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Progressive neurologic deterioration and renal failure due to storage of glutamyl ribose-5-phosphate
Insights
This study identifies a new glycoproteinosis in a child with neurological decline. The disorder involves cytoplasmic storage of glutamyl ribose-5-phosphate, impacting gene expression and DNA repair.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- X-linked recessive inheritance patterns can manifest with severe neurological symptoms.
- Lysosomal storage diseases are a group of genetic disorders characterized by the accumulation of undigested substances within lysosomes.
Observation:
- A six-year-old boy exhibited progressive neurological deterioration, seizures, proteinuria, and distinctive physical features.
- Standard metabolic and enzyme assays for known storage diseases were negative, but electron microscopy revealed enlarged lysosomes in conjunctival and renal biopsies.
Findings:
- Purification of glutamyl ribose-5-phosphate from brain and kidney tissue identified it as the accumulated compound.
- This compound is crucial in ADP-ribosylation, a process vital for gene expression and DNA repair.
Implications:
- This case represents a novel glycoproteinosis characterized by cytoplasmic storage of glutamyl ribose-5-phosphate.
- Understanding this disorder may offer new insights into the pathogenesis of neurodegenerative diseases and lysosomal storage disorders.
Abstract:
A six-year-old boy presented with a history of seizures, progressive neurologic deterioration, and proteinuria. Physical examination revealed mildly coarse facies, failure to thrive, generalized hypotonia with muscle wasting, and optic atrophy; there was no organomegaly. The family history suggested an X-linked recessive inheritance. The electroencephalogram, electroretinogram, evoked potentials, and computed axial tomography of the brain were abnormal. Urine oligosaccharide chromatography, urine amino acids and organic acids, and results of leukocyte and fibroblast lysosomal-enzyme assays for the known storage diseases were normal; however, conjunctival and renal biopsy specimens contained enlarged lysosomes on electron microscopy. The patient had progressive neurologic deterioration and died of renal failure at eight years of age. A compound identified as glutamyl ribose-5-phosphate was purified from the brain (0.96 mumol per gram, wet weight) and kidney (0.60 mumol per gram, wet weight). This compound is the linkage group in ADP-ribosylation of proteins, an important regulatory process in gene expression and DNA repair. We believe this new disorder represents a glycoproteinosis that results in the cytoplasmic storage of glutamyl ribose-5-phosphate.