Johannes F. W. Weigel

Roles of the LHX3 and LHX4 LIM-Homeodomain Factors in Pituitary Development

The LHX3 and LHX4 LIM-homeodomain transcription factors play essential roles in pituitary gland and nervous system development. Mutations in the genes encoding these regulatory proteins are associated with combined hormone deficiency diseases in humans and animal models. Patients with these diseases have complex syndromes involving short stature, and reproductive and metabolic disorders. Analyses of the features of these diseases and the biochemical properties of the LHX3 and LHX4 proteins will facilitate a better understanding of the molecular pathways that regulate the development of the specialized hormone-secreting cells of the mammalian anterior pituitary gland.

Transient Hyperammonemia Due to L -Asparaginase Therapy in Children with Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma

The standard treatment protocol for acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) in childhood includes intravenous therapy with asparaginase (Asp), which may cause hyperammonemia. In this study, all patients receiving asparaginase therapy at the Hospital for Children and Adolescents of the University of Leipzig between January 2002 and December 2007 were reviewed for the occurrence of hyperammonemia. Fifty-four patients were identified (22 girls, 32 boys; mean age 5.8 years). Blood ammonia concentrations were determined in 4 patients due to suspicious clinical signs. All showed hyperammonemia with NH3 concentrations between 260 and 700 μmol/L. They received specific acute detoxification therapy consisting in protein restriction, administration of benzoic acid, glucose/insulin. All 4 recovered completely. All patients receiving therapeutic regimes that include asparaginase (Asp) should be monitored for the development of transient hyperammonemia.

Nutritional Changes and Micronutrient Supply in Patients with Phenylketonuria Under Therapy with Tetrahydrobiopterin (BH 4 )

BACKGROUND Since 2008 patients with BH(4)-sensitive phenylketonuria can be treated with sapropterin dihydrochloride (Kuvan®) in addition to the classic phenylalanine (Phe) restricted diet. The aim of this study was to evaluate the nutritional changes and micronutrient supply in patients with phenylketonuria (PKU) under therapy with tetrahydrobiopterin (BH(4)). SUBJECTS AND METHODS 19 children with PKU (4-18 years) and potential BH(4)-sensitivity were included, 14 completed the study protocol. Dried blood Phe concentrations as well as detailed dietary records were obtained throughout the study at preassigned study days. RESULTS Eight patients could increase their Phe tolerance from 629 ± 476 mg to 2131 ± 1084 mg (P = 0.006) under BH(4) while maintaining good metabolic control (Phe concentration in dried blood 283 ± 145 μM vs. 304 ± 136 μM, P = 1.0), therefore proving to be BH(4)-sensitive. They decreased their consumption of special low protein products and fruit while increasing their consumption of high protein foods such as processed meat, milk and dairy products. Intake of vitamin D (P = 0.016), iron (P = 0.002), calcium (P = 0.017), iodine (P = 0.005) and zinc (P = 0.046) significantly declined during BH(4) treatment while no differences in energy and macronutrient supply occurred. CONCLUSION BH(4)-sensitive patients showed good metabolic control under markedly increased Phe consumption. However, the insufficient supply of some micronutrients needs consideration. Long-term multicenter settings with higher sample sizes are necessary to investigate the changes of nutrient intake under BH(4) therapy to further evaluate potential risks of malnutrition. Supplementation may become necessary.

