Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A clinical and neuropathological study of a case of xeroderma pigmentosum with severe neurological abnormalities was performed. The patient developed sensitivity to the sun, followed by freckles and malignant skin tumors. Some years after the onset of the cutaneous symptoms, a slowly progressive mental deterioration was noted. Subsequently, dysarthria, increased sensitivity and a tendency to cry and to be easily frightened developed together with ataxia and spasticity of the limbs. Late in the course of the disease the patient was severely disabled because of spastic tetraplegia. The clinical examination revealed generalized slowing in EEG, mixed sensory and motor neuropathy in EMG, thick skull, both cerebral cortical atrophy and ventricular dilatation in computed tomography and marked decrease in cerebrospinal homovanillic acid content. The neuropathological study showed marked loss of neurons in the basal nucleus of Meynert, the substantia nigra, the cerebellum, medulla and spinal cord. Diffuse loss of neurons was noted in the cerebral cortex and in the deep cerebral nuclei. In the nerve cells, a high amount of cytoplasmic lipofuscin was observed in some areas of CNS. The sciatic nerve showed marked loss of axons and heavy deposition of collagen around the remaining nerve fibers. The present neuropathological findings explain many of the clinical symptoms observed in xeroderma pigmentosum and show similarities with those observed in olivopontocerebellar atrophy, although the basic mechanism for the CNS damage is still unclear.
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PMID:Xeroderma pigmentosum with neurological abnormalities. A clinical and neuropathological study. 370 28

Cockayne syndrome and xeroderma pigmentosum-Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31(1/2) years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum-Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known.
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PMID:Cockayne syndrome in adults: review with clinical and pathologic study of a new case. 1709 72

In this Review, familial and sporadic neurological disorders reported to have an etiological link with DNA repair defects are discussed, with special emphasis placed on the molecular link between the disease phenotype and the precise DNA repair defect. Of the 15 neurological disorders listed, some of which have symptoms of progeria, six--spinocerebellar ataxia with axonal neuropathy-1, Huntington's disease, Alzheimer's disease, Parkinson's disease, Down syndrome and amyotrophic lateral sclerosis--seem to result from increased oxidative stress, and the inability of the base excision repair pathway to handle the damage to DNA that this induces. Five of the conditions (xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Down syndrome, and triple-A syndrome) display a defect in the nucleotide excision repair pathway, four (Huntington's disease, various spinocerebellar ataxias, Friedreich's ataxia and myotonic dystrophy types 1 and 2) exhibit an unusual expansion of repeat sequences in DNA, and four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimer's disease) exhibit defects in genes involved in repairing double-strand breaks. The current overall picture indicates that oxidative stress is a major causative factor in genomic instability in the brain, and that the nature of the resulting neurological phenotype depends on the pathway through which the instability is normally repaired.
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PMID:Mechanisms of disease: DNA repair defects and neurological disease. 1734 92

Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington's disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.
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PMID:DNA repair deficiency in neurodegeneration. 2155 Mar 79

Deficient repair of ubiquitous errