Cerebral germinoma revealed through a polydipsic polyuric syndrome in a 10-year-old girl: case report.

Cerebral germinoma is rare. Although the imaging of the germinoma is very evocative, it's very polymorphic clinical expression is at the origin of misguided diagnosis, as illustrated in our case. We report the case of a 10-year-old girl with diabetes insipidus evolving for 12 months associated with a decrease in visual acuity. Brain MRI (Magnetic Resonance Imaging) revealed a tumor process in the suprasellar region. The stereotaxic biopsy of the tumor confirmed the diagnosis of the hypothalamic germinoma, which allowed the patient to be treated by radiotherapy and chemotherapy. The incidence of cerebral germinoma, its clinical (principally diabetes insipidus) and radiological features as well as therapeutic strategies are discussed hereby.

[Multiple bladder diverticula caused by occipital horn syndrome]. / Diverticulose vésicale liée à un syndrome de la corne occipitale.

We report on the case of a child who presented with recurrent, multiple, and voluminous bladder diverticula. Bladder diverticula are defined as a herniation of the mucosa through the bladder muscle or the detrusor. Causes are numerous and diverticula can be classified into primary congenital diverticula (para-ureteral - or Hutch diverticula - and posterolateral diverticula); secondary diverticula (resulting from chronic mechanical obstruction or from neurological disease; and diverticula secondary to connective tissue or muscle fragility. The latter is seen in disease entities such as prune belly syndrome, Ehlers-Danlos syndrome, cutis laxa syndrome, OHS (occipital horn syndrome), Menkes disease, and Williams-Beuren syndrome. In this patient, the cause of these diverticula was OHS, a genetic, recessive X-chromosome-linked syndrome, responsible for abnormal tissue caused by a disorder in copper metabolism. This case reminds us of the importance of pushing the diagnostic workup when presented with multiple and/or large bladder diverticula, and in particular to search for rare malformation syndromes after exclusion of an obstacle.

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits.

Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.

L-2-Hydroxyglutaric aciduria: clinical, genetic, and brain MRI characteristics in two adult sisters.

L-2-Hydroxyglutaric (L-2-HG) aciduria is a rare inherited metabolic disease usually observed in children. Patients present a very slowly progressive deterioration with cerebellar ataxia, mild or severe mental retardation, and various other clinical signs including extrapyramidal and pyramidal symptoms, and seizures. The disease is characterized by increased levels of L-2-HG in body fluids such as urine and cerebrospinal fluid. We report on two sisters from consanguineous parents, in whom L-2-HG aciduria was diagnosed at an adult age. Although magnetic resonance imaging and spectroscopic findings were severely abnormal in both, they experienced a different clinical course. The older sister presented with severe mental retardation, recurrent epileptic seizures, and progressive deterioration in her ability to walk and to talk; she is now confined to a wheelchair with severe speech deficit. In contrast, the younger sister only had a few epileptic seizures in childhood and moderate mental retardation, is still able to walk, and performs manual work, and has a social life in a specialized institution for moderately mentally handicapped persons. For the two patients, a complete deletion of exon 9 was demonstrated in a gene located on chromosome 14q22.1, which most probably encodes for L-2-hydroxyglutarate dehydrogenase. The pathological findings observed in this metabolic disorder could therefore be related to a toxic effect of L-2-hydroxyglutarate on the central nervous system, although the presence of other toxic metabolites cannot be excluded.

Long-term follow-up of neonatal mitochondrial cytopathies: a study of 57 patients.