A case of maternal PKU syndrome despite intensive patient counseling

ZusammenfassungEine 21-jährige Patientin mit klassischer Phenylketonurie stellte sich in der 14. Schwangerschaftswoche in der Ambulanz vor. Sie hatte trotz ausführlicher präkonzeptioneller Aufklärungen über die Gefahr hoher Phenylalanin (Phe)-Spiegel für das Ungeborene keine Diät eingehalten und daher entsprechend erhöhte Phe-Konzentrationen im Blut. Obwohl der Phe-Spiegel während eines stationären Aufenthaltes gesenkt werden konnte, gelang es der Schwangeren aufgrund von Incompliance nicht, die Zielwerte für Phe zu erhalten. Die Patientin brachte ein Neugeborenes mit klassischem maternalen PKU-Syndrom (Mikrozephalie, Brachygnathie, kongenitaler Herzfehler und psychomotorischer Retardierung) zur Welt. Unter Phe-armer Ernährung kommt dieses Syndrom heutzutage nur noch selten vor. Der Fallbericht untermauert die Notwendigkeit, junge Mädchen mit PKU bereits vor der Pubertät über das Risiko des maternalen PKU-Syndroms aufzuklären, da immer mehr ansonsten gesunde Frauen mit PKU das gebärfähige Alter erreichen. Eine entscheidende Rolle zur Prävention der Phe-Embryopathie spielt die Ernährung und somit die Patientencompliance, welche in dem Fallbericht leider unzureichend war.SummaryWe report on a 21-year-old woman with classic phenylketonuria, who presented at our outpatient clinic at week 14 of pregnancy. Despite intensive preconceptional counselling about the risk of raised Phenylalanine (Phe) levels for the offspring and nutritional consultations about the necessity to be on a Phe-restricted diet she had elevated blood Phe concentrations. Phe level could be lowered to the recommended range during a stay as an inpatient, but the patient was not able to maintain the recommended levels due to non-compliance. The patient delivered a newborn with classic maternal PKU syndrome (microcephaly, brachygnathia, congenital heart defect and psychomotoric retardation), which is nowadays rarely seen under preconceptional Phe-restricted diet. With more PKU patients reaching the childbearing age, intensive preconception counselling about maternal PKU syndrome is of pivotal importance for the women. However, a major factor in preventing Phe embryopathy is patient compliance in keeping the diet, which was insufficient in the case presented.

Growth and Final Height Among Children With Phenylketonuria

This article describes growth data of a large cohort of patients with PKU, including height development, growth rate, and comparisons of individual expected height with measured final height. BACKGROUND AND OBJECTIVES: Growth is an important criterion to evaluate health in childhood and adolescence, especially in patients depending on special dietary treatment. Phenylketonuria (PKU) is the most common inherited disease of amino acid metabolism. Patients with PKU depend on a special phenylalanine-restricted diet, low in natural protein. The study aimed to evaluate growth, growth rate, and target height in 224 patients with PKU. METHODS: Retrospective, longitudinal analysis of standardized, yearly measurements of height, weight, and calculated growth rate (SD score [SDS]) of patients with PKU aged 0 to 18 years were conducted by using the national computerized CrescNet database. Inclusion was restricted to patients carried to term with a confirmed diagnosis of PKU or mild hyperphenylalaninemia determined by newborn screening and early treatment initiation. RESULTS: From birth to adulthood, patients with PKU were significantly shorter than healthy German children (height SDS at 18 years: −0.882 ± 0.108, P < .001). They missed their target height by 3 cm by adulthood (women: P = .02) and 5 cm (men: P = .01). In patients receiving casein hydrolysate during childhood, this was more pronounced compared with patients receiving amino acid mixtures (P < .001). Growth rate was significantly reduced during their first 2 years of life and in puberty (growth rate SDS: −1.1 to −0.5 m/year, P < .001 and −0.5; P < .02). CONCLUSIONS: Early diagnosed, treated, and continuously monitored patients with PKU showed reduced height from birth onward. During the last 2 decades, this phenomenon attenuated, probably because of advances in PKU therapy related to protein supplements and special low-protein foods.

Das Smith-Lemli-Opitz-Syndrom

Das Smith-Lemli-Opitz-Syndrom wird durch einen Defekt des letzten Schrittes der Cholesterolbiosynthese, den Mangel an 7-Dehydrocholesterolreduktase, verursacht. Die Akkumulation der Metaboliten 7-Dehydrocholesterol und 8-Dehydrocholesterol, die die wichtigsten biochemischen Marker fur die Diagnose der Erkrankung darstellen, sowie der Mangel an Cholesterol konnen zu multiplen kongenitalen Anomalien fuhren. Die Ursache des Enzymmangels sind Mutationen innerhalb des DHCR7-Gens, welches auf Chromosom 11q13 lokalisiert ist. Therapeutische Moglichkeiten bestehen in der Gabe von Cholesterol und im Notfall Fresh Frozen Plasma (FFP); der therapeutische Nutzen von Statinen befindet sich zurzeit in der klinischen Erprobung.