PKU dietary handbook to accompany PKU guidelines.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. MAIN BODY: In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment. CONCLUSION: This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.

Cinacalcet treatment for stable kidney transplantation patients with hypercalcemia due to persistent secondary hyperparathyroidism: a long-term follow-up.

BACKGROUND: Cinacalcet is an effective treatment for hypercalcemia due to persistent hyperparathyroidism (HPT) in patients who have undergone kidney transplantation (KT). Few data are available about their long-term follow-up. OBJECTIVE: We aimed to evaluate the long-term efficacy of cinacalcet in functioning stable KT subjects with hypercalcemia secondary to persistent HPT. MATERIAL AND METHODS: Twenty-three patients (6 men) with a stable KT showed persistent hypercalcemia (>12 months) secondary to HPT (parathyroid hormone by radioimmunoassay [iPTH] > 150 pg/mL). The mean age was 54 ± 13 years. Time after KT to beginning cinacalcet treatment was 36.5 ± 37.9 (range 12 to 172) months. Initial cinacalcet doses were 30 mg/d. Median follow-up was 53 ± 7.4 months (range 42 to 60 months). We determined serum calcium, phosphorus, alkaline phosphatase, iPTH, creatinine, and immunosuppressant concentrations at baseline as well as 3, 6, and 12 months and after every 6 months thereafter. RESULTS: Initial serum calcium was 11 ± 0.65 mg/dL and mean calcium during treatment, 10.25 ± 0.81 mg/dL (P < .001). Initial serum phosphorus was 2.8 ± 0.58 mg/dL and mean value serum phosphorus during the treatment period, 3.13 ± 0.6 mg/dL (P = 0.015). Initial iPTH was 260 ± 132 pg/mL and during the treatment period; 237 ± 131 pg/mL (P = ns). There was no change in renal function nor in immunosuppressant blood levels. Doses of cinacalcet at the end of the follow-up were 40.4 ± 18.9 mg/d. CONCLUSION: Cinacalcet was effective for long-term control of hypercalcemia related to persistent HPT for patients with stable KT.

Cinacalcet de novo in persistent hypercalcemia after kidney transplantation secondary to hyperparathyroidism: long-term follow-up and effect of withdrawal.

BACKGROUND: Secondary hyperparathyroidism that persists after kidney transplantation (KT), is the main cause of hypercalcemia. Cinacalcet has been used to control hypercalcemia in KT patients. OBJECTIVE: The aim of this study was to evaluate the effect of de novo cinacalcet in KT patients with hypercalcemia and the evolution after its withdrawal. METHODS: This observational study included 41 KT patients (17 men) with persistent hypercalcemia (>6 months), defined as serum calcium (sCa) ≥10.5 mg/dL, and a mean age of 51.1 ± 13.3 years with a functional allograft for >12 months. The time after surgery to begin cinacalcet was 33 months (range, 12.5-81.3). The initial dose of cinacalcet was 30 mg/d. In a subgroup of 14 patients cinacalcet was stopped after 1 year. We studied the evolution of serum levels of calcium, phosphorus, intact pathyroid hormone (iPTH), and serum creatinine. RESULTS: Calcemia normalized in all patients (sCa <10.2 mg/dL). iPTH decreased (basal 267 ± 212 pg/mL vs final: 219 ± 160 pg/mL; P = ns) Serum phosphorus increased (basal 2.85 ± 0.48 mg/dL vs final 3.16 ± 0.50 mg/dL; P = ns). Renal function remained stable (basal creatinine 1.49 ± 0.48 vs final 1.47 ± 0.32 mg/dL; P = ns). After stopping cinacalcet, in group 1 calcemia persisted at normal levels in 50% (n = 7), but the drug had to be reintroduced in the other 50% after 10 ± 7.9 months. No adverse events were documented. CONCLUSIONS: Cinacalcet is an effective alternative for the treatment of hypercalcemia in patients with persistent hyperparathyroidism after KT. Once the treatment is started, there is presently no invice to disclose to who tolerate its withdrawal or the time to do so.

[Neurological dysfunction induced by bilirrubin]. / Disfunción neurológica inducida por bilirrubina.

