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In recent years, the clinical spectrum of pyridoxine phosphate oxidase (PNPO) deficiency has broadened. There are a growing number of patients with a transient or lasting response to pyridoxine in addition to cases that respond more traditionally to pyridoxal-phosphate. However, among pyridoxine-responsive patients with PNPO gene mutation, there are only a few reports on electroencephalogram (EEG) ictal/interictal patterns, and data regarding the outcomes are inconsistent. We describe a case of neonatal onset epilepsy with missense mutation c(674G>A) p(R225 H) in PNPO gene and pyridoxine responsiveness. Comparing this patient with 24 cases of previously described pyridoxine-responsive pyridoxine phosphate oxidase deficiency epilepsy, we found that patients carrying the missense mutation c(674G>A) p(R225 H) of the PNPO gene might have a more severe epileptic phenotype, possibly because of their lower residual PNPO activity. Indeed, pyridoxine-responsive pyridoxine phosphate oxidase deficiency epilepsy remains a challenge, with neurodevelopmental disabilities occurring in about half of the cases.

Pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency is a rare autosomal recessive vitamin-responsive epileptic encephalopathy that manifests with a clinically and electrographically observable antiepileptic response to pyridoxine or pyridoxal 5′-phosphate (P5P). We report a preterm infant who presented with fetal distress and hypoxic ischemic encephalopathy (HIE) as well as seizures that responded to pyridoxine in the first day of life. The patient was diagnosed with PNPO deficiency and homozygosity for a missense-mutation in exon 7 of the PNPO gene, c.673 c > T (Arg225Cys), which disrupts the P5P binding site on PNPO. P5P with folinic acid achieved good control of the seizures. Riboflavin was introduced in the second year of life. The patient continued to have episodes of breakthrough seizures with sickness. P5P therapy resulted in marked seizure cessation but did not improve neurocognitive function in this patient, who had significant global psychomotor delay at the age of 3 years despite early treatment. We conclude from this report and other reports that HIE is a co-occurring condition with some inborn errors of metabolism. Therefore, PNPO deficiency should be investigated and P5P trial should be considered in case of presumed HIE particularly with familial recurrence of epileptic encephalopathy and refractory seizure.

Highlights • Treatment of PNPO deficiency related neonatal status epilepticus is challenging. • Pyridoxine responsiveness is seen in huge number of cases of PNPO deficiency. • Various phenotypic variants in terms of response to pyridoxine are known in PNPO disorder making the treatment complex. • Immediate complete cessation of seizures or normalization of EEG on pyridoxine or pyridoxal 5 phosphate therapy is not necessary for the diagnosis, and treatment should be continued till the genetic tests are available., Pyridox(am)ine- 5- phosphate Oxidase deficiency (PNPO) is a rare cause of neonatal metabolic encephalopathy associated with refractory status epilepticus. We report a case of a premature neonate presenting with drug-resistant seizures beginning at 2 hours of life. The baby showed initial transient response to pyridoxine followed by recurrence. Genetic report confirmed the diagnosis of PNPO deficiency. A literature review on phenotypic variants in terms of response to pyridoxine is also presented along with a proposed algorithm to manage a case of suspected vitamin responsive epilepsy. This case highlights our limited understanding of why variation in response to treatment exists in children with PNPO deficiency.

Pyridox(am)ine-5-phosphate oxidase deficiency is an autosomal recessive disorder of pyridoxine metabolism. Intractable neonatal epileptic encephalopathy is the classical presentation. Pyridoxal-5-phosphate or pyridoxine supplementation improves symptoms. We report a patient with myoclonic and tonic seizures at the age of 1 hour. Pyridoxal-5-phosphate was started on the first day of life and seizures stopped at the age of 3 days, but encephalopathy persisted for 4 weeks. She had normal neurodevelopmental outcome at the age of 12 months on pyridoxal-5-phosphate monotherapy. She had novel homozygous pathogenic frameshift mutation (c.448_451del;p.Pro150Argfs*27) in the PNPO gene. Long-lasting encephalopathy despite well-controlled clinical seizures does neither confirm nor exclude pyridox(am)ine-5-phosphate oxidase deficiency. Normal neurodevelopmental outcome of our patient emphasizes the importance of pyridoxal-5-phosphate treatment. Pyridox(am)ine-5-phosphate oxidase deficiency should be included in the differential diagnosis of Ohtahara syndrome and neonatal myoclonic encephalopathy as a treatable underlying cause. In addition, we reviewed the literature for pyridox(am)ine-5-phosphate oxidase deficiency and summarized herein all confirmed cases.

