Vitamin B12 deficiency in adolescents and young adults with phenylketonuria.
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Adolescent↗
Biomedical subjects
J T Clarke
Publications and source records attributed to J T Clarke.
An unusual patient with the neonatal Marfan phenotype and mitochondrial complex I deficiency.
We report the case of a 16-month-old male with the neonatal appearance of Marfan syndrome (NMS), with dolichocephaly, a long midface, deep-set eyes, arachnodactyly, dislocated lenses and carciovascular abnormalities. The presence of persistent lactic acidosis led to studies which disclosed mitochondrial complex I deficiency. We speculate that this unusual association may be due to the combination of an inherited mutation affecting complex I activity along with a de novo mutation disrupting the corresponding locus and an adjacent NMS locus on the homologous autosome. The possibility that the phenotype observed in this patient is directly due to the mitochondrial defect cannot be excluded.
Electron Transport Complex I↗
Low iron stores in infants and children with treated phenylketonuria: a population at risk for iron-deficiency anaemia and associated cognitive deficits.
A retrospective study of 53 patients with phenylketonuria (PKU), whose disease was managed with a low-phenylalanine diet, revealed a high incidence of iron depletion (as reflected by subnormal serum ferritin concentrations). Serum ferritin concentrations under 10 micrograms/l were found in one out of six infants aged 5-12 months. Concentrations under 16 micrograms/l were found in 16 of 22 children aged 1-3 years and in 11 of 25 children aged 4-12 years. Dietary iron, estimated from prescribed intakes of medical foods, exceeded the Canadian recommended nutrient intake, suggesting that low stores of iron may be secondary to reduced bioavailability and absorption of iron. These findings suggest that the current dietary management of PKU is associated with an increased risk for low iron stores. Investigators have reported an association in young children between iron-deficiency anaemia and both cognitive and motor disturbances. Children with PKU, already at risk of neurological damage because of phenylalanine neurotoxicity, may be at increased risk as a result of iron depletion. Serum ferritin as well as haemoglobin concentration should be monitored, along with plasma phenylalanine and tyrosine, to ensure optimum treatment of affected children.
Anemia, Hypochromic↗
Copper-histidine therapy for Menkes disease.
Menkes disease is an X-linked genetic disorder of copper transport that results in death from severe progressive neurodegeneration by the age of 3 years. We report here our 17 years' experience with the treatment of Menkes disease with subcutaneous administration of copper-histidine. Two patients (16 and 6 years of age) whose therapy was begun within 1 month of birth have done well neurologically. The other five patients have done poorly despite treatment initiated at 2 to 7 months of age. Copper-histidine therapy may be an effective treatment if started early.
Adolescent↗
Atypical nonketotic hyperglycinemia confirmed by assay of the glycine cleavage system in lymphoblasts.
A 13-year-old girl with early-onset, mild, slowly progressive mental retardation caused by nonketotic hyperglycinemia is described. The plasma and cerebrospinal fluid glycine concentrations were elevated, but the cerebrospinal fluid/plasma glycine ratio was only mildly elevated. The diagnosis was confirmed by demonstration of a defect in the activity of the glycine cleavage system in cultured lymphoblasts.
Adolescent↗
Ornithine transcarbamylase deficiency presenting with strokelike episodes.
A girl with ornithine transcarbamylase deficiency had a history of recurrent strokelike episodes. The differential diagnosis of unexplained stroke should include primary urea cycle defects.
Cerebrovascular Disorders↗
Pulmonary embolus and patent foramen ovale: a rare cause of refractory hypoxaemia.
A patient with a large pulmonary embolus is described. The striking features were those of cardiovascular stability with hypoxaemia and hypercapnia. Cardiac catheterization confirmed the pulmonary embolus; in addition there was found to be a patent foramen ovale (PFO), causing a large right-to-left shunt. Removal of the pulmonary embolus and closure of the PFO dramatically improved alveolar-arterial oxygen gradient and ventilatory requirements.
Heart Septal Defects, Atrial↗
Retrospective diagnosis of medium chain acyl-CoA dehydrogenase deficiency.
