SMART MODE:

NORMAL GENOMIC

• Zulfiqar M et al.
• Novel proton MR spectroscopy findings in adenylosuccinate lyase deficiency.
• J Magn Reson Imaging. 2013; 37: 974-80
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• Adenylosuccinate lyase (ADSL) deficiency is a rare inborn error of metabolism resulting in accumulation of metabolites including succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado) in the brain and other tissues. Patients with ADSL have progressive psychomotor retardation, neonatal seizures, global developmental delay, hypotonia, and autistic features, although variable clinical manifestations may make the initial diagnosis challenging. Two cases of the severe form of the disease are reported here: an 18-month-old boy with global developmental delay, intractable neonatal seizures, progressive cerebral atrophy, and marked hypomyelination, and a 3-month-old girl presenting with microcephaly, neonatal seizures, and marked psychomotor retardation. In both patients in vivo proton magnetic resonance spectroscopy (MRS) showed the presence of S-Ado signal at 8.3 ppm, consistent with a prior report. Interestingly, SAICAr signal was also detectable at 7.5 ppm in affected white matter, which has not been reported in vivo before. A novel splice-site mutation, c.IVS12 + 1/G > C, in the ADSL gene was identified in the second patient. Our findings confirm the utility of in vivo proton MRS in suggesting a specific diagnosis of ADSL deficiency, and also demonstrate an additional in vivo resonance (7.5 ppm) of SAICAr in the cases of severe disease.

• Baresova V et al.
• Mutations of ATIC and ADSL affect purinosome assembly in cultured skin fibroblasts from patients with AICA-ribosiduria and ADSL deficiency.
• Hum Mol Genet. 2012; 21: 1534-43
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• The purinosome is a multienzyme complex composed by the enzymes active in de novo purine synthesis (DNPS) that cells transiently assemble in their cytosol upon depletion or increased demand of purines. The process of purinosome formation has thus far been demonstrated and studied only in human epithelial cervical cancer cells (HeLa) and human liver carcinoma cells (C3A) transiently expressing recombinant fluorescently labeled DNPS proteins. Using parallel immunolabeling of various DNPS enzymes and confocal fluorescent microscopy, we proved purinosome assembly in HeLa, human hepatocellular liver carcinoma cell line (HepG2), sarcoma osteogenic cells (Saos-2), human embryonic kidney cells (HEK293), human skin fibroblasts (SF) and primary human keratinocytes (KC) cultured in purine-depleted media. Using the identical approach, we proved in cultured skin fibroblasts from patients with AICA-ribosiduria and ADSL deficiency that various mutations of ATIC and ADSL destabilize to various degrees of purinosome assembly and found that the ability to form purinosomes correlates with clinical phenotypes of individual ADSL patients. Our results thus shown that the assembly of functional purinosomes is fully dependent on the presence of structurally unaffected ATIC and ADSL complexes and presumably also on the presence of all the other DNPS proteins. The results also corroborate the hypothesis that the phenotypic severity of ADSL deficiency is mainly determined by structural stability and residual catalytic capacity of the corresponding mutant ADSL protein complexes, as this is prerequisite for the formation and stability of the purinosome and at least partial channeling of succinylaminoimidazolecarboxamide riboside-ADSL enzyme substrates-through the DNPS pathway.

• Thomas B, Al Dossary N, Widjaja E
• MRI of childhood epilepsy due to inborn errors of metabolism.
• AJR Am J Roentgenol. 2010; 194: 36774-36774
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• OBJECTIVE: The purpose of this pictorial essay is to classify epilepsy syndromes due to inborn errors of metabolism according to age at onset and type of seizure and to show the MRI features of many of the syndromes. CONCLUSION: Epilepsy syndromes due to inborn errors of metabolism are rare, but it is important to detect them at an early stage because some are treatable. MRI is an important tool in the assessment of these patients.

• Zidkova L et al.
• Oligodendroglia from ADSL-deficient patient produce SAICAribotide and SAMP.
• Mol Genet Metab. 2010; 101: 286-8
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• Succinylpurines accumulate in the body fluids of patients with adenylosuccinate lyase (ADSL) deficiency but their source in the cerebrospinal fluid remains obscure. Study based on the incorporation of 13C-stable isotope-labeled glycine into cultured oligodendroglia from ADSL-deficient patient and the measurement of labeled products by LC/MS/MS showed total intracellular concentrations of succinylpurines from 45 to 99mumol/l and so these results suggest that these cells can be the source of the compounds in vivo.

• Lundy CT et al.
• Adenylosuccinate lyase deficiency in the United Kingdom pediatric population: first three cases.
• Pediatr Neurol. 2010; 43: 351-4
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• Adenylosuccinate lyase deficiency is an autosomal recessive disorder of purine metabolism resulting from mutations in the ADSL gene on chromosome subband 22q13.1 and associated with a wide range of clinical manifestations. Although there is currently no effective treatment of ADSL deficiency, recognition of the condition is important, because prenatal genetic diagnosis can be offered to affected families. Reported here are the cases of the only three children diagnosed to date in the United Kingdom with adenylosuccinate lyase deficiency, to further delineate the clinical phenotype and to raise awareness of this disorder.

• Velasco-Sanchez D et al.
• Cerebellar hemorrhage in a patient with propionic acidemia.
• Cerebellum. 2009; 8: 352-4
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• Cerebellar hemorrhage (CH) is a well-known complication in newborns. Among metabolic patients, it has been classically described but rarely reported. This is the first description of a patient with propionic acidemia in whom magnetic resonance imaging (MRI) allowed diagnosis of asymptomatic CH. Due to the usual silent presentation of CH at early ages, we suggest the possibility of including a brain MRI study as part of the routine neurological evaluation in metabolic patients, especially when neurological signs appear.

• Bruggink JL, van Spronsen FJ, Wijnberg-Williams BJ, Bos AF
• Pilot use of the early motor repertoire in infants with inborn errors of metabolism: outcomes in early and middle childhood.
• Early Hum Dev. 2009; 85: 461-5
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• BACKGROUND: Predicting later outcome in neonates presenting with severe inborn errors of metabolism (IEM) is difficult. The assessment of the early motor repertoire is a reliable method of evaluating the integrity of the central nervous system in young infants. This method is based on an age-specific qualitative assessment of general movements (GMs, 0-8 weeks of age), fidgety movements (FMs) and the concurrent motor repertoire (9-20 weeks of age). AIM: To determine the quality of the early motor repertoire (at 0-20 weeks post term age) in relation to later neurological outcome in infants with severe IEM. STUDY DESIGN: Prospective cohort study. The quality of the motor repertoire was assessed from serial videotape recordings. SUBJECTS: Five infants with IEM. Four presented with a severe IEM in the neonatal period: an undefined gluconeogenesis defect, propionic acidemia, arginosuccinate synthetase and arginosuccinate lyase deficiency. One neonate was antenatally diagnosed with arginosuccinate synthetase deficiency. OUTCOME MEASURES: Outcome at the age of at least 18 m was determined by neurological examination and developmental tests. RESULTS: All infants initially had abnormal GMs: hypokinesia, followed by GMs of a poor repertoire. The quality of the early motor repertoire normalised in 3 infants, and remained abnormal in 2. The more severe and persistent abnormalities of the motor repertoire were considered with the more abnormal neurological and developmental scores, later on. CONCLUSIONS: The quality of the early motor repertoire might be related to later neurological outcome in infants with inborn errors of metabolism.

• Veit-Sauca B, Cambonie G, Salloum R, Plan O, Blanchet P, Picaud JC
• [A moderate intrauterine growth delay with lethal outcome: neonatal Menkes disease].
• Arch Pediatr. 2009; 16: 41-5
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• We report a case of moderate intrauterine growth delay with a congenital skull fracture and subdural hematoma, related to Menkes disease. The diagnosis was established in the neonatal period and absorptiometry showed global osteopenia. This disorder has an X-linked recessive inheritance pattern. It results from an abnormality in copper transport with a reduction in the ability to incorporate copper into certain enzymes that need it as a cofactor. The clinical phenotype stems from a deficiency of these enzymes, which explains the diversity of the symptoms. It begins in the first months of life with neurological disorders (hypotonia, seizures) and bone and vascular abnormalities. Usually, death occurs before the age of 5.

