Severe acute necrotizing pancreatitis associated with lipoprotein lipase deficiency in childhood

An 11-year-old girl with lipoprotein lipase deficiency experienced recurring episodes of abdominal pain. She initially underwent appendectomy for suspected appendicitis; however, the appendix was normal. Pancreatitis was subsequently identified as the cause of her pain

Functional hyperactivity of hepatic glutamate dehydrogenase as a cause of the hyperinsulinism/hyperammonemia syndrome: effect of treatment

OBJECTIVE: The combination of persistent hyperammonemia and hypoketotic hypoglycemia in infancy presents a diagnostic challenge. Investigation of the possible causes and regulators of the ammonia and glucose disposal may result in a true diagnosis and predict an optimum treatment. PATIENT: Since the neonatal period, a white girl had been treated for hyperammonemia and postprandial hypoglycemia with intermittent hyperinsulinism. Her blood level of ammonia varied from 100 to 300 micromol/L and was independent of the protein intake. METHODS: Enzymes of the urea cycle as well as glutamine synthetase and glutamate dehydrogenase (GDH) were assayed in liver tissue and/or lymphocytes. RESULTS: The activity of hepatic GDH was 874 nmol/(min.mg protein) (controls: 472-938). Half-maximum inhibition by guanosine triphosphate was reached at a concentration of 3.9 micromol/L (mean control values:.32). The ratio of plasma glutamine/blood ammonia was unusually low. Oral supplements with N-carbamylglutamate resulted in a moderate decrease of the blood level of ammonia. The hyperinsulinism was successfully treated with diazoxide. CONCLUSION: A continuous conversion of glutamate to 2-oxoglutarate causes a depletion of glutamate needed for the synthesis of N-acetylglutamate, the catalyst of the urea synthesis starting with ammonia. In addition, the shortage of glutamate may lead to an insufficient formation of glutamine by glutamine synthetase. As GDH stimulates the release of insulin, the concomitant hyperinsulinism can be explained. This disorder should be considered in every patient with postprandial hypoglycemia and diet-independent hyperammonemia

Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: data from a cohort study

<p><b>Abstract</b></p> <p><b>Background</b></p> <p>Since the introduction of medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency in population newborn bloodspot screening (NBS) programs, subjects have been identified with variant <it>ACADM</it> (gene encoding MCAD enzyme) genotypes that have never been identified in clinically ascertained patients. It could be hypothesised that residual MCAD enzyme activity can contribute in risk stratification of subjects with variant <it>ACADM</it> genotypes.</p> <p><b>Methods</b></p> <p>We performed a retrospective cohort study of all patients identified upon population NBS for MCAD deficiency in the Netherlands between 2007–2010. Clinical, molecular, and enzymatic data were integrated.</p> <p><b>Results</b></p> <p>Eighty-four patients from 76 families were identified. Twenty-two percent of the subjects had a variant <it>ACADM</it> genotype. In patients with classical <it>ACADM</it> genotypes, residual MCAD enzyme activity was significantly lower (median 0%, range 0-8%) when compared to subjects with variant <it>ACADM</it> genotypes (range 0-63%; 4 cases with 0%, remainder 20-63%). Patients with (fatal) neonatal presentations before diagnosis displayed residual MCAD enzyme activities <1%. After diagnosis and initiation of treatment, residual MCAD enzyme activities <10% were associated with an increased risk of hypoglycaemia and carnitine supplementation. The prevalence of MCAD deficiency upon screening was 1/8,750 (95% CI 1/7,210–1/11,130).</p> <p><b>Conclusions</b></p> <p>Determination of residual MCAD enzyme activity improves our understanding of variant <it>ACADM</it> genotypes and may contribute to risk stratification. Subjects with variant <it>ACADM</it> genotypes and residual MCAD enzyme activities <10% should be considered to have the same risks as patients with classical <it>ACADM</it> genotypes. Parental instructions and an emergency regimen will remain principles of the treatment in any type of MCAD deficiency, as the effect of intercurrent illness on residual MCAD enzyme activity remains uncertain. There are, however, arguments in favour of abandoning the general advice to avoid prolonged fasting in subjects with variant <it>ACADM</it> genotypes and >10% residual MCAD enzyme activity.</p

The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature

OBJECTIVE: Infantile Pompe's disease is a lethal cardiac and muscular disorder. Current developments toward enzyme replacement therapy are promising. The aim of our study is to delineate the natural course of the disease to verify endpoints of clinical studies. METHODS: A total of 20 infantile patients diagnosed by the collaborative Dutch centers and 133 cases reported in literature were included in the study. Information on clinical history, physical examination, and diagnostic parameters was collected. RESULTS: The course of Pompe's disease is essentially the same in the Dutch and the general patient population. Symptoms start at a median age of 1.6 months in both groups. The median age of death is 7.7 and 6 months, respectively. Five percent of the Dutch patients and 8% of all reported patients survive beyond 1 year of age. Only 2 patients from literature became older than 18 months. A progressive cardiac hypertrophy is characteristic for infantile Pompe's disease. The diastolic thickness of the left ventricular posterior wall and cardiac weight at autopsy increase significantly with age. Motor development is severely delayed and major d

Genetic basis of hyperlysinemia

Background: Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia. Methods. We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features. Results: We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1. Conclusions: Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient

Variant-vormen van fenylketonurie in Nederland.

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Tetrahydrobiopterin loading test in xanthine dehydrogenase and molybdenum cofactor deficiencies.

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Enzyme therapy for pompe disease with recombinant human alpha-glucosidase from rabbit milk.

Pompe disease is a metabolic myopathy caused by deficiency of lysosomal acid alpha-glucosidase. In this report we review the first 36 weeks of a clinical study on the safety and efficacy of enzyme therapy aimed at correcting the deficiency. Four patients with infantile Pompe disease were enrolled. They received recombinant human alpha-glucosidase from transgenic rabbit milk. The product is generally well tolerated and reaches the primary target tissues. Normalization of alpha-glucosidase activity in skeletal muscle was obtained and degradation of PAS-positive material was seen in tissue sections. The clinical condition of all patients improved. The effect on heart was most significant, with an impressive reduction of the left ventricular mass index (LVMI). Motor function improved. The positive preliminary results stimulate continuation and extension of efforts towards the realization of enzyme therapy for Pompe disease

Retinal dystrophy in long chain 3-hydroxy-acyl-CoA dehydrogenase deficiency

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