Globoid cell leukodystrophy in cairn and West Highland white terriers (original) (raw)
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Molecular Genetics and Metabolism, 2001
Globoid cell leukodystrophy (Krabbe disease) is a severe leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene leading to extremely low (less than 5% of normal activity) GALC activity. Human patients include primarily severely affected infants as well as patients with a later onset of symptoms. The infants usually die before 2 years of age, but it is difficult to predict the clinical course in older patients. In addition to these patients, additional individuals identified in this laboratory have 10 -20% of normal GALC activity measured in accessible tissues. These individuals have a wide range of clinical presentations involving neurological degeneration. On molecular analysis of the GALC gene they all have three or more mutations considered to be normal polymorphisms resulting in amino acid changes in the two copies of the GALC gene. In order to investigate the role these amino acid changes may play on clinical, biochemical, and pathological findings, a new transgenic mouse was generated by homologous recombination. After preliminary studies determined what effect each amino acid change had on mouse GALC activity in transient transfection experiments, mice containing a cysteine residue at codon 168 instead of histidine (H168C) were produced. These mice developed symptoms, but they were delayed by 10 -15 days from the well-characterized twitcher (twi) mouse. They accumulated psychosine slightly slower than twi mice, showed pathological changes less severe than twi mice in the central and peripheral nervous systems, and live about 15 days longer than twi mice. They have large litters and will play a role in therapy trials using new procedures currently under development.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2017
Krabbe disease (KD) is an inherited leukodystrophy due to a defect in the GALC gene which encodes the lysosomal galactosylceramide β-galactosidase (GALC). About two thirds of patients show the early onset form of KD dominated by cerebral demyelination leading to death in early infancy. Late onset forms include a spectrum of late infantile, juvenile and adult clinical courses. The deficiency of GALC leads to a galactosylceramide lipidosis in which lysosomal storage phenomena are seen almost only at the ultrastructural level. In a 4-year-old boy, the clinical suspicion of KD was high according to neurologic and neuroimaging findings. However, laboratory results were inconclusive; white blood cell GALC activity being at 23 to 25% of the normal level, and GALC genotyping revealing the new homozygous p.Ala543Pro variant which, ex silico, was of unclear significance. Studying a skin biopsy, cultured fibroblasts showed the GALC activity at 21 to 30% of the normal level; ultrastructurally, ...
A hypomyelinating leukodystrophy in German Shepherd dogs
Journal of Veterinary Internal Medicine, 2021
Background: Shaking puppy syndrome is commonly attributed to abnormal myelination of the central nervous system. Hypothesis/Objectives: To report the long-term clinical course and the imaging characteristics of hypomyelinating leukodystrophy in German Shepherd dogs. Animals and Methods: Three related litters with 11 affected dogs. Results: The 11 affected dogs experienced coarse, side-to-side tremors of the head and trunk, which interfered with normal goal-oriented movements and disappeared at rest. Signs were noticed shortly after birth. Nine dogs were euthanized, 3 dogs underwent pathological examination, and 2 littermates were raised by their breeder. Tremors improved gradually until 6 to 7 months of age. Adult dogs walked with severe residual pelvic limb ataxia. One dog developed epilepsy with tonic-clonic seizures at 15 months of age. Conventional magnetic resonance imaging (MRI) disclosed homogenous hyperintense signal of the entire subcortical white matter in 3 affected 7-week-old dogs and a hypointense signal in a presumably unaffected littermate. Subcortical white matter appeared isointense to gray matter at 15 and 27 weeks of age on repeated MRI. Abnormal white matter signal with failure to display normal gray-white matter contrast persisted into adulthood. Cerebellar arbor vitae was not visible at any time point. Clinical signs, MRI findings, and pathological examinations were indicative of a hypomyelinating leukodystrophy. All parents of the affected litters shared a common ancestor and relatedness of the puppies suggested an autosomal recessive mode of inheritance. Conclusion: We describe a novel hypomyelinating leukodystrophy in German Shepherd dogs with a suspected inherited origin.