OBJECTIVES: We sought to determine the long-term clinical and biochemical outcome of newborns with mitochondrial cytopathies (MCs) and to identify possible prognostic factors that may modify the course of these diseases. MATERIAL AND METHODS: Fifty-seven newborns with MCs were identified in a retrospective review (1983-2002). We defined 2 different outcome categories: clinical (neurologic, hepatic, myopathic, and multiorganic) and biochemical (lactate level normalization or initially normal remaining unchanged, decreased but not normalized, and persistently high). We used 2 different statistical approaches: (1) survival studies depending on the initial symptoms and lactate and enzymatic deficiencies using the Kaplan-Meier method; and (2) the same variables compared with different survival age groups and clinical and biochemical outcome categories using the chi2 test. RESULTS: Thirty-three patients died (57.8%), 12 remain alive (21%), and 12 were lost in the follow-up; 6 of them are currently older than 4 years. Most of the patients manifested multiorganic disease (64.8%) and high lactate level (77.1%) over time. Children surviving to 2.5 to 3 years of age were more likely to survive for a long period of time. Initial neurologic and hepatic presentation increased the risk to develop neurologic disease and severe persistent hyperlactacidemia, respectively. Initial severe hyperlactacidemia and combined enzyme deficiencies were significant risk factors for higher mortality and multiorganic disorders. Two patients with exclusively myopathic outcome are alive and cognitively normal at 12 years of life. CONCLUSIONS: Children with neonatal-onset MCs have very high mortality and poor prospects. However, some with life-threatening presentations may gradually improve, giving rise to less severe diseases. Those with exclusively myopathic symptoms have a better prognosis.

Urea cycle defects: management and outcome.

This paper reviews the clinical presentation of 217 patients with urea cycle defects, including 121 patients with neonatal-onset forms and 96 patients with late-onset forms. Long-term outcome of these patients is also reported with the severity of the neonatal forms of these disorders, mostly for ornithine carbamoyltransferase-deficient males. Patients with late-onset forms may present at any age and carry a 28% mortality rate and a subsequent risk of subsequent disabilities.

Magnetic resonance imaging for the diagnosis of acute leukoencephalopathy in children treated with tacrolimus.

The leukoencephalopathy induced by tacrolimus is increasingly recognised as an important cause of neurological complications after transplantation. Magnetic resonance imaging (MRI) is of major help in the differential diagnosis of infection or vascular injury. We describe two children with coma and seizures after transplantation, in whom the results of MRI with FLAIR (fluid-attenuated inversion-recovery) and DWI (diffusion-weighted images) were the main positive elements for the diagnosis of drug-induced toxicity. The results of DWI favoured the role of oedema and/or demyelination in the pathophysiology of this disorder. Unlike other reported patients, in whom all symptoms resolved, lesions persisted, albeit improved, on the control MRI, and both children demonstrated learning disabilities after several years of follow-up.

Impaired mitochondrial pyruvate importation in a patient and a fetus at risk.

The patient was the first child of healthy consanguineous parents. She presented at birth with hypotonia, mild facial dysmorphism, periventricular cysts, marked metabolic acidosis, hyperlactacidemia with normal lactate/pyruvate molar ratios, normoglycemia, and normal ammonia. Hyperlactacidemia was severe (5-14 mmol/l) and not corrected with bicarbonate, thiamine (10 mg/d), 2-chloropropionate (100 mg/kg/d) and a ketogenic diet. Pyruvate dehydrogenase (PDHC) activity was normal in lymphocytes and fibroblasts. Functional assays were performed in digitonin-permeabilized fibroblasts to measure oxidation rates from radiolabeled pyruvate and malate. The production of [14C]acetylcarnitine or [14C]citric cycle intermediates derived from [2-14C]pyruvate as well as the release of 14CO(2) from [1-14C]pyruvate was severely impaired, whereas decarboxylation of [U-14C]malate was normal. With increasing concentrations of [1-14C]pyruvate, the patient's fibroblasts behave like control fibroblasts incubated in the presence of alpha-cyano-4-hydroxycinnamate, a specific inhibitor of mitochondrial pyruvate uptake: a progressive increase in 14CO(2) production was observed, likely due to passive diffusion of [1-14C]pyruvate through the mitochondrial membranes. Our results are consistent with a defect of mitochondrial pyruvate transport in the patient. Mutational analysis was precluded as the cDNA sequence of the pyruvate carrier has not been identified as yet in any organism. An affected fetus was recognized in a subsequent dichorionic twin pregnancy using the coupled assay measuring [2-14C]pyruvate oxidation rates on digitonin-permeabilized trophoblasts. After selective feticide, the pregnancy was uncomplicated with delivery at 37w of a healthy female, who is currently 2-month old.

