F. Maillot

Late diagnosis of ornithine transcarbamylase defect in three related female patients: polymorphic presentations.

Objective To describe three female patients of one family with different phenotypes of the same mutation of the ornithine transcarbamylase gene. X-linked inherited ornithine transcarbamylase deficiency is the most frequent urea cycle disorder. Many of the hemizygous males die during the neonatal period. Women, who are mostly healthy carriers, can also develop symptomatic hyperammonemia. Design Case study. Setting Intensive care unit and internal medicine unit at a university hospital. Patients The 20-yr-old female propositus was hospitalized for unexplained coma. She had a history of headaches, recurrent vomiting, specific anorexia for high-protein foods, and an acute neurologic crisis with alleged food poisoning 8 yrs before. The present episode began with psychiatric symptoms and seizures treated by diazepam and valproate. This unexplained coma, associated with respiratory alkalosis and major brain swelling on brain computed tomography scan, revealed hyperammonemia leading to the diagnosis of ornithine transcarbamylase deficiency. Continuous venovenous hemodiafiltration and treatment with sodium benzoate and phenylbutyrate improved the situation. However, the patient had some neurologic sequelae. DNA studies have disclosed a pathogenic mutation in the ornithine transcarbamylase gene of the patient, her mother, and her sister. For the mother, the disease was overlooked despite the onset of unusual headaches and neurologic signs that mimicked a cerebral tumor 12 yrs before. The 28-yr-old sister of the propositus has always been asymptomatic, even during pregnancy. Conclusions Diagnosis of urea cycle disorder should be considered in any patient with unexplained neurologic and psychiatric disorders with selective anorexia, even in adulthood. Unexplained coma with cerebral edema and respiratory alkalosis requires urgent measurement of ammonemia and metabolic work-up.

Key European guidelines for the diagnosis and management of patients with phenylketonuria

We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 μmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 μmol/L and 600 μmol/L, and lifelong treatment is recommended if the concentration is more than 600 μmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 μmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 μmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 μmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy.

Adult phenylketonuria outcome and management

The problem to evaluate treatment outcome in adult PKU (phenylketonuric) patients lies in the heterogeneity of the adult PKU population. This heterogeneity is not only based on the different treatment history of every individual patient but also on the different severity of the underlying defect of the enzyme phenylalanine hydroxylase. Recent, partly double blind studies in adult PKU patients further support recommendation for lifelong treatment. However, it has become evident that dietary treatment is suboptimal and continuation to adulthood often not accepted. Late detected PKU patients (up to 4-6 years of age) benefit from strict dietary treatment and are able to catch up in intellectual performance. Untreated, severely retarded patients with behavioral changes may benefit from introduction of dietary treatment. However, individual decision is necessary and based on the personal situation of the patient. In early and well treated patients a number of studies have demonstrated that cognitive and neurosychologic tests are different from controls. In addition there is evidence that patients with higher blood phenylalanine (phe) levels demonstrate more often psychiatric symptoms like depression and anxiety. Medical problems are more often observed: there are certain risks as impaired growth, decreased bone mineral density and nutrional deficits probably caused by dietary treatment with an artificial protein substitute and/or missing compliance with an unpleasant diet. The long term risk of a strict dietary treatment must be balanced with the risk of higher blood phe (mean blood phenylalanine >600-900 μmol/L) on cognitive and neuropsychological functions and psychiatric symptoms. Further studies should consider the role of blood phe exposure for brain development in childhood and for brain function in all ages. Besides mean blood phe, fluctuation of blood phe over time is important. Fluctuation of blood phe is decreased by sapropterin treatment in responsive patients which would on the long term may have positive effects on cognitive outcome. Further studies also should include adult PKU patients.

