Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient.

Lesch-Nyhan (LN) disease is a severe X-linked recessive neurological disorder associated with a loss of hypoxanthine guanine phosphoribosyltransferase activity (HPRT, EC 2.4.2.8). We have studied the second example of a female patient with LN disease. The molecular basis of HPRT deficiency in this patient was a previously undescribed nucleotide substitution in exon 6. In this gene, designated HPRT PARIS, a single nucleotide substitution from T to G at base position 558 changed a tyrosine (TAT) to a codon STOP (TAG) (Y153X). Analysis of the mother revealed a normal sequence of the HPRT cDNA and demonstrated that this mutation arose through a de novo gametic event. Allele-specific amplification of exon 6 from the patient's genomic DNA confirmed the single base substitution and showed that the patient was heterozygous for this mutation. Investigation of X-chromosomal inactivation by comparison of methylation patterns of patient's DNA isolated from fibroblasts, T lymphocytes, and polymorphonuclear cells digested with PstI and BstXI, with or without HpaII, and hybridized with M27 beta probe indicated a nonrandom pattern of X-chromosomal inactivation in which there was preferential inactivation of the maternal allele. The data indicate that nonrandom X-inactivation leading to selective inactivation of the maternal gene and a de novo point mutation in the paternal gene were responsible for the lack of HPRT activity in this patient.

A new patient with alpha-ketoglutaric aciduria and progressive extrapyramidal tract disease.

A 4.5-year-old boy with chronic progressive encephalopathy is described. The clinical presentation initially included seizures and hypotonia which later evolved into severe extrapyramidal disease and dementia. The gas chromatography/mass spectrometry (GC/MS) analysis of urine indicated that alpha-ketoglutarate was increased 210 times and aconitic acid 80 times. No disturbance of acid/base balance, lactic acid or ammonia metabolism accompanied this clinical picture. The fibroblasts contained 29% of normal alpha-ketoglutarate dehydrogenase activity, while the activity of another mitochondrial marker enzyme, glutamate dehydrogenase, was normal. The neuroimaging studies revealed bilateral striatal necrosis. The clinical and biochemical findings were almost identical to two previously reported patients. Experience with this patient emphasizes the need for detailed organic acid biochemical investigation in any progressive encephalopathy and that extrapyramidal tract signs should evoke the possibility of alpha-ketoglutaric aciduria, among other 'neurologic organic acidemias'.

Unusual presentations of propionic acidemia.

The files of 25 patients with propionic acidemia (PA), followed by the Inborn Errors of Metabolism Service (IEMS) at King Faisal Specialist Hospital and Research Centre (KFSH & RC) from 1990 to 1993, were studied retrospectively. In 14 patients PA presented acutely with acidosis, hyperammonemia and thrombocytopenia, while in 11 patients the presentation of the disease was unusual. In the latter group, two neonates with PA initially appeared as a primarily hyperammonemic metabolic disease. In two other neonates the vomiting was so severe that they were diagnosed as intestinal obstruction in referral hospitals. The presentation in three infants was primarily as an immune disorder. In four infants, PA appeared as an acute or chronic encephalopathy, i.e. as a silent organic acidemia, with few other findings of the disease. The clinical picture of PA includes facial and nipple dysmorphia, severe hypotonia and vomiting. Severe thrombocytopenia is the hallmark of the metabolic crisis. In one patient it was noticed late and caused intracranial hemorrhage, while in three others intracranial bleeding caused death. The prognosis in PA remained grave despite rigorous treatment. Only seven of the 25 PA patients remained to have a normal life-style, while eight patients expired. The diagnosis is readily achieved by urine gas chromatography/mass spectrometry (GC/MS), by tandem mass spectrometry (MS/MS), or by enzyme analysis of fibroblasts. While there may be both examiner- and patient-related reasons for the variations in the presentation of PA, one other reason may be the heterogeneity of the molecular defect in propionyl-CoA carboxylase.

4-Hydroxybutyric aciduria.

The clinical findings in six patients from three families with 4-hydroxybutyric aciduria are described. The onset of disease was in early infancy in all cases. All infants presented with severe global delay and severe hypotonia, and all patients had seizure disorder. Eye findings included optic atrophy in two patients, and retinitis pigmentosa in one. Three patients had choreoathetosis, two had myoclonus and one had severe dystonia. The urine 4-hydroxybutyric acid was 300-1000 times that of normal, and other organic acids related to its further metabolism or to its inhibitory effect on beta-oxidation were also increased. The administration of vigabatrine rapidly reduced the excretion of 4-hydroxybutyric acid promptly, and in the long-term its excretion could be kept at 80-200 times that of normal. However, the clinical course of the disease improved in only two, remained the same in two, and worsened in the remaining two patients.

Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism.

The Institution's experience with hypoglycemia in different types of organic acidemias, branched chain amino acidemia (MSUD), and disorders of fructose metabolism was reviewed retrospectively. The charts of 144 patients who were followed for 1-5 years were studied for the severity and frequency of hypoglycemia. The patients were mainly Saudi; however, 10-25% were from neighboring countries. Therefore, the observations pertain to the genetic groups in the Arabian peninsula. Organic acidemias which primarily manifest with neurologic signs, such as 4-hydroxybutyric aciduria, infantile onset 3-methylglutaconic aciduria, and glutaric aciduria type 1 never showed hypoglycemia. Patients with beta-ketothiolase deficiency, biotinidase deficiency, or intermittent or intermediate MSUD, also did not have hypoglycemia during metabolic crisis. Hypoglycemia was rare and mild among neonates with classic MSUD, ethylmalonic aciduria, and isovaleric acidemia. Less than 50% of the patients with MSUD older than 8 months, pyruvate carboxylase deficiency, methylmalonic acidemia, or propionic acidemia had hypoglycemia during metabolic crisis. On the other hand, patients with 3-hydroxy-3-methyl glutaryl-CoA lyase deficiency, holocarboxylase synthetase deficiency, medium or long-chain acyl-CoA dehydrogenase deficiency, neonatal onset 3-methylglutaconic aciduria, glutaric aciduria type 2, and disorders of fructose metabolism invariably had moderate-to-severe hypoglycemia associated with metabolic crisis. The purpose of this report is to provide the pediatrician, particularly in the Middle East, with a diagnostic guideline to the identification and management of different types of organic acidemias, based on co-existing hypoglycemia.

Glutaric aciduria yype 1: First reported cases in three Saudi patients.

The clinical and biochemical findings in three patients with glutaric aciduri Type 1 (GAT1) are presented. They had a normal postnatal period of three to 14 months. They developed sudden and severe encephalopathy following an infection or trauma (patient 3) that gradually progressed to severe dystonia, choreathetosis, spastic quadriplegia and mental retardation. Neuroradiologic studies of the brain revealed while matter disease and frontotemporal lobe hypoplasia. The urine findings by gas chromatography/mass spectrometry (GC)/(MS) were characteristic of GAT1. Since GAT1 is an organic acidemia without intermittent acidotic attacks, but primarily manifests with progressive encephalopathy, it is important to recognize the potential of its existence among handicapped children in chronic care facilities. The good clinical response in two of the patients urges early diagnosis in subsequent newborn siblings of the families with the disease. The diagnosis of three patients in less than two years indicate the need for neonatal screening for the recognition of this disease, among other treatable metabolic diseases, in Saudi Arabia.