INTRODUCTION: "Kernicterus" is a term currently used to describe bilirrubin induced brain injury in the neuro-pathological studies. This is a confusing term and nowadays we prefer bilirrubin encephalopathy or bilirrubin induced neurological dysfunction. The clinical signs vary and it is clearly decreasing in prevalence in developed countries. MATERIAL AND METHODS: We review a series of 7 patients with bilirrubin encephalopathy and variable neurological manifestations, who were seen in the Neuropaediatric Department in the last 10 years. Only one patient died in the neonatal period with hyperbilirubinaemia, sepsis and multi-organ failure. RESULTS: Diverse aetiological factors were related to hyperbilirubinaemia. All patients had clinical symptoms due to hyperbilirubinaemia. Neuroimaging during the neonatal period showed involvement of the nucleus pallidus, with hyperintensity in T1 in the brain MR scan as the most consistent finding. All the patients who survived developed neurological signs and we try to correlate them with biochemical, clinical, neuroimaging and neurophysiological parameters. CONCLUSIONS: An increase in the number of patients with bilirrubin encephalopathy has been observed over the last few years, and we attempt to find out the causes. The increased survival of the low birth weight newborns, the increase in the immigration population and the use of diagnostic neuroimaging contribute to this increase. It is a great challenge for the neonatologist and for neuropaediatricians to prevent its occurrence and to minimise the effects of bilirrubin encephalopathy.

Arginine supplementation in four patients with X-linked creatine transporter defect.

BACKGROUND: Treatment with oral creatine monohydrate has not shown efficacy in patients with creatine transporter deficiency (CRTR-D). Another therapeutic option proposed is L-arginine, the substrate for the enzyme L-arginine:glycine amidinotransferase (AGAT). We evaluate clinical characteristics and cerebral creatine replenishment after L-arginine therapy in four patients with CRTR-D. PATIENTS AND METHODS: Four boys with genetically confirmed diagnosis of CRTR-D (ages 9-16 years) were supplemented with L-arginine (0.4 g/kg per day) for a period of 9 months. Treatment efficacy was evaluated by clinical and neuropsychological assessment and determination of creatine signals by brain proton magnetic resonance spectroscopy ((1)H-MRS). RESULTS: Epileptic seizures remained well controlled with antiepileptic drugs in three cases, both before and after L-arginine supplementation. Vineland Adaptive Behaviour Scale did not show any change in communication, daily living skills, socialization or motor skills, and a lack of improvement in brain (1)H-MRS follow-up was observed. L-Arginine was discontinued at the end of the observation period. CONCLUSIONS: Nine months of L-arginine supplementation did not show effectiveness in the four patients affected with CRTR-D in this protocol.

Platelet serotonin concentrations in PKU patients under dietary control and tetrahydrobiopterin treatment.

Tetrahydrobiopterin (BH4) supplementation has been applied in PKU treatment, resulting in successful control of blood phenylalanine (Phe) concentrations. We evaluated serotonin status in PKU patients under classical dietary treatment (n = 40) and in a group of 11 PKU patients under BH4 treatment, both during a 6-month period. Platelet serotonin values were significantly lower in PKU patients under dietary treatment when compared with controls. A negative correlation was observed between plasma Phe and platelet serotonin concentrations (r = -0.367, p = 0.017) in PKU patients. Platelet serotonin concentration increased significantly after both 1 and 6 months of BH4 therapy when compared with baseline conditions (Wilcoxon test: p = 0.013 and p = 0.021, respectively), while no differences were observed when comparing plasma Phe concentrations at the different points. Our results indicate that PKU patients under classical treatment have decreased platelet serotonin concentrations, probably owing to continued high Phe values, while BH4 supplementation restored platelet serotonin values.

Plasma thiols and their determinants in phenylketonuria.

OBJECTIVE: Treatment of phenylketonuria (PKU) patients consists of a phenylalanine-restricted diet supplemented with a tyrosine-, vitamin- and oligoelement-enriched amino-acid mixture. Vitamins and oligoelements may be deficient when compliance with the supplemented special formula is poor. Plasma thiol concentrations (especially homocysteine) depend mainly on B-vitamin intake. Our aim was to evaluate the plasma thiol concentrations (homocysteine, cysteine and glutathione) and their determinants (methionine, cobalamin and folate) in PKU patients under dietary treatment compared with age-matched controls. DESIGN AND SETTING: Cross-sectional study performed in a tertiary care Hospital. SUBJECTS: PKU (42) patients under dietary treatment compared with 42 age-matched controls. INTERVENTIONS: Plasma total homocysteine, cysteine and glutathione were analyzed by HPLC with fluorescence detection. Plasma phenylalanine and methionine were analyzed by ion exchange chromatography. Serum folate and cobalamin were analyzed by radioimmunoassay procedures. RESULTS: Total homocysteine concentrations were significantly lower in the PKU patients compared with the control group (Students t-test; P<0.0001). Serum folate and cobalamin were significantly higher in the PKU group (t-Student; P<0.0001) compared with controls. A significantly negative correlation was observed between total homocysteine and folate (r=-0.378; P=0.016), and between cobalamin and phenylalanine concentrations (r=-0.367; P=0.022) in the PKU group. CONCLUSIONS: Plasma total homocysteine values are lower in the PKU group than in the controls, probably because of high folate values. High phenylalanine values, an indicator of poor dietary compliance, are negatively associated with cobalamin, which might be deficient in some cases.

