8 research outputs found
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
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
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
574-586 Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting
Mutations in PCBD1 are causative for transient neonatal hyperphenylalaninemia and primapterinuria (HPABH4D). Until now, HPABH4D has been regarded as a transient and benign neonatal syndrome without complications in adulthood. In our study of three adult patients with homozygous mutations in the PCBD1 gene, two patients were diagnosed with hypomagnesemia and renal Mg 2+ loss, and two patients developed diabetes with characteristics of maturity onset diabetes of the young (MODY), regardless of serum Mg2+ levels. Our results suggest that these clinical findings are related to the function of PCBD1 as a dimerization cofactor for the transcription factor HNF1B. Mutations in the HNF1B gene have been shown to cause renal malformations, hypomagnesemia, and MODY. Gene expression studies combined with immunohistochemical analysis in the kidney showed that Pcbd1 is expressed in the distal convoluted tubule (DCT), where Pcbd1 transcript levels are upregulated by a low Mg2+-containing diet. Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg2+ reabsorption in the DCT. Of seven PCBD1 mutations previously reported in HPABH4D patients, five mutations caused proteolytic instability, leading to reduced FXYD2 promoter activity. Furthermore, cytosolic localization of PCBD1 increased when coexpressed with HNF1B mutants. Overall, our findings establish PCBD1 as a coactivator of the HNF1B-mediated transcription necessary for fine tuning FXYD2 transcription in the DCT and suggest that patients with HPABH4D should be monitored for previously unrecognized late complications, such as hypomagnesemia and MODY diabetes. Copyrigh
Erratum: Prediction of outcome in isolated methylmalonic acidurias: Combined use of clinical and biochemical parameters (J Inherit Metab Dis (2009) (DOI 10.1007/s10545-009-1189-6))
Erratum: Prediction of outcome in isolated methylmalonic acidurias: Combined use of clinical and biochemical parameters (J Inherit Metab Dis (2009) (DOI 10.1007/s10545-009-1189-6))
Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk
OBJECTIVE: Recent reports warn that the worldwide cell culture capacity is
insufficient to fulfill the increasing demand for human protein drugs.
Production in milk of transgenic animals is an attractive alternative.
Kilogram quantities of product per year can be obtained at relatively low
costs, even in small animals such as rabbits. We tested the long-term
safety and efficacy of recombinant human -glucosidase (rhAGLU) from rabbit
milk for the treatment of the lysosomal storage disorder Pompe disease.
The disease occurs with an estimated frequency of 1 in 40,000 and is
designated as orphan disease. The classic infantile form leads to death at
a median age of 6 to 8 months and is diagnosed by absence of
alpha-glucosidase activity and presence of fully deleterious mutations in
the alpha-glucosidase gene. Cardiac hypertrophy is characteristically
present. Loss of muscle strength prevents infants from achieving
developmental milestones such as sitting, standing, and walking. Milde