Enrico Parano

Identification and Analysis of Mutations in the Wilson Disease Gene (ATP7B): Population Frequencies, Genotype-Phenotype Correlation, and Functional Analyses

Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-terminus and the poly(A) tail. Over one-half of all WD mutations occur only rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in-frame, 39-bp insertion in mRNA of patients homozygous, but not heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts, this mutation deviated from Hardy-Weinberg equilibrium, with an overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices, including age of onset, clinical manifestation, ceruloplasmin activity, hepatic copper levels, and the presence of Kayser-Fleischer rings. Finally, lymphoblast cell lines from individuals homozygous for His1069Glu and 4 other mutations all demonstrated significantly decreased copper-stimulated ATPase activity.

Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection

The objective of this study was to assess brain involvement through the presence of antineuronal antibodies in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) and in uncomplicated active Group A streptococcal infection. We compared serum antibrain antibody to human basal ganglia sections assessed by indirect tissue immunofluorescence in two groups: a PANDAS group, comprised of 22 patients (mean age 10.1 years; 20 male, 2 female) who met strict National Institutes of Mental Health diagnostic criteria for PANDAS and had clinically active tics or obsessive-compulsive disorder, or both; and a GABHS control group consisting of 22 patients (mean age 9.1 years; 15 mol/L, 7 female) with clinical evidence of active Group A beta-hemolytic streptococcal (GABHS) infection confirmed by throat culture and elevated antistreptolysin O titers but without history or clinical evidence of tics or obsessive-compulsive disorder. We observed positive anti-basal ganglia staining (defined as detectable staining at 1:10 serum dilution) in 14/22 patients in the PANDAS group (64%) but only 2/22 (9%) in the GABHS control group (P < 0.001, Fishers exact test). These results suggest that antibrain antibodies are present in children with PANDAS that cannot be explained merely by a history of GABHS infection.

Electrophysiologic Correlates of Peripheral Nervous System Maturation in Infancy and Childhood

Peripheral nervous system maturation in infancy and childhood varies with age, especially during the first 2 years of life. Electrophysiologic values therefore change significantly between different age groups within these first 2 years and are different from adult values. Normal values of motor and sensory nerve conduction, distal motor latency, F-wave latency, and evoked response amplitude of peripheral nerves commonly tested are reported in 155 healthy children in seven age groups from 1 week to 14 years. Interval changes are clearly shown, and in comparison with adult values, the whole group has significantly slower nerve conduction velocities, with reduced muscle and nerve evoked response amplitudes. These differences are important to recognize when evaluating the peripheral nervous system of children. (J Child Neurol 1993;8:336-338).

Acute Disseminated Encephalomyelitis: A Long-Term Prospective Study and Meta-Analysis

BACKGROUND There are only a few series in the literature on acute disseminated encephalomyelitis (ADEM) in children. OBJECTIVES AND METHODS the aims of this study were to perform (i) a prospective clinical/imaging study (1992-2009) on ADEM in children consecutively referred to our institution in Catania, Italy, and (ii) to undertake a systematic review and meta-analysis of published ADEM pediatric cohorts (>10 cases). RESULTS We identified 17 patients with ADEM (incidence <10 years of age=1.1 per 100 000 person-years). 15 previously published cohorts were compared with our cohort: (i) systematically reviewed (750 cases); and (ii) meta-analyzed (492/750 cases). The 17 patients had the following characteristics: (a) male-to-female ratio, 1.4 (vs. 1.2-1.3 in previous cohorts); (b) mean age at presentation, 3.6 years (vs. 7.1 years in previous cohorts); (c) specific preceding triggering factor, 88% (vs. 69-79% in previous cohorts); (d) the most common initial signs were ataxia, seizures, headache, and thalamic syndrome; (e) brain imaging revealed >3 lesions in 100% (vs. 92% in previous cohorts); (f) the outcome was good in 94% (vs. 70-75% in previous cohorts); and (g) 12% relapsed once (vs. 18% in previous cohorts). CONCLUSIONS ADEM is generally a benign condition that mosly affects boys more than girls and rarely recurs.