A male infant is reported who died suddenly and who at post-mortem had pathological evidence suggestive of a genetic defect of fatty acid beta-oxidation. A specific diagnosis could not be made enzymatically because of unavailability of suitable tissue for assay. The diagnosis of medium chain acyl-CoA dehydrogenase (MCAD) deficiency was made by specific mutation analysis using the polymerase chain reaction and DNA extracted from the newborn screening card of this infant. This powerful new molecular diagnostic technique should prove to be of use in similar circumstances.
Acyl-CoA Dehydrogenases↗
Hyperplasia of pulmonary arterial media in infantile familial pulmonary hypertension associated with severe metabolic acidosis.
Two female siblings, offspring of consanguinous parents, died at 10 and 12 wk of age following short illnesses characterized clinically by hypoxia and severe metabolic acidosis. Cardiac catheterization confirmed severe pulmonary hypertension in the second infant, who survived 6 wk after onset of symptoms and 4 wk after admission to hospital; extensive investigations failed to identify any inborn metabolic error. At autopsy, small pulmonary arteries/arterioles in both cases showed marked medial thickening due to smooth muscle hyperplasia; concentric intimal fibrosis was present focally in the older infant. Compared morphometrically with small pulmonary arteries in 20 infantile controls who died of Reye's syndrome (n = 8), a Reye's-like illness (n = 5) or an identified metabolic error associated with metabolic acidosis (n = 7), intraacinar pulmonary arteries in both cases, were significantly more numerous and had a significantly greater relative medial thickness. We suggest that an autosomal recessive gene caused or potentiated the pulmonary medial hyperplasia. The latter finding, compared with medial hypertrophy, is rarely described as the morphologic basis of pulmonary hypertension, and its occurrence may be restricted to early infancy. In this family, the relationship between hypertensive pulmonary arteriopathy and severe metabolic acidosis remains speculative.
Acidosis↗
A mutation common in non-Jewish Tay-Sachs disease: frequency and RNA studies.
Tay-Sachs disease (TSD) is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, beta-N-acetylhexosaminidase A (Hex A). We have discovered that a Tay-Sachs mutation, IVS-9 + 1 G-->A, first detected by Akli et al. (Genomics 11:124-134, 1991), is a common disease allele in non-Jewish Caucasians (10/58 alleles examined). A PCR-based diagnostic test, which detects an NlaIII site generated by the mutation, revealed a frequency among enzyme-defined carriers of 9/64 (14%). Most of those carrying the allele trace their origins to the United Kingdom, Ireland, or Western Europe. It was not identified among 12 Black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers who did not carry any of the mutations common to this population. No normally spliced RNA was detected in PCR products generated from reverse transcription of RNA carrying the IVS-9 mutation. Instead, the low levels of mRNA from this allele were comprised of aberrant species resulting from the use of either of two cryptic donor sites, one truncating exon 9 and the other within IVS-9, spliced to exon 10. Numerous additional splice products were detected, most involving skipping of one or more surrounding exons. Together with a recently identified allele responsible for Hex A pseudodeficiency (Triggs-Raine et al. Am J Hum Genet, 1992), these two alleles accounted for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening tests in non-Jewish Caucasians.
Alleles↗
Fatal combined defects in mitochondrial multienzyme complexes in two siblings.
A female child suffering from intrauterine growth retardation was born by caesarean section at 32 weeks. In the immediate newborn period there was a metabolic acidosis but this resolved. Hypotonia, muscular weakness and poor respiratory effort were evident and the child died at 6 days of age. A previous male sibling had died at 3 months of age after similar symptoms with seizures and a dysmyelination disorder. Post-mortem examination of both children showed damage to the basal ganglia. Defects in the activities of the pyruvate dehydrogenase complex, cytochrome oxidase and succinate cytochrome c reductase were found in cultured skin fibroblasts. Similar defects were found in isolated muscle mitochondria but not in isolated liver mitochondria from the patient. Immunoblotting for cytochrome oxidase showed that the multienzyme complex was not assembled in muscle and skin fibroblast mitochondria, but was assembled in liver mitochondria. Similar results were obtained in cultured skin fibroblast mitochondria for complex I of the mitochondrial respiratory chain. This is the first occasion that multiple defects have been demonstrated both in tissue and in culture skin fibroblasts in mitochondrial respiratory chain complexes.
