Serine-deficiency syndromes

PURPOSE OF REVIEW: Serine-deficiency disorders comprise a new group of neurometabolic diseases and are caused by defects in the biosynthesis of the amino acid L-serine. In contrast to most neurometabolic disorders, serine-deficiency disorders are potentially treatable. Furthermore, the severe neurological symptoms observed in patients underscore the important roles of the serine biosynthetic pathway in brain tissue. An overview of the patients with serine-deficiency disorders reported to date, the biochemical findings and the results of treatment with amino acids is presented. RECENT FINDINGS: L-Serine biosynthesis plays an important role in multiple cellular reactions, particularly in the brain, as L-serine is a precursor of important metabolites such as nucleotides, phospholipids and the neurotransmitters glycine and D-serine. Disturbances of serine-glycine metabolism in relation to N-methyl-D-aspartate-receptor activation are supposed to play a role in psychiatric disease as well. Recent findings concerning these roles of L-serine-derived phospholipids and neurotransmitters are presented. SUMMARY: Congenital microcephaly, seizures and severe psychomotor retardation are symptoms of serine deficiency and can be treated with supplementation of L-serine, sometimes combined with glycine. The symptoms observed in serine deficiency confirm that L-serine and L-serine-derived metabolites play important roles in the central nervous system.     

Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1

BACKGROUND: Hereditary tyrosinemia type 1 (HT1), which is associated with severe liver and kidney damage, is caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of the tyrosine breakdown cascade. HT1-associated liver and kidney failure can be prevented by blocking an enzyme upstream of FAH in the tyrosine breakdown pathway with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). FAH knockout mice develop the HT1 phenotype when NTBC treatment is discontinued. METHODS: The occurrence of cell death was investigated in kidneys of Fah(-/-) mice on and off NTBC either unchallenged or injected with 800 mg/kg of homogentisic acid (HGA), an intermediate of tyrosine breakdown. RESULTS: No cell death could be detected in kidneys of Fah(-/-) mice on NTBC. A slight increase of cleaved caspase-3 was the only apoptosis-related feature that could be detected in kidneys of Fah(-/-) mice off NTBC. Challenge of Fah(-/-) mice on NTBC with HGA led to massive death of renal proximal tubular cells, with positive terminal deoxynucleotidyl transferase-mediated deoxyuridine diphosphate (dUDP) nick-end labeling (TUNEL) and DNA fragmentation assays, but hardly any cleavage of caspase-9 and caspase-3. Fah(-/-) mice off NTBC acquired resistance to HGA-induced renal cell death and the kidneys exhibited relatively few features of apoptosis upon challenge with HGA, with a small increase in expression of cleaved caspase-9 and caspase-3. CONCLUSION: Kidneys of adult Fah(-/-) mice, withdrawn from NTBC for 15 days, reveal limited characteristics of apoptosis, and have acquired resistance to a caspase-9- and caspase-3-independent form of cell death provoked by HGA.     

Frequency measurements in real-time US equipment: variations from expected values

The frequency responses of nine real-time mechanical probes and two pulsed Doppler probes from four manufacturers were measured. The reflected frequency was measured in a clinical environment by evaluating the pulser, transducer assembly, and receiver as a system. Two independent systems were used for these measurements: a spectrum analyzer and a data acquisition system that computed the fast Fourier transform of the reflected waveform. Results showed that probe frequency (calibrated by the manufacturer in the transmit mode with a hydrophone) was as much as 30% higher than that found by means of frequency measurement procedures with the probe attached to the ultrasound system and evaluated in the receive mode. Such large discrepancies indicate that if acceptance testing of the frequency spectrum is not performed at a clinical facility, prolonged clinical evaluation of new equipment should be arranged.     

MR imaging of the knee. Part II. Chronic disorders

Sixty patients with symptoms of chronic disease of the knee joint were evaluated with high-resolution, thin-section magnetic resonance (MR) imaging. MR imaging depicted a wide variety of knee joint abnormalities including osteochondritis dissecans, medullary infarcts, epiphyseal osteonecrosis, intraarticular osteochondral fragments, synovial cysts, joint effusions, intraarticular soft-tissue tumors, synovial disease, leukemic infiltration of bone marrow, Osgood-Schlatter disease, and nonossifying fibroma. In two cases MR imaging depicted bone infarcts not seen on both radionuclide bone scans and standard radiographs. The highly detailed depiction of the articular cartilage was of particular importance in predicting arthroscopic findings in cases of osteochondritis dissecans. In two cases, a soft-tissue mass (pigmented villonodular synovitis) and a large osteochondral fragment undetected at arthroscopy were accurately localized with MR imaging. The results indicate that MR imaging is capable of providing information that might otherwise require multiple, sometimes invasive diagnostic procedures.     