A practical approach to maternal phenylketonuria management

SummaryMore women with phenylketonuria are becoming pregnant and need appropriate management to avoid the effects of raised phenylalanine on the fetus: facial dysmorphism, microcephaly, growth retardation, developmental delay and congenital heart disease. Here we describe our experiences from a single centre gained over almost three decades. A series of six cases is presented to illustrate key points in management. Ideally, phenylalanine-restricted diet is started before conception in a planned fashion, but some women present pregnant and blood phenylalanine must be lowered rapidly. The aims of management are to maintain blood phenylalanine concentration in the target range (100–250 μmol/L) before and throughout the pregnancy, and to ensure adequate maternal nutrition and appropriate weight gain. Blood phenylalanine is monitored twice, three times a week, before and after conception respectively. Weight is monitored on a weekly basis and key micronutrients are monitored every 6–8 weeks in clinic. From the second trimester onwards, dietary phenylalanine intake has to be promptly increased, as phenylalanine tolerance increases rapidly. Postnatal management includes a neurological assessment of the infant at 4–8 weeks and an echocardiogram for infants conceived off diet. Subsequently, offspring are seen at 1 year, 4 years, 8 years and 14 years for neuropsychometric evaluations. Regular follow-up of the mother remains important whether on or off a phenylalanine-restricted diet.

Exercise intolerance in Glycogen Storage Disease Type III: Weakness or energy deficiency?

Myopathic symptoms in Glycogen Storage Disease Type IIIa (GSD IIIa) are generally ascribed to the muscle wasting that these patients suffer in adult life, but an inability to debranch glycogen likely also has an impact on muscle energy metabolism. We hypothesized that patients with GSD IIIa can experience exercise intolerance due to insufficient carbohydrate oxidation in skeletal muscle. Six patients aged 17-36-years were studied. We determined VO 2peak (peak oxygen consumption), the response to forearm exercise, and the metabolic and cardiovascular responses to cycle exercise at 70% of VO 2peak with either a saline or a glucose infusion. VO 2peak was below normal. Glucose improved the work capacity by lowering the heart rate, and increasing the peak work rate by 30% (108 W with glucose vs. 83 W with placebo, p=0.018). The block in muscle glycogenolytic capacity, combined with the liver involvement caused exercise intolerance with dynamic skeletal muscle symptoms (excessive fatigue and muscle pain), and hypoglycemia in 4 subjects. In this study we combined anaerobic and aerobic exercise to systematically study skeletal muscle metabolism and exercise tolerance in patients with GSD IIIa. Exercise capacity was significantly reduced, and our results indicate that this was due to a block in muscle glycogenolytic capacity. Our findings suggest that the general classification of GSD III as a glycogenosis characterized by fixed symptoms related to muscle wasting should be modified to include dynamic exercise-related symptoms of muscle fatigue. A proportion of the skeletal muscle symptoms in GSD IIIa, i.e. weakness and fatigue, may be related to insufficient energy production in muscle.

Reduced cardiolipin content decreases respiratory chain capacities and increases ATP synthesis yield in the human HepaRG cells

Cardiolipin (CL) is a unique mitochondrial phospholipid potentially affecting many aspects of mitochondrial function/processes, i.e. energy production through oxidative phosphorylation. Most data focusing on implication of CL content and mitochondrial bioenergetics were performed in yeast or in cellular models of Barth syndrome. Previous work reported that increase in CL content leads to decrease in liver mitochondrial ATP synthesis yield. Therefore the aim of this study was to determine the effects of moderate decrease in CL content on mitochondrial bioenergetics in human hepatocytes. For this purpose, we generated a cardiolipin synthase knockdown (shCLS) in HepaRG hepatoma cells showing bioenergetics features similar to primary human hepatocytes. shCLS cells exhibited a 55% reduction in CLS gene and a 40% decrease in protein expression resulting in a 45% lower content in CL compared to control (shCTL) cells. Oxygen consumption was significantly reduced in shCLS cells compared to shCTL regardless of substrate used and energy state analyzed. Mitochondrial low molecular weight supercomplex content was higher in shCLS cells (+60%) compared to shCTL. Significant fragmentation of the mitochondrial network was observed in shCLS cells compared to shCTL cells. Surprisingly, mitochondrial ATP synthesis was unchanged in shCLS compared to shCTL cells but exhibited a higher ATP:O ratio (+46%) in shCLS cells. Our results suggest that lowered respiratory chain activity induced by moderate reduction in CL content may be due to both destabilization of supercomplexes and mitochondrial network fragmentation. In addition, CL content may regulate mitochondrial ATP synthesis yield.

