Awareness is the name of the game: clinical and biochemical evaluation of a case of a girl diagnosed with acute intermittent porphyria associated with autism.

Neuroporphyrias, a heterogeneous group of metabolic diseases, are diagnosed less often than their true prevalence justifies. Lack of awareness of porphyrias and their protean clinical and biochemical manifestations, is the most significant hurdle to their recognition and diagnosis. These points are reflected in the unusual case reported here, which highlights the potential damage that inappropriate management may cause when the diagnosis is missed over a long period. We diagnosed heterozygous Acute Intermittent Porphyria (AIP) in a 15 yr old girl, who first presented with autism at the age of 4 years. This phenotypic association has not been previously reported. In addition to the unrecognized phenotype, her normal urinary aminolevulinic acid and porphobilinogen, findings which are not compatible with symptomatic porphyria according to well established criteria, could also have led to a missed diagnosis of neuroporphyria. However, the diagnosis of AIP was established on the basis of a 64% reduction in erythrocyte hydroxymethylbilane synthase (HMBS) activity and the finding of a known causative AIP mutation (p.D178N). We therefore recommend that porphyria should be considered in autistic children especially when there is an atypical course or unexpected abreaction to medications. The biochemical and genetic data should be carefully evaluated in a specialized porphyria center.

Amnionless (AMN) mutations in Imerslund-Gräsbeck syndrome may be associated with disturbed vitamin B12 transport into the CNS.

Familial selective vitamin B12 (cobalamin, Cbl) malabsorption (Imerslund-Gräsbeck syndrome, IGS, OMIM 261100) is a group of autosomal recessive disorders characterized by selective malabsorption of Cbl from the terminal ileum in the presence of normal histology. Mutations in the amnionless (AMN) and cubilin (CUBN) genes are known to be causes of IGS. Their gene products combine to form a receptor complex (cubam), which is instrumental in the binding and transport of Cbl in the gut. As opposed to Cbl transport in the terminal ileum, normal transport of Cbl into the CNS is poorly understood and little is known regarding its molecular basis. Studies in adults with neuropsychiatric disease have suggested the presence of an active transport mechanism into the central nervous system constituting a blood-brain barrier (BBB) for Cbl. A child with IGS, compound heterozygous for a missense and a nonsense mutation in the amnionless (AMN) protein gene, was noted to have a high daily cobalamin (Cbl) requirement for neuropsychiatric, but not for systemic metabolic and haematological, remission. Measurements of CSF Cbl revealed evidence that the transport of Cbl into the central nervous system was impaired, and a standard Schilling test was consistent with a dose response of cobalamin transport across the terminal ileum. Amnionless protein is known to be expressed in the fetal and postnatal central nervous system, and is known to be involved in Cbl transport in other tissues such as kidney as well as the gut. It is possible that an active Cbl transport mechanism at the BBB exists, and that the amnionless (AMN) protein may be part of this mechanism, as it is in cobalamin transport in the terminal ileum.

Chronic lung disease and cystic fibrosis phenotype in prolidase deficiency: a newly recognized association.

Six families with prolidase deficiency (PD) and chronic lung disease are reported, a previously unrecognized association. In one family with a classic cystic fibrosis (CF) phenotype, no evidence for CF Transmembrane Conductance Regulator (CFTR)-related mutations could be found. Chronic lung disease and CFTR-mutation negative CF may be associated with PD.

Nebuliser hood compared to mask in wheezy infants: aerosol therapy without tears!

BACKGROUND: Small volume nebulisers (SVNs) with masks commonly provide aerosol therapy for infants with lung diseases. However, infants and toddlers are often disturbed by and thus reject masks. AIMS: To compare the lung deposition efficiency of the "usual" SVN aerosol mask and a prototype hood attached to an SVN. The advantage of the hood is that no mask is needed and medication can readily be administered during sleep. METHODS: 99mTc salbutamol solution was administered at random by SVN plus mask or hood to 14 wheezy infants (mean age 8 (SD 5) months). The dose and distribution of salbutamol were evaluated using gamma scintigraphy. Clinical response, tolerability by the infants, and parent preference were also compared. RESULTS: Mean total lung deposition was 2.6% with the hood and 2.4% with the mask (p > 0.05). Variability with the mask was greater than with the hood (coefficient of variation (CoV) 54% v 39%). Both treatments provided similar clinical benefit and side effects as reflected in improved oxygen saturation, reduced respiratory frequency, and increased heart rate. Infants accepted the hood better than the mask and there was a positive correlation between poor acceptance and upper airways and stomach deposition for both treatment modalities. Parents preferred the hood treatments. CONCLUSIONS: Aerosol therapy by hood is as efficient as by mask but provides a better therapeutic index. It is much better tolerated by infants and preferred by parents. Hood nebulisation is a simple and patient friendly mode of aerosol therapy in wheezy infants.

