Sporadically, patients with a proven defect in either mFAO or OXPHOS are described presenting with a metabolic profile and clinical phenotype expressing concurrent defects in both pathways. Biochemical linkages between both processes are tight. Therefore, it is striking that concurrent dysfunction of both systems occurs so infrequent. In this review, the linkages between OXPHOS and mFAO and the hypothesized processes responsible for concurrent problems in both systems are reviewed, both from the point of view of primary biochemical connections and secondary cellular responses, i.e. signaling pathways constituting nutrient-sensing networks. We propose that affected signaling pathways may play an important role in the phenomenon of concurrent defects. Recent data indicate that interference in the affected signaling pathways may resolve the pathological phenotype even though the primary enzyme deficiency persists. This offers new (unexpected) prospects for treatment of these inborn errors of metabolism. This article is part of a Special Issue entitled: From Genome to Function.

Glycogen storage disease type Ia (GSD Ia) is characterized by severe hypercholesterolaemia and hypertriglyceridaemia. Little is known about the aetiology of the hyperlipidaemia in GSD Ia. Adipokines play an important regulatory role in lipid metabolism. We investigated whether adipokine concentrations were correlated with the degree of hyperlipidaemia in GSD Ia patients. Six patients with GSD Ia were studied in semi-fasted conditions. Adiponectin, but not leptin, correlated (r(2) = -0.79, p = 0.02) with plasma triglyceride concentrations in the GSD Ia patients. Leptin correlated well with BMI (r(2) = 0.59, p < 0.01). However, neither body mass index (BMI) nor homeostasis model assessment (HOMA), as a marker of insulin sensitivity, correlated with triglyceride concentrations. Although a small number of patients were studied, these results indicate that adiponectin concentrations are correlated with the degree of hypertriglyceridaemia in GSD Ia. Pharmacological treatment aimed at increasing adiponectin levels might improve the metabolic status of these patients.

A 23-year-old woman and a 13-year-old boy were diagnosed with mitochondrial respiratory chain disease. The woman had muscle pain, fatigue and bilateral ophthalmoplegia--symptoms consistent with Kearns-Sayre syndrome. The boy had aspecific symptoms; eventually, reduced activity of complex 1 was found to be the cause of the mitochondrial respiratory chain disease in the boy and his mother, who had suffered from unexplained fatigue and muscle pain for 15 years. Mitochondrial diseases often involve several organ systems. Diagnosis can be difficult, because laboratory tests such as serum and urinary lactate and creatine kinase have low sensitivity and specificity. Biochemical assessment of muscle biopsy can reveal reduced oxidation ATP synthesis and sometimes specific abnormalities in individual protein complexes. DNA analysis may be helpful in demonstrating mitochondrial or nuclear mutations or deletions. The goal of treatment is to increase mitochondrial ATP production, improve clinical symptoms and enhance stamina. Replacement of the following substances (also referred to as cofactors) may be attempted: co-enzyme Q10, antioxidants (lipoic acid, vitamins C and E), riboflavin, thiamine, creatine and carnitine. Evidence regarding the optimal treatment approach is lacking; one usually has to rely on observing effects in the individual patient.

Om inzicht te krijgen in hun mening over de uitbreiding van de hielprik werd aan 396 moeders die in het UMCG waren bevallen een enquêteformulier gestuurd. Iets minder dan de helft van de vragenlijsten werd ingevuld retour ontvangen. De respondenten staan positief tegenover de uitbreiding van het neonatale screeningsprogramma. Dat een aandoening maar uiterst zelden voorkomt of de test met veel fout-positieve uitslagen gepaard gaat is voor velen van ondergeschikt belang. Eenzelfde houding wordt aangetroffen als het gaat om aandoeningen waarvoor geen behandelingsmogelijkheden bestaan. De nieuwe hielprik toont ook dragerschap van sikkelcelanemie aan. Een grote meerderheid van de respondenten wil over deze uitslag worden geïnformeerd. Bij gevonden dragerschap zouden veel ouders ook zichzelf laten onderzoeken en hun familie gaan informeren.

Summary The outcome was determined of population‐wide neonatal screening for medium‐chain acyl‐CoA dehydrogenase (MCAD) deficiency using tandem mass spectrometry (MS/MS) in The Netherlands, between October 2003 and September 2005. Prospective population‐wide neonatal screening for MCAD deficiency was performed in the northern part of The Netherlands. In newborns with blood octanoylcarnitine (C 8:0 ) concentrations ≥0.3 μmol/L, clinical and laboratory follow‐up was initiated, including MCAD enzymatic measurements which played a decisive role. In a 2‐year period, 66 216 newborns were investigated for MCAD deficiency and follow‐up was initiated in 28 newborns. True‐positives ( n = 14) were identified based upon MCAD enzyme activity <50%, measured with hexanoyl‐CoA as substrate. The observed prevalence of MCAD deficiency was 1/6600 (95% CI: 1/4100–1/17 400). In addition to an elevated C 8:0 concentration, a C 8:0 /C 10:0 molar ratio >5.0 turned out to differentiate between false‐positives and true‐positives. Measurement of MCAD activity using phenylpropionyl‐CoA as a substrate further discriminated between newborns with MCAD deficiency and so‐called mild MCAD deficiency. To summarize, neonatal screening for MCAD deficiency in the northern part of The Netherlands resulted in the predicted number of affected newborns. Measurement of MCAD activity in leukocytes or lymphocytes using phenylpropionyl‐CoA as a substrate can be regarded as the gold standard to diagnose MCAD deficiency upon initial positive screening test results.

While the presence of hyperlipidaemia in glycogen storage disease (GSD) type Ia and Ib is generally accepted, few investigators have adequately assessed lipid profiles of GSD III in children, in whom the presence of hyperlipidaemia may be most prominent. We analysed the lipid profiles in 44 GSD III patients from 6 months to 30 years of age. Hypertriglyceridaemia and hypercholesterolaemia were common in children younger than 3 years of age. Hypertriglyceridaemia correlated negatively with age, and may reflect increased severity of hypoglycaemia in this younger population. The presence of hyperlipidaemia during childhood in these patients identifies another GSD population that could be at risk for early cardiovascular disease (CVD). Consequently, the outcome of clinical trials investigating the vascular effect of hyperlipidaemia in GSD applies to types other than GSD I.

Despite their unfavourable cardiovascular risk profile, patients with glycogen storage disease type Ia (GSD Ia) do not develop premature atherosclerosis. We hypothesized that this paradox might be related to a decreased formation of advanced glycation end products (AGEs) resulting from lifetime low plasma glucose levels and decreased oxidative stress.

We describe a 16-year old boy with glycogen storage disease type Ib, homozygous for the common 1211-1212delCT mutation, who never experienced neutropenia, and did not suffer from frequent infections or inflammatory bowel disease. In addition, neutrophil function tests showed no abnormalities.