• Klemba M
• On the location of the aminopeptidase N homolog PfA-M1 in Plasmodium falciparum.
• Proc Natl Acad Sci U S A. 2009; 106: 5556-5556

• Mao J, Chen LY, Fu JH, Li J, Duan Y, Xue XD
• [Clinical evaluation of neonatal hypoglycemic brain injury demonstrated by serial MRIs].
• Zhongguo Dang Dai Er Ke Za Zhi. 2008; 10: 115-20
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• OBJECTIVE: To study the relationship between clinical and imaging features in neonates with hypoglycemic brain injury. METHODS: Sixteen neonates with hypoglycemic brain injury received a MRI scan with the sequences of T1WI, T2WI and DWI within 48 hrs after admission. Of the 16 patients, 11 received second MRI scan at two weeks of their lives, and 3 received a third scan at ages of 1-5 months. RESULTS: Repeated seizures, lethargy and hypotonia were common clinical manifestations. Five severe hypoglycemia cases presented coma, respiratory failure and even cardiorespiratory arrest. The minimum mean value of whole blood glucose (WBG) in the 16 patients was 0.98+/-0.43 mmol/L, and that of the 5 severe cases was 0.72+/-0.42 mmol/L. EEG showed intermittent low voltage in the mild hypoglycemia cases. Flatten pattern and even electrocerebral silence was noted in the severe cases. Occipital and parietal cortexes (OPC) injuries were found in all of the 16 patients and 2 patients had concurrent periventricular white matter injury. A widespread involvement of cortex was found in the 5 severe hypoglycemia cases in which 1 showed widespread involvement of white matter, and 2 showed involvement of basal ganglia and thalamus. The 5 patients with widespread cortex injury and the 2 patients with OPC and periventricular white matter injury showed lower minimum WBG levels compared with those with OPC alone (0.71+/-0.35 mmol/L vs 1.19+/-0.42 mmol/L; t= 2.4124, P<0.05). The appearance of high-intensity signals on DWI was shown as early changes of signals in all of the 16 patients. The second MRI scan for 7 patients with OPC showed abnormal signals on T1WI and T2WI in 5 patients and abnormal signals on DWI in 3 cases. Cerebral atrophy and multicystic encephalomalacia were found in four patients with widespread involvement of cortex on DWI. In the follow-up one patient with OPC presented delayed myelination and one with concurrent white matter injury showed spastic diplegia. One patient with widespread involvement of cortex showed diffused encephalomalacia. CONCLUSIONS: The severity of hypoglycemic brain injury demonstrated by serial MRIs relates to the severity of hypoglycemia. The occipital and parietal areas are the most vulnerable following hypoglycemia in neonates. Severe hypoglycemic brain injury manifests as a widespread involvement of cortex, or combined with white matter, or basal ganglia and thalamus. DWI can show early hypoglycemic brain injury.

• Soares-Fernandes JP et al.
• Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings.
• Pediatr Radiol. 2008; 38: 559-62
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• Pyruvate dehydrogenase (PDH) deficiency is one of the most common causes of congenital lactic acidosis. Correlations between the genetic defect and neuroimaging findings are lacking. We present conventional and diffusion-weighted MRI findings in a 7-day-old male neonate with PDH deficiency due to a mosaicism for the R302H mutation in the PDHA1 gene. Corpus callosum dysgenesis, widespread increased diffusion in the white matter, and bilateral subependymal cysts were the main features. Although confirmation of PDH deficiency depends on specialized biochemical analyses, neonatal MRI plays a role in evaluating the pattern and extent of brain damage, and potentially in early diagnosis and clinical decision making.

• Moslemi AR, Darin N, Tulinius M, Wiklund LM, Holme E, Oldfors A
• Progressive encephalopathy and complex I deficiency associated with mutations in MTND1.
• Neuropediatrics. 2008; 39: 24-8
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• Complex I of the oxidative phosphorylation system is composed of at least 45 subunits, seven of which are encoded by mitochondrial DNA (mtDNA). In this study we have investigated two children with complex I deficiency in muscle mitochondria. Patient 1 had cerebellar ataxia from early infancy and an abnormal MRI of the brain compatible with Leigh syndrome (LS). The course was rapidly progressive with frequent exacerbations and death at 2 years and 10 months of age. Patient 2 had a lactic acidosis in the newborn period and had a severe psychomotor developmental retardation. In her teens she developed hypertrophic cardiomyopathy and died at 26 years of age because of cardiac insufficiency. Sequencing analysis of mitochondrial encoded ND genes (MTND) showed two DE NOVO mutations in MTND1 in both patients. Patient 1 had a novel heteroplasmic G3890A mutation, R195Q. Patient 2 had a heteroplasmic G3481A mutation, E59K. The G3890A mutation in patient 1 is the first identified mutation in MTND1 in association with LS and complex I deficiency. The findings in this patient as well as in patient 2 demonstrate new clinical expressions of mutations in MTND1. The findings in patient 2 also illustrates that MTND mutations may be pathogenic even at a low percentage.

• Burr ML, Roos JC, Ostor AJ
• Metabolic myopathies: a guide and update for clinicians.
• Curr Opin Rheumatol. 2008; 20: 639-47
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• PURPOSE OF REVIEW: The present review will focus on the clinical features, and recent advances in the investigation and treatment, of metabolic muscle disease. The aim is to present a summary of this vast and complex topic emphasizing key points of relevance to nonspecialists in the field. Salient examples from each category will be highlighted to illustrate characteristic features and potential sources of diagnostic confusion. The general approach to management will then be outlined. RECENT FINDINGS: Awareness of these diseases has grown over recent years, as has appreciation of their variable clinical presentation. Many of the precise genetic and biochemical abnormalities underlying these conditions have been elucidated and novel enzyme defects continue to be discovered. Perhaps the greatest progress, however, has been made in the management of disease. Advances in tandem mass spectrometry techniques have facilitated the introduction of nationwide neonatal screening programmes for a large number of metabolic disorders. Enzyme replacement in Pompe disease has proved successful, improving outcome in a hitherto untreatable condition. Progress towards gene therapy, perhaps the ultimate goal, has been made in animal models. SUMMARY: Although individually rare, the metabolic myopathies together constitute a significant group of disabling and potentially life-threatening disorders. Appropriate investigations, timely treatment and genetic counselling are paramount to ameliorate the short and long-term consequences of disease.

• Downie MJ, Kirk K, Mamoun CB
• Purine salvage pathways in the intraerythrocytic malaria parasite Plasmodium falciparum.
• Eukaryot Cell. 2008; 7: 1231-7

• Xie LJ, Zhu JX, Zhu XD, Li HJ, Han LS, Gu XF
• [Combined use of tandem mass spectrometry with urine gas chromatography/mass spectrometry is useful for diagnosis of inborn errors of metabolism in children].
• Zhongguo Dang Dai Er Ke Za Zhi. 2008; 10: 31-4
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• OBJECTIVE: Many inborn errors of metabolism have similar presenting clinical manifestations, making early diagnosis difficult. We report our experience with tandem mass spectrometry combined with urine gas chromatography/mass spectrometry as a means of definitively diagnosing inborn errors of metabolism. METHODS: One hundred and thirty-two children with suspected inborn errors of metabolism but without specific clinical manifestations, admitted to the Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine between June 1, 2003 and September 30, 2006, were studied. Children received routine biochemical examinations, as well as mass spectrometry and gas chromatography-mass spectrometry. RESULTS: Fifteen cases (11.5%) were confirmed as having inborn errors of metabolism, including 6 cases of methylmalonic acidemia, 2 of propionic academia, 2 of Type II citrullinemia, 1 of biotinidase deficiency, 1 of tyrosinemia, 1 of maple syrup urine disease, 1 of omithine transcarbamylase deficiency and 1 of very long chain Acyl CoA dehydrogenase deficiency. CONCLUSIONS: The combined use of tandem mass spectrometry with urine gas chromatography mass spectrometry is useful for early diagnosis of inborn errors of metabolism in children with suspected inborn errors of metabolism but without specific clinical manifestations.

