Alternative titles; symbols
SNOMEDCT: 724576005; ORPHA: 79096; DO: 0111329;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.32 | Pyridoxamine 5'-phosphate oxidase deficiency | 610090 | Autosomal recessive | 3 | PNPO | 603287 |
A number sign (#) is used with this entry because of evidence that pyridoxamine 5-prime-phosphate oxidase deficiency (PNPOD) is caused by homozygous or compound heterozygous mutation in the PNPO gene (603287) on chromosome 17q21.
PNPOD is an autosomal recessive inborn error of metabolism resulting in vitamin B6 deficiency that manifests as neonatal-onset severe seizures and subsequent encephalopathy. Patients with PNPO mutations tend to respond better to treatment with pyridoxal 5-prime phosphate (PLP) than with pyridoxine (summary by Plecko et al., 2014).
Brautigam et al. (2002) described twins, born of first-cousin parents, who were born at 29 weeks' gestation and suffered from birth from severe convulsions, myoclonus, rotatory eye movements, sudden clonic contractions, burst suppression electroencephalogram (EEG), hypoglycemia, and acidosis. The patients showed an improvement of the clonic contractions with vitamin B6 supplementation, but died in the third week of life. Biochemical analysis of cerebrospinal fluid and urine suggested aromatic L-amino acid decarboxylase (AADC) deficiency (608643), but molecular analysis excluded genetic defect in the AADC gene (107930). Brautigam et al. (2002) suggested that the epileptic encephalopathy in the twins was in the pathway of vitamin B6 metabolism.
Clayton et al. (2003) presented a boy born at 35 weeks' gestation by cesarean section for fetal distress. His consanguineous parents were of East African Asian origin. Seizures commenced on day 1 and rapidly progressed to status epilepticus. Electroencephalogram showed severe generalized burst suppression. Biochemistry was suggestive of reduced AADC activity; seizures responded dramatically to pyridoxal phosphate (PLP).
In a study of 5 patients, including those of Brautigam et al. (2002) and Clayton et al. (2003), with PNPO deficiency, Mills et al. (2005) reviewed the phenotype. All patients were born prematurely and all but one had low Apgar scores and/or required intubation. Early acidosis was also common. Thus, PNPO deficiency must enter the differential diagnosis of hypoxic-ischemic encephalopathy in a prematurely born infant. Seizures commenced on the first day of life, with EEG showing a burst suppression pattern. Biochemical abnormalities in CSF and urine were as for AADC deficiency with the additional features of raised glycine (in all 5), threonine (4 of 5), taurine (4 of 5), histidine (all 5), and low arginine (3 of 5).
Ruiz et al. (2008) reported a male infant with PNPO deficiency. The mother reported repetitive fetal rhythmic movements 2 weeks before delivery, thought to be related to seizures. At birth he had a faltering cry, hypersalivation with orobuccal rhythmic movements accompanied by myoclonus and marked hyperexcitability requiring intubation and ventilation. EEG showed severe myoclonic epilepsy. Brain imaging at 23, 25, and 35 days showed progressive hypomyelination and global atrophy. Laboratory studies showed anemia, leukopenia, thrombocytopenia, and coagulopathy. Analysis of urinary organic acids, plasma amino acids, and CSF neurotransmitters suggested PNPO deficiency. He died of multiorgan failure due to uncontrollable fungal infection at 48 days of life. Genetic analysis identified a homozygous mutation in the PNPO gene (603287.0004). Prenatal diagnosis using chorionic villus sampling in a subsequent pregnancy identified the same homozygous mutation in the fetus.
Plecko et al. (2014) reported 11 children from 7 families with PNPOD, confirmed by genetic analysis, who had a complete or partial response to pyridoxine treatment. All patients presented in the neonatal period with recurrent myoclonic and tonic jerks accompanied by rolling eye movements and desaturation. EEG showed burst-suppression patterns and/or discontinuous tracings. Ten of 11 patients had pyridoxine administration in the first week of life, and 1 had pyridoxine treatment at age 6 weeks. Pyridoxine led to prompt cessation of seizures in 4 patients, delayed seizure reduction in 2, initial EEG improvement only in 2, and no effect in 2, although 1 of these last patients had remission after subsequent treatment with pyridoxine. Two patients developed status epilepticus after pyridoxine was replaced with PLP. Breakthrough seizures while on pyridoxine were observed in 5 of 9 living patients. Five patients had a favorable overall outcome, 2 had global developmental delay, 2 had severe neurologic sequelae, and 2 died in the absence of continuous pyridoxine treatment.