[Acute infantile bilateral thalamic necrosis]. / Necrosis talámica bilateral aguda infantil.

INTRODUCTION: Acute necrotizing encephalitis is a clinical entity recently described in previously healthy Japanese children. Following a respiratory or gastrointestinal infection of a viral nature, these patients present a sudden deterioration in the level of consciousness. Since neuroimaging shows a bilateral thalamic disorder in all cases, the name infantile bilateral thalamic necrosis has been put forward to refer to this affection. CASE REPORT: We report the case of an 11 month old Spanish patient who was brought into the hospital with disconnection from the surroundings and hypertonia in the upper extremities, within the context of a febrile gastrointestinal picture. Blood sample analysis revealed haemoconcentration and metabolic acidosis, although it did not suggest an infection. The computerised tomography scan of the brain showed a striking hypodensity of both thalami. The initial hypertonia was followed by a generalised hypotonia, accompanied by haemodynamic and respiratory deterioration. The patient died 40 hours after admission. CONCLUSIONS: Acute necrotizing encephalitis was initially described in Japanese children but in recent years isolated cases have also been reported in the Western world. In the case of the patient we have described, one of the most outstanding points is that evolution was unfavourable in spite of mechanical ventilation and the use of inotropic drugs, together with the clinical state of brain death that occurred on the second day after admission. Since neuroimaging showed a selective disorder of the thalami in all cases, and the fact it is an entity that affects small children, it seems more appropriate to use the term acute infantile thalamic necrosis

Aplicaciones de la biología molecular en el trasplante renal / Mollecular biology in renal transplantation

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Necrosis talámica bilateral aguda infantil / Acute infantile bilateral thalamic necrosis

Introducción. La encefalitis necrosante aguda es una entidad descrita recientemente en niños japoneses previamente sanos.Estos pacientes presentan, tras una infección viral respiratoria o gastrointestinal, un deterioro brusco del nivel de consciencia. Dado que la neuroimagen muestra en todos los casos una afectación talámica bilateral, se ha propuesto el término `necrosis talámica bilateral infantil'. Caso clínico. Presentamos un paciente español de 11 meses de edad que acude al hospital al desarrollar, en el contexto de un cuadro gastrointestinal febril, una desconexión ambiental e hipertonía en las extremidades superiores. La analítica sanguínea muestra hemoconcentración y acidosis metabólica, sin que sea sugestiva de infección. En la tomografía computarizada craneal se observa una llamativa hipodensidad de ambos tálamos. A la hipertonía inicial le sigue una hipotonía generalizada, acompañada de un deterioro hemodinámico y respiratorio. El paciente falleció a las 40 horas de su ingreso. Conclusiones. La encefalitis necrosante aguda se describió inicialmente en niños japoneses, pero en los últimos años se han comunicado casos aislados en Occidente. En el paciente que presentamos, destaca la evolución desfavorable a pesar de la ventilación mecánica y los fármacos inotrópicos, con estado clínico de muerte cerebral el segundo día de ingreso. Dado que la neuroimagen demuestra en todos los casos una afectación selectiva de los tálamos, y se trata de una entidad propia del niño pequeño, parece más apropiado el término `necrosis talámica aguda de la infancia' (AU)

Introduction. Acute necrotizing encephalitis is a clinical entity recently described in previously healthy Japanese children. Following a respiratory or gastrointestinal infection of a viral nature, these patients present a sudden deterioration in the level of consciousness. Since neuroimaging shows a bilateral thalamic disorder in all cases, the name ‘infantile bilateral thalamic necrosis’ has been put forward to refer to this affection. Case report. We report the case of an 11-month-old Spanish patient who was brought into the hospital with disconnection from the surroundings and hypertonia in the upper extremities, within the context of a febrile gastrointestinal picture. Blood sample analysis revealed haemoconcentration and metabolic acidosis, although it did not suggest an infection. The computerised tomography scan of the brain showed a striking hypodensity of both thalami. The initial hypertonia was followed by a generalised hypotonia, accompanied by haemodynamic and respiratory deterioration. The patient died 40 hours after admission. Conclusions. Acute necrotizing encephalitis was initially described in Japanese children but in recent years isolated cases have also been reported in the Western world. In the case of the patient we have described, one of the most outstanding points is that evolution was unfavourable in spite of mechanical ventilation and the use of inotropic drugs, together with the clinical state of brain death that occurred on the second day after admission. Since neuroimaging showed a selective disorder of the thalami in all cases, and the fact it is an entity that affects small children, it seems more appropriate to use the term acute infantile thalamic necrosis (AU)

Children with stroke: polymorphism of the MTHFR gene, mild hyperhomocysteinemia, and vitamin status.