• Riedl S et al.
• Refining clinical phenotypes in septo-optic dysplasia based on MRI findings.
• Eur J Pediatr. 2008; 167: 1269-76
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• Septo-optic dysplasia (SOD) is a heterogeneous brain midline anomaly associated with ophthalmological, endocrinological, and/or neurodevelopmental symptoms. The clinical phenotype correlates with abnormal brain magnetic resonance imaging (MRI) findings. However, variations of the septum pellucidum (SP) appearance and their clinical impact have not been studied in depth. Sixty-eight patients with optic nerve hypoplasia (ONH) were investigated for the presence of associated SP anomalies and correlations between clinical findings and their MRI abnormalities established. Thirty patients had either complete (n = 22) or partial (n = 8) absence of the SP. Pituitary hormone deficiencies were present in 64% or 25% of the cases, respectively. Neurological symptoms did not occur in patients with SP remnants or unilateral ONH. Hippocampus abnormalities (43%) that have not been described before in SOD and falx abnormalities (17%) correlated significantly with neurological symptoms and developmental delay (p < 0.05 and p < 0.01, respectively). Maternal age at birth was low (21.2 years) and drug abuse during pregnancy was reported in 27% of the patients. Twelve patients with pituitary anomaly and ONH but normal SP showed similar clinical and MRI features, and were classified as SOD-like. The remaining 26 patients were not assigned to SOD. We conclude that unilateral ONH and SP remnants are associated with a milder SOD phenotype. Hippocampus abnormalities and falx abnormalities seem to constitute important features of severe clinical disease, irrespective of SP appearance. Our anamnestic data support the hypothesis of vascular disruption during embryogenesis.

• Mierzewska H et al.
• Clinical, biochemical, neuropathological and molecular findings of the first Polish case of adenylosuccinase deficiency.
• Folia Neuropathol. 2008; 46: 81-91
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• Adenylosuccinase (ADSL) deficiency is an autosomal recessive disorder affecting mainly the nervous system. The disease causes psychomotor retardation, frequently with autistic features and epilepsy. ADSL deficiency may be diagnosed by detection of two abnormal metabolites in body fluids--succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr). It is assumed that the former metabolite is neurotoxic. We present clinical, biochemical and neuropathological findings of a child affected by a severe form of ADSL deficiency. She had progressive neurological symptoms that started immediately after birth and died at 2.5 months of age. Macroscopically the brain showed signs of moderate atrophy. Histological examination of all grey matter structures showed widespread damage of neurons accompanied by microspongiosis of neuropile. Cerebral white matter showed lack of myelination in the centrum semiovale and diffuse spongiosis of neuropile. Myelination appropriate for the age was visible in posterior limb of internal capsule, in striatum, thalamus and in brain stem structures but diffuse destruction of myelin sheets was seen with severe marked astroglial reaction with signs of destruction of the cells and their processes. Ultrastructural examination showed enormous destruction of all cellular elements, but astonishingly mitochondria were relatively spared. The neuropathological changes can be considered as the neurotoxic result of metabolic disturbances connected with adenylosuccinase deficiency.

• Leijser LM, Liauw L, Veen S, de Boer IP, Walther FJ, van Wezel-Meijler G
• Comparing brain white matter on sequential cranial ultrasound and MRI in very preterm infants.
• Neuroradiology. 2008; 50: 799-811
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• INTRODUCTION: Periventricular white matter (WM) echodensities, frequently seen in preterm infants, can be associated with suboptimal neurodevelopment. Major WM injury is well detected on cranial ultrasound (cUS). cUS seems less sensitive for diffuse or more subtle WM injury. Our aim was to assess the value of cUS and magnetic resonance imaging (MRI) for evaluating WM changes and the predictive value of cUS and/or MRI findings for neurodevelopmental outcome in very preterm infants with normal to severely abnormal WM on sequential high-quality cUS. MATERIALS AND METHODS: Very preterm infants (<32 weeks) who had sequential cUS and one MRI within the first three postnatal months were included. Periventricular WM on cUS and MRI was compared and correlated with neurodevelopmental outcome at 2 years corrected age. RESULTS: Forty preterm infants were studied; outcome data were available in 32. WM changes on sequential cUS were predictive of WM changes on MRI. Severely abnormal WM on cUS/MRI was predictive of adverse outcome, and normal-mildly abnormal WM of favorable outcome. Moderately abnormal WM on cUS/MRI was associated with variable outcome. Additional MRI slightly increased the predictive value of cUS in severe WM changes. CONCLUSION: Sequential cUS in preterm infants is reliable for detecting WM changes and predicting favorable and severely abnormal outcome. Conventional and diffusion-weighted MRI sequences before term equivalent age in very preterm infants, suggested on cUS to have mild to moderately abnormal WM, do not seem to be warranted.

• Thauvin-Robinet C et al.
• The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum.
• J Neurol Neurosurg Psychiatry. 2008; 79: 725-8
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• BACKGROUND: Cobalamin C disease is the most common inborn error of cobalamin metabolism with an autosomal recessive mode of inheritance and mutations within the MMACHC gene. Clinical features, including systemic, haematological and neurological abnormalities, usually occur in the first year of life. Adolescent and adult onset presentations are rare. METHODS: We report on the clinical, molecular and imaging features in three patients aged 40, 42 and 42 years at the last follow-up. We examine these cases together with eight previously described cases to determine the clinical and molecular features of the disease in adults. RESULTS: Mean age at onset of clinical symptoms was 26 years; clinical features included predominant neurological disturbances and thromboembolic complications. White matter abnormalities on brain MRI were sometimes observed. Most patients (eight of nine patients investigated) were compound heterozygotes for the 271dupA mutation and a missense mutation. Intramuscular or intravenous hydroxycobalamin therapy stopped the progression of the disease and resulted in a better clinical outcome and favourable biological status in 7/9 treated cases, while the two untreated patients died quickly. CONCLUSIONS: As cobalamin C disease and related disorders of homocysteine metabolism are treatable conditions, homocysteinaemia should be included in the investigations of patients with progressive neurological deterioration, unexplained psychiatric disturbances or recurrent thromboembolic events.

• Maton B, Jayakar P, Resnick T, Morrison G, Ragheb J, Duchowny M
• Surgery for medically intractable temporal lobe epilepsy during early life.
• Epilepsia. 2008; 49: 80-7
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• PURPOSE: Temporal lobe epilepsy (TLE) in early life is often a catastrophic disorder with pharmacoresistant seizures and secondary neurological deterioration. there is little data available regarding epilepsy surgery performed in infants and young children and no prior study has focused on tle. METHODS: We analyzed the results of temporal resection for epilepsy as the primary indication in children less than age 5 years who had at least 2 years of follow-up. RESULTS: 20 children (14 males) were identified with a mean age at surgery of 26 months and a mean age at seizure onset of 12 months. Clinical presentation was diverse. Typical psychomotor seizures (n = 4; mean age at surgery 37 months) were followed by prominent motor changes (n = 7; 30 months) and were occasionally isolated (n = 3; 23 months). Epileptic spasms were noted in six patients and were frequently associated with lateralizing features. The interictal EEG was lateralizing in 15 patients and the ictal EEG was lateralizing in 18 patients. Brain MRI provided localizing value in 16 patients, ictal SPECT was concordant in 4/8 cases. Invasive EEG was employed in six cases. At mean follow-up of 5.5 years, 65% of the children were seizure-free and 15% had >90% seizure reduction. Morbidity included infection and hydrocephalus in one case and stroke-related hemiparesis in two cases. Cortical dysplasia was identified in eight children, tumors in eight including two DNET, two ganglioglioma, and four malignant tumors. Hippocampal sclerosis was present in four cases, always as dual pathology. CONCLUSION: TLE presents in early life with varied and severe manifestations. Excisional procedures in this age group are associated with favorable seizure reduction similar to older children and in adults.

