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Biomedical subjects

A A M Morris

Publications and source records attributed to A A M Morris.

15 recordsLinked to original sources
PubMed2006

Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy.

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis. We report a patient who presented at 10 months of age with hypotonia and global developmental delay. Subsequently, she developed seizures and choreoathetosis. Magnetic resonance imaging showed high signal bilaterally in the globus pallidus on T2-weighted images. Mitochondrial respiratory chain studies revealed low complex I activity (in muscle 0.052 nmol NADH oxidized per min per unit citrate synthase, controls 0.166 +/- 0.047; in fibroblasts 0.080 nmol NADH oxidized per min per unit citrate synthase, controls 0.197 +/- 0.034). The true diagnosis was suspected at 21 months of age because of persistent low plasma and urine creatinine concentrations. GAMT activity was undetectable in fibroblasts and compound heterozygous mutations were found in the GAMT gene (c.327G>A and c.522G>A). The patient was treated with creatine, dietary arginine restriction and ornithine supplements. Her movement disorder and seizures resolved but she still has severe cognitive impairment and no expressive language. The occurrence of secondary respiratory chain abnormalities in GAMT deficiency may lead to misdiagnosis, particularly as the clinical and radiological features resemble those seen in mitochondrial encephalopathies. It is important to establish the correct diagnosis because specific treatment is available.

Brain↗
PubMed2006

Hyperlipidaemia due to carnitine palmitoyltransferase I deficiency.

We report a patient with carnitine palmitoyltransferase I (CPT I) deficiency, who presented with acute encephalopathy at 6 months of age. This was precipitated by an episode of gastroenteritis. No hypoglycaemia was documented, but there was hepatomegaly; blood tests revealed raised transaminases, a coagulopathy and severe hypertriglyceridaemia (48.8 mmol/L) and hypercholesterolaemia (9.5 mmol/L). The hyperlipidaemia resolved within 3 days of treatment and did not recur. At 2 years of age, the patient's liver function, growth and development are all normal. Hyperlipidaemia has been reported during acute illness in previous patients with CPT I deficiency but it is not a well-recognized feature; it should alert metabolic specialists to this potential diagnosis.

Brain Diseases↗
PubMed2006

Pyruvate dehydrogenase E3 binding protein (protein X) deficiency.

Pyruvate dehydrogenase (PDH) deficiency is a major cause of neurological dysfunction and lactic acidosis in infancy and early childhood. The great majority of cases (>80%) result from mutations in the X-linked gene for the E1alpha subunit of the complex (PDHA1). Mutations in the genes for the other subunits have all been described, but only dihydrolipoamide dehydrogenase (E3) and E3 binding protein (E3BP) defects contribute significantly to the total number of patients with PDH deficiency. Although previously considered rare, with only 13 reported cases, we have found that mutations in PDX1, the gene for the E3 binding protein, are in fact relatively common. Clinical, biochemical, and genetic features of six new patients (four males, two females; age range 15mo-6y) with mutations in this gene are compared with previously reported cases. All patients with E3BP deficiency identified to date have mutations which completely prevent synthesis of the protein product. However, they are generally less severely affected than patients with PDHA1 mutations, although there is considerable overlap in clinical and neuroradiological features.

Child↗
PubMed2005

Cerebral ketone body metabolism.

Ketone bodies (KBs) are an important source of energy for the brain. During the neonatal period, they are also precursors for the synthesis of lipids (especially cholesterol) and amino acids. The rate of cerebral KB metabolism depends primarily on the concentration in blood; high concentrations occur during fasting and on a high-fat diet. Cerebral KB metabolism is also regulated by the permeability of the blood-brain barrier (BBB), which depends on the abundance of monocarboxylic acid transporters (MCT1). The BBB's permeability to KBs increases with fasting in humans. In rats, permeability increases during the suckling period, but human neonates have not been studied. Monocarboxylic acid transporters are also present in the plasma membranes of neurons and glia but their role in regulating KB metabolism is uncertain. Finally, the rate of cerebral KB metabolism depends on the activities of the relevant enzymes in brain. The activities vary with age in rats, but reliable results are not available for humans. Cerebral KB metabolism in humans differs from that in the rat in several respects. During fasting, for example, KBs supply more of the brain's energy in humans than in the rat. Conversely, KBs are probably used more extensively in the brain of suckling rats than in human neonates. These differences complicate the interpretation of rodent studies. Most patients with inborn errors of ketogenesis develop normally, suggesting that the only essential role for KBs is as an alternative fuel during illness or prolonged fasting. On the other hand, in HMG-CoA lyase deficiency, imaging generally shows asymptomatic white-matter abnormalities. The ability of KBs to act as an alternative fuel explains the effectiveness of the ketogenic diet in GLUT1 deficiency, but its effectiveness in epilepsy remains unexplained.

