Klaziena Niezen-Koning

Glycogen storage disease type II: birth prevalence agrees with predicted genotype frequency

Objectives: To compare the overall birth prevalence of diagnosed glycogen storage disease type II (GSD II) with the predicted frequency based on mutation screening, in order to determine whether GSD II is an underdiagnosed condition, and to analyze which medical disciplines recognize GSD II. Methods: Retrospective data on all enzymatic diagnoses of GSD II were collected from diagnostic labs throughout the Netherlands, covering the period from January 1, 1972 to December 31, 1996. Age-specific diagnostic incidence rates were calculated for the entire study period. By adding together the diagnostic incidences for all age groups, we calculated the birth prevalence of diagnosed GSD II and compared these figures with the predicted frequency based on mutation screening in a random sample from the general population. The medical specialization of the referring clinicians was also recorded. Results: GSD II was diagnosed in 154 individuals, including 11 prenatal diagnoses. The birth prevalences of the various phenotypes were 1/101,000 (infantile form), 1/720,000 (juvenile form) and 1/53,000 (adult form). The birth prevalence of the adult and infantile phenotype together was 1/35,000. Eighty-two percent of the patients were diagnosed in university hospitals. Of the patients with infantile GSD II, 71% were diagnosed by a pediatrician, whereas most patients with adult GSD II were diagnosed by a neurologist (80%). Conclusions: There is no evidence for the underdiagnosis of GSD II in the Netherlands, as the calculated birth prevalences of the disease are consistent with previous predictions based on mutation screening in a random sample of newborns. The worldwide birth prevalence of the disease may well be higher than 1 in 100,000. GSD II is mainly diagnosed in university hospitals.

A patient with lethal cardiomyopathy and a carnitine-acylcarnitine translocase deficiency

In the last few years, increasing attention has been paid to the diagnosis of defects in mitochondrial fatty acid beta-oxidation in man (Stanley 1987). Clinical diagnosis of these disorders is difficult, because affected patients are often free of symptoms between metabolic crises (Hale and Bennett 1992). A total of 13 inherited beta-oxidation defects have been described (Coates and Tanaka 1992). Among those 13 disorders there are four that affect the transport into mitochondria of long-chain fatty acids that are activated to their CoA esters. Defects have been described for the plasma-membrane carnitine transporter and carnitine palmitoyltransferase types 1 and 2 (CPT I and II). Recently three patients have been described with a carnitine- acylcarnitine translocase deficiency, a defect in the transfer of fatty acylcarnitines across the inner mitochondrial membrane in exchange for free carnitine (Pande et al 1993; Stanley et al 1992; Brivet et al 1994). In this short communication we describe what is to our knowledge the fourth case of a carnitine-acylcarnitine translocase deficiency.

Clinical and diagnostic approach in unsolved CDG patients with a type 2 transferrin pattern

Dysmorphic features, multisystem disease, and central nervous system involvement are common symptoms in congenital disorders of glycosylation, including several recently discovered Golgi-related glycosylation defects. In search for discriminative features, we assessed eleven children suspected with a Golgi-related inborn error of glycosylation. We evaluated all genetically unsolved patients, diagnosed with a type 2 transferrin isofocusing pattern in the period of 1999-2009. By combining biochemical results with characteristic clinical symptoms, we used a diagnostic flow chart to approach the underlying defect in patients with congenital disorders of glycosylation-IIx. According to specific symptoms and laboratory results, we initiated additional, targeted biochemical and genetic studies. We found a distinctive spectrum of congenital disorders of glycosylation type 2-associated anomalies including sudden hearing loss, brain malformations, wrinkled skin, and epilepsy in combination with skeletal dysplasia, dilated cardiomyopathy, sudden cardiac arrest, abnormal copper and iron metabolism, and endocrine abnormalities in our patients. One patient with severe cortical malformations and mild skin abnormalities was diagnosed with a known genetic syndrome, due to an ATP6V0A2 defect. Here, we present unique congenital disorders of glycosylation type 2-associated anomalies, including both ATPase-related and unrelated cutis laxa and sensorineural hearing loss, a recently recognized symptom of congenital disorders of glycosylation. Based on our findings, we recommend clinicians to consider congenital disorders of glycosylation in patients with cardiac rhythm disorders, spondylodysplasia and biochemical abnormalities of the copper and iron metabolism even in absence of intellectual disability.

Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: Disease spectrum and natural course in attenuated patients

Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-B], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD-B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients. Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6-12 months for pulmonary function tests, 6 minute walk test (6 MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers. Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13years, range 1-59 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2, 3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6 MWT. Bone marrow fat fractions were decreased, indicating the presence of storage macrophages. Lung involvement was not related to the extent of visceromegaly, cytopenia or bone marrow involvement. In conclusion, in NPD-B patients pulmonary disease is the most debilitating feature. Disease manifestations are mostly stable in attenuated patients. Bone marrow infiltration is a less prominent feature of the disease.