• Parvaneh N, Ashrafi MR, Yeganeh M, Pouladi N, Sayarifar F, Parvaneh L
• Progressive multifocal leukoencephalopathy in purine nucleoside phosphorylase deficiency.
• Brain Dev. 2007; 29: 124-6
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• Progressive multifocal leukoencephalopathy is a demyelinating disease caused by JC virus, an opportunistic infection of the central nervous system. Although the majority of cases are infected with the human immunodeficiency virus (HIV), other immunocompromised patients are also at risk. Purine nucleoside phosphorylase is an enzyme in the purine salvage pathway that reversibly converts inosine to hypoxanthine and guanosine to guanine. Purine nucleoside phosphorylase deficiency is a combined immunodeficiency with a profound cellular defect. Neurologic abnormalities are salient features of this syndrome. We describe for the first time a patient with this rare disorder presented with progressive multifocal leukoencephalopathy.

• Hornik P, Vyskocilova P, Friedecky D, Janostakova A, Adamova K, Adam T
• Analysis of aminoimidazole ribosides by capillary electrophoresis--diagnosing defects in second part of purine biosynthetic pathway.
• Clin Chim Acta. 2007; 376: 184-9
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• BACKGROUND: Only three inherited metabolic defects have been identified in purine de novo synthesis (PDNS). We present here CE methods for diagnosing defects in the second half of PDNS (from sixth to tenth enzymatic conversion) based on analysis of aminoimidazole ribosides - dephosphorylated intermediates - in urine. METHODS: Assays were performed in an uncoated fused-silica capillary using two electrophoretic separation systems: 60 mmol/l borate - 2-amino-2-methyl-1-propanol-80 mmol/l sodium dodecylsulfate (pH 9.6) and 200 mmol/l phosphate - sodium (pH 1.8). RESULTS: The reported conditions allowed separation of all metabolites from major urinary constituents with analysis time less than 10 min and separation efficiency of 220 and 350 thousands theoretical plates per meter for borate and phosphate system, respectively. The intra- and interday imprecisions were less than 4.4% and 9.9% CV. Potential usefulness of the methods was demonstrated on samples from a patient with adenylosuccinate lyase deficiency and Chinese hamster ovary cell lines defective in PDNS. CONCLUSIONS: CE is a useful and effective tool in the analysis of aminoimidazole ribosides which enables diagnosis of known as well as not so far identified inherited defects of PDNS pathway.

• Chung WY, Gardiner DL, Anderson KA, Hyland CA, Kemp DJ, Trenholme KR
• The CLAG/RhopH1 locus on chromosome 3 of Plasmodium falciparum: two genes or two alleles of the same gene?
• Mol Biochem Parasitol. 2007; 151: 229-32

• Paprocka J, Jamroz E, Szwed-Bialozyt B, Jezela-Stanek A, Kopyta I, Marszal E
• Angelman syndrome revisited.
• Neurologist. 2007; 13: 305-12
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• OBJECTIVES: Angelman syndrome (AS) is characterized by severe mental retardation, epilepsy, absent speech, dysmorphic facial features, and a characteristic behavioral phenotype. It is caused by deficiency of gene expression from maternally derived chromosome 15q11-q13. STUDY DESIGN: The authors present the clinical picture of 9 children (median age, 4.9 years; range, 1 to 10 years) with confirmed Angelman syndrome. The patients complied with the international consensus criteria for AS and were consecutively investigated for psychomotor development, epilepsy, and electroencephalogram (EEG) profiles. RESULTS: The median age at diagnosis was 3.9 years. The motor milestones were delayed. Median developmental quotient level was 26. All patients but 1 experienced predominantly polymorphic seizures. In 4 cases, the epilepsy was refractory to treatment. The EEG of all patients displayed an abnormal sleep pattern and generalized abnormalities, with a maximum over the posterior areas. CONCLUSIONS: Milder or less typical phenotypes of AS may remain undiagnosed, leading to an overall underdiagnosis of the disease. The EEG shows no clear relation to genotype, clinical picture, or to the presence and severity of epilepsy. AS should be considered in the differential diagnosis of children with severe cryptogenic epilepsy and a characteristic configuration of clinical features.

• Wyllie E et al.
• Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings.
• Neurology. 2007; 69: 389-97
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• OBJECTIVE: To understand the role of epilepsy surgery in children with generalized or bilateral findings on preoperative scalp EEG. METHODS: From our pediatric epilepsy surgery series, we identified 50 patients in whom 30 to 100% of preoperative epileptiform discharges (ictal, interictal, or both) were generalized or contralateral to the side of surgery. RESULTS: All patients had severe refractory epilepsy and an epileptogenic lesion on brain MRI. Ninety percent of the lesions were congenital, perinatal, or acquired during infancy, predominantly malformations of cortical development (44%) or cystic encephalomalacia (40%). Age at surgery was 0.2 to 24 (median 7.7) years. Surgeries were hemispherectomy (64%) or lobar or multilobar resection. At last follow-up (median 24.0 months), 72% of patients were seizure-free, 16% had marked improvement with only brief episodes of staring or tonic stiffening, and 12% were not improved. The rate of seizure-free outcome was not significantly associated with age at seizure onset or surgery, presence of hemiparesis or focal clinical features during seizures, type of lesion, or surgery type. Postoperative seizure-free rate did not differ from that in a comparison group of similar patients who matched the study group except for their high percentage (70 to 100%) of ipsilateral ictal and interictal epileptiform discharges on preoperative EEG. CONCLUSIONS: Epilepsy surgery may be successful for selected children and adolescents with a congenital or early-acquired brain lesion, despite abundant generalized or bilateral epileptiform discharges on EEG. The diffuse EEG expression may be due to an interaction between the early lesion and the developing brain.

• Cornejo VE, Cabello JF, Colombo MC, Raimann EB
• [Glucose transponer type 1 deficiency sindrome (GLUT-1 SD) treated with ketogenic diet. Report of one case].
• Rev Med Chil. 2007; 135: 631-5
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• The glucose transporter type 1 deficiency syndrome (GLUT-1 SD) (OMIM 606777) is an inborn error of metabolism of brain glucose transport. The characteristic clinical manifestations are seizures, hypotonia, developmental delay, microcephaly and hypoglycorrhachia. We report a girl with normal weight and height at birth. At 6 weeks of age she started with convulsions reaching up to 20 myoclonic seizures a day. She was treated with valproate, phenobarbital and carbamazepine without response. Blood analysis including aminoacids and acylcarnitines were all normal. The brain MRI showed frontal atrophy with an increased subarachnoidal space and Electroencephalography was abnormal. Blood glucose was 84 mg/dl and spinal fluid glucose 26 mg/dl with a ratio of 0.31 (Normal Ratio >0.65+/-00.1). These results suggested the diagnosis of GLUT-1 SD, and was confirmed with erythrocyte glucose uptake of 44% (Normal range 80-100%). A molecular study found the mutation 969del, C971T in exon 6 of the gene Glut-1. Treatment with a ketogenic diet was started immediately and after 7 days with this diet seizures ceased. Anticonvulsants were progressively suspended. At present, the patient is 6 years old, she continues on a ketogenic diet and supplements with L-carnitine, lipoic acid, vitamins and minerals. Growth and development are normal with an intelligence quotient of 103. It is concluded that it is necessary to include GLUT-1 SD in the differential diagnosis of children with early seizures that are non responsive to pharmacological treatment.

• Hyde JE
• Targeting purine and pyrimidine metabolism in human apicomplexan parasites.
• Curr Drug Targets. 2007; 8: 31-47
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• Synthesis de novo, acquisition by salvage and interconversion of purines and pyrimidines represent the fundamental requirements for their eventual assembly into nucleic acids as nucleotides and the deployment of their derivatives in other biochemical pathways. A small number of drugs targeted to nucleotide metabolism, by virtue of their effect on folate biosynthesis and recycling, have been successfully used against apicomplexan parasites such as Plasmodium and Toxoplasma for many years, although resistance is now a major problem in the prevention and treatment of malaria. Many targets not involving folate metabolism have also been explored at the experimental level. However, the unravelling of the genome sequences of these eukaryotic unicellular organisms, together with increasingly sophisticated molecular analyses, opens up possibilities of introducing new drugs that could interfere with these processes. This review examines the status of established drugs of this type and the potential for further exploiting the vulnerability of apicomplexan human pathogens to inhibition of this key area of metabolism.