Abnormalities, Multiple↗
Rapid nonradioactive tracer method for detecting carriers of the major Ashkenazi Jewish Tay-Sachs disease mutations.
Tay-Sachs disease (TSD, GM2 gangliosidosis, Type I) is an autosomal recessive lysosomal storage disease caused by deficiency of beta-hexosaminidase A (Hex A) resulting from mutations in the gene (HEXA) encoding the alpha-subunit of the enzyme. Three mutations, in exons 7 and 11 and at the exon 12-intron 12 junction, account for > 90% of alleles identified in obligate Ashkenazi Jewish carriers. Mutation analysis requires amplification of available DNA by separate polymerase chain reactions (PCRs) and either restriction digestion and gel electrophoresis or 32P-labeled allele-specific oligonucleotide (ASO) probes. We developed a simple, nonradioisotopic method for rapidly identifying TSD carriers by a triplex PCR reaction followed by dot-blot analysis, using three wild-type and three mutant ASOs end-labeled with digoxigenin-dUTP (dig-ASO). Hybridization was demonstrated immunologically by reaction with an anti-digoxigenin-alkaline phosphatase conjugate followed by colorimetric demonstration of phosphatase activity. The results of analyses by the dig-ASO method of 65 carriers identified by serum enzyme activity and of 6 high-risk fetuses in prenatal testing were the same as those obtained by more conventional restriction analysis. Dig-ASO testing correctly reclassified 10 individuals who had tested inconclusively on analysis for leukocyte beta-hexosaminidase A activity; 3 were identified as carriers and 7 as noncarriers. The simplicity of the assay and the avoidance of the radioisotopes make this a potentially useful method for TSD carrier detection by mutation analysis in Ashkenazi Jews from populations in whom the identity and frequencies of the common TSD mutations are known.
Colorimetry↗
Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high.
A female infant showing lacticacidemia, hypotonia, and neurodegenerative disease died at 7 mo of age. Autopsy revealed lesions typical of Leigh disease, both in the basal ganglia and in the brain stem. A maternal aunt and uncle died 1 year and 5 mo, respectively, after following a similar clinical course, while another uncle, presently 33 years of age, has retinitis pigmentosa and ataxia and is mentally retarded. PCR restriction-digest analysis of mtDNA isolated from the proband revealed a T-to-G change at position 8993, creating a new AvaI restriction site. The mutation present in the ATP 6 gene results in the substitution of an arginine residue for a leucine. The indexed patient had greater than 95% abnormal mtDNA in her skin fibroblasts, brain, kidney, and liver tissues, as measured by laser densitometry. The maternal aunt who died at age 1 year had greater than 95% abnormal mtDNA in her lymphoblasts. The uncle with retinitis pigmentosa had 78% and 79% abnormal mtDNA in his skin fibroblasts and lymphoblasts, respectively, while an asymptomatic maternal aunt and her son had no trace of this mutation. The mother of the index case had 71% and 39% abnormal mtDNA in her skin fibroblasts and lymphoblasts, respectively, showing that the heteroplasmy can be variable, on a tissue-specific basis, within one individual. This shows that mtDNA mutations at 8993 can produce the clinical phenotype of Leigh disease in addition to the phenotype of ataxia and retinitis pigmentosa described by Holt et al.(ABSTRACT TRUNCATED AT 250 WORDS)
DNA, Mitochondrial↗
Characterization of a deletion at Xq27-q28 associated with unbalanced inactivation of the nonmutant X chromosome.