The aim of this study was to investigate a possible association among the thermolabile polymorphism, nucleotide 677 cytosine to thymidine point mutation (677 C-->T) of the methylenetetrahydrofolate reductase (MTHFR) gene, hyperhomocysteinemia, serum folate, vitamins B12 and B6, and stroke in children. Allele and genotype frequencies for the 677 C-->T polymorphism in 21 children with stroke and 28 healthy children of the same age were studied. No differences in allelic frequency were detected between the two populations. However, the prevalence of homozygous 677 C-->T was doubled in the stroke population (28.6%) compared to the healthy group (14.3%). Total plasma homocysteine (tHcy) levels were significantly increased in children aged 2 months to 15 years with stroke compared to reference values. No association was observed between the homozygous genotype (T/T) and hyperhomocysteinemia, nor between the T/T genotype and low folate levels (below the 95th percentile) in this group of patients. Vitamin concentrations in patients were not significantly different from reference values. Significant negative correlations were found between tHcy and folate and between tHcy and cobalamin, but not between tHcy and B6 concentrations. In summary, a higher prevalence of hyperhomocysteinemia and the 677 C-->T polymorphism were observed in children with stroke, but were not always associated. The systematic study of both abnormalities in children with stroke is recommended, so that hyperhomocysteinemia of any genetic origin can be corrected with vitamin supplementation. Moreover, the 677 C-->T genotype is a strong factor for predisposition to hyperhomocysteinemia and recurrent risk of stroke that might also be prevented with folate supplementation.

Uremic tumoral calcinosis in patients receiving longterm hemodialysis therapy.

OBJECTIVE: To analyze a series of uremic tumoral calcinosis (UTC) in patients receiving longterm dialysis therapy. METHODS: Twelve patients receiving longterm hemodialysis affected by tumoral calcinosis were analyzed. Clinical, radiological, and pathological features were evaluated and pathogenic factors were reviewed. RESULTS: The most common sites for UTC were the elbow, hip, hand, and wrist. The lesions were multiple (67%, n = 8), of large size, and symptomatic with joint mobility impairment (75%, n = 9) as well as nerve compression (33%, n = 4). High serum calcium and phosphate concentrations were detected in 50% (n = 6) and 100% of the patients, respectively. An increased calcium-phosphorus product (Ca x P) was observed in all patients, either due to overt secondary hyperparathyroidism (42%, n = 5), or secondary to iatrogenic hypercalcemia and/or severe hyperphosphoremia of multifactorial etiology (i.e., prolonged and excessive administration of calcitriol and calcium carbonate, insufficient dialysis and inadequate phosphorus chelating therapy, etc.) (58%, n = 7). Several treatment strategies were followed (surgical excision, parathyroidectomy, renal transplant) in combination with aggressive medical therapy to decrease Ca x P product, achieving complete remission in 83% of the patients. CONCLUSION: UTC lesions show clinical and pathogenic features that differ from those of idiopathic tumoral calcinosis. The most important pathogenic factor involved in UTC is an increase in Ca x P, not necessarily related to hyperparathyroidism. Combined treatment strategies allow complete remission in a high proportion of patients. A low Ca x P is necessary to prevent development of UTC.

Acute necrotizing encephalopathy of childhood (infantile bilateral thalamic necrosis): two non-Japanese cases.

This report describes two Spanish cases of acute necrotizing encephalopathy of childhood, a rare disease first described in Japan by Mizuguchi and colleagues. Similar cases have been reported from Taiwan and other countries of the Far East. Two cases have been reported from the UK and one from the USA. The disease affects young children and is characterized by acute encephalopathy after a viral illness, with seizures and decreased levels of consciousness. The hallmark of the disease is diffuse and symmetrical CNS lesions of both thalami, internal capsules, upper brainstem tegmentum, and cerebral white matter. The aetiology is unknown but an infectious or parainfectious process seems likely. Because of the predominant involvement of the thalami, we propose the term 'infantile bilateral thalamic necrosis', a more specific term and one which distinguishes the entity from other basal ganglia diseases in childhood.

Tocopherol in inborn errors of intermediary metabolism.