Clinical approach to inherited metabolic disorders in neonates: an overview.

There are almost one hundred inborn errors of metabolism which can start in the neonatal period, but less than 20 are amenable to treatment. In general, an extremely evocative clinical setting is the course of a full-term baby born after normal pregnancy and delivery who, after an initial symptom-free period deteriorates relentlessly for no apparent reason and does not respond to symptomatic therapy. Investigations routinely performed in all sick neonates yield normal results. Emergency treatment must be undertaken in parallel with investigations. Five main presentations can be observed: a neurologic deterioration 'intoxication' type mostly suggests maple syrup urine disease, methylmalonic, propionic, isovaleric acidaemias and urea cycle disorders. Isolated seizures is the revealing symptom of pyridoxine-responsive and folinic acid responsive seizures. A jaundice or a liver failure suggest galactosaemia, fructosaemia, tyrosinaemia type I (after 3 weeks), phosphomannoisomerase deficiency or bile acid synthesis defects. Cardiac failure and heartbeat disorders should first suggest mitochondrial fatty acid oxidation (FAO) disorders. Persistent hypoglycaemia is the presenting sign of glyco/gluconeogeneis defects, hyperinsulinism and FAO disorders. The first line investigation relies upon the collection at the same time of a few samples including blood gases electrolytes, prothrombin time, transaminases, ammonia and lactic acid, and the search for ketonuria. The storage of plasma, urine and blood (on filter paper) is an important element in the diagnosis. The utilization of these samples should be carefully planned after taking advice from specialists in inborn errors.

Mutation of a nuclear respiratory factor 2 binding site in the 5' untranslated region of the ADSL gene in three patients with adenylosuccinate lyase deficiency.

Adenylosuccinate lyase (ADSL; also called "adenylosuccinase") catalyzes two steps in the synthesis of purine nucleotides: (1) the conversion of succinylaminoimidazolecarboxamide ribotide into aminoimidazolecarboxamide ribotide and (2) the conversion of adenylosuccinate into adenosine monophosphate. ADSL deficiency, a recessively inherited disorder, causes variable-but most often severe-mental retardation, frequently accompanied by epilepsy and/or autism. It is characterized by the accumulation, in body fluids, of succinylaminoimidazolecarboxamide riboside and succinyladenosine, the dephosphorylated derivatives of the two substrates of the enzyme. Analysis of the ADSL gene of three unrelated patients with ADSL deficiency, in whom one of the ADSL alleles displayed a normal coding sequence, revealed a -49T-->C mutation in the 5' untranslated region of this allele. Measurements of the amount of mRNA transcribed from the latter allele showed that it was reduced to approximately 33% of that transcribed from the alleles mutated in their coding sequence. Further investigations showed that the -49T-->C mutation provokes a reduction to 25% of wild-type control of promoter function, as evaluated by luciferase activity and mRNA level in transfection experiments. The mutation also affects the binding of nuclear respiratory factor 2 (NRF-2), a known activator of transcription, as assessed by gel-shift studies. Our findings indicate that a mutation of a regulatory region of the ADSL gene might be an unusually frequent cause of ADSL deficiency, and they suggest a role for NRF-2 in the gene regulation of the purine biosynthetic pathway.

Partial elective pancreatectomy is curative in focal form of permanent hyperinsulinemic hypoglycaemia in infancy: A report of 45 cases from 1983 to 2000.