Iron Metabolism Disturbance in a French Cohort of ALS Patients

Objective. The aim of this study was to assess iron status in a cohort of amyotrophic lateral sclerosis (ALS) patients compared to controls in order to evaluate these parameters as a risk factor or a modifying factor of ALS. Methods. We collected serum iron, ferritin, transferrin, total iron-binding capacity, and transferrin saturation coefficient (TSC) from 104 ALS patients at the time of diagnosis and from 145 controls. We reported phenotypic characteristics and evolution parameters such as ALSFRS-R and forced vital capacity at diagnosis and after one year of follow-up. In a first step we compared iron status between ALS patients and controls, and then we evaluated the relation between iron status and disease evolution of ALS patients using univariate and multivariate analysis. Results. We observed increased concentrations of serum iron (P = 0.002) and ferritin (P < 0.0001) and increased TSC (P = 0.017) in ALS patients. We also showed an association between markers of iron status and high body weight loss in ALS patients. The multivariate analysis of survival highlighted a significant relation between ferritin level and disease duration (P = 0.038). Conclusion. This is the first study showing a higher concentration of serum iron in ALS patients, strengthening the involvement of a deregulation of iron metabolism in ALS.

P-ANCA cranial pachymeningitis : a case report

Pachymeningitis is an inflammatory process that thickens the dura mater. This disease has various etiologies including infectious, neoplastic, or autoimmune diseases. We present the case of a patient who developed cranial pachymeningitis with a clinical and biological picture suggestive of a neurological form of vasculitis. A 51-year-old woman developed rhinitis, otitis media, headaches, and deterioration of her condition after a course of recombinant hepatitis B vaccine. After a booster dose of the vaccine, she developed unilateral visual loss and impairment of multiple cranial nerves. Blood analysis showed inflammation and presence of antimyeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA). Cranial magnetic resonance imaging (MRI) showed pachymeningitis. A complete remission was obtained with immunosuppressive therapy. The initial clinical presentation and subsequent remission under immunosuppressive therapy were suggestive of a vasculitis with nervous system involvement. Though vasculitis was not proven histologically in this patient, we believe that MPO-ANCA-related autoimmunity provoked the patient’s disease as already reported in similar cases. As pachymeningitis is a fibrosing process, early recognition and treatment of an autoimmune etiology, even in the absence of previous pulmonary or renal involvement, is required to prevent definitive neurological impairment.

The complete European guidelines on phenylketonuria: diagnosis and treatment

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

Comparison of idiopathic (isolated) aortitis and giant cell arteritis-related aortitis. A French retrospective multicenter study of 117 patients.

OBJECTIVES The aim of the study was to compare clinical/imaging findings and outcome in patients with idiopathic (isolated aortitis, IA) and with giant cell arteritis (GCA)-related aortitis. METHODS Patients from 11 French internal medicine departments were retrospectively included. Aortitis was defined by aortic wall thickening >2mm and/or an aortic aneurysm on CT-scan, associated to inflammatory syndrome. Patients with GCA had at least 3 ACR criteria. Aortic events (aneurysm, dissection, aortic surgeries) were reported, and free of aortic events-survival were compared. RESULTS Among 191 patients with non-infectious aortitis, 73 with GCA and 44 with IA were included. Patients with IA were younger (65 vs 70 years, p=0.003) and comprised more past/current smokers (43 vs 15%, p=0.0007). Aortic aneurisms were more frequent (38% vs 20%, p=0.03), and aortic wall thickening was more pronounced in IA. During follow-up (median=34 months), subsequent development of aortic aneurysm was significantly lower in GCA when compared to IA (p=0.009). GCA patients required significantly less aortic surgery during follow-up than IA patients (p=0.02). Mean age, sex ratio, inflammatory parameters, and free of aortic aneurism survival were equivalent in patients with IA ≥ 60 years when compared to patients with GCA-related aortitis. CONCLUSIONS IA is more severe than aortitis related to GCA, with higher proportions of aortic aneurism at diagnosis and during follow-up. IA is a heterogeneous disease and its prognosis is worse in younger patients <60 years. Most patients with IA ≥ 60 years share many features with GCA-related aortitis.