D-amino acids in the central nervous system in health and disease

Recent evidence has shown that d-amino acids are present in animals and humans in high concentrations and fulfill specific biological functions. In the central nervous system, two d-amino acids, d-serine and d-aspartate, occur in considerable concentrations. d-Serine is synthesized and metabolized endogenously and the same might account for d-aspartate. d-Serine has been studied most extensively and was shown to play a role in excitatory amino acid metabolism, being a co-agonist of the N-methyl-d-aspartate (NMDA) receptor. Insight into d-serine metabolism is relevant for physiological NMDA receptor (NMDAr) activation and for all the disorders associated with an altered function of the NMDAr, such as schizophrenia, ischemia, epilepsy, and neurodegenerative disorders. d-Aspartate appears to play a role in development and endocrine function, but the precise function of d-aspartate and other d-amino acids in animals and humans requires further investigation. As d-amino acids play biological roles, alterations in the concentrations of d-amino acids might occur in some disorders and relate to the pathogenesis of these disorders. d-Amino acid concentrations may then not only help in the diagnostic process, but also provide novel therapeutic targets. Consequently, the presence and important roles of d-amino acids in higher organisms do not only challenge former theories on mammalian physiology, but also contribute to exciting new insights in human disease.     

From gene to disease; Wilson disease: copper storage due to mutations in ATP7B

Wilson disease is an autosomal recessive disorder of copper metabolism. The gene defective in Wilson disease encodes a copper transporting P-type ATPase expressed in the liver. The disturbed export of copper into bile results in accumulation of copper in liver and secondarily in other organs such as the brain. These patients generally present with either hepatic or neurological symptoms.     

Paraneoplastic leukemoid reaction and rapid progression in a patient with malignant melanoma: establishment of KT293, a novel G-CSF-secreting melanoma cell line

Paraneoplastic leukemoid reaction (PLR) is a rare condition of leucocytosis in cancer patients. Here we report the rapid progression of a patient suffering from a metastasized malignant melanoma and PLR. The patient's white blood cell count exceeded 200,000 cells per mul and the serum level of Granulocyte Colony-Stimulating Factor (G-CSF) was elevated up to 780 pg/mul. A Tc-m99-labeled anti-NCA90/95 based granulocyte scan demonstrated reactive bone marrow expansion, splenomegaly and granulocyte infiltration into the tumor. KT293, a S100, gp100 and CD68 positive melanoma cell line derived from an axillary metastasis, produced large amounts of G-CSF in vitro and induced rapidly growing tumors and PLR after subcutaneous inoculation in SCID mice. In contrast to G-CSF-secreting cancer cells of other tissue origin, G-CSF-neutralizing antibodies failed to inhibit the growth of KT293 cells. In addition, KT293 cells did not express G-CSF-receptor. These observations suggest that paracrine effects of G-CSF-secretion and PLR might promote an aggressive melanoma phenotype, as seen in this patient.     

Shoulder instability: evaluation with MR imaging

Instability of the glenohumeral joint is a common cause of chronic shoulder pain and disability. One or more episodes of subluxation or dislocation may result in a tear, detachment, or attenuation of the glenoid labrum, stripping of the joint capsule from the scapula, or trauma to the tendons or muscles of the rotator cuff. A series of 27 shoulders examined with magnetic resonance (MR) imaging showed changes of glenohumeral instability, which were confirmed with open or arthroscopic surgery. MR imaging was capable of displaying common types of pathologic conditions resulting from instability, including labral trauma, capsular detachment, and retraction of the subscapularis muscle. MR imaging is a valuable diagnostic tool for the evaluation of glenohumeral instability.     

Malignant melanoma of the eye: treatment of posterior uveal lesions by Co-60 plaque radiotherapy versus enucleation

Survival rates and visual acuity of 100 patients treated for posterior uveal malignant melanoma by cobalt-60 plaque radiotherapy were compared with 150 patients treated by enucleation for the same disease. Life-table comparisons of the entire group showed significant differences in survival rates, with plaque radiotherapy patients appearing to fare better. However, when patients with small or medium tumors were compared, only slight differences were seen, implying that criteria used to select patients for treatment may affect interpretation. The two groups were also compared using the Cox proportional hazards model, which predicts survival based on the impact of clinical variables. In this analysis, the survival rates of the plaque radiotherapy group were no worse than those of the enucleation group. The advantage of conservative therapy lies in the potential to preserve useful vision over a considerable time. Because patients were specifically selected for treatment modality and because the study size used to calibrate the Cox model was small, the results of this study must be interpreted with caution.     

Methodology of in vivo human sodium MR imaging at 1.5 T

The methodology of sodium-23 (Na-23) imaging is reported in relationship to the physiological factors that determine the chemical environment of the Na-23 nucleus. Contrast resolution is given as a function of imaging time and spatial resolution. Data showing the optimal relaxation time for sodium imaging are given, and the linear quantitative relationship between sodium concentration and voxel intensity for our imaging system is confirmed. The major problem facing in vivo sodium imaging is the ability to differentiate intracellular sodium from extracellular sodium. The sodium in blood serum (extracellular) and packed red blood cells (intracellular) both exhibit biexponential T2 decay. These results indicate that T2 measurements alone will be insufficient for discriminating extracellular from intracellular sodium. Instead, other methods based on the underlying physiological properties of in vivo sodium imaging, such as the diffusion coefficient, will be necessary to truly separate extracellular from intracellular sodium.