BACKGROUND/PURPOSE: Permanent hyperinsulinemic hypoglycaemia in infancy (PHHI)I is a severe disease that leads to brain damage. Since 1989, pathologists have identified 2 different forms of the disease: a diffuse form (DiPHHI) and a focal form (FoPHHI). The purpose of this study was to adapt surgical techniques in case of FoPHHI to cure these infants without risk of diabetes. METHODS: All patients with PHHI underwent pancreatic venous sampling (PVS) and elective partial pancreatectomy (EPP). Molecular biology and immunohistochemistry were used to ascertain that FoPHHI was a different disease from DiPHHI. RESULTS: 45 EPPs were performed, guided by PVS and peroperative pathology. The lesions were 17 in the head, 4 in the isthmus, 6 in the body, 15 in the tail of the pancreas. Age at surgery ranged from 25 days to 4 years. Two patients already had been operated on elsewhere, and the focal lesion could be found at second operation. All 45 patients except one, were cured with euglycemia at both fasting and hyperglycaemic tests. Molecular biology has shown a specific anomaly in FoPHHI, which never has been encountered in DiPHHI. CONCLUSIONS: PHHI is not a homogeneous disease. In one third of cases, only a small amount of endocrine pancreas is abnormal, and conservative surgery is mandatory. The pre- and perioperative conditions to point out the focal pancreatic lesion are described.

Pancreatic arterial calcium stimulation in the diagnosis and localisation of persistent hyperinsulinemic hypoglycaemia of infancy.

BACKGROUND: Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is often resistant to medical therapy. Surgery is therefore necessary. It is due to focal adenomatous islet-cell hyperplasia treatable by partial pancreatectomy, or diffuse beta-cell hyperfunction, which requires near-total pancreatectomy. Pancreatic venous sampling (PVS) is the reference technique for the preoperative diagnosis and localization of focal forms of PHHI in the pancreas. However, hypoglycaemia is necessary to analyse the results and PVS is technically challenging. Pancreatic arterial calcium stimulation (PACS) is technically easier and does not require hypoglycaemia. AIM: To study the accuracy in the diagnosis and localization of PHHI. MATERIALS AND METHODS: PACS was performed in 12 patients and correlated with histology. RESULTS: The accuracy of PACS is poor in diffuse lesions since only two of six cases were correctly identified by this test. Five of six focal lesions were correctly recognized and located. CONCLUSIONS: PACS is less accurate than PVS in PHHI. Currently, it should be performed only when PVS fails.

[Hereditary metabolic causes of stroke and pseudo-stroke in adulthood]. / Stroke et pseudo-stroke d'origine héréditaire métabolique à l'âge adulte.

Metabolic diseases are a rare cause of strokes. However, prevention and treatment are available for some of them. This work describes some metabolic diseases generating strokes by disturbing directly vascular function (homocysteine disorders, Fabry disease, congenital defects of glycosylation) and those for which clinical presentation is similar to a stroke (urea cycle disorders, branched-chain organic acidurias, mitochondrial diseases).

Polymicrogyria and motor neuropathy in Micro syndrome.

Micro syndrome is a rare condition in which congenital cataracts, microphthalmia, and facial dysmorphism are associated with severe neurological disorders, namely: microcephaly and psychomotor retardation. We report on polymicrogyria and motor neuropathy in a patient with Micro syndrome. These findings provide new insights into developmental defects underlying motor and mental disabilities.

Identification of undescribed medium-chain acylcarnitines present in urine of patients with propionic and methylmalonic acidemias.

In urine of patients with propionyl-CoA carboxylase deficiency or with methylmalonic acidemia, carnitine esters of 2-methyl-branched fatty acids of all chain lengths between 4 and 9 atoms of carbon were identified during the acute phase of the diseases. The chemical structure of these compounds was obtained by gas chromatography-mass spectrometry analysis of their fatty acid moieties in their free and picolinyl ester forms. We suggest mechanisms for the biosynthesis of these branched fatty acids, and their accumulation in urine during episodes of caloric imbalance.