Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Morphological study of peripheral nerves in two patients with globoid cell leucodystrophy (Krabbe's disease) demonstrates: 1degree segmentary demyelination; 2degrees marked loss of large (8-10 micra) myelinated fibres; 3degrees significant increase of the mean transverse fascicular area by proliferating collagen fibres; 4degrees electron-microscopic signs of remyelination with small onion-bulb formations. These findings can explain clinical features such as the disappearance of the deep tendon reflexes, the gradual transition of hypertonia into combined hypertonia-hypotonia and the concomitant slowing of nerve conduction velocity. The ultrastructural study reveals the presence of large and small inclusions which are either located within lysosomes or free in the cytoplasm of Schwann cells and fibroblasts. The inclusions are probably consequences of the disturbed metabolism of cerebrosides. Their appearance is sufficiently specific in order to allow a diagnosis of Krabbe's disease.
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PMID:[Globoid cell leucodystrophy (Krabbe's disease). Peripheral nerve lesion (author's transl)]. 437 97

A two year and ten-month-old girl with cerebello-brain stem leukodystrophy is presented. She was hypotonic with spasticity and showed delayed motor development until she was twelve months old, when regression of motor activities began. Progressive hypotonia, dysphagia and fatal respiratory abnormalities developed. Auditory brain stem response was absent. Pathological examination revealed primary demyelination with a predilection for the cerebellum, brain stem and spinal cord, in association with changes of the cerebellar cortex, pontine nuclei, inferior olivary nuclei and part of the basal ganglia. Clinical, pathological and biochemical studies revealed that this disease is different from metachromatic leukodystrophy, Krabbe's globoid cell leukodystrophy and adrenoleukodystrophy. The clinical entity of cerebello-brain stem orthochromatic leukodystrophy is discussed.
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PMID:Cerebello-brain stem orthochromatic leukodystrophy with floppiness and bulbar paralysis. 647 80

Hypotonia and weakness developed in a 12-month-old boy whose psychomotor development had previously been normal. The muscle biopsy demonstrated a disparity in the mean diameters of type 1 and type 2 fibers and satisfied major histologic criteria for diagnosis of congenital fiber type disproportion (CFTD). However, deterioration of motor and mental function, which developed subsequently, strongly suggested progressive encephalopathy. Examination of leukocyte cerebral enzymes at 15 months of age revealed a complete lack of galactosylceramide-beta-galactosidase. Selective type 1 fiber atrophy with type 1 fiber predominance has been observed in various conditions, including Krabbe disease. We report an additional case of Krabbe leukodystrophy associated with CFTD. The finding on the molecular level will resolve the dilemma of whether CFTD is a congenital myopathy or whether these patterns of disproportion may result from a number of different processes that interfere with the maturation of the developing motor unit.
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PMID:Association of Krabbe leukodystrophy and congenital fiber type disproportion. 885 9

Early infantile Krabbe disease is a progressive neurodegenerative disease caused by deficiency of lysosomal enzyme galactocerebroside beta-galactosidase, with onset before the age of 6 months. We present serial clinical, radiological and neurophysiological findings of a patient with early infantile Krabbe disease, presenting at the third day of life with hypotonia, macrocephaly and neonatal seizures. The patient had a deceptively normal initial magnetic resonance imaging examination at the age of 3 months, with progression of the white matter disease over the following 9 months, showing a clinical picture of profound hypotonia with pyramidal and pseudobulbar signs, as well as mild optic atrophy. Assay of galactocerebroside beta-galactosidase activity in leukocyte culture disclosed a marked deficiency of the enzyme (0.00 nmol/mg protein per h with normal values > 0.7 nmol/mg protein per h), thus confirming the diagnosis of Krabbe disease. Nerve conduction velocity and evoked potential studies, as well as the electroencephalogram, were abnormal at the age of 6 months, while serial neurophysiological studies at the age of 12 and 18 months demonstrated the progressive nature of the disease.
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PMID:Early infantile Krabbe disease: deceptively normal magnetic resonance imaging and serial neurophysiological studies. 940 97

Krabbe disease or globoid cell leukodystrophy (GLD) is an autosomal recessive disorder resulting from the defective lysosomal hydrolysis of specific galactolipids found primarily in myelin. This leads to severe neurological symptoms including seizures, hypotonia, blindness, and death, usually before 2 years of age in human patients. In addition to human patients, several animals, including dog, mouse, and monkey, have the same disease caused by a deficiency of galactocerebrosidase (GALC) activity. In this article we describe studies in cairn and West Highland white terriers (WHWT) affected with GLD. Through a screening test based on the molecular defect found in these breeds, over 50 cairn terrier carriers have been identified and a colony of five carrier dogs has been established. Affected dogs from this colony plus an affected WHWT were available for study. An affected WHWT was evaluated by magnetic resonance imaging at 6 and 11 months of age and pronounced changes in the T-2 weighted fast spin-echo images were found. Biochemical and pathological evaluation of the same dog after euthanasia at 12 months of age showed a large accumulation of psychosine in the brain and white matter filled with globoid cells. Some comparisons were made to younger affected and carrier dogs. Studies have shown successful transduction of cultured skin fibroblasts from an affected dog and normal canine bone marrow using a retroviral vector containing the human GALC cDNA. Successful treatment of this canine model will lead to studies in some humans with GLD.
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PMID:Globoid cell leukodystrophy in cairn and West Highland white terriers. 998 21