• Delgado C, Macias C, de la Sierra Garcia-Valdecasas M, Perez M, del Portal LR, Jimenez LM
• Subacute presentation of propionic acidemia.
• J Child Neurol. 2007; 22: 1405-7
• Display abstract

• Propionic acidemia is a hereditary metabolic disease caused by a deficiency of enzyme propionyl-CoA carboxylase, which is involved in the catabolism of ramified amino acids, odd-chain fatty acids, and other metabolites; the deficiency of this enzyme leads to an accumulation of toxic substances in the body. There are various forms of clinical presentation (severe neonatal, chronic intermittent, or slow and gradual). The case presented in this study was of a slow and insidious evolution form that was diagnosed when the child was 9 months old. Intracranial magnetic resonance imaging showed a slight increase in the signal intensity in sequences measured in T2 in addition to a restriction of the diffusion at the level of both putamens, which, together with biochemical and genetic analyses, confirmed the diagnosis of propionic acidemia. After initiating treatment involving a diet that was low in proteins, carnitine, and biotin, and an open-formula diet of ramified amino acids, the patient made progress, showing signs of improved hypotonia and increased weight gain. His vomiting stopped, and ketoacidosis was corrected.

• Assmann B et al.
• Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency.
• Neuropediatrics. 2006; 37: 20-5
• Display abstract

• The clinical, neurophysiological and neuroradiological work-up as well as the results of a specific treatment trial are presented of the first patient diagnosed with beta-ureidopropionase deficiency (E.C. 3.5.1.6, McKusick 606673). The patient presented with an early-onset dystonic movement disorder, severe developmental delay with marked impairment of visual responsiveness in combination with severely delayed myelination in magnetic resonance imaging studies. In addition, there were partial optic atrophy, pigmentary retinopathy and mild cerebellar hypoplasia. The enzyme defect was expected to lead to intracerebral deficiency of beta-alanine which seems to be a neuromodulator at inhibitory synapses. Therefore, a therapeutic trial with supplementation of beta-alanine was undertaken over 1.5 years with no convincing clinical improvement.

• Polson HE, Conway DJ, Fandeur T, Mercereau-Puijalon O, Longacre S
• Gene polymorphism of Plasmodium falciparum merozoite surface proteins 4 and 5.
• Mol Biochem Parasitol. 2005; 142: 110-5

• Loffler M, Fairbanks LD, Zameitat E, Marinaki AM, Simmonds HA
• Pyrimidine pathways in health and disease.
• Trends Mol Med. 2005; 11: 430-7
• Display abstract

• Genetic defects involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into the vital physiological functions of these molecules in addition to nucleic acid synthesis. Such aberrations disrupt the haematological, nervous or mitochondrial systems and can cause adverse reactions to analogue therapy. Regulation of pyrimidine pathways is also known to be disrupted in malignancies. Nine genetic defects have now been identified but only one is currently treatable. Diagnosis is aided by the accumulation of specific metabolites. Recently, progress has been made in understanding the molecular mechanisms underlying inborn errors of pyrimidine metabolism, together with the key clinical issues and the implications for the future development of novel drugs and therapeutic strategies.

• Crifo C, Siems W, Soro S, Salerno C
• Inhibition of defective adenylosuccinate lyase by HNE: a neurological disease that may be affected by oxidative stress.
• Biofactors. 2005; 24: 131-6
• Display abstract

• Adenylosuccinate lyase is an enzyme of fumarase superfamily that participates in the purine biosynthetic pathway, catalysing the nonhydrolytic cleavage of succinyl groups from SAICA ribotide and adenylosuccinate. Enzyme defects are associated with a human inherited disease, which arises from single point mutations to the gene and results in mild to severe psychomotor retardation, epilepsy, muscle wasting, and autistic features. Adenylosuccinate lyase activity is lost to a different extent in the patients. Diminished levels of enzyme have been attributed to loss of catalytic activity, protein instability, or environmental factors. P100A/D422Y mutation represents a feasible model for studying the effect of cell milieu on the activity of the impaired enzyme. The defective enzyme is inhibited by micromolar concentrations of trans-4-hydroxy-2-nonenal (HNE), a major product of membrane peroxidation that has been found to accumulate in brain tissues of patients with neurodegenerative disorders. It is suggested that inactivation of defective adenylosuccinate lyase by HNE and other membrane peroxidation products may account, at least in part, for the impairment of neurological functions and recurrent worsening of the symptoms.

• Salerno C, Crifo C
• Biochemical and molecular genetic correlation in adenylosuccinate lyase deficiency.
• Nucleosides Nucleotides Nucleic Acids. 2004; 23: 1253-5
• Display abstract

• An homology model of human adenylosuccinate lyase structure shows that P100A substitution distorts the amino acid chain of domain I in the proximity of His-86, which behaves as general acid in the catalysis, and may expose Cys-98 and Cys-99 to oxidising agents. This model is in line with the observation that the defective protein is strongly inhibited by 4-hydroxy-2-nonenal, an hydroxyalkenal that is known to form thio-ether linkage with proteins.

• Topolska AE, Black CG, Coppel RL
• Identification and characterisation of RAMA homologues in rodent, simian and human malaria species.
• Mol Biochem Parasitol. 2004; 138: 237-41

• Kirchgatter K, Portillo Hdel A
• Association of severe noncerebral Plasmodium falciparum malaria in Brazil with expressed PfEMP1 DBL1 alpha sequences lacking cysteine residues.
• Mol Med. 2002; 8: 16-23
• Display abstract

• BACKGROUND: Cytoadherence and rosetting contribute to the development of severe Plasmodium falciparum malaria. In Brazil,severe falciparum malaria is mostly associated with renal or pulmonary complications and very rarely with cerebral malaria. The most N-terminal DBL1 alpha domain of PfEMP1, a protein encoded by the var multigene family mediates rosetting. We analyzed parasites of Brazilian patients with severe malaria to determine whether there were particular DBL1 alpha var sequences predominantly expressed in such patients. MATERIALS AND METHODS: DBL1 alpha var sequences were obtained from parasites of Brazilian patients with severe and mild malaria and were analyzed by standard bioinformatic programs. Three hundred twenty var DBL1 alpha sequences obtained from 80 Brazilian patients with mild malaria were spotted in high-density filters and hybridized to probes representing predominantly expressed sequences in parasites from patients with severe malaria. A DBL1 alpha domain was expressed in bacteria and used to demonstrate its binding capacity to erythrocytes by immunofluorescence. RESULTS: Forty-three different and unreported DBL1 alpha amino acid sequences were obtained. Sequences predominantly expressed in patients with severe malaria could be subgrouped due to deletions of 1-2-cysteine residues. These sequences were commonly found in the var gene repertoire of parasites from patients with mild malaria, yet they were rarely expressed in these patients. A recombinant protein representing the most abundantly expressed sequence detected in one patient with severe malaria bound directly to uninfected erythrocytes. CONCLUSIONS: This is the first report showing an association of severe noncerebral malaria from Brazil with particular DBL1 alpha sequences.

