Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sphingolipidoses are an heterogeneous group of inherited disorders of lipid metabolism affecting primarily the central nervous system. These disorders occur chiefly in the pediatric population, and the degenerative nature of the disease processes is generally characterized by diffuse and progressive involvement of neurones (gray matter) with psychomotor retardation and myoclonus or of fiber tracts (white matter) with weakness and spasticity. Biochemical research has identified the defects in the sphingolipidoses to specific lysosomal enzymes. For example, Niemann-Pick disease lacks sphingomyelinase; Krabbe's disease lacks galactocerebrosidase; Gaucher's disease lacks beta-D-glucosidase; metachromatic leukodystrophy lacks sulfatase; Tay-Sachs disease lacks hexosaminidase A; and generalized gangliosidosis lacks beta-galactosidase. Although there are no currently available modes of rendering corrective therapy in these disorders, a definitive diagnosis is possible both antepartum as well as postpartum. This information provides a sound and accurate basis for genetic counseling.
 ...
PMID:Sphingolipidoses. 555 2

Progressive spasticity, blindness, loss of skills, and neuropathy developed in a 4.5-month-old boy. When examined at 13 months, galactocerebrosidase and galactosylceramide-beta-galactosidase activities were deficient in leukocytes. Intramuscular nerves and a sural nerve biopsy specimen showed loss of nerve fibers, interstitial fibrosis, and axonal degeneration, rather than the segmental demyelination that predominates in most cases. A muscle biopsy specimen showed congenital muscle fiber-type disproportion (CMFTD). This case confirms a previous report of CMFTD in Krabbe's disease and supports a neurogenic mechanism as the basis for CMFTD.
 ...
PMID:Congenital muscle fiber-type disproportion in Krabbe's leukodystrophy. 727 38

Krabbe disease (KD) (globoid cell leukodystrophy) is a degenerative, lysosomal storage disease, caused by a severe loss of galactocerebrosidase (GALC) enzymatic activity. The inheritance is autosomal recessive. KD affects the white matter of the central and peripheral nervous systems. We present a 3 year old boy in whom the disease had an 'infantile' or 'classic' presentation, with spasticity, irritability, and developmental delay. In addition the boy showed progressive severe motor and mental deterioration, difficulties in swallowing and decerebration. Molecular analysis revealed that the child is a compound heterozygote: p.Asp187Val (c.560A>T) and p.Ile250Thr (c.749T>C). The father was the carrier of p.Asp187Val (c.560A>T), while the mother was the carrier of the p.Ile250Thr (c.749T>C) in exon 6 of the GALC gene. The clinical course in this compound heterozygote is severe and the patient passed away at the age of 3 years. Genotype-phenotype relations are discussed in this Macedonian patient with KD.
...
PMID:Compound Galactosylceramidase Gene (GALC) Heterozygosity in a Boy with Infantile Krabbe Disease (KD). 2744 2

BACKGROUND Krabbe disease, or globoid cell leukodystrophy, is an autosomal recessive disease caused by the deficiency of lysosomal galactocerebrosidase. The most common form is infantile Krabbe disease, which is usually diagnosed within the first year of life and has high morbidity and mortality. Patients usually present with irritability, progressive neurodegeneration, spasticity, and peripheral neuropathy. This report is of a 6-year-old girl who had Krabbe disease since she was 5 weeks of age. CASE REPORT A 6-year-old female Saudi patient had initially presented at 5 weeks of age with hypoventilation, recurrent attacks of fever, and failure to thrive. The patient also skin hypopigmentation involving the face, neck, upper extremities, and lower extremities. Peripheral blood galactocerebrosidase enzyme activity was normal but was reduced in tissue fibroblasts. Whole exome sequencing (WES) and whole genome sequencing (WGS) showed a homozygous mutation in the GALC gene c.334A>G (p.Thr112Ala), which was previously reported in a compound heterozygous state with another mutation. CONCLUSIONS This case report describes a patient with homozygous mutation status Krabbe disease. Although this patient had the phenotype of early infantile-onset Krabbe disease, which usually has high morbidity and mortality, her condition is now relatively stable at 6 years of age, which could be due to relatively higher enzyme activity. This case also expanded the presentation or typical phenotype of infantile Krabbe disease as the patient also presented with hypoventilation and skin hypopigmentation.
 ...
PMID:Report of a Case that Expands the Phenotype of Infantile Krabbe Disease. 3105

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.
 ...
PMID:Pathogenic Variants in GALC Gene Correlate With Late Onset Krabbe Disease and Vision Loss: Case Series and Review of Literature. 3317 8