Ware et al. (2014) reported 2 unrelated boys with PNPOD. Both developed multifocal myoclonic seizures on the first day of life. One of the boys showed hemiclonic seizures, hypertonia, mild encephalopathy, and high-pitched cry until pyridoxine therapy was added on day 7 of life. Breakthrough seizures occurred whenever pyridoxine doses were missed. At age 4 years, the patient had autism spectrum disorder. EEG showed centrotemporal spikes with rare generalized spike-wave bursts. Sequencing of the ALDH7A1 gene was normal, and a trial of monotherapy with pyridoxal 5-prime phosphate (PLP) was commenced, but seizures recurred. After a pathogenic mutation in the PNPO gene was found, the patient had combination therapy with both pyridoxine and PLP, with subsequent reduction of the pyridoxine. At age 7, the patient took only PLP and experienced no significant additional seizures. The second patient had a good initial and subsequent response to monotherapy with high-dose PLP beginning in infancy. At age 21 months, he had moderate global developmental delay and hemiparesis. The report indicated that some patients with PNPOD can respond to pyridoxine treatment.
The transmission pattern of PNPOD in the families reported by Plecko et al. (2014) was consistent with autosomal recessive inheritance.
Among 5 patients in 3 families with neonatal epileptic encephalopathy, Mills et al. (2005) found evidence in cerebrospinal fluid and urine for reduced activity of aromatic L-amino acid decarboxylase (AADC; 107930) and other PLP-dependent enzymes. Seizures ceased with the administration of PLP, having been resistant to treatment with pyridoxine, suggesting a defect of pyridox(am)ine 5-prime-phosphate oxidase (PNPO; 603287). Sequencing of the PNPO gene identified homozygous missense, splice site, and stop codon mutations. Expression studies in Chinese hamster ovary cells showed that the splice site (IVS3-1G-A; 603287.0002) and stop codon (X262Q; 603287.0003) mutations were null activity mutations and that the missense mutation (R229W; 603287.0001) markedly reduced pyridox(am)ine phosphate oxidase activity. The authors suggested that maintenance of optimal PLP levels in the brain may be important in many neurologic disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon). Only one infant, treated with PLP, survived the newborn period, but exhibited seizures, dystonic spasms, microcephaly, and severe developmental delay at 2 years of age.
In 11 patients from 7 unrelated families with PNPOD, Plecko et al. (2014) identified 3 different biallelic mutations in the PNPO gene; 6 of the families carried the same homozygous missense mutation (R225H; 603287.0005). In vitro functional expression studies in CHO cells showed that the R225H mutant protein had no detectable enzyme activity. Most of the patients had a partial or even complete response to pyridoxine treatment. The 6 families derived from the former Yugoslavia.
In 2 unrelated boys with PNPOD, Ware et al. (2014) identified 2 different homozygous missense mutations in the PNPO gene (603287.0005 and 603287.0006). Functional studies of the variants were not performed.
Brautigam, C., Hyland, K., Wevers, R., Sharma, R., Wagner, L., Stock, G.-J., Heitmann, F., Hoffmann, G. F. Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic L-amino acid decarboxylase deficiency. Neuropediatrics 33: 113-117, 2002. [PubMed: 12200739] [Full Text: https://doi.org/10.1055/s-2002-33673]
Clayton, P. T., Surtees, R. A. H., DeVile, C., Hyland, K., Heales, S. J. R. Neonatal epileptic encephalopathy. Lancet 361: 1614 only, 2003. [PubMed: 12747882] [Full Text: https://doi.org/10.1016/s0140-6736(03)13312-0]
Mills, P. B., Surtees, R. A. H., Champion, M. P., Beesley, C. E., Dalton, N., Scambler, P. J., Heales, S. J. R., Briddon, A., Scheimberg, I., Hoffmann, G. F., Zschocke, J., Clayton, P. T. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5-prime-phosphate oxidase. Hum. Molec. Genet. 14: 1077-1086, 2005. [PubMed: 15772097] [Full Text: https://doi.org/10.1093/hmg/ddi120]
Plecko, B., Paul, K., Mills, P., Clayton, P., Paschke, E., Maier, O., Hasselmann, O., Schmiedel, G., Kanz, S., Connolly, M., Wolf, N., Struys, E., Stockler, S., Abela, L., Hofer, D. Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology 82: 1425-1433, 2014. [PubMed: 24658933] [Full Text: https://doi.org/10.1212/WNL.0000000000000344]
Ruiz, A., Garcia-Villoria, J., Ormazabal, A., Zschocke, J., Fiol, M., Navarro-Sastre, A., Artuch, R., Vilaseca, M. A., Ribes, A. A new fatal case of pyridox(am)ine 5-prime-phosphate oxidase (PNPO) deficiency. Molec. Genet. Metab. 93: 216-218, 2008. [PubMed: 18024216] [Full Text: https://doi.org/10.1016/j.ymgme.2007.10.003]
Ware, T. L., Earl, J., Salomons, G. S., Struys, E. A., Peters, H. L., Howell, K. B., Pitt, J. J., Freeman, J. L. Typical and atypical phenotypes of PNPO deficiency with elevated CSF and plasma pyridoxamine on treatment. Dev. Med. Child Neurol. 56: 498-502, 2014. [PubMed: 24266778] [Full Text: https://doi.org/10.1111/dmcn.12346]