• Kaneko O, Mu J, Tsuboi T, Su X, Torii M
• Gene structure and expression of a Plasmodium falciparum 220-kDa protein homologous to the Plasmodium vivax reticulocyte binding proteins.
• Mol Biochem Parasitol. 2002; 121: 275-8

• Ntoumi F, Ekala MT, Makuwa M, Lekoulou F, Mercereau-Puijalon O, Deloron P
• Sickle cell trait carriage: imbalanced distribution of IgG subclass antibodies reactive to Plasmodium falciparum family-specific MSP2 peptides in serum samples from Gabonese children.
• Immunol Lett. 2002; 84: 9-16
• Display abstract

• Several mechanisms have been proposed for explaining the protection of young children with hemoglobin AS from severe Plasmodium falciparum malaria. In a previous study carried out in Gabon, we have shown an association between hemoglobin AS carriage and a greater P. falciparum infection complexity. In the present study, we have investigated the presence and fine specificity of merozoite surface protein 2 (MSP2) reactive antibodies using different peptides covering conserved and polymorphic regions (Blocks 1-3) of P. falciparum MSP2 molecules. A cross-sectional study was conducted in the city of Bakoumba (Gabon), where malaria is hyperendemic with perennial P. falciparum transmission. Among the 641 children included, 135 were heterozygous for the sickle cell trait (HbAS). There was no significant difference in age distribution (mean age: 5 years, 0.5-11 years) and sex ratio in both hemoglobin groups (HbAA vs. HbAS). Blood group O was, however, associated with the sickle cell trait (P=0.02). P. falciparum isolates obtained from children with HbAS had a trend to higher infection complexity before the age of 5 years. Plasma samples were tested for the presence of antibodies to the different MSP2 peptides. Total IgG antibodies with a predominant reactivity against the FC27 type (the predominant P. falciparum MSP2 genotype) were found in serum samples from both groups. The profile of the IgG subclasses varied according to the hemoglobin phenotype. IgG3 and IgG2 were predominantly detected in plasma samples from HbAS children, whereas mainly IgG3 was found in children with HbAA. The role of the high multiclonal carriage associated with high family-specific antibodies reactive to MSP2 in HbAS children with asymptomatic P. falciparum parasitism is discussed.

• Xu X, Yamasaki H, Feng Z, Aoki T
• Molecular cloning and characterization of Plasmodium falciparum transportin.
• Parasitol Res. 2002; 88: 391-4
• Display abstract

• A cDNA encoding transportin, a protein involved in the nuclear import of M9 nuclear localization signal-bearing proteins, has been cloned from the malaria parasite Plasmodium falciparum. The complete cDNA consists of 3,667 bp encoding 1,136 amino acid residues. Amino acid sequence analysis revealed that Ran-GTP and M9 binding domains are highly conserved in P. falciparum, suggesting that the transportin-mediated nuclear transport pathway exists in this protozoan parasite. Southern blot analysis revealed that the transportin gene exists as a single copy in the malarial genome.

• Huestis R, Fischer K
• Prediction of many new exons and introns in Plasmodium falciparum chromosome 2.
• Mol Biochem Parasitol. 2001; 118: 187-99
• Display abstract

• The current prediction of genes in the Plasmodium falciparum genome database relies upon a limited number of specially developed computer algorithms. We have re-annotated the sequence of chromosome 2 of P. falciparum by a computer-assisted manual analysis, which is described here. Of 161 newly predicted introns, we have experimentally confirmed 98. We regard 110 introns from the previously published analyses as probable, we delete 3, change 26 and add 135. We recognise 214 genes in chromosome 2. We have predicted introns in 121 genes. The increased complexity of gene structure on chromosome 2 is likely to be mirrored by the entire genome.

• Tabucchi A, Carlucci F, Rosi F, Guerranti R, Marinello E
• Determination, activity and biological role of adenylosuccinate lyase in blood cells.
• Biomed Pharmacother. 2001; 55: 277-83
• Display abstract

• Adenylosuccinate lyase deficiency, which is associated with severe mental retardation and autistic features, was discovered in 1984. Since then this enzyme has been analyzed in many human tissues and it is now generally agreed that screening for this enzyme defect should be performed in all unexplained neurological diseases. The aim of the present study was to analyze adenylosuccinate lyase activity in blood cells by a fast simple method adaptable to screening purposes. The activity was also analyzed in B-lymphocytes from patients with B-cell chronic lymphocytic leukemia. The biological role of adenylosuccinate lyase and its importance in regulating cellular levels of AMP is discussed.

• Sim TS, Loke P, Lee MA, Singh M, Flotow H
• Cloning and sequence characterisation of falcipain-2 from Plasmodium falciparum Gombak A strain (Malaysia).
• Parasitol Res. 2001; 87: 683-6
• Display abstract

• In this study, the genome of the Plasmodium falciparum Gombak A strain was examined for the presence of a gene encoding falcipain-2, a cysteine protease, using homology-based polymerase chain reaction cloning. The nucleotide sequence obtained from the gene cloned (designated pFG1) is approximately 99% homologous to other falcipain-2 genes from different strains. Comparatively, it is 69% homologous to falcipain-3 genes. Direct cloning of the falcipain-2 gene and its resemblance to the reported corresponding mRNA transcript suggests the absence of introns in this gene. Sequence alignment and comparison revealed four amino acid differences at positions 15, 51, 59 and 414 in the falcipain-2 from P. falciparum Gombak A as compared to other falcipain-2 proteins from different strains.

• Theisen M, Thomas AW, Jepsen S
• Cloning, nucleotide sequencing and analysis of the gene encoding the glutamate-rich protein (GLURP) from Plasmodium reichenowi.
• Mol Biochem Parasitol. 2001; 115: 269-73

• Taylor HM, Kyes SA, Newbold CI
• Var gene diversity in Plasmodium falciparum is generated by frequent recombination events.
• Mol Biochem Parasitol. 2000; 110: 391-7

• Kocken CH et al.
• Molecular characterisation of Plasmodium reichenowi apical membrane antigen-1 (AMA-1), comparison with P. falciparum AMA-1, and antibody-mediated inhibition of red cell invasion.
• Mol Biochem Parasitol. 2000; 109: 147-56
• Display abstract

• Apical membrane antigen 1 is a candidate vaccine component for malaria. It is encoded by a single copy gene and has been characterised in a number of malaria species as either an 83-kDa de novo product (Plasmodium falciparum; Pf AMA-1) or a 66-kDa product (all other species). All members of the AMA-1 family are expressed during merozoite formation in maturing schizonts and are initially routed to the rhoptries. Processed forms may subsequently be associated with the merozoite surface. Because of the unique occurrence of the 83-kDa form in P. falciparum we were interested to determine whether the phylogenetically closely related chimpanzee malaria Plasmodium reichenowi shared characteristics with Pf AMA-1. Here we show that the molecular structure, the localisation and processing are similar to that of Pf AMA-1 and that in vitro growth inhibitory mAbs reactive with Pf AMA-1 also inhibit P. reichenowi growth in an in vitro assay. Polymorphism in the 83-kDa AMA-1 family was analysed through comparison of Pr ama-1 with Pf ama-1 alleles, which showed the most significant evidence for selection maintaining polymorphism in Domains I-III of AMA-1 in P. falciparum. The most substantial divergence between Pr AMA-1 and Pf AMA-1 sequences was in the N-terminal region unique to the 83-kDa form of AMA-1. It was confirmed that the specific Pr ama-1-type allele was not present among P. falciparum parasites in an African population, and an allele coding for lysine at amino acid 187 was uniquely associated with field isolates in this population.

• Kmoch S, Hartmannova H, Stiburkova B, Krijt J, Zikanova M, Sebesta I
• Human adenylosuccinate lyase (ADSL), cloning and characterization of full-length cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in six patients.
• Hum Mol Genet. 2000; 9: 1501-13
• Display abstract

• Adenylosuccinate lyase (ADSL) is a bifunctional enzyme acting in de novo purine synthesis and purine nucleotide recycling. ADSL deficiency is a selectively neuronopathic disorder with psychomotor retardation and epilepsy as leading traits. Both dephosphorylated enzyme substrates, succinylaminoimidazole-carboxamide riboside (SAICAr) and succinyladenosine (S-Ado), accumulate in the cerebrospinal fluid (CSF) of affected individuals with S-Ado/SAICAr concentration ratios proportional to the phenotype severity. We studied the disorder at various levels in a group of six patients with ADSL deficiency. We identified the complete ADSL cDNA and its alternatively spliced isoform resulting from exon 12 skipping. Both mRNA isoforms were expressed in all the tissues studied with the non-spliced form 10-fold more abundant. Both cDNAs were expressed in Escherichia coli and functionally characterized at the protein level. The results showed only the unspliced ADSL to be active. The gene consists of 13 exons spanning 23 kb. The promotor region shows typical features of the housekeeping gene. Eight mutations were identified in a group of six patients. The expression studies of the mutant proteins carried out in an attempt to study genotype-phenotype correlation showed that the level of residual enzyme activity correlates with the severity of the clinical phenotype. All the mutant enzymes studied in vitro displayed a proportional decrease in activity against both of their substrates. However, this was not concordant with strikingly different concentration ratios in the CSF of individual patients. This suggests either different in vivo enzyme activities against each of the substrates and/or their different turnover across the CSF-blood barrier, which may be decisive in determining disease severity.

