Cases reported "Canavan Disease"

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11/30. Effect of topiramate on enlargement of head in canavan disease: a new option for treatment of megalencephaly.

    canavan disease (CD) is a rare autosomal recessive genetic disorder characterized by early onset progressive spongy degeneration of the brain involving the axon's myelin sheath. patients with CD have leukoencephalopathy and megalencephaly; clinically they show a variable course ranging from slow neurodegenerative course to no neurological development or rapid regression. Current treatment is symptomatic including management of seizures and spasticity. Topiramate (TPM) is a novel antiepileptic drug for treatment of a broad spectrum of seizure types in adults and children. We used TPM in two of our patients diagnosed with CD at six months of age. At seven months and 15 months' follow-up, respectively, each patient showed a decrease in head growth velocity. We suggest that TPM can be used in patients with CD and possibly in other childhood neurodegenerative diseases with leukoencephalopathy and megalencephaly. Further studies are required to reveal the underlying mechanisms that lead to decreased head growth velocity, and to conclude whether this ameliorates the clinical course of CD. ( info)

12/30. Possible genotype-phenotype correlations in children with mild clinical course of canavan disease.

    canavan disease is characterised as a rare, neurodegenerative disease that usually causes death in early childhood. It is an autosomal recessive disorder due to an aspartoacylase (ASPA) deficiency. The causative gene has been mapped to chromosome 17 pter-p13. Here we describe three affected children from two Greek families with an unusually mild course of canavan disease. All children presented with muscular hypotonia and macrocephaly. diagnosis was based on elevated N-acetylaspartate in urine, reduced aspartoacylase activity in fibroblasts, and marked white matter changes on cerebral imaging. All three affected individuals exhibited continuous psychomotor development without any regression. Genetic analyses revealed compound heterozygous mutations (Y288 C; F295 S) in two individuals. The Y288 C variant was previously described in a child with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia, partial cortical blindness and retinitis pigmentosa, and slightly elevated N-acetylaspartate in the urine. Demonstration of the same variant in two unusually mildly affected canavan disease patients and absence of this variant in 154 control chromosomes suggest a possible pathogenic role in mild canavan disease. In the third individual, two homozygous sequence variants were identified, which comprise the known G274R mutation and a novel K213E variant. ( info)

13/30. lithium citrate for canavan disease.

    Current evidence suggests that the effects of lithium on metabolic and signaling pathways in the brain may vary depending on the specific clinical condition or disease model. For example, lithium increases levels of cerebral N-acetyl aspartate in patients with bipolar disorder but does not appear to affect N-acetyl aspartate levels in normal human subjects. Conversely, lithium significantly decreases whole-brain levels of N-acetyl aspartate in a rat genetic model of canavan disease in which cerebral N-acetyl aspartate is chronically elevated. While N-acetyl aspartate is a commonly used surrogate marker for neuronal density and correlates with neuronal viability, grossly elevated whole-brain levels of N-acetyl aspartate in canavan disease are associated with dysmyelination and mental retardation. This report describes the first clinical application of lithium in a human subject with canavan disease. Spectroscopic and clinical changes were observed over the time period in which lithium was administered, which reversed during a 2-week wash-out period after withdrawal of lithium. This investigation reports decreased N-acetyl aspartate levels in the brain regions tested and magnetic resonance spectroscopic values that are more characteristic of normal development and myelination, suggesting that a larger, controlled trial of lithium may be warranted as supportive therapy for canavan disease by decreasing abnormally elevated N-acetyl aspartate. ( info)

14/30. Atypical MRI findings in canavan disease: a patient with a mild course.

    canavan disease is a severe, progressive leukodystrophy with an autosomal recessive inheritance, caused by aspartoacylase (ASPA) deficiency. The characteristic MRI features include diffuse, symmetrical white matter degeneration in the subcortical areas, with bilateral involvement of the globus pallidus. Proton magnetic resonance spectroscopy of the brain shows an increase in the concentration of N-acetylaspartic acid (NAA). The altered NAA metabolism has been traced to mutations in the gene encoding ASPA, located on chromosome 17 (17p13-ter). We present here a patient with a mild form of canavan disease confirmed with the absent ASPA activity, atypical MRI findings, related to compound heterozygosity for a missense mutation, p.Tyr288Cys, and the known pan-European mutation, the p.Ala305Glu. ( info)

15/30. Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene.