MPDU1 mutations underlie a novel human congenital disorder of glycosylation, designated type If.

Deficiencies in the pathway of N-glycan biosynthesis lead to severe multisystem diseases, known as congenital disorders of glycosylation (CDG). The clinical appearance of CDG is variable, and different types can be distinguished according to the gene that is altered. In this report, we describe the molecular basis of a novel type of the disease in three unrelated patients diagnosed with CDG-I. Serum transferrin was hypoglycosylated and patients' fibroblasts accumulated incomplete lipid-linked oligosaccharide precursors for N-linked protein glycosylation. Transfer of incomplete oligosaccharides to protein was detected. Sequence analysis of the Lec35/MPDU1 gene, known to be involved in the use of dolichylphosphomannose and dolichylphosphoglucose, revealed mutations in all three patients. Retroviral-based expression of the normal Lec35 cDNA in primary fibroblasts of patients restored normal lipid-linked oligosaccharide biosynthesis. We concluded that mutations in the Lec35/MPDU1 gene cause CDG. This novel type was termed CDG-If.

Physiological and practical evaluation of a biological/chemical protective device for infants.

The Chemical Infant Protective System (CHIPS) is a special hood-like system into which a small battery-operated blower delivers filtered air. Because it is a semiclosed system, there is a risk of dangerous CO2 accumulation within the device, which particularly affects infants with acute or chronic respiratory disorders. Eleven infants hospitalized with various respiratory illnesses wore the device for 15 minutes. Inspired O2, inspired CO2, heart rate, respiratory rate, oxygen saturation, and inside temperature and humidity were measured before and during this test period. Inspired O2 and heart rate during the test period were significantly lower than baseline levels (O2, 19.1 vs. 20.1%; heart rate, 133 vs. 142 beats/min). Inspired CO2 and inside temperature during the test period were significantly higher than baseline levels (CO2, 0.23 vs. 0.06%; temperature, 25.0 vs. 23.1 degrees C). Oxygen saturation, respiratory rate, and humidity were not different from baseline levels. A short-term stay within the CHIPS in well-ventilated surroundings did not result in significant clinical and physiological impact for sick infants. Nevertheless, trends were identified that may be worrisome during longer periods and in sealed rooms.

Hypoxia and chest pain due to acute constipation: an underdiagnosed condition?

An obese, previously healthy, 10-year-old boy presented with acute respiratory distress, chest, and abdominal pain. He was hypoxic and dyspneic in the emergency room. The abdomen was distended and tender, and the rectum was full of hard stool. Following catharsis, he made a complete recovery with resolution of all clinical signs. A review of the literature reveals that acute constipation as a cause of hypoxia and respiratory distress has been recognized, but has rarely been reported. We believe that this is a common phenomenon but probably infrequently recognized.

Ala244Val is a common, probably ancient mutation causing factor VII deficiency in Moroccan and Iranian Jews.

We investigated the molecular basis for factor VII (FVII) deficiency in Israel and found that 13 patients were homozygous and 10 heterozygous for a C to T substitution at nucleotide 10648 of the FVII gene. This predicted an Ala244Val change and was associated with decreased FVII activity and antigen level. Of the 36 Ala244Val positive alleles, 20 were observed in patients of Moroccan origin, 10 in Iranian-Jewish patients and 6 in patients of other origins. A computer model of the serine protease domain of FVII suggested that the Ala244Val substitution may cause distortion of the entire protein structure. Intragenic polymorphic sites analyses disclosed a founder effect for the Moroccan and Iranian-Jewish patients. A survey of the Ala244Val mutation revealed an allele frequency of 1:42.5 in Moroccan Jews and 1:40 in Iranian Jews. As Moroccan Jews have been separated from Iranian Jews for more than two millennia, the data suggest that the Ala244Val mutation occurred in ancient times.

Mucolipidosis type IV: a mild form with late onset.

A 16-year-old girl is presented with mild clinical manifestations and late onset of mucolipidosis type IV (MLIV). The patient, an Ashkenazi Jew, has had minor motor difficulties and mild psychological disturbances since early childhood. Her vision began deteriorating at 12 years of age, due to bilateral corneal opacities and retinal degeneration. At present she attends a regular high school, although she is slow and scholastic achievements are lower than average. Electron microscopic examination and biochemical studies were typical for MLIV, namely, abnormal ganglioside retention and typical pattern of phospholipids accumulation. This very mild presentation of MLIV suggests a broader spectrum of heterogeneity of this disorder and raises the possibility that MLIV, at least among Ashkenazi Jews, might be more frequent than estimated hitherto, due to undiagnosed mild patients.

Protracted clinical course for patients with Canavan disease.