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

AbstractMolecular chaperones assist protein folding, and variations in their encoding genes may be disease-causing in themselves or influence the phenotypic expression of disease-associated or susceptibility-conferring variations in many different genes. We have screened three candidate patient groups for variations in the HSPD1 and HSPE1 genes encoding the mitochondrial Hsp60/Hsp10 chaperone complex: two patients with multiple mitochondrial enzyme deficiency, 61 sudden infant death syndrome cases (MIM: #272120), and 60 patients presenting with ethylmalonic aciduria carrying non-synonymous susceptibility variations in the ACADS gene (MIM: *606885 and #201470). Besides previously reported variations we detected six novel variations: two in the bidirectional promoter region, and one synonymous and three non-synonymous variations in the HSPD1 coding region. One of the non-synonymous variations was polymorphic in patient and control samples, and the rare variations were each only found in single patients and absent in 100 control chromosomes. Functional investigation of the effects of the variations in the promoter region and the non-synonymous variations in the coding region indicated that none of them had a significant impact. Taken together, our data argue against the notion that the chaperonin genes play a major role in the investigated diseases. However, the described variations may represent genetic modifiers with subtle effects.

Determination of medium chain acyl-CoA dehydrogenase activity in cultured skin fibroblasts using mass spectrometry.

Medium chain acyl-CoA dehydrogenase deficiency, a defect of mitochondrial beta-oxidation, is one of the most frequently occurring among inborn errors of metabolism. We describe a rapid and sensitive gas chromatographic/mass spectrometric method allowing reliable assessment of medium chain acyl-CoA dehydrogenase activity in cultured skin fibroblasts. We investigated MCAD activity in three presumed medium chain acyl-CoA dehydrogenase deficient (MCADD) patients and 10 control subjects. The medium chain acyl-CoA dehydrogenase activity determined in three patients was 1.0 +/- 0.4 nmol.min-1.mg-1 protein (mean +/- SD; range: 0.6-1.4) and in controls it was 2.8 +/- 1.0 nmol.min-1.mg-1 protein (mean +/- SD; range: 1.6-4.4).

External quality assurance programme for enzymatic analysis of lysosomal storage diseases : A pilot study

Inborn errors of metabolism are rare and laboratories performing diagnostic tests in this field must participate in external quality assurance (EQA) schemes to demonstrate their competence and also to maintain sufficient experience with patient material. EQA schemes for metabolite analyses are available (ERNDIM), but corresponding EQA schemes for enzyme analyses are nonexistent. In this paper we describe a pilot study on lysosomal enzyme testing by four centres in The Netherlands. Quantitative aspects of EQA were studied by interlaboratory comparison of activities of six lysosomal enzymes in a series of buffy coat samples. Interlaboratory variance was enormous. To reduce variance caused by methodological differences, participants reported enzyme activities relative to mean normal values. β-D-Galactosidase activities compared well between the participating laboratories (average interlaboratory CV 13%), but for other enzymes large differences were observed, e.g. sphingomyelinase (average CV 38%). Diagnostic proficiency was tested with cultured fibroblasts. In 45 out of a total of 48 tests (12 cell lines, 4 participants) the correct diagnosis was accomplished on the basis of merely biochemical investigations, i.e. without clinical data of the patients. In a survey using blood of a late-onset Pompe disease patient, less conclusive results were obtained. A stable enzyme source was developed for easy distribution. Most lysosomal enzymes were stable upon lyophilization of leukocyte homogenates and during subsequent storage of the freeze-dried material at room temperature, in particular when cryolyoprotectant was added. Shipment of such lyophilized samples is simple and cheap and ideal for an EQA scheme. Our study shows that an EQA programme for enzymatic testing of lysosomal storage diseases is necessary to accomplish reliable diagnostic procedures for lysosomal storage diseases. We recommend that EQA for lysosomal enzymes be implemented through ERNDIM.

Long-Term and Short-Term Effects of Dietary Cholesterol and Fats in the Mongolian Gerbil

In long-term and short-term experiments with Mongolian gerbils the effects of various dietary fats and different amounts of cholesterol on progeniture and liver pathology were studied. In contrast to palm kernel oil, with 8.75% (w/w) of sunflower seed oil we observed fewer litters and a decreased survival of the sucklings. On 0.2% of cholesterol we observed severe hypercholesterolemia and storage of cholesterol ester in the liver, ultimately leading to cirrhosis. On 0.05% for 6 months the gerbils stayed in good health. Progeniture was unaffected on this level of intake.

Effects of dietary cholesterol in the Mongolian gerbil and the rat : a comparative study

To come to a better understanding of the diet-induced cholesterol-ester storage in the gerbil liver, the reactions of the gerbil to 0·2% of cholesterol in the diet during 4 weeks were compared with those of the rat consuming the same diet. The major reason for the increased hepatic cholesterol-ester storage in the cholesterol-fed gerbil is the low cholesterol turnover in this species. This contrasts with the rat. Although faecal acidic steroid excretion can be slightly increased during cholesterol feeding in the gerbil, this increase is not sufficient to compensate for the quantity of dietary cholesterol when administered at the 0·2% level.

Pre-eclampsia in a woman whose child suffered from lethal carnitine-acylcarnitine translocase deficiency

WB Geven,a KE Niezen-Koning,b A Timmer,c AJ van Loon,d RJA Wanders,e FJ van Spronsenf a Department of Pediatrics, Martini Hospital, Groningen, the Netherlands b Laboratory for Metabolic Diseases and cDepartment of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, d Department of Obstetrics, Martini Hospital, Groningen, the Netherlands e Department of Clinical Chemistry and Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands f Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Correspondence: Dr WB Geven, Department of Pediatrics, Martini Hospital, PO Box 30033,9700 RM Groningen, the Netherlands. Email w.b.geven@MZH.nl