Jukka Rajantie

Childhood idiopathic thrombocytopenic purpura in the Nordic countries: Epidemiology and predictors of chronic disease

Aim: To describe the epidemiology of idiopathic thrombocytopenic purpura (ITP) in the Nordic countries, to define clinical subgroups and to investigate factors predicting chronic disease. Methods: A prospective registration was done from 1998 to 2000, including all children with newly diagnosed ITP aged 0–14 y and at least one platelet count <30×109/l. Results: 506 children were registered and 423 followed for 6 mo. The incidence was 4.8/105 per year. Most children were aged 0–7 y (78%), with a predominance of boys, while patients aged 8–14 y had equal representation of the two sexes. There were seasonal variations determined by variations in postinfectious cases with sudden onset. The platelet count was <10×109/l in 58%, but bleeding manifestations were mild or moderate in 97%. The insidious form (symptoms for more than 2 wk) was more frequent in older children and girls, showed little seasonal variation, had milder manifestations and ran a chronic course in more than half the cases. Intracranial haemorrhages did not occur in the first 6 mo after diagnosis. Chronic ITP developed in 25%. The strongest predictor of chronic disease was insidious onset of symptoms (OR 5.97).

Duration and morbidity of newly diagnosed idiopathic thrombocytopenic purpura in children: a prospective nordic study of an unselected cohort☆

OBJECTIVE To determine the duration of the risk period with platelet counts <20 x 10(9)/L and the frequency of bleeding episodes in unselected children with idiopathic thrombocytopenic purpura (ITP). STUDY DESIGN We established a registry for patients with newly diagnosed ITP in the five Nordic countries, enrolling children aged 0 to 14 years with platelet counts <30 x 10(9)/L. Treatment centers prospectively reported presenting features, management details, and disease-related events during the first six months after diagnosis. RESULTS At presentation (n=501), more than half of the children had a platelet count <10 x 10(9)/L, but only 15 (3.0%) had a hemorrhage requiring blood transfusion. During follow-up of 409 patients, thrombocytopenia resolved uneventfully in 277. A risk period was present in 376 cases. Among 283 with self-limiting ITP, 26 were at risk >1 month and 25 had 30 events. Among 93 patients with chronic ITP, 73 were at risk >1 month and 44 had 111 events. Events occurred with an average frequency of 0.39 per month at risk. Life-threatening hemorrhages did not occur in the first six months after diagnosis. CONCLUSION Most children with ITP are at risk for serious bleeding for less than one month. Continuing severe thrombocytopenia is associated with little morbidity, bleeding episodes being infrequent and very rarely serious.

Waste nitrogen excretion via amino acid acylation: benzoate and phenylacetate in lysinuric protein intolerance.

ABSTRACT: Benzoate and phenylacetate improve prognosis in inherited urea cycle enzyme deficiencies by increasing waste nitrogen excretion as amino acid acylation products. We studied metabolic changes caused by these substances and their pharmacokinetics in a biochemically different urea cycle disorder, lysinuric protein intolerance (LPI), under strictly standardized induction of hyperammonemia. Five patients with LPI received an intravenous infusion of 6.6 mmol/kg L-alanine alone and separately with 2.0 mmol/kg of benzoate or phenylacetate in 90 min. Blood for ammonia, serum urea and creatinine, plasma benzoate, hippurate, phenylacetate, phenylacetylglutamine, and amino acids was obtained at 0, 120, 180, and 270 min. Urine was collected in four consecutive 6-h periods. Alanine caused hyperammonemia: maximum increase 107, 28-411 µM (geometric mean, 95% confidence interval); ammonia increments were nearly identical after alanine + benzoate (60, 17-213 µM) and alanine + phenylacetate (79, 13-467 µM) (NS). Mean plasma benzoate was 6.0 mM when extrapolated to the end of alanine + benzoate infusions; phenylacetate was 4.9 mM at the end of alanine + phenylacetate. Transient toxicity (dizziness, nausea, vomiting) occurred in four patients at the end of combined infusions, and we suggest upper therapeutic plasma concentrations of 4.5 mM for benzoate and 3.5 mM for phenylacetate. Benzoate and phenylacetate then decreased following first-order kinetics with t1/2s of 273 and 254 min, respectively. Maximal plasma hippurate (0.24, 0.14-0.40 mM) was lower than maximal phenylacetylglutamine (0.48, 0.22-1.06 mM, p=0.008). Orotic acid excretion was 5.62, 1.84-17.14 µmol/kg per h after alanine, but only 1.07, 0.04-25.62 µmol/kg per h after alanine + benzoate (p<0.151) and 2.74,0.01-16.25 µmol/ kg per h after alanine + phenylacetate (p<0.016). Urea excretions were in the same range after all loads. Urinary hippurate nitrogen after alanine + benzoate and phenylacetylglutamine, nitrogen after alanine + phenylacetate accounted for an average of 12 and 22 of that in urea in the first 6 h. Of the benzoate and phenylacetate given, 65 and 51% were excreted in 24 h as hippurate and phenylacetyl-glutamine, respectively; less than 3.5% appeared unchanged in urine.