• Verra F, Hughes AL
• Evidence for ancient balanced polymorphism at the Apical Membrane Antigen-1 (AMA-1) locus of Plasmodium falciparum.
• Mol Biochem Parasitol. 2000; 105: 149-53

• Peterson DS, Wellems TE
• EBL-1, a putative erythrocyte binding protein of Plasmodium falciparum, maps within a favored linkage group in two genetic crosses.
• Mol Biochem Parasitol. 2000; 105: 105-13
• Display abstract

• The Duffy binding-like (DBL) superfamily of Plasmodium falciparum encompasses genes which encode ligands for host cell receptors. This superfamily includes two distinct groups of genes, the var genes which encode antigenically variant cytoadherence proteins (PfEMP1), and the eba-175 gene which encodes a glycophorin A binding protein involved in erythrocyte invasion. Here we describe another DBL superfamily member related to eba-175, the ebl-1 gene. Like the eba-175 gene, ebl-1 is a single copy gene encoding DBL domains that have sequences and an overall arrangement distinct from var genes. The inheritance of ebl-1 was found to be strongly favored in two genetic crosses in which one parental clone lacked a chromosome segment carrying the gene. A proliferation phenotype has been previously linked to the same chromosome segment in the first genetic cross. These results suggest that ebl-1 and eba-175 are related members of a multigene family involved in the invasion of erythrocytes by P. falciparum.

• Marie S, Race V, Vincent MF, Van den Berghe G
• Adenylosuccinate lyase deficiency: from the clinics to molecular biology.
• Adv Exp Med Biol. 2000; 486: 79-82

• Wu T, Black CG, Wang L, Hibbs AR, Coppel RL
• Lack of sequence diversity in the gene encoding merozoite surface protein 5 of Plasmodium falciparum.
• Mol Biochem Parasitol. 1999; 103: 243-50
• Display abstract

• The gene encoding merozoite surface protein 5 (MSP5) of Plasmodium falciparum is situated between the genes encoding MSP2 and MSP4 on chromosome 2. Both MSP4 and MSP5 encode proteins that contain hydrophobic signal and glycosylphosphatidylinositol (GPI) attachment signals and a single epidermal growth factor (EGF)-like domain at their carboxyl termini. The similar gene organization, location and similar structural features of the two genes suggest that they have arisen from a gene duplication event. In this study we provide further evidence for the merozoite surface location of MSP5 by demonstrating that MSP5 is present in isolated merozoites, partitions in the detergent-enriched phase following Triton X-114 fractionation and shows a staining pattern consistent with merozoite surface location by indirect immunofluorescence confocal microscopy. Analysis of antigenic diversity of MSP5 shows a lack of sequence variation between various isolates of P. falciparum from different geographical locations, a feature unusual for surface proteins of merozoites and one that may simplify vaccine formulation.

• Eisen DP, Marshall VM, Billman-Jacobe H, Coppel RL
• A Plasmodium falciparum apical membrane antigen-1 (AMA-1) gene apparently generated by intragenic recombination.
• Mol Biochem Parasitol. 1999; 100: 243-6

• Bory C, Chantin C, Boulieu R
• Capillary electrophoretic analysis of hypoxanthine and xanthine for the diagnosis of xanthinuria.
• Adv Exp Med Biol. 1998; 431: 765-7

• Chen Q et al.
• Developmental selection of var gene expression in Plasmodium falciparum.
• Nature. 1998; 394: 392-5
• Display abstract

• The protozoan Plasmodium falciparum causes lethal malaria. Adhesion of erythrocytes infected with P. falciparum to vascular endothelium and to uninfected red blood cells (rosetting) may be involved in the pathogenesis of severe malaria. The binding is mediated by the antigenically variant erythrocyte-membrane-protein-1 (PfEMP-1), which is encoded by members of the P. falciparum var gene family. The control of expression and switching of var genes seems to lack resemblance to mechanisms operating in variant gene families of other microbial pathogens. Here we show that multiple, distinct var gene transcripts (about 24 or more) can be detected by reverse transcription and polymerase chain reaction in bulk cultures of the rosetting parasite FCR3S1.2, despite the adhesive homogeneity of the cultures. We also detected several var transcripts in single erythrocytes infected with a ring-stage parasite of FCR3S1.2, and found that different var genes are transcribed simultaneously from several chromosomes in the same cell. In contrast, we detected only one var transcript, FCR3S1.2 var-1, which encodes the rosetting PfEMP-1 protein, in individual rosette-adhesive trophozoite-infected cells, and we found only one PfEMP-1 type at the erythrocyte surface by labelling with 125iodine and immunoprecipitation. We conclude that a single P. falciparum parasite simultaneously transcribes multiple var genes but, through a developmentally regulated process, selects only one PfEMP-1 to reach the surface of the host cell.

• Milek RL, Kocken CH, Kaan AM, Jansen J, Meijers H, Konings RN
• Plasmodium reichenowi: deduced amino acid sequence of sexual stage-specific surface antigen Prs48/45 and comparison with its homologue in Plasmodium falciparum.
• Exp Parasitol. 1997; 87: 150-2

• Irion A, Beck HP, Felger I
• New repeat unit and hot spot of recombination in FC27-type alleles of the gene coding for Plasmodium falciparum merozoite surface protein 2.
• Mol Biochem Parasitol. 1997; 90: 367-70

• Okenu DM, Malhotra P, Lalitha PV, Chitnis CE, Chauhan VS
• Cloning and sequence analysis of a gene encoding an erythrocyte binding protein from Plasmodium cynomolgi.
• Mol Biochem Parasitol. 1997; 89: 301-6

• Scopes DA, Bautista JM, Vulliamy TJ, Mason PJ
• Plasmodium falciparum glucose-6-phosphate dehydrogenase (G6PD)-the N-terminal portion is homologous to a predicted protein encoded near to G6PD in Haemophilus influenzae.
• Mol Microbiol. 1997; 23: 847-8

• Morimatsu K, Morikawa T, Tanabe K, Bzik DJ, Horii T
• Sequence diversity in the amino-terminal 47 kDa fragment of the Plasmodium falciparum serine repeat antigen.
• Mol Biochem Parasitol. 1997; 86: 249-54

• Putman CW, Rotteveel JJ, Wevers RA, van Gennip AH, Bakkeren JA, De Abreu RA
• Dihydropyrimidinase deficiency, a progressive neurological disorder?
• Neuropediatrics. 1997; 28: 106-10
• Display abstract

• A case of a child presenting with congenital abnormalities at birth is reported. The early development remained severely retarded and acquired skills minimally. The head circumference centile decreased. Magnetic resonance imaging showed progressive neuronal atrophy and secondary delay in myelination. Dihydropyrimidine concentrations in body fluids were quantitated by NMR spectroscopy. Enzymatic assay in the liver biopsy revealed total deficiency of dihydropyrimidinase (DHP) (5,6-dihydropyrimidine amidohydrolase; EC 3.5.2.2). As such, the patient is the first with enzymatically proven DHP deficiency. Thus far dihydropyrimidinuria has been reported in three other patients with a variety of neurological abnormalities. A relation of the enzyme deficiency with the neurodegenerative clinical course in our patient is suggested.