Human gene therapy, 2018
Globoid cell leukodystrophy (GLD), or Krabbe disease, is an inherited, neurologic disorder that results from deficiency of a lysosomal enzyme, galactosylceramidase (GALC). Most commonly, deficits of GALC result in widespread central and peripheral nervous system (CNS, PNS) demyelination and death in affected infants typically by 2 years of age. Hematopoietic stem cell transplantation is the current standard of care in children diagnosed prior to symptom onset; however, disease correction is incomplete. Herein we present the first adeno-associated virus (AAV) gene therapy experiments in a naturally occurring canine model of GLD that closely recapitulates the clinical disease progression, neuropathological alterations, and biochemical abnormalities observed in human patients. Adapted from studies in the twitcher mice, GLD dogs were treated by combination intravenous (IV) and intracerebroventricular (ICV) injections of AAVrh10 to target both PNS and CNS. Combination of IV and ICV AAV g...
Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy
American journal of human genetics, 1996
Globoid-cell leukodystrophy (GLD) is an autosomal recessive inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of the myelin glycolipid galactocerebroside. Although the most common form of the disease is the classical infantile form (Krabbe disease), later-onset forms also have been described. We have analyzed the galactocerebrosidase gene in 17 patients (nine families) with late-onset GLD and in 1 patient with classical Krabbe disease. Half of the patients were heterozygous for the large gene deletion associated with the 502C-->T polymorphism, the most common mutation in infantile patients. Several novel mutations that result in deficient galactocerebrosidase activity were also identified in these patients. They include the missense mutations R63H, G95S, M101L, G268S, Y298C, and I234T; the nonsense mutation S7X; a one-base deletion (805delG); a mutation that interferes with the splicing of intron 1; and a 34-...
Clinicopathological Features of Globoid Cell Leucodystrophy in Cats
Journal of Comparative Pathology, 2005
Clinical and pathological findings consistent with globoid cell leucodystrophy (GLD) were evaluated in two domestic shorthaired cats, aged 3 and 4 months. Both showed neurological signs mainly characterized by progressive pelvic limb ataxia, paraplegia with loss of deep pain perception in the pelvic limb, and intentional tremors of the thoracic limbs. Pathological changes affecting the central and peripheral nervous systems were characterised by diffuse, bilateral and symmetrical myelin loss, and marked astrogliosis. In the leucodystrophic areas there was perivascular accumulation of large PAS-positive, nonmetachromatic macrophages (globoid cells), with intracytoplasmic accumulation of crystalloid tubular aggregates. Peripheral nerves showed demyelinating features with thin myelin sheaths, myelin splitting, and ballooning; the nerve fibres had bizarre shapes due to the presence of pale inclusions in the Schwann cells. GLD in cats shares clinical and pathological features with the disease described in other animals and human beings. The neurological signs differed from those of other feline inborn neurometabolic diseases and cerebellar hypoplasia.
Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease
Human molecular genetics, 2013
Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production. The currently used mouse model, twitcher, has a nonsense mutation not found in Krabbe patients, although it is similar to the human 30 kb deletion in abrogating GALC expression. Here, we identify a spontaneous mutation in GALC, GALC twi-5J , that precisely matches the E130K missense mutation in patients with infantile Krabbe disease. GALC twi-5J homozygotes show loss of enzymatic activity despite normal levels of precursor protein, and manifest a more severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks such as gliosis, globoid cells and psychosine accumulation are present throughout the nervous system, the CNS does not manifest significant demyelination. In contrast, the PNS is severely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a demyelinating process. Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression. Furthermore, our results argue against a causative relationship between psychosine accumulation, white matter loss and gliosis.
Clinica Chimica Acta, 2002
Background: Krabbe disease (globoid-cell leukodystrophy; GLD) is caused by mutations in the GALC gene. ßgalactocerebrosidase (GALC) is a specific ß-galactosidase which is defective in GLD. About 90% of GLD patients have an infantile course by fatal cerebral demyelination, hut 10% have a later onset (LOGLD) of symptoms and survive für one or several decades. Methods: Activities of GALC towards galactosylceramide (GC) and galactosylsphingosine (psychosine; PS) , were determined in white blood cells and cultured fibroblasts derived from GLD patients and controls using tritium-labe lIed can lead to enzymatic and clinical signs ofLOGLD in the absence of marked GALC-PS deficiency. If an active PS hydro lysis in f.;i the fibroblasts of a LOGLD patient also reflected such hydrolysis in the brain, the psychosine hypothesis für GLD may need to be revised. 7472-has a lethal cours~ by severe cerebral demyelmation 931-826. during infancy iri about 90% ofthe patients. In about E-mail address: Harzer-Rottenburg@t-online.de (K. Harzer).