Phosphohydroxylysinuria

A number sign (#) is used with this entry because of evidence that phosphohydroxylysinuria is caused by compound heterozygous mutation in the AGXTL2 gene (PHYKPL; 614683) on chromosome 5q35. One such patient has been reported.

Description

Phosphohydroxylysinuria is characterized by elevated phosphohydroxylysine in the urine. There is no clinical phenotype associated with this finding other than the urinary metabolites. This was confirmed by population genetic studies performed by Veiga-da-Cunha et al. (2013) (Hamosh, 2013).

Clinical Features

Dorland et al. (1990) reported 2 unrelated patients with neurologic abnormalities and an abnormal ninydrin-positive compound in the urine. The first patient was a Turkish girl, 1 of 5 children. She had a measles infection at the age of 2 and developed neurologic deterioration including seizures and ataxia at the age of 6. CSF showed anti-measles antibody, which established the diagnosis of subacute sclerotic panencephalitis. Her condition deteriorated and she died at the age of 7. The second patient was a boy who developed tonic-clonic seizures and cyanosis with a shigella infection at the age of 4 years. He had no long-term sequelae at age 17 but had not been followed up since childhood. The abnormal ninydrin-positive compound, which was persistently present in urine in both patients, was shown to be O-phosphohydroxylysine by FAB mass spectrometry and NMR spectroscopy.

Veiga-da-Cunha et al. (2013) described a previously unreported patient who had been evaluated by the same laboratory as the patients reported by Dorland et al. (1990). This patient developed a severe phenotype reminiscent of Ehlers-Danlos syndrome at the age of 4, with extreme hyperlaxity of the joints leading to immobility and limited mobility as a teenager. She had no neurologic problems but did have severe growth retardation with low final height. Cardiac evaluation was normal. She achieved normal educational milestones. Urinary phosphohydroxylysine was 5 mmol/mol creatinine in the patient and undetectable in control samples.

Population Genetics

Veiga-da-Cunha et al. (2013) reported allele frequencies of 0.007 and 0.001 for the heterozygous missense mutations E437V and G240R, respectively, found in their patient with phosphohydroxylysinuria. These frequencies suggested that phosphohydroxylysinuria should be found in at least 1/16,000 subjects in the European population. This rather high frequency agreed with the identification of 2 patients in a screening for inborn errors of metabolism performed on 8,000 subjects in the Netherlands by Duran et al. (1994).

Molecular Genetics

Veiga-da-Cunha et al. (2013) sequenced the AGXT2L2 gene in their patient with phosphohydroxylysinuria and detected compound heterozygous missense mutations at conserved residues (see 614683.0001, 614683.0002). Functional studies showed that these mutations resulted in an insoluble, nonfunctional protein. Veiga-da-Cunha et al. (2013) noted that the patients reported by Dorland et al. (1990) had neurologic problems which were likely caused by infections, whereas their patient had a different phenotype with no neurologic symptoms. They concluded that phosphohydroxylysinuria is unlikely to be the cause of the phenotype in the 3 patients and more likely to be a harmless metabolic abnormality.