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1/11. 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.
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2/11. 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.
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3/11. Allogeneic bone marrow transplantation for infantile globoid-cell leukodystrophy (Krabbe's disease).

    A 4-month-old-girl affected by early expression of Krabbe's disease was treated with allogeneic bone marrow transplantation (BMT). The stem cell donor was her heterozygous HLA-identical mother. The central nervous system (CNS) involvement at diagnosis was evident, but minimal. After BMT the child presented a severe hypotonia and an acute tetraventricular hydrocephalus; she died 180 days after the BMT with progressive severe neurologic deterioration. Leukocyte galactocerebrosidase (GALC) activity was present at donor levels 20 days after BMT. Full donor chimerism was evident 18 days after BMT. This report confirms that in early onset "Krabbe's syndrome" if the diagnosis is delayed after the birth, the progression of the neurologic deterioration is not reversed by BMT. It is to be demonstrated if a very early hemopoietic stem cell transplantation during the first weeks of life, could be appropriate and efficacious.
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4/11. Late infantile onset krabbe disease in siblings with cortical degeneration and absence of cerebral globoid cells.

    Krabbe disease, a disorder caused by the deficiency of lysosomal galactosylceramidase, is typically associated with cerebral white matter degeneration, cortical sparing, accumulation of macrophages ("globoid cells"), and ultrastructural needle-shaped inclusions. Two sisters presented with progressive neurological deterioration beginning before the age of 2.5 years. The first, who died at the age of 9 years, exhibited profound destruction of cerebral white matter with sparing of subcortical fibers but no globoid cells. The brain of the second, who died at the age of 15 years and who had a proven galactosylceramidase deficiency, exhibited white matter destruction, previously undescribed circumscribed spongiform cortical degeneration (postcentral, inferior temporal, cingulate), and cerebellar atrophy, but no globoid cells. The peripheral nerve biopsies from both girls exhibited typical needle-shaped inclusions in schwann cells. These observations confirm the rare reports that Krabbe disease is not always associated with globoid cells in the brain. psychosine, which accumulates in the brain, might be toxic to cortical neurons following prolonged survival. The reason for the regional susceptibility in the cerebral cortex is unknown.
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5/11. Krabbe's disease. A light and electron microscopic study.

    Ultrastructural studies of brain and sural nerve biopsy specimens from a patient with Krabbe's disease disclosed periodically constricted or twisted tubules in addition to the more abundant and characteristic crystalloid and prismatic structures within macrophages. It is suggested that the twisted tubules may result from the intracellular accumulation of lactosyl ceramide. Familiarity with these unusual tubular structures is of practical as well as theoretical importance since they may be encountered in brain and peripheral nerve biopsy specimens obtained for the morphological diagnosis of Krabbe's disease.
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6/11. Late juvenile-onset Krabbe's disease.

    Krabbe's disease is an autosomal recessive leukodystrophy characterized by a lack of galactocerebroside beta-galactosidase activity. In contrast to the classic early infantile-onset form of Krabbe's disease, less recognized, late-onset variants exist. The authors present a case of late juvenile-onset Krabbe's disease, including the associated magnetic resonance imaging (MRI) findings. Most patients with late-onset Krabbe's disease present with visual loss due to optic atrophy. Associated gait abnormalities and parental consanguinity should increase the clinician's suspicion that a child may have late-onset Krabbe's disease. Because of the prolonged survival in late-onset Krabbe's disease, the recent development of bone marrow transplantation for these patient makes diagnosis of this disorder particularly important.
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7/11. Sphingolipid activator protein deficiency in a 16-week-old atypical gaucher disease patient and his fetal sibling: biochemical signs of combined sphingolipidoses.

    We describe a patient who presented shortly after birth with hyperkinetic behaviour, myoclonia, respiratory insufficiency and hepatosplenomegaly. Gaucher-like storage cells were found in bone marrow. A liver biopsy showed massive lysosomal storage morphologically different to that in known lipid storage disorders. Biochemically, the patient had partial deficiencies of beta-galactocerebrosidase, beta-glucocerebrosidase and ceramidase in skin fibroblast extracts, but the sphingomyelinase activity was normal. Glucosyl ceramide and ceramide were elevated in liver tissue. Loading of cultured fibroblasts with radioactive sphingolipid precursors indicated a profound defect in ceramide catabolism. Immunological studies in fibroblasts showed a total absence of cross-reacting material to sphingolipid activator protein 2 (SAP-2). The patient died at 16 weeks of age. The fetus from his mother's next pregnancy was similarly affected. The possibility that the disorder results from a primary defect at the level of SAP-2 is discussed. We have named this unique disorder SAP deficiency.
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8/11. A histochemical study of the enzyme profile of Krabbe's cells.

    A histochemical study of the enzyme profile of Krabbe's cells revealed a high activity of lysosomal enzymes, including the tartrate-resistant isoenzyme of acid phosphatase, and considerable activity of extralysosomal nonspecific esterase and mitochondrial and extramitochondrial dehydrogenases. The presence of lysozyme was demonstrated. This generally high metabolic activity was found closely reminiscent of that in Gaucher's cells and in epitheloid transformed macrophages though quite unlike the exclusive predominance of lysosomal enzyme activity typical of classical foamy storage cells in Niemann-Pick and Wolman's disease.
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9/11. Early infantile variant of Krabbe globoid cell leucodystrophy with lung involvement.

    An 8-week-old boy presented with a history of irritability, progressive feeding difficulty, generalised weakness, tachypnoea, and minor motor seizures. The clinical course was characterised by rapidly progressive respiratory failure, and neurological deterioration culminating in death at age 15 weeks. Electron microscopical examination and histological studies of the lung showed the presence of numerous intra-alveolar and a few interstitial macrophages. Enzyme studies and subsequent histopathological studies on brain confirmed the diagnosis of an unusual variant of Krabbe globoid cell leucodystrophy.
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10/11. Differentiation of rare leukodystrophies by post-mortem morphological and biochemical studies: female adrenoleukodystrophy-like disease and late-onset Krabbe disease.

    Two 6-year-old patients with clinical signs of leukodystrophy had no nosological diagnoses in vivo. Neuropathological studies revealed scavenger cells to be clustered in perivascular regions of the demyelinated brains. Histochemical and ultrastructural details of the non-metachromatic storage macrophages suggested lipid storage and prompted a biochemical analysis of cerebral tissue. The detection of increased amounts of very long chain fatty acids in the cholesterol ester fraction from formalin tissue in one patient was consistent with a diagnosis of an adrenoleukodystrophy-like condition, while the marked reduction in beta-galactocerebrosidase activity in a frozen brain sample of the second patient indicate Krabbe disease. The diagnostic potential of post-mortem studies in rare leukodystrophies is addressed.
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