Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich ataxia patients with a membranepermeant chelator capable of shuttling chelated iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain magnetic resonance imaging (MRI) of Friedreich ataxia patients compared with agematched controls revealed smaller and irregularly shaped dentate nuclei with significantly (P < .027) higher H-relaxation rates R2*, indicating regional iron accumulation. A 6-month treatment with 20 to 30 mg/kg/d deferiprone of 9 adolescent patients with no overt cardiomyopathy reduced R2* from 18.3 s ؊1 (؎ 1.6 s ؊1 ) to 15.7 s ؊1 (؎ 0.7 s ؊1 ; P < .002), specifically in dentate nuclei and proportionally to the initial R2* (r ‫؍‬ 0.90). Chelator treatment caused no apparent hematologic or neurologic side effects while reducing neu- IntroductionTissue iron overload and ensuing organ damage have generally been identified with transfusional hemosiderosis and genetic hemochromatosis. 1 Liver, heart, and endocrine glands are among the most affected organs in these forms of systemic iron overload. 1 The source of tissue iron overload has been traced to plasma iron originating from enteric hyperabsorption of the metal and/or enhanced red cell destruction. The labile forms of plasma iron (LPI) that appear as transferrin become saturated, permeate into particular cell types by unregulated mechanisms, and cause labile iron pools to raise and challenge cellular antioxidant capacities. 2 However, in chronic inflammation 3 and in various genetic disorders, 4 iron accumulates in particular cell types attaining toxic levels, even in the absence of circulating LPI and often even in iron-deficient plasma. In Friedreich ataxia (FA), an expansion of a GAA repeat in the first intron of the nuclear encoded frataxin gene 5,6 results in underexpression of a mitochondrial protein involved in the assembly of iron-sulphur cluster proteins (ISPs) and/or in protecting mitochondria from iron-mediated oxidative damage. 7 The defective ISP formation that causes a combined aconitase and respiratory chain deficiency (complex I-III) leads in turn to mitochondrial accumulation of labile iron 8,9 and ensuing oxidative damage in brain, heart, and endocrine glands. However, the pathophysiologic role of mitochondrial iron accumulation in oxidative damage found in FA 5,9 and other neurologic disorders [10][11][12][13] has not been resolved.In analogy to transfusional iron overload, histopathologic and magnetic resonance imaging (MRI) studies of FA patients have shown that iron accumulates not only in the heart but also in the spinocerebellar tracts (dentate nuclei) and spinal cord. 10 Those and othe...

Congenital lumbosacral lipomas can be responsible for progressive defects. The general feeling is that tethering of roots, filum, or cord probably explains this evolution, and that untethering of these structures could prevent late deterioration. Like the vast majority of neurosurgeons, we too have routinely and systematically operated on lumbosacral lipomas, even in the absence of neurological deficits. This policy stemmed from our belief that spontaneous neurological deterioration was frequent, recovery from preoperative deficits rare, and surgery both efficient and benign in nature. After 22 years of experience, we felt that it was necessary to review our series of 291 lipomas (38 lipomas of the filum and 253 of the conus) operated on from 1972 to 1994. To reassess the value of prophylactic surgery, we attempted an accurate evaluation of (1) the risk of pathology, (2) the risks involved in surgery, (3) the postoperative outcome with respect to preoperative deficits, and (4) the postoperative outcome in asymptomatic patients at 1 year and at maximum follow-up. Special attention was paid to 93 patients whose postoperative follow-up was more than 5 years (average 8.7, median 8, range 5-23 years). Of these 93 patients, 39 were asymptomatic preoperatively (7 with lipoma of the filum and 32 with lipoma of the conus). Lipomas of the filum and of the conus are entirely different lesions and were studied separately. In 6 cases prenatal diagnosis had been possible. The mean age at surgery was 6.4 years. Low back skin stigmata were present in 89.4% of cases. Preoperative neurological deficits existed in 57% of the patients and were congenital in 22%. Clinical signs and symptoms recorded were pain in 13.3% of the patients and/or neurological deficits affecting sphincter (52%), motor (27.6%) and sensory (22.4%) functions. Deficits were progressive in 22.4% of cases, slowly progressive in 58.8% of these and rapidly progressive in the remaining 41.2%. In 36 patients (13.2%) the lipomas were seen to grow either subcutaneously or intraspinally. Among these patients, 21 were infants, 2 were obese adolescents, and 10 were pregnant women. The metabolism of the fat within the lipomas was studied in 11 patients and found to be similar to that at other sites. Lipomas were associated with various other malformations, either intra- or extraspinal. These associated anomalies were rare in the case of lipomatous filum (5.2%) but frequent with lipomas of the conus, except for intracranial malformations (3.6%). Therapeutic objectives were spinal cord untethering and decompression, sparing of functional neural tissue and prevention of retethering. Procedures used to achieve these goals were subtotal removal of the lipoma, intraoperative monitoring, duroplasty, and sometimes closure of the placode. Histologically, lipomas consisted of normal mature fat. However, 77% of them also included a wide variety of other tissues, originating from ectoderm, mesoderm, or entoderm. This indicates that lipomas are either simple or complex teratomas. The r...

Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.

Hyperinsulinism in infancy is one of the most diYcult problems to manage in contemporary paediatric endocrinology. Although the diagnosis can usually be achieved without diYculty, it presents the paediatrician with formidable day to day management problems. Despite recent advances in understanding the pathophysiology of hyperinsulinism, the neurological outcome remains poor, and there is often a choice of unsatisfactory treatments, with life long sequelae for the child and his or her family. This paper presents a state of the art overview on management derived from a consensus workshop held by the European network for research into hyperinsulinism (ENRHI). The consensus is presented as an educational aid for paediatricians and children's nurses. It oVers a practical guide to management based on the most up to date knowledge. It presents a proposed management cascade and focuses on the clinical recognition of the disease, the immediate steps that should be taken to stabilise the infant during diagnostic investigations, and the principles of definitive treatment. (Arch Dis Child Fetal Neonatal Ed 2000;82:F98-F107)

Impairments in social interaction are a key feature of autism and are associated with atypical social information processing. Here we report functional magnetic resonance imaging (fMRI) results showing that individuals with autism failed to activate superior temporal sulcus (STS) voice-selective regions in response to vocal sounds, whereas they showed a normal activation pattern in response to nonvocal sounds. These findings suggest abnormal cortical processing of socially relevant auditory information in autism.

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Among neonates with hyperinsulinism, about half may have focal islet-cell hyperplasia that can be treated with partial pancreatectomy. These neonates can be identified through pancreatic catheterization and intraoperative histologic studies.