A holistic approach to the patients/ Families with inborn errors of metabolism.

BACKGROUND: Diagnosis, treatment, and care of inborn errors of metabolism require well organized interdisciplinary teams. Holistic approaches comprise the system of all elements and relations between elements necessary for an optimal function of the system. METHODS: Following the rule "structure follows function" based on scientific, academic, and clinical experience the elements of the system providing diagnosis, treatment, and care for inborn errors of metabolism are defined and described. RESULTS: A holistic approach to inborn errors of metabolism comprising 10 elements is suggested, established, and controlled by an interdisciplinary metabolic team organized as a disease, and a case management program based on evidence-based guidelines is suggested. Quality assurance and quality control will not only improve the treatment of the individual but also the health system. CONCLUSION: The holistic approach is a joint project of the team of health care professionals and the person with a condition, allowing them to see the patient's individual medical, behavioral, social, legal, and economic context. For practical, technical, and economic reasons this will only be possible in centers caring for a critical number of individuals.

Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation.

Studies over the last 20 years have demonstrated that increased inflammation and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are two of the most consistent biological findings in major depression and are often associated: but the molecular and clinical mechanisms underlying these abnormalities are still unclear. These findings are particularly enigmatic, especially considering the accepted notion that high levels of cortisol have an anti-inflammatory action, and therefore the coexistence of inflammation and hypercortisolemia in the same diagnostic group appears counter-intuitive. To celebrate the 2015 Anna-Monika Foundation Award to our laboratory, this review will discuss our own 20 years of research on the clinical and molecular evidence underlying the increased inflammation in depression, especially in the context of a hyperactive HPA axis, and discuss its implications for the pathogenesis and treatment of this disorder.

Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency.

BACKGROUND: SLC6A8, an X-linked gene, encodes the creatine transporter (CRTR) and its mutations lead to cerebral creatine (Cr) deficiency which results in mental retardation, speech and language delay, autistic-like behaviour and epilepsy (CRTR-D, OMIM 300352). CRTR-D represents the most frequent Cr metabolism disorder but, differently from Cr synthesis defects, that are partially reversible by oral Cr supplementation, does not respond to Cr treatment even if precociously administrated. The precursors of Cr are the non-essential amino acids Glycine (Gly) and Arginine (Arg), which have their own transporters at the brain-blood barrier level and, therefore, their supplementation appears an attractive and feasible therapeutic option aimed at stimulating Cr endogenous synthesis and, in this way, at overcoming the block of Cr transport within the brain. However, until now the effects of Arg and/or Gly supplementation on Cr brain levels and behaviour have been controversial. METHODS: In this study five Italian male patients affected by CRTR-D were supplemented with oral L-Arg at a dosage of 300 mg/kg/day divided into 3 doses, for 24-36 months. Biochemical and plasmatic amino acids examinations and thyroid hormone dosages were periodically performed. Moreover, Proton and Phosphorus Magnetic Resonance Spectroscopy (MRS) was monitored during follow-up in concurrence with neuropsychological evaluations. RESULTS: During L-Arg treatment a clinical improvement in motor skills and to a lesser extent in communication and attention was observed. In addition, all patients had a reduction in the number and frequency of epileptic seizures. Daily living skills appeared also to be positively influenced by L-Arg treatment. Moreover, Total Cr and especially PhosphoCr, evaluated by proton and phosphorus spectroscopy, showed a mild increase, although well below the normal range. CONCLUSION: This study provides information to support the effectiveness of L-Arg supplement treatment in CTRT-D patients; in fact the syndromic pattern of cognitive and linguistic deficit presented by CRTR-D patients was partially altered by L-Arg supplementation especially at a qualitative clinical level. Oral L-Arg may represent not only a protective factor towards a further cognitive decline, but can lead to the acquisition of new skills.

Vitamins, minerals, and mood.

In this article, the authors explore the breadth and depth of published research linking dietary vitamins and minerals (micronutrients) to mood. Since the 1920s, there have been many studies on individual vitamins (especially B vitamins and Vitamins C, D, and E), minerals (calcium, chromium, iron, magnesium, zinc, and selenium), and vitamin-like compounds (choline). Recent investigations with multi-ingredient formulas are especially promising. However, without a reasonable conceptual framework for understanding mechanisms by which micronutrients might influence mood, the published literature is too readily dismissed. Consequently, 4 explanatory models are presented, suggesting that mood symptoms may be expressions of inborn errors of metabolism, manifestations of deficient methylation reactions, alterations of gene expression by nutrient deficiency, and/or long-latency deficiency diseases. These models provide possible explanations for why micronutrient supplementation could ameliorate some mental symptoms.

Cranial MR spectroscopy of tetrahydrobiopterin deficiency.

BACKGROUND AND PURPOSE: Severe and progressive neurologic disease remains a problem for patients with hyperphenylalaninemia due to a deficiency of tetrahydrobiopterin (BH4), even with early diagnosis and despite treatment with BH4 and neurotransmitter precursors. Few reports have included the associated imaging characteristics. Our purpose was to describe the imaging features of BH4-deficient patients identified by neonatal screening in a Taiwanese population and to correlate the imaging features with the treatment. METHODS: This study analyzed the cases of eight BH4-deficient patients who were examined by MR imaging and MR spectroscopy. Analysis of the findings was correlated with the clinical findings. RESULTS: One patient whose intelligence quotient score was lower than those of the other seven patients experienced seizures in conjunction with central white matter signal changes on MR images and a lactate peak on MR spectroscopy. Lactate peak was revealed in another patient who had marked elevations of N-acetylaspartate:creatine and N-acetylaspartate:choline ratios. Although most patients had a higher than average N-acetylaspartate:creatine or N-acetylaspartate:choline ratio, the patient who had decreases of both ratios possessed the highest intelligence quotient scores among the eight patients. In addition, the myoinositol:choline ratio correlated positively with the average BH4 dosage (P =.027, r = 0.027) and the choline:creatine ratio correlated negatively with the average 5-hydroxytryptophan dosage (P =.035, r = -0.742). CONCLUSION: Compared with classical phenylketonuria, patients with BH4 deficiency have fewer white matter changes revealed by MR imaging but more changes revealed by MR spectroscopy. MR spectroscopy is a potential method with which to monitor the dosages of supplements used to treat this disorder. In addition, MR spectroscopy may be helpful in gaining understanding of the neurophysiological changes that occur in association with this disease.

[Prenatal diagnosis: a chance? risk? dilemma?]. / Diagnostyka prenatalna: szansa? Zagrozenie? Dylemat?

PIP: In research on congenital metabolic disorders, a biochemist can choose between the theoretical and the practical approach. The diagnosis of metabolic diseases relies on 1) the determination of the presence of metabolites under normal conditions that are direct substrates of the defective enzyme (e.g., the Gm2 ganglioside in the brain tissue of a patient with Tay-Sachs disease); 2) the determination of the lack or insufficiency of the direct product of the defective enzyme (e.g., aryl sulfatase A in the cells of patients with metachromatic leukodystrophy), hormone (hypothyroidism), or receptor (congenital hypercholesterolemia); 3) determination of substance whose reduction was established by experimentation, but the cause of the decrease is not known (ceruloplasmin in Wilson's disease); and 4) DNA analysis. Metabolic impairment of genetic origin is not treatable. The disease can be prevented by 1) removing the inappropriate metabolite (e.g., copper accumulation can be avoided by giving penicillamine or zinc salts); 2) limiting those substances in the critical phase of childhood that are components of the defective enzyme (e.g. gluten reduction in colic and protein in phenylketonuria); 3) supplementing the insufficient metabolite (e.g., phosphate in hypophosphatemia by sound for 12 hours a day); 4) protecting the patients (e.g. from light in porphyria); and 5) treatment by substances (giving coagulation factor VIII in hemophilia and thyroid hormones in hypothyroidism). There is a dilemma in subjecting patients to a diagnosis of progression to Huntington's chorea 20 years in advance or informing them about the high risk of hereditary disease for the next child (25% for the recessive and 50% for the dominant mode). Ethical committees have usually opted for a recommendation of selective abortion in clear-cut cases. Increasingly refined diagnostic methods have magnified the responsibility of the biochemist.^ieng