We report the results of studies on the characterization of the mutation associated with marked unbalanced expression of the mutant X chromosome in a karyotypically normal girl with Hunter disease (mucopolysaccharidosis type II). Southern analysis of DNA extracted from somatic cell hybrids containing only the mutant X chromosome showed deletion of the Xq27.3-q28 loci: DXS297 (VK23AC), DXS293 (VK16), FRAXA (pfxa3), DXS296 (VK21A), and the 3' end of the iduronatesulfatase (IDS) gene. The flanking loci--DXS52 (St14-1), DXS304 (U6.2), and DXS369 (RN1)--were intact. On the basis of these results, we concluded that the mutation was a simple deletion extending a maximum of 3-5 cM to the centromeric side of the IDS gene. Both Southern analysis of DNA from somatic cell hybrids, using short segments of IDS cDNA, and PCR of reverse-transcribed RNA from cultured skin fibroblasts indicated that the telomeric terminus of the deletion was localized to a region near the middle of the coding sequences of the gene.
Autoradiography↗
Autosomal recessive inheritance of vasopressin-resistant diabetes insipidus.
We report on 2 intellectually normal sisters with vasopressin-resistant (nephrogenic) diabetes insipidus (NDI). The sex of the patients, the history of parental consanguinity, and the fact that both parents formed normally concentrated urine suggested that the NDI in the 2 sisters was the result of inheritance of an autosomal recessive mutation affecting renal tubular water reabsorption. The results of DNA analysis of the DXS52 locus with the use of St14 as probe, shown by Knoers et al. [1988] to be tightly linked to the NDI locus on the X-chromosome, showed that each girl inherited different Xq28 regions of the maternal X chromosomes, ruling out a diagnosis of classical X-linked NDI.
Consanguinity↗
Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in muscle: a new cause for recurrent myoglobinuria and encephalopathy.
We report on a 16-year-old girl with short-chain L-3-hydroxyacyl-coenzyme A (CoA) dehydrogenase deficiency resulting in juvenile-onset recurrent myoglobinuria, hypoketotic hypoglycemic encephalopathy, and hypertrophic/dilatative cardiomyopathy. Urinary organic acids showed traces of 3-hydroxy-dodecanedioic acids and small amounts of suberic, sebacic, and adipic acids. There was a marked decrease in L-3-hydroxyacyl-CoA dehydrogenase activity in muscle with acetoacetyl-CoA as substrate (2.48 mumol/min/gm; normal = 6.90 +/- 1.80 mumol/min/gm of tissue; n = 11), contrasting with normal L-3-hydroxyacyl-CoA dehydrogenase activity with 3-ketooctanoyl-CoA and 3-ketopalmitoyl-CoA as substrates. Short-chain L-3-hydroxyacyl-CoA dehydrogenase activity was normal in fibroblasts, suggesting a tissue-specific defect.
3-Hydroxyacyl CoA Dehydrogenases↗
High-level gentamicin resistance in Enterococcus faecalis bacteremia.
In a retrospective analysis, patients with bacteremia due to Enterococcus faecalis with and without high-level gentamicin resistance (GRE; MIC greater than 2000 micrograms/ml) were compared. Bacteremic patients with GRE (n = 32) had significantly higher rates of nosocomial acquisition and bladder catheterization, longer hospitalizations, and more frequent prior treatment with cephalosporins than did bacteremic patients without high-level resistance (n = 19). Overall mortality was significantly associated with septic shock, high-risk source (intraabdominal, wound, respiratory tract, multiple, unknown), and polymicrobial bacteremia. Higher mortality was observed in GRE bacteremia (47%) than in bacteremia without high-level resistance (37%), but this difference was not statistically significant. For patients with monomicrobial bacteremia, low-risk source (genitourinary tract, intravascular), or treatment with antibiotics appropriate for the enterococcus, higher mortality with GRE bacteremia approached statistical significance. These results suggest that high-level resistance adversely affects survival with a pure E. faecalis bacteremia or low-risk bacteremic source. Also, response to antibiotic therapy may be diminished by high-level resistance.
Adult↗
A serious complication of minitracheotomy.
A previously unreported complication of minitracheotomy is described. The minitracheotomy introducer was lost into the pleural cavity and a thoracotomy was required to remove it.
Adult↗