Animals↗
PubMed2004

Cerebral edema associated with betaine treatment in classical homocystinuria.

A child with cystathionine beta-synthase deficiency developed cerebral edema 4 to 6 weeks after starting betaine therapy. There was no evidence of intracranial thrombosis, but there was widespread edema of the white matter. He recovered fully after emergency decompressive craniotomy and withdrawal of betaine.

Betaine↗
PubMed2004

Lipid-storage myopathy and respiratory insufficiency due to ETFQO mutations in a patient with late-onset multiple acyl-CoA dehydrogenation deficiency.

We report a patient with lipid-storage myopathy due to multiple acyl-CoA dehydrogenation deficiency (MADD). Molecular genetic analysis showed that she was compound heterozygous for mutations in the gene for electron transfer flavoprotein:ubiquinone oxidoreductase (ETFQO). Despite a good initial response to treatment, she developed respiratory insufficiency at age 14 years and has required long-term overnight ventilation. Thus, MADD is one of the few conditions that can cause a myopathy with weakness of the respiratory muscles out of proportion to the limb muscles.

Acyl-CoA Dehydrogenases↗
PubMed2004

Biotinidase deficiency: a treatable leukoencephalopathy.

The clinical history and the neuroradiological findings have been reviewed for 5 patients with biotinidase deficiency. Patients were diagnosed in the UK, where neonatal screening for this disorder is not done. The age at presentation ranged from 4 weeks to 5 months and the median interval between presentation and diagnosis was 5.5 months. The main abnormalities on cerebral imaging were leukoencephalopathy and widening of the ventricles and extra-cerebral CSF spaces. White matter abnormalities included delayed myelination but, in some patients, the increased signal was too great to be explained just by failure of myelination. Subtle subcortical changes were the only abnormality in one patient. Follow-up studies after treatment with biotin showed improved myelination; in one case, this was accompanied by normalisation of the CSF spaces but another patient showed progressive atrophy and cystic degeneration. Most of these patients have neurological sequelae. Biotinidase deficiency should be excluded in all patients with unexplained neurological problems. Neonatal screening provides the best chance of a good outcome.

Biotinidase Deficiency↗
PubMed2004

The significance of a high plasma ammonia value.

At a tertiary referral centre, just over 50% of patients with plasma ammonia values over 200 micro mol/l had inborn errors of metabolism. To distinguish artefactual high values from those requiring treatment, the measurement should be repeated immediately if the result is above 200 micro mol/l and at lower concentrations if the patient is encephalopathic.

Ammonia↗
PubMed2003

What is the role of medium-chain triglycerides in the management of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency?

Cardiomyopathy is common in infants with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Resolution of the cardiomyopathy can often be achieved by avoidance of fasting and changing from a conventional infant formula to one in which most long-chain fat is replaced by medium-chain triglycerides (MCT). It is uncertain whether the clinical improvement is due to the restriction of long-chain fat or whether the MCT have specific beneficial effects. To clarify this, the metabolic effects of MCT were examined in 5 patients. When given at around the level found in MCT-based infant formula, MCT had no effect on blood concentrations of ketone bodies, specific fatty acids or acylcarnitines. The present study cannot, however, exclude the possibility that MCT per se may have beneficial effects.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2003

Acute respiratory distress syndrome in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial trifunctional protein deficiencies.

Inborn errors of metabolism have not previously been recognized as a risk factor for acute respiratory distress syndrome (ARDS). We report this complication in four patients with defects of the mitochondrial trifunctional protein (MTP). This enzyme catalyses three steps in the beta-oxidation of long-chain fatty acids. Three of the patients were homozygous for the 'common' 1528G>C mutation in the alpha-subunit of the MTP, giving rise to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. The fourth patient did not carry this mutation but had severely decreased activities of long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketoacyl-CoA thiolase. One patient died and histology in this patient showed severe interstitial pulmonary fibrosis. The other three patients recovered after being ventilated for up to 6 months. The high frequency of ARDS in patients with MTP defects suggests that this inborn error may be a risk factor for ARDS.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2003

Rhabdomyolysis in glutaric aciduria type I.

