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1/119. Protracted course of Krabbe disease in an adult patient bearing a novel mutation.

    BACKGROUND: Krabbe disease, or globoid cell leukodystrophy, is an autosomal recessive disorder caused by the deficiency of galactocerebrosidase (GALC) activity. Although most cases are diagnosed in infancy and show a fatal outcome in childhood, adult patients have been identified, showing progressive spastic hemiparesis to tetraparesis, followed by optic atrophy, dementia, and neuropathy. The disease can be diagnosed by detecting the deficiency of GALC activity (less than 5% of normal) in any available tissue sample. The cloning of the human GALC gene allowed the molecular characterization of newly diagnosed patients. More than 75 disease-causing mutations and polymorphisms in this gene have been identified. OBJECTIVE: To describe a 28-year-old woman with Krabbe disease, correlating clinical and biochemical abnormalities to a novel mutation on the GALC gene. methods: Clinical investigation was enriched by neurophysiological and neuroimaging data. The activity of GALC was assayed in white blood cells using radiolabeled natural substrate. Genomic dna was isolated from peripheral blood, and the GALC gene was sequenced. The mutated gene was expressed and GALC activity was measured in transfected COS-1 cells. RESULTS: The patient had progressive and bilateral amaurosis starting at 8 years of age. Although she was experiencing weakness in all her extremities, her intellect remained intact. She was found to be homozygous for a previously unreported missense mutation (T1886G), which leads to low, but not totally deficient, GALC activity. CONCLUSIONS: Expression of this mutation in COS-1 cells using the pcDNA3 expression vector (Invitrogen, Carlsbad, Calif) resulted in low, although not null, GALC activity, which can explain the protracted clinical course in this patient. patients carrying the mutation described herein might be potential candidates for therapeutic trials, such as bone marrow transplantation or gene therapy. ( info)

2/119. Characterization of the GALC gene in three Japanese patients with adult-onset Krabbe disease.

    Krabbe disease, a neurodegenerative disorder of autosomal recessive inheritance, is caused by mutations in the galactosylceramidase (GALC) gene. However, its clinical manifestations in terms of time of onset and severity are heterogeneous. Thus, elucidation of the relationship of symptoms to the site and type of mutation is important, both for an understanding of the etiology of the disease and for diagnostic purposes. We examined the genomic structure of the GALC gene in three unrelated adult-onset Krabbe disease patients. One patient was homozygous for an Ile66Met mutation. Another patient who appeared to express only one mutated mRNA species was, in fact, a compound heterozygote for an Ile66Met mutation and a nonsense mutation, Tyr354ter. Because the allele with the nonsense mutation was not detectable by mRNA analysis, a rapid degradation of the mRNA caused by premature chain termination was suggested. The third patient who carried two inactiving mutations--Leu618Ser and a second resulting in exon 6 skipping--was also found to carry an intronic mutation, IVS6 5G > A. transfection experiments using a GALC mini-gene proved that this intronic mutation was the cause for the exon 6 skipping. ( info)

3/119. optic nerve enlargement in Krabbe's disease.

    We report imaging and gross pathologic findings from two cases of Krabbe disease in which there was marked enlargement of the intracranial optic nerves. Numerous globoid cells were observed in the optic nerves at autopsy in one case. Krabbe disease should be included in the differential diagnosis of children with enlargement of the optic nerves. ( info)

4/119. Clinical and cerebral FDG PET scan in a patient with Krabbe's disease.

    A 2-year, 6-month-old Saudi male with infantile Krabbe's disease was studied with fluorine-18-labeled-2-fluoro-2-deoxyglucose positron emission tomography (FDG PET) scan. The patient presented with a gradual loss of developmental milestones, irritability, and crying. At the advanced stage of the disease, he developed tonic-clonic seizures and became a microcephalic, extremely irritable, blind, spastic quadriplegic child, with no deep tendon reflexes. Laboratory studies revealed normal blood chemistry, muscle enzymes, very long chain fatty acids, and acylcarnitines. No abnormal urinary organic acids were detected. The cerebrospinal fluid protein concentration was increased. magnetic resonance imaging of the brain revealed mild brain atrophy and white matter disease mainly in the centrum semiovale. electroretinography was normal; however, electroencephalography and visual-evoked potentials were abnormal. Peripheral nerve conduction studies documented a demyelinating neuropathic process. The FDG PET study of the brain demonstrated a marked decrease in the metabolism of the left cerebral cortex and no uptake in the caudate heads. Normal glucose uptake was observed in the thalami, lentiform nuclei, and cerebellum. The patient did not present for subsequent clinic visits and is presumed dead. ( info)

5/119. Is congenital fibre type disproportion a true myopathy?