Inborn defects of cholesterol biosynthesis are metabolic disorders presenting with multi-organ and tissues anomalies. Recently, a new autosomal recessive defect in 4 patients involving the demethylating enzyme C4-methylsterols (SC4MOL) has been described. In infancy, all showed congenital cataracts, growth delay, microcephaly,psoriasiform dermatitis, immune dysfunction, and intellectual disability (1). Here, we describe a new case of SC4MOL deficiency, showing bilateral congenital cataracts, psychomotor and development delay and learning disabilities in the early life. At 15 years, he showed small stature and behavioral disorder. His skin never demonstrated a marked psoriasiform rash, but only abundant dandruff of scalp. Despite numerous biochemical and genetic examinations, the diagnosis was missed until 19 years. Based on clinical evidences, such as congenital cataracts and developmental delay, a cholesterol biosynthesis defect was suspected. Blood C4-monomethyland C4-dimethylsterols levels, analyzed by gas-chromatography and mass spectrometry, were significantly higher than controls, suggesting a deficiency of SC4MOL. Sequencing analysis of SC4MOL gene showed mutations in both alleles (1st variant: c.731A>G, p.Y244C, already known; 2nd one: c.605G>A, p.G202E, new variant). Both mutations were absent in both EXAC database and healthy controls. His parents were found heterozygous. Finally, integrating clinical, metabolic, and genetic tests, we diagnosed the SC4MOL deficiency definitively. Notably, the interactions of multifield skills are fruitful to diagnose a new defect of cholesterol biosynthesis. Therefore, we suggest that plasma sterol profile should be taken early into account for all undiagnosed patients showing clinical signs overlapping that of patient presented here. (Reference: 1. He et al., 2014, BBA 1841:331).

1. The aim of the present study was to explore the effect of dietary sulphite supplementation on vascular responsiveness in sulphite oxidase (SO)-deficient rats. 2. Male albino rats were divided into four groups, namely control (n = 8), sulphite-treated (n = 8), SO-deficient (n = 8) and sulphite-treated SO-deficient (n = 8) groups. Sulphite oxidase deficiency was induced by administration of a low-molybdenum diet with concurrent addition of 200 p.p.m. tungsten in the form of sodium tungstate in the drinking water for 9 weeks. Sulphite, in the form of sodium metabisulphite (Na2O5S2; 25 mg/kg) was given in the drinking water to sulphite-treated and sulphite-treated SO-deficient groups for the last 6 weeks. The vascular responsiveness of isolated aortic rings to acetylcholine (ACh), sodium nitroprusside (SNP) and histamine was investigated in organ baths. 3. The responsiveness of aortic rings to SNP and histamine did not differ significantly between groups. Conversely, there was a significant decrease in ACh-induced relaxation in aortic rings from the sulphite-treated SO-deficient group compared with the control group (pD(2) 6.2 +/- 0.3 and 7.5 +/- 0.1, respectively; P < 0.05). Incubation of aortic rings in the presence of either L-arginine or superoxide dismutase significantly improved the ACh-induced vasorelaxation in sulphite-treated SO-deficient group (pD(2) 7.2 +/- 0.3 and 7.4 +/- 0.3, respectively). 4. The findings of the present study suggest that the increased production of reactive oxygen species and the resultant increment in L-arginine/nitric oxideconsumption may play a role in the reduced endothelium-dependent vasorelaxation in sulphite-treated SO-deficient rats.

We report a rare case of straight-chain acyl-CoA oxidase deficiency (McKusick 264470) presenting with dysmorphism, neurodevelopmental regression and leukodystrophy.

We studied the physiologic adaptation of patients with mitochondrial myopathies to aerobic training. Ten patients underwent individually supervised, moderate-intensity aerobic training on a treadmill for 8 weeks. Biochemical and functional measures improved with training. Estimated aerobic capacity increased by 30%. Blood lactate concentrations at rest and after exercise decreased by 30%. Muscle phosphorus magnetic resonance spectroscopy measurements of adenosine diphosphate recovery after exercise improved by more than 60%. Fatigue and tolerance to daily activities also improved. Although the improvement in exercise tolerance may be due in part to reversal of the effects of secondary deconditioning, this uncontrolled clinical trial suggests that aerobic training can benefit patients with mitochondrial myopathies.

Le deficit en cytochrome c oxydase est une anomalie rare du systeme de transport mitochondrial. Rappel de 4 cas dans la litterature pour lesquels le deficit est localise aux muscles du squelette. Dans l'article on decrit 2 cas ou le deficit est mis en evidence a la fois sur la biopsie de muscles du squelette, mais aussi au niveau du cerveau et sur culture de fibroblastes cutanes. Cette etude illustre un defaut genetique en cytochrome c oxydase et suggere que ce defaut est une cause d'encephalomyelopathie de Leigh

A sural nerve obtained three hours after death from a patient with hypertyrosinemia due to 4-hydroxyphenylpyruvic acid oxidase deficiency was examined. The diameter of the myelinated fibers, as seen on the histogram, was similar to those in an age matched control. However, the number of smaller fibers was greater. Electron-microscopically, the findings of de- and hypomyelination were noted, and occasional dense bodies and multimembranous bodies were seen in some axoplasms. Since his mother was also suffering from hypertyrosinemia, the serum tyrosine level during the fetal and newborn infant periods seemed to be constantly elevated, which may have caused the abnormalities of nerve fibers observed in the present case.