Before the establishment of N-acetylaspartic aciduria due to aspartoacylase deficiency as the cause of Canavan disease, diagnosis was based on the characteristic clinical features and spongiform encephalopathy, a pathological response shared by a number of other unrelated conditions. Thus confusion exists in the literature about the phenotype of spongiform encephalopathy (Canavan disease), with reports of 'juvenile' and 'congenital' forms, as well as the classical infantile type. In this report, six of 22 patients with infantile-onset Canavan disease survived beyond six years of age. This phenotypical pattern might be the result of better medical management and care, rather than evidence of genetic heterogeneity.

Hyperuricemia in medium-chain acyl-coenzyme A dehydrogenase deficiency.

Six infants and children with medium-chain acyl-coenzyme A dehydrogenase deficiency were found to have hyperuricemia during an acute episode. Hyperuricemia may be a clue to the diagnosis of medium-chain acyl-coenzyme A dehydrogenase deficiency.

Persistent hypermethioninaemia with dominant inheritance.

A clinically benign form of persistent hypermethioninaemia with probable dominant inheritance was demonstrated in three generations of one family. Plasma methionine concentrations were between 87 and 475 mumol/L (normal mean 26 mumol/L; range 10-40 mumol/L); urinary methionine and homocystine concentrations were normal. Plasma homocystine, cystathionine, cystine and tyrosine were virtually normal. The concentrations in serum and urine of metabolites formed by the methionine transamination pathway were normal or moderately elevated. Methionine loading of two affected family members revealed a diminished ability to catabolize methionine, but the activities of methionine adenosyltransferase and cystathionine beta-synthase were not decreased in fibroblasts from four affected family members. Fibroblast methylenetetrahydrofolate reductase activity and its inhibition by S-adenosylmethionine were also normal, indicating normal regulation of N5-methyltetrahydrofolate-dependent homocysteine remethylation. Serum folate concentrations were not increased. The findings in this family differ from those previously described for known defects of methionine degradation. Since the hepatic and fibroblast isoenzymes of methionine adenosyltransferase differ in their genetic control, this family's biochemical findings appear consistent with a mutation in the structural gene for the hepatic methionine adenosyltransferase isoenzyme.

Inactivation of beef brain alpha-ketoglutarate dehydrogenase complex by valproic acid and valproic acid metabolites. Possible mechanism of anticonvulsant and toxic actions.

The anticonvulsant valproic acid (VPA, 2-n-propylpentanoic acid) causes inhibition of the citric acid cycle and elevations of central nervous system (CNS) gamma-aminobutyric acid (GABA) levels, which correlates with anticonvulsant action. No unifying mechanism for these actions of VPA has won general acceptance. alpha-Ketoglutarate dehydrogenase complex (KDHC) is a critical control enzyme in the CNS. We hypothesized that VPA may be an inhibitor of this enzyme since decreased KDHC activity would reduce substrate flux through the citric acid cycle and may increase flux into GABA synthesis. To test this hypothesis, inhibition of purified beef brain KDHC by VPA and its metabolites 2-n-propylpent-2-enoic acid (delta 2,3 VPE) and their coenzyme A (CoA) derivatives were studied. Preincubation of the NADH-reduced enzyme with delta 2,3 VPE, VPA-CoA, and delta 2,3 VPE-CoA caused time-dependent inactivation, reversible by addition of CoA. Under steady-state conditions, delta 2,3 VPE and VPA-CoA were competitive inhibitors of KDHC and delta 2,3 VPE-CoA was a mixed inhibitor. These observations have implications for the molecular mechanisms of VPA action. VPA derivatives cause inactivation and inhibition of KDHC, which may explain the anticonvulsant and some toxic actions of VPA.

Evidence for a defect in NADH: ubiquinone oxidoreductase (complex I) in Huntington's disease.

We evaluated electron transport chain activity in platelet mitochondria taken from HD patients. All 5 patients studied had striking depressions of NADH:ubiquinone oxidoreductase activity (complex I) (5.36 +/- 2.91 nmol/min/mg; control mean, 19.12 +/- 5.64 nmol/min/mg). Other electron transport chain activities were not significantly different from control values. HD may be caused by a mutation in 1 of the nuclear coded subunits of NADH:ubiquinone oxidoreductase.

Maternal phenylketonuria and hyperphenylalaninemia: implications for medical practice in the United States.

The risk of maternal phenylketonuria and hyperphenylalaninemia syndrome, a preventable cause of severe birth defects and retardation with a near 100% recurrence risk if untreated, is increasing in the United States. The reasons for this are reviewed. Women with hyperphenylalaninemia and those with phenylketonuria diagnosed and treated at birth are intellectually normal, as are some women with undiagnosed phenylketonuria. Both groups are at risk for maternal phenylketonuria syndrome in their offspring if blood phenylalanine levels are not controlled by diet during pregnancy. The problems and pitfalls of suspecting, diagnosing, and managing the condition are discussed. Suggested strategies for reversing the increasing trend include the greater use of genetic registers, increased clinical awareness, and some form of rescreening. The advantages and costs of rescreening a subset of pregnant women or all pregnant women at or before their first registration are examined.