    The authors report a case of congenital fibre type disproportion in a 32-month-old male patient. A pathogenetic role of alcohol ("fetal alcohol syndrome") could be discussed here because the mother drank daily large quantities of alcohol during pregnancy. Histochemical features undistinguishable from those reported in congenital fibre type disproportion were also observed in two cases of globoid cell leucodystrophy (Krabbe's disease) and in one case of infantile acid maltase deficiency (Pompe's disease). Morphometric studies confirmed this analogy. The occurrence of a similar fibre type disproportion in conditions so completely different from each other casts doubts as to the specificity of these histoenzymatic features. It is suggested that at least some cases of congenital fibre type disproportion could result from a maturational insufficiency of type I motor neurons or from a damage brought to the schwann cells. ( info)

6/119. MR imaging and proton MR spectroscopy in adult Krabbe disease.

    We present the MR imaging findings in four patients (two pairs of siblings from two unrelated families) with adult Krabbe disease. In the first family, clinical presentation mimicked familial spastic paraplegia. Their MR images showed selective, increased signal intensity on T2-weighted sequences along the corticospinal tracts, most prominently in the proband and barely detectable in her brother. Proton MR spectroscopy showed increased choline and myo-inositol in the affected white matter. In the second family, the clinical presentation differed in that the signs of pyramidal tract involvement were asymmetrical, with concomitant asymmetry on MR images in one. In adults, Krabbe disease may present on MR imaging with selective pyramidal fiber involvement. ( info)

7/119. Partial seizures in leukoencephalopathy with swelling and a discrepantly mild clinical course.

    We report a patient with 'Leukoencephalopathy with swelling and a discrepantly mild clinical course', an entity of leukoencephalopathy recently clarified. Our patient presented with complex partial seizures in addition to characteristic radiological findings and clinical course. A review of the literature revealed that this new neurodegenerative disease complicates epilepsy in more than half of the patients, and that partial components in the seizure symptomatology are not infrequent. ( info)

8/119. A new familial adult-onset leukodystrophy manifesting as cerebellar ataxia and dementia.

    BACKGROUND: Among hereditary leukodystrophies, a considerable number remain unclassified. patients AND RESULTS: We investigated the clinical course and histopathology of one patient in a family of adult-onset leukodystrophy with possible dominant inheritance. A 44-year-old man presented with cerebellar ataxia as the initial symptom, and later, dementia and hyperreflexia with ankle clonus developed. T2-weighted brain MRI showed brain atrophy and diffuse high signal intensity of the cerebral white matter and the brain stem. The patient's mother and older brother also had cerebellar ataxia and dementia, and his older brother had been diagnosed as having spinocerebellar degeneration. An older sister of our patient possibly had similar neurological symptoms of adult-onset. Our patient died of pneumonia 5 years after the onset of disease. The histopathological findings consisted mainly of patchily observed vacuolar changes in the cerebral and cerebellar white matter and the brain stem. The subcortical regions and the cortex were unaffected. It is suggested that the pathological changes began in the cerebellum, and later spread to the frontal lobe and the brain stem. In the occipital regions, the vacuolations were associated with accumulation of macrophages and astrocytosis, which implied that the vacuolations were of recent origin. CONCLUSIONS: The diagnosis in this patient is adult-onset leukodystrophy with possibly autosomal dominant inheritance. The clinicopathological features are different from those, of previously reported adult-onset leukodystrophies. ( info)

9/119. Steroid-induced hypertrophic cardiomyopathy following stem cell transplantation in a neonate: a case report.

    We report a case of severe left ventricular outflow tract obstruction complicating steroid therapy in an infant undergoing allogeneic transplant in the first few weeks of life for treatment of Krabbe's disease. While this complication is well known to those treating premature infants, it has not been reported in the stem cell transplant setting. For young infants undergoing allogeneic transplant who require steroid therapy, cardiac monitoring after 2--3 weeks of therapy is recommended. ( info)

10/119. magnetic resonance spectroscopy and magnetic resonance imaging findings in Krabbe's disease.

    Two twins with late infantile globoid cell leukodystrophy of Krabbe's disease were studied with conventional magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy. Brain MRI demonstrated brain atrophy with extensive bilateral symmetric abnormal T2 signal in the posterior periventricular white matter, parietal lobes, corona radiata, centrum semiovale, and splenium of the corpus callosum. magnetic resonance imaging-guided proton magnetic resonance spectroscopy revealed prominent peaks from choline-containing compounds, total creatine, and inositols. The N-acetylaspartate peak was markedly reduced, and the choline-to-N-acetylaspartate ratio was abnormally high; in one of the twins, lactic acid was also detected. The constellation of magnetic resonance spectroscopy findings is indicative of extensive demyelination, gliosis, and loss of axons in the involved white matter; the latter two events occur in the later stages of globoid cell leukodystrophy. In conjunction with brain MRI, these magnetic resonance spectroscopy findings may alert clinicians to the possibility of leukodystrophy in children with progressive encephalopathy. ( info)
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