• Sumi S, Kidouchi K, Hayashi K, Ohba S, Wada Y
• Dihydropyrimidinuria without clinical symptoms.
• J Inherit Metab Dis. 1996; 19: 701-2

• Rosenthal PJ
• Conservation of key amino acids among the cysteine proteinases of multiple malarial species.
• Mol Biochem Parasitol. 1996; 75: 255-60

• Trottein F, Cowman AF
• The primary structure of a putative phosphatidylethanolamine-binding protein from Plasmodium falciparum.
• Mol Biochem Parasitol. 1995; 70: 235-9

• Zalis MG, Wilson CM, Zhang Y, Wirth DF
• Characterization of the pfmdr2 gene for Plasmodium falciparum.
• Mol Biochem Parasitol. 1994; 63: 311-311

• Simmonds HA
• Diagnosis and treatment of inborn errors of purine and pyrimidine metabolism: an overview.
• Adv Exp Med Biol. 1994; 370: 1-6

• Schmid SR, Linder P, Reese RT, Stanley HA
• Characterization of a putative ornithine aminotransferase gene of Plasmodium falciparum.
• Mol Biochem Parasitol. 1993; 61: 311-4

• Kappes B, Suetterlin BW, Hofer-Warbinek R, Humar R, Franklin RM
• Two major phosphoproteins of Plasmodium falciparum are heat shock proteins.
• Mol Biochem Parasitol. 1993; 59: 83-94
• Display abstract

• Two major phosphoproteins of Plasmodium falciparum could be identified by partial amino acid sequencing as the plasmodial members of the hsp 70 heat shock protein family, Pfhsp and Pfgrp. According to phosphoamino acid analyses of Pfhsp and Pfgrp isolated from [32P]orthophosphate-labeled malarial cultures, both proteins were phosphorylated in Ser and Thr. While Pfhsp contains higher amounts of labeled phosphoserine, Pfgrp contains higher amounts of phosphothreonine. Phosphorylation of both proteins increased throughout the entire erythrocytic growth cycle. At the trophozoite and schizont stages Pfhsp and Pfgrp are the most prominent phosphoproteins of Plasmodium falciparum. Using multiply redundant oligonucleotides directed against the N-terminus of Pfgrp we cloned and sequenced the entire Pfgrp gene. The gene encodes a product with a predicted length of 652 amino acids. The deduced amino acid sequence has identities of 65.5% and 65.0% to the human and rat grp78 proteins, respectively. Pfgrp possesses a classical N-terminal leader sequence. The published grp78 related gene sequences of Plasmodium falciparum are all fragments of the same plasmodial gene.

• Creedon KA, Kaslow DC, Rathod PK, Wellems TE
• Identification of a Plasmodium falciparum histone 2A gene.
• Mol Biochem Parasitol. 1992; 54: 113-5

• Van den Berghe G, Bontemps F, Vincent MF, Van den Bergh F
• The purine nucleotide cycle and its molecular defects.
• Prog Neurobiol. 1992; 39: 547-61
• Display abstract

• Three enzymes of purine metabolism, adenylosuccinate synthetase, adenylosuccinate lyase and AMP deaminase, have been proposed to form a functional unit, termed the purine nucleotide cycle. This cycle converts AMP into IMP and reconverts IMP into AMP via adenylosuccinate, thereby producing NH3 and forming fumarate from aspartate. In muscle, the purine nucleotide cycle has been shown to function during intense exercise; the metabolic flux through the cycle has been proposed to play a role in the regeneration of ATP by pulling the adenylate kinase reaction in the direction of formation of ATP, and by providing Krebs cycle intermediates. In kidney, the purine nucleotide cycle was shown to account for the release of NH3 under the normal acid-base status, but not under acidotic conditions. In brain, the purine nucleotide cycle might function under conditions that induce a loss of ATP, and thereby contribute to its recovery. There is no evidence that the purine nucleotide cycle operates in liver. Deficiency of muscle AMP deaminase is an apparently frequent disorder, which might affect approximately 2% of the general population. The observation that it can be found in clinically asymptomatic individuals suggests, paradoxically, that the ATP-regenerating function which has been attributed to the purine nucleotide cycle is not essential for muscle function. Further work should be aimed at identifying the conditions under which AMP deaminase deficiency becomes symptomatic. Adenylosuccinate lyase deficiency provokes psychomotor retardation, often accompanied by autistic features. Its clinical heterogeneity justifies systematic screening in patients with unexplained mental deficiency. Additional studies are required to determine the mechanisms whereby this enzyme defect results in psychomotor retardation.

• Jaeken J, Van den Bergh F, Vincent MF, Casaer P, Van den Berghe G
• Adenylosuccinase deficiency: a newly recognized variant.
• J Inherit Metab Dis. 1992; 15: 416-8

• Barshop BA, Alberts AS, Gruber HE
• Kinetic studies of mutant human adenylosuccinase.
• Biochim Biophys Acta. 1989; 999: 19-23
• Display abstract

• Residual adenylosuccinase activity was studied in cultured lymphoblasts from a pair of siblings with infantile autism who have been previously shown to have a deficiency of the enzyme. The rates and distribution of de novo purine synthesis by intact cells were nearly normal. There was no evidence of inhibitory activity in the lysates of the mutant cells. The optimal pH was indistinguishable from that in control cells. The apparent Km in the two mutant cells lines is not significantly different from normal, but the mutants displayed markedly decreased maximum steady-state velocities. Residual activities in mutant cells show decreased thermal stability, suggesting that there is a structural mutation of the adenylosuccinase in the mutant cells.

• Jaeken J et al.
• Adenylosuccinase deficiency: an inborn error of purine nucleotide synthesis.
• Eur J Pediatr. 1988; 148: 126-31
• Display abstract

• Clinical and biochemical data are presented on eight children with adenylosuccinase deficiency. This newly discovered inborn error of purine metabolism is characterized by an accumulation in body fluids of succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICA riboside), the dephosphorylated derivatives of the two substrates of adenylosuccinase. Six living children (three boys and three girls) and one deceased sibling displayed severe psychomotor retardation. Epilepsy was documented in five cases, autistic features in three, and growth retardation associated with muscular wasting in a brother and sister. In the cerebrospinal fluid, plasma and urine of these patients, the S-Ado/SAICA riboside ratio was between 1 and 2. In striking contrast, the eighth patient (a girl) was markedly less mentally retarded. Most noteworthy, the S-Ado/SAICA riboside ratio in her body fluids was around 5, suggesting that her milder psychomotor retardation was causally linked to this higher ratio. Adenylosuccinase deficiency was demonstrated in the liver of all seven living children, in the kidney of three patients in whom the enzymatic activity was measured, and in the muscle of three patients, including the two with muscular wasting. In fibroblasts of the six severely retarded patients, adenylosuccinase activity was reduced to approximately 40% of normal; in the patient with the higher S-Ado/SAICA riboside ratio, it reached only 6% of normal. The clinical heterogeneity of adenylosuccinase deficiency justifies systematic screening for the enzyme defect in unexplained neurological disease.

• Mattei D, Ozaki LS, de Silva LP
• A Plasmodium falciparum gene encoding a heat shock-like antigen related to the rat 78 Kd glucose-regulated protein.
• Nucleic Acids Res. 1988; 16: 5204-5204

• Jendoubi M, Bonnefoy S
• Identification of a heat shock-like antigen in P. falciparum, related to the heat shock protein 90 family.
• Nucleic Acids Res. 1988; 16: 10928-10928

• Couto A, Rosario VE, Walliker D
• [Enzymatic analysis of 56 samples of Plasmodium falciparum of the Amazonian Basin (Brazil)].
• Rev Bras Malariol Doencas Trop. 1983; 35: 11-9

• Paradis D, Giguere R, Auray-Blais C, Draper P, Lemieux B
• An automated method for the determination of orotic acid in the urine of children being screened for metabolic disorders.
• Clin Biochem. 1980; 13: 160-3
• Display abstract

• Urinary orotic acid is believed to be a valuable probe for early diagnosis of inborn errors of metabolism leading to hyperammonemia and increased pyrimidine synthesis. For the purpose of our urinary mass screening programme, we developed an automated colorimetric method which is reliable in the range of 1 to 50 micrograms/ml orotic acid and allows analyses at a rate of 160 samples per hour. Preliminary results are presented which illustrate that various disorders can be recognized by measuring orotic acid in urine.

• SMITH LH Jr
• HEREDITARY OROTIC ACIDURIA--PYRIMIDINE AUXOTROPHISM IN MAN.
• Am J Med. 1965; 38: 1-6

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