    We describe two sisters with a mild-onset variant of Canavan's disease who presented at age 50 and 19 months with developmental delay but without macrocephaly, hypotonia, spasticity, or seizures. Remarkably, both patients had age-appropriate head control, gross motor development, and muscle tone. There were very mild deficits in fine motor skills, coordination, and gait. Both sisters had a history of strabismus, but otherwise vision was normal. The older child showed evidence of mild cognitive and social impairment, whereas language and behavior were normal for age in the infant. Both patients were found to be compound heterozygotes for C914A (A305E) and G212A (R71H) mutations in ASPA. Like all other known ASPA mutations, this previously unknown G212A mutation appears to have low absolute enzyme activity. Nevertheless, it is associated in these patients with an extremely benign phenotype that is highly atypical of Canavan's disease. Biochemical and clinical data were evaluated using a generalized linear mixed model generated from 25 other subjects with Canavan's disease. There were statistically significant differences in brain chemistry and clinical evaluations, supporting a distinct variant of Canavan's disease. Future studies of ASPA enzyme structure and gene regulation in these subjects could lead to a better understanding of Canavan's pathophysiology and improvements in ASPA gene therapy. ( info)

16/30. canavan disease: from spongy degeneration to molecular analysis.

    Establishing the basic defect in canavan disease has led to reliable biochemical methods for the diagnosis of this disease. The isolation of the gene and identification of mutations causing canavan disease have led to the possibility of using dna methods for the diagnosis of canavan disease and for carrier detection. A surprising finding is the high carrier frequency of this gene defect among Ashkenazi Jewish people. Analysis for two mutations leads to the identification of 97% of Jewish patients with canavan disease, and screening of Ashkenazi jews is possible. N-Acetylaspartic acid has been considered to be an inert compound. The pathophysiology of canavan disease links lack of NAA hydrolysis to a severe, debilitating white matter disease. Currently, NAA is being studied in many other brain disorders, such as alzheimer disease, huntington disease, and stroke. However, the only disease with a specific defect in the metabolism of NAA is canavan disease. An animal model for canavan disease is needed to study some of the questions regarding the role of NAA in brain tissue, and for the study of therapeutic modalities, including gene therapy. ( info)

17/30. Primary intracranial atypical teratoid/rhabdoid tumor in a child with canavan disease.

    A primary intracranial atypical teratoid/rhabdoid tumor was encountered in a child (age 4 years and 9 months) with canavan disease. The tumor contained a large spindled cell component as well as classical rhabdoid morphology and focal areas resembling a primitive neuroectodermal tumor. The rhabdoid areas of the neoplasm were immunoreactive with antibodies against epithelial membrane antigen and vimentin, in the classically described pattern. Ultrastructurally these portions of the tumor displayed the characteristic perinuclear whorls of intermediate filaments reported in rhabdoid tumors of all body sites. Thought to be purely coincidental, this is also the first description of any intracranial neoplasm associated with canavan disease. ( info)

18/30. Oculodentodigital dysplasia with cerebral white matter abnormalities in a two-generation family.

    Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder involving eye and face abnormalities, syndactyly, and enamel hypoplasia. Some individuals with ODDD also have spastic paraparesis. Previously, we reported on a woman with sporadic ODDD and progressive neurologic dysfunction who had cerebral white matter abnormalities demonstrated by magnetic resonance imaging (MRI). We now describe a 2-generation family with ODDD and progressive paraparesis associated with leukodystrophic changes documented by MRI. This family represents one of the largest pedigrees with ODDD described so far. The presence of abnormal white matter changes in both sporadic and inherited forms of ODDD suggests that the phenotype of ODDD should be expanded to include spastic paraparesis. ( info)

19/30. Deletion of mitochondrial dna in patient with chronic tubulointerstitial nephritis.

    We report a mitochondrial dna deletion (2.6 kb) in a boy with tubulointerstitial nephritis in whom chronic renal failure and leukodystrophy subsequently developed. Elevated lactate values in plasma and cerebrospinal fluid were suggestive of a defect in the mitochondrial respiratory chain. High amounts of deleted mitochondrial dna were present in muscle and cerebral white matter. On the basis of this observation, we suggest giving consideration to genetic defects of oxidative phosphorylation in any attempt to determine the origin of unexplained chronic tubulointerstitial nephritis, especially when seemingly unrelated organs are involved. ( info)

20/30. magnetic resonance imaging in juvenile canavan disease.

    We present a 2-year-old boy and a 6-year-old girl with mild canavan disease (CD). Aspartoacylase activity in skin fibroblasts was deficient. magnetic resonance imaging (MRI) of the brain did not show the prominent leucodystrophy previously reported in CD, but there was a hyperintense signal from the lentiform nuclei and the heads of the caudate nuclei on the T2-weighted MR images. This suggests a specific vulnerability of the corpus striatum in these patients. In the older patient, the white matter became affected at the age of 6 years. Proton magnetic resonance spectroscopy (1H-MRS) of white matter revealed a normal concentration of N-acetyl-L-aspartate (NAA) and a markedly decreased concentration of choline containing compounds (Cho) in the boy but a normal ratio of NAA to Cho in the girl. We conclude that deficient NAA catabolism affects myelin metabolism. This may present as changes in the striatum and/or as a low concentration of Cho before leucodystrophy appears on MRI. ( info)
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