We report three children, each of whom seemed to have a primary mitochondrial disorder at presentation but was eventually diagnosed with an extramitochondrial inherited metabolic disease. The first patient presented at 6 months with developmental delay. Magnetic resonance imaging showed an abnormal signal in the white matter, and magnetic resonance spectroscopy showed elevated lactate peaks. A muscle biopsy showed complex IV deficiency, but leukocyte measurement of galactosylceramide beta-galactosidase activity was markedly diminished, consistent with Krabbe's disease. The second patient presented at birth with seizures and later had developmental delays. There was brain atrophy on neuroimaging. Serum and cerebrospinal fluid lactate levels were elevated. She had persistently elevated urine thiosulfate, which was diagnostic for molybdenum cofactor deficiency. The third child presented at 2 months with seizures and hypotonia. Magnetic resonance imaging showed an abnormal signal in the basal ganglia and surrounding white matter, whereas magnetic resonance spectroscopy showed elevated lactate peaks. A brain biopsy was diagnostic for Alexander's disease. These cases and others in the literature suggest that lactic acid elevation in the central nervous system can be found in a number of extramitochondrial neurologic diseases. Such diseases would constitute a third category of lactic acidosis.
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PMID:Lactic acid elevation in extramitochondrial childhood neurodegenerative diseases. 1157 6

Globoid cell leukodystrophy (GLD; Krabbe disease), is a rare heritable metabolic disorder in humans, dogs, mutant twitcher mice, and rhesus monkeys that is caused by a deficiency in the lysosomal enzyme galactocerebrosidase (GALC). GALC deficiency results in the accumulation of psychosine, which is toxic to oligodendrocytes and Schwann cells of the central and peripheral nervous systems. Clinical signs include hypotonia, mental regression, and death by 2 years of age in most human patients. Here we describe a domestic longhaired kitten with rapidly progressive neurologic disease and brain and spinal cord lesions characteristic of GLD. Pathologic hallmarks of the disease reflect the loss of oligodendrocytes and include myelin loss, gliosis, and the perivascular accumulation of large mononuclear cells with fine cytoplasmic vacuoles (globoid cells) in the peripheral and central nervous systems. Globoid cells were CD68 and ferritin positive, confirming their monocytic origin, and cytoplasmic contents were nonmetachromatic and periodic acid-Schiff positive.
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PMID:Globoid cell-like leukodystrophy in a domestic longhaired cat. 1212 53

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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PMID:Allogeneic bone marrow transplantation for infantile globoid-cell leukodystrophy (Krabbe's disease). 1239 Apr 32

Background: Krabbe disease is an autosomal recessive demyelinating disorder resulting from deficiency of the lysosomal enzyme galactocerebrosidase. While blindness is often described as a characteristic finding of the disease, it is more common in the infantile phenotype, where vision loss typically arises in the late stages of disease. In comparison, reports of vision loss in late onset phenotypes are less well-described and may be subject to variation between genotypes. Methods: Charts of Krabbe patients with a confirmed diagnosis, who presented with substantial visual impairment, were retrospectively reviewed from a larger group of 199 Krabbe patients. Assessment of clinical status was obtained through review of neurological evaluations, neurodevelopmental assessments, ophthalmological evaluations, visual evoked potentials (VEP), electroretinogram (ERG), nerve conduction velocity (NCV) studies, auditory brainstem responses (ABR), and brain magnetic resonance imaging. Results: Five late onset patients with Krabbe disease (four juvenile and one late-infantile) were included. Three patients were homozygous for c.956A>G_p.Y319C, one was compound heterozygous for c.296+1G>T and c.956A>G_p.Y319C, and one was compound heterozygous for c.1186C>T_p.R396W and c.1901T>C_p.L634S. All patients were of Asian descent and presented initially with vision impairment. Notably, the patients did not present with marked appendicular spasticity or axial hypotonia and all five reached developmental milestones within the normal time frame. For neurophysiological testing, no patient showed abnormalities in NCV or ABR. However, abnormalities in VEP or ERG were seen in all patients. The one patient who underwent transplantation stabilized following treatment. Conclusions: Depending on their genotype, patients with late onset Krabbe disease may initially present with vision loss. Furthermore, patients with p.L634S and p.Y319C should be closely monitored for changes in vision and VEP. This knowledge will become increasingly important as physicians may otherwise overlook these signs and symptoms when monitoring children identified through newborn screening who have the variants described in this report.
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PMID:Pathogenic Variants in GALC Gene Correlate With Late Onset Krabbe Disease and Vision Loss: Case Series and Review of Literature. 3317 8