Recurrent rhabdomyolysis has previously been reported in one patient with glutaric aciduria type I. We report rhabdomyolysis in a second, unrelated patient, suggesting that there may be a specific association with thismetabolic disorder.

Child, Preschool↗
PubMed2003

Cataract in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD).

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare metabolic disorder that can lead to acute encephalopathy, liver disease, cardiomyopathy, rhabdomyolysis, and long-term complications involving the eye and peripheral nerves. LCHADD is a peroxisome biogenesis disorder (PBD). Except for the series presented by Tyni and colleagues (Ophthalmology 1998;105:810-824), which described visually insignificant lens opacities in association with LCHADD, previous ophthalmic papers have only reported retinal complications. We report on one case with progressive asymmetrical cataract. The more mildly affected eye had a similar morphology to that previously reported and the more severely affected eye had an unusual morphology we believe is unique to LCHADD. We discuss the range of ophthalmic presentations in our cases and in the literature. The variability of the severity of ocular complications, even between eyes in one individual, makes it difficult to test the effectiveness of therapeutic options upon the ophthalmic complications.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2003

Are tablets a practical source of protein substitute in phenylketonuria?

BACKGROUND: A phenylalanine-free amino acid based protein substitute is necessary to provide the major source of protein in phenylketonuria (PKU). Protein substitutes in PKU are usually given as drinks. These are unpalatable and compliance is often poor. Tablets containing a suitable mixture of phenylalanine-free amino acids (Aminogran Food Supplement, UCB) are now available. AIMS: To compare the effectiveness and acceptability of these tablets with conventional protein substitute drinks. METHODS: Twenty one subjects with PKU, aged 8-25 years, participated in a randomised crossover study. During one phase, subjects received at least 40% of their protein substitute requirements from the amino acid tablets and the rest from their usual protein substitute tablets. During the other phase, they received their usual protein substitute. Each period lasted 12 weeks. Blood phenylalanine concentrations were measured at least once every two weeks and other plasma amino acids were measured at the beginning, at crossover, and at the end of the study. The subjects kept a diary of all protein substitute taken. RESULTS: Compliance appeared to be better with the new tablets than with patients' usual protein substitutes. Ninety per cent (18/20) recorded that they took the tablets as prescribed, compared with 65% (13/20) fully compliant with their usual protein substitute. Moreover, plasma phenyalanine was lower on the amino acid tablets, and the median difference in blood concentrations between the two groups was 46 micro mol/l (95% CI 14.8 to 89.0, p = 0.02). Tyrosine increased by a median of 16 micro mol/l daily on the amino acid tablets (95% CI 7.1 to 40.5, p = 0.01). Most subjects (70%) preferred incorporating the new tablets into their usual protein substitute regimen. CONCLUSIONS: Amino acid tablets are an effective and relatively popular protein substitute in older children, teenagers, and adults with PKU.

Adolescent↗
PubMed2002

Urea cycle disorders.

Most patients with urea cycle disorders who present as neonates, do so with deteriorating feeding, drowsiness and tachypnoea, following a short initial period when they appear well. The plasma ammonia should be measured at the same time as the septic screen in such patients. Ammonia levels above 200 micromol/l are usually caused by inherited metabolic diseases and it is essential to make a diagnosis for genetic counselling, even if the patients die. The aim of treatment is to lower the ammonia concentrations as fast as possible. Sodium benzoate, sodium phenylbutyrate and arginine can exploit alternative pathways for the elimination of nitrogen but haemodialysis or haemofiltration should be instituted if ammonia concentrations are >500 micromol/l or if they do not fall promptly. Long-term management involves drugs, dietary protein restriction and use of an emergency regimen during illness. Severe hyperammonaemia is usually associated with irreversible neurological damage, particularly if levels have been above 800 micromol/l for >24 hours, and the option of withdrawing treatment should be discussed with the family.

Ammonia↗