Recurrent peripheral neuropathy in a girl with celiac disease

The involvement of the peripheral nervous system (PNS) in children with celiac disease is particularly rare. Furthermore, in both children and adults with celiac disease, neurological complications are chronic and progressive.1 We report on a 12 year old girl affected by celiac disease, who on two separate occasions presented with an acute peripheral neurological syndrome after accidental reintroduction of gluten in her diet. This patient was born uneventfully to healthy non-consanguineous parents with no family history of neurological or metabolic diseases. At the age of 6 months she was diagnosed as having celiac disease according to the European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) criteria. Since then she was on a strict gluten free diet and was asymptomatic until the age of 10 years when severe diarrhoea, vomiting, and abdominal pain manifested 6 days after the intake of corn flakes erroneously thought to be gluten free. No previous infections had been noticed. One week after the onset of these symptoms she experienced acute weakness and pins and needles sensation confined to her legs. At that time her parents stopped her intake of corn flakes on the suspicion that these were responsible for the symptoms. Despite this, symptoms worsened during the next 2 days, confining her to bed. At hospital admission, she was alert and mentally stable. Results of general physical examination were unremarkable. Neurological examination disclosed symmetric, predominantly distal, weakness of the legs; …

Perrault syndrome: Evidence for progressive nervous system involvement

Perrault syndrome (PS) comprises gonadal dysgenesis and sensorineural deafness in females, and deafness in affected males. More recent studies have asked whether the neurological signs in some of the patients are a coincidental finding or part of the syndrome. We report on two pairs of sisters with gonadal dysgenesis and deafness, cerebral, and ocular involvement who developed a progressive, severe sensory, and motor neuropathy. This observation constitutes further evidence of peripheral nervous system involvement in PS. Based on the clinical observations of known patients, two forms of PS may be distinguished: one apparently non‐progressive form and another (exemplified by our two sets of sisters) with apparently progressive axonal‐cerebellar degeneration.

Late-onset globoid cell leukodystrophy

During the past 12 years, ten cases of globoidcell leukodystrophy (GLD) have been followed up: seven of these patients were affected by the late infantile form. The authors point out the clinical aspects and the course of these patients and stress the high frequency of this form of GLD in Sicily.

White matter changes mimicking a leukodystrophy in a patient with Mucopolysaccharidosis: characterization by MRI

Mucopolysaccharidosis (MPS) type I (alpha-iduronidase deficiency) is characterized by storage and massive urinary excretion of dermatan sulfate and heparan sulfate; it may be distinguished into three different subtypes based on age at onset and severity of the clinical symptoms. We report on progressive white matter involvement documented by serial MR imaging in a patient with the MPS type I, severe skeletal involvement and preserved mental capabilities (intermediate phenotype or Hurler/Scheie syndrome).The natural history of white matter abnormalities in patients with MPS is still unclear; based on the present study, it appears that degenerative changes of the white matter mimicking a leukodystrophy may mark the course of MPS type I. We also suggest that the degree of MR changes in patients with MPS does not always reflect their neurological impairment.

Lack of progression of brain atrophy in Aicardi-Goutières syndrome

Aicardi-Goutières syndrome is a severe and progressive familial encephalopathy that is characterized by acquired microcephaly, intracranial calcification (mainly of the basal ganglia), signs of white matter disease, and chronic lymphocytosis with elevated levels of interferon-alpha in the cerebrospinal fluid in the absence of other evidence of infection. Although the degree of calcification and the severity of brain atrophy are variable, typically the brain lesions appear to progress on successive examinations. In this article a 4-year-old male patient with Aicardi-Goutières syndrome who manifested the typical neurologic signs of the disease was re-evaluated. The evaluation revealed, on successive cranial computed tomography and magnetic resonance imaging scans, increasing calcification with remarkable reduction of brain atrophy. To the best of our knowledge, there is only one previously mentioned study of a 4-year-old female patient with progressive features of Aicardi-Goutières syndrome, including intracranial calcification, who displayed a lack of progression of brain atrophy at MRI scan.

Aicardi syndrome with multiple tumors: a case report with literature review

A 5-year-old girl with Aicardi syndrome, choroid plexus papilloma and multiple gastric hyperplastic polyps is reported. Gastric polyposis is unusual in the pediatric age group and has not previously been reported in a patient with Aicardi syndrome. A variety of uncommon benign and malignant tumors have been associated with Aicardi syndrome; this literature is briefly reviewed. The increased frequency of tumors in Aicardi syndrome should be kept in mind when evaluating these patients.