BASOLATERAL-MEMBRANE TRANSPORT DEFECT FOR LYSINE IN LYSINURIC PROTEIN INTOLERANCE

In lysinuric protein intolerance intestinal, hepatic, and renal diaminoacid transport is defective, causing malnutrition. In patients fed with lysylglycine plasma glycine increased normally, but lysine increased as poorly as with free lysine. This is the first demonstration of defective peptide absorption. The primary defect is suggested to be at the basolateral cell membrane.

Renal manifestations of Henoch–Schönlein purpura in a 6-month prospective study of 223 children

Objective To assess the risk factors for developing Henoch–Schönlein purpura nephritis (HSN) and to determine the time period when renal involvement is unlikely after the initial disease onset. Design A prospective study of 223 paediatric patients to examine renal manifestations of Henoch–Schönlein purpura (HSP). The patients condition was monitored with five outpatient visits to the research centre and urine dipstick testing at home. Results HSN occurred in 102/223 (46%) patients, consisting of isolated haematuria in 14%, isolated proteinuria in 9%, both haematuria and proteinuria in 56%, nephrotic-range proteinuria in 20% and nephrotic-nephritic syndrome in 1%. The patients who developed HSN were significantly older than those who did not (8.2±3.8 vs 6.2±3.0 years, p<0.001, CI for the difference 1.1 to 2.9). Nephritis occurred a mean of 14 days after HSP diagnosis, and within 1 month in the majority of cases. The risk of developing HSN after 2 months was 2%. Prednisone prophylaxis did not affect the timing of the appearance of nephritis. The risk factors for developing nephritis were age over 8 years at onset (OR 2.7, p=0.002, CI 1.4 to 5.1), abdominal pain (OR 2.1, p=0.017, CI 1.1 to 3.7) and recurrence of HSP disease (OR 3.1, p=0.002, CI 1.5 to 6.3). Patients with two or three risk factors developed nephritis in 63% and 87% of cases, respectively. Laboratory tests or blood pressure measurement at onset did not predict the occurrence of nephritis. Conclusion The authors recommend weekly home urine dipstick analyses for the first 2 months for patients with HSP. Patients with nephritis should be followed up for more than 6 months as well as the patients with HSP recurrence.

Clinical course of extrarenal symptoms in Henoch–Schönlein purpura: a 6-month prospective study

Objective To describe the extrarenal symptoms and clinical course of Henoch–Schönlein purpura (HSP). Design A prospective national multicentre trial with 6-month follow-up. Patients A total of 223 newly diagnosed paediatric HSP patients. Results Purpura was the initial symptom in 73% of the patients and was preceded by joint or gastrointestinal manifestations in the rest by a mean of 4 days. Joint symptoms, abdominal pain, melena, nephritis and recurrences occurred in 90%, 57%, 8%, 46% and 25% of the patients, respectively. Orchitis affected 17/122 (14%) of the boys. Seven patients developed protein-losing enteropathy characterised by abdominal pain, oedema and serum albumin under 30 g/l, and an additional 49 patients had subnormal albumin levels without any proteinuria. Positive fecal occult blood (26/117, 22%) and α1-antitrypsin (7/77, 9%) suggested mucosal injury even in the patients without gastrointestinal symptoms. HSP was often preceded by various bacterial, especially streptococcal (36%) and viral infections. Previous streptococcal infection did not induce changes in the level of complement component C3. Recurrences were more frequent in patients >8 years of age (OR 3.7, CI 2.0 to 7.0, p<0.001) and in patients with nephritis (OR 4.6, CI 2.3 to 8.9, p<0.001). Patients with severe HSP nephritis had more extrarenal symptoms up to 6 months. There was no difference in the clinical course between the prednisone-treated and non-treated patients during the 6-month follow-up. Conclusions Serum albumin is often low in HSP patients without proteinuria, due to protein loss via the intestine. Although corticosteroids alleviate the symptoms, they seem not to alter the clinical course of HSP during 6 months of follow-up.

Lysinuric protein intolerance: A two-year trial of dietary supplementation therapy with citrulline and lysine†

In lysinuric protein intolerance, a disease resulting from an autosomal recessive disorder of diamino acid transport, citrulline, unlike arginine and lysine, is absorbed normally from the intestine. In 19 patients with LPI, the status after 2 years of treatment with citrulline or citrulline + lysine was compared with that during the preceding period of treatment with arginine. Administration of citrulline led to improved protein nutrition, as indicated by increases in daily protein intake, blood hemoglobin values, and plasma albumin and valine concentrations. Normal excretion of orotic acid indicated adequate urea cycle function. Seven of the nine stunted children had marked catch-up growth. Of four patients biopsied twice and having initially severe fatty degeneration of the liver, two had improved histology. However, hepato- and splenomegaly, and several biochemical abnormalities in the serum remained unchanged. Giving additional lysine did not enhance the favorable effect, but in some patients provoked abdominal cramps and diarrhea. Citrulline is the most valuable agent for treatment of LPI. Although not curative, it corrects the deficiency of the urea cycle intermediates and protects the patients from hyperammonemia and its consequences.

New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies

Background:We report a new mutation in the human DNAJC19 gene that causes early onset dilated cardiomyopathy syndrome (DCMA).Methods:Two brothers of Finnish origin presented with an unusual combination of early onset dilated cardiomyopathy syndrome, a disease which was associated with cardiac noncompaction, microcytic anemia, ataxia, male genital anomalies and methylglutaconic aciduria type V. Suspicion of a DCMA syndrome prompted sequencing of the human DNAJC19 gene.Results:Sequencing of the human DNAJC19 gene showed a homozygous single nucleotide (A) deletion in alanine 63 coding triplet in exon 6, which does not immediately cause amino acid change but leads 11 amino acids later to a stop codon and to premature termination of the peptide. This DNAJC19 protein is located in the inner mitochondrial membrane and has been shown to function as a mitochondrial chaperone.Conclusion:This is the first clinical report of DCMA syndrome, a human DNAJC19 deficiency, that is related to cases of severe dilated cardiomyopathy diagnosed in Europe. DNAJC19 deficiency causes a relatively specific finding in urinary organic acid analysis (methylglutaconic aciduria type V), which together with the clinical features of the ensuing cardiac disease, allows for effective screening before undertaking molecular genetic analysis.

A clinical score predicting a brief and uneventful course of newly diagnosed idiopathic trombocytopenic purpura in children

The Nordic idiopathic thrombocytopenic purpura study data showed that morbidity occurred mainly in children with thrombocytopenia lasting >3 months, whereas, the risk period with platelet counts <20 × 109/l was short and the number of bleeding events low in children with shorter disease duration. These brief, uneventful courses were predicted by developing a scoring system based on six clinical features: abrupt onset (weight 5), age <10 years (3), preceding infection (2), platelet count <5 × 109/l, wet purpura (1) and male gender (1). The score was derived and validated in two different cohorts of children. High scores (10–14) clearly identified low‐risk patients. The score provides valid prognostic information and may be useful in clinical decision‐making.

Orotic Aciduria in Lysinuric Protein Intolerance: Dependence on the Urea Cycle Intermediates

Summary: Urinary excretion of orotic acid was measured in controls and in subjects homozygous and heterozygous for lysinuric protein intolerance under various conditions of amino nitrogen intake. In all situations, the controls excreted less than 28 μg/kg/hr. Only one of the two heterozygotes studied differed from the controls. The orotic aciduria of homozygotes was normal in fasting but increased on a self-chosen low-protein diet (log mean, 80; range, 8 to 588 μg/kg/hr in 24-hr urine), after cows milk protein, 0.5 g/kg (769; 251 to 1747 μg/kg/hr in 4 to 6-hr urine), oral ammonium lactate, 2.5 mmoles/kg (95; 15 to 1127 μg/kg/hr in 1.5-hr urine), and IV alanine, 6.6 mmoles/kg (519; 47 to 1831 μg/kg/hr in 6-hr urine).Giving ornithine or citrulline IV with the infusion of alanine prevented the increase in orotic acid excretion. Given orally, citrulline was more efficient than ornithine or arginine. To prevent the hyperammonemic and orotic aciduric responses with ornithine, its plasma concentrations needed to be higher than normal.Orotic aciduria is a reliable indicator of the function of the urea cycle in lysinuric protein intolerance and facilitates monitoring of the treatment of this disease.Speculation: The parallel changes in urinary orotic acid and blood ammonia concentrations in lysinuric protein intolerance suggest a close link between the urea cycle and the pyrimidine pathway, probably via carbamyl phosphate and asparate. Follow-up of orotic aciduria is a simple and presumably accurate method for monitoring the home treatment of disorders of the urea cycle.