 1 mg/kg daily).
• Bone health: vitamin D 400 to 800 international units daily in children (1000 to 2000 international units in adults), calcium by diet, and bisphosphonate treatment under specialist care in fractures.
• Kidney disease: ACE inhibitors for proteinuria, with enalapril 0.1 mg/kg daily increasing to 0.5 mg/kg daily (adults 5 mg daily increasing to 20 mg daily).
• Growth: growth hormone 0.033 mg/kg daily (specialist, limited evidence) in selected children.
• Pregnancy: specialist obstetric and metabolic care, because of risks of anaemia, haemorrhage and hyperammonaemia.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with carrier testing in populations with founder variants.

Special groups.

• Illness and surgery: provide an emergency letter with a dextrose and ammonia plan, and avoid prolonged fasting.

Monitoring. Ammonia, orotic acid, amino acids and growth every 3 months in childhood. Lung function, chest imaging, bone density and kidney function yearly.

Referral and escalation. Refer to clinical genetics, metabolic medicine, respiratory medicine and nephrology. Emergency for hyperammonaemic coma, respiratory failure or haemophagocytic lymphohistiocytosis.