Red blood cell tocopherol was measured in a group of 92 children with inborn errors of intermediary metabolism to evaluate the peroxidative damage in different mitochondrial and cytosolic defects, and to consider the need for treatment or vitamin supplementation. Tocopherol was determined by HPLC with UV detection. Results were expressed in nanomoles red blood cell tocopherol per gram protein. Significant differences (Mann-Whitney; P < 0.001) were found between tocopherol levels in untreated patients: 19 with mitochondrial defects versus 23 with cytosolic enzyme or transport defects, and versus 58 age-matched reference values. In conclusion, mitochondrial enzyme deficiencies, either amino and organic acidurias or defects of energy metabolism, seem to produce an excess of free radicals with the consequent utilization of tocopherol as antioxidant. This is not apparent in the cytosolic enzyme defects studied, whose tocopherol levels are in the normal range. Treatment with tocopherol completely corrects the deficient antioxidant status.

Cellular bioenergetics after erythropoietin therapy in chronic renal failure.

After erythropoietin (rHuEPO) therapy, patients with chronic renal failure (CRF) do not improve peak O2 uptake (VO2 peak) as much as expected from the rise in hemoglobin concentration ([Hb]). In a companion study, we explain this phenomenon by the concurrent effects of fall in muscle blood flow after rHuEPO and abnormal capillary O2 conductance observed in CRF patients. The latter is likely associated with a poor muscle microcirculatory network and capillary-myofiber dissociation due to uremic myopathy. Herein, cellular bioenergetics and its relationships with muscle O2 transport, before and after rHuEPO therapy, were examined in eight CRF patients (27 +/- 7.3 [SD] yr) studied pre- and post-rHuEPO ([Hb] = 7.8 +/- 0.7 vs. 11.7 +/- 0.7 g x dl-1) during an incremental cycling exercise protocol. Eight healthy sedentary subjects (26 +/- 3.1 yr) served as controls. We hypothesize that uremic myopathy provokes a cytosolic dysfunction but mitochondrial oxidative capacity is not abnormal. 31P-nuclear magnetic resonance spectra (31P-MRS) from the vastus medialis were obtained throughout the exercise protocol consisting of periods of 2 min exercise (at 1.67 Hz) at increasing work-loads interspersed by resting periods of 2.5 min. On a different day, after an identical exercise protocol, arterial and femoral venous blood gas data were obtained together with simultaneous measurements of femoral venous blood flow (Qleg) to calculate O2 delivery (QO2leg) and O2 uptake (VO2leg). Baseline resting [phosphocreatine] to [inorganic phosphate] ratio ([PCr]/[Pi]) did not change after rHuEPO (8.9 +/- 1.2 vs. 8.8 +/- 1.2, respectively), but it was significantly lower than in controls (10.9 +/- 1.5) (P = 0.01 each). At a given submaximal or peak VO2leg, no effects of rHuEPO were seen on cellular bioenergetics ([PCr]/[Pi] ratio, %[PCr] consumption halftime of [PCr] recovery after exercise), nor in intracellular pH (pHi). The post-rHuEPO bioenergetic status and pHi, at a given VO2leg, were below those observed in the control group. However, at a given pHi, no differences in 31P-MRS data were detected between post-rHuEPO and controls. After rHuEPO, at peak VO2, Qleg fell 20% (P < 0.04), limiting the change in QO2leg to 17%, a value that did not reach statistical significance. The corresponding O2 extraction ratio decreased from 73 +/- 4% to 68 +/- 8.2% (P < 0.03). These changes indicate that maximal O2 flow from microcirculation to mitochondria did not increase despite the 50% increase in [Hb] and explain how peak VO2leg and cellular bioenergetics (31P-MRS) did not change after rHuEPO. Differences in pHi, possibly due to lactate differences, between post-rHeEPO and controls appear to be a key factor in the abnormal muscle cell bioenergetics during exercise observed in CRF patients.

Controlled diet in phenylketonuria may cause serum carnitine deficiency.

Serum carnitine levels may be reduced in patients with phenylketonuria (PKU) owing to low carnitine intake, deficient carnitine synthesis and acylcarnitine production from phenylalanine metabolites. In order to investigate the possible carnitine deficiency we determined serum carnitine in its different forms and the precursors and cofactors involved in its synthesis in a group of patients with PKU or hyperphenylalaninaemia. Free, total and acylcarnitine values were significatively reduced only in PKU patients with Phe-restricted diet which had not been supplemented with carnitine. Acylcarnitine/free carnitine ratio and all the other parameters studied were normal in all patients. We conclude that the low serum carnitine levels in PKU patients with a strict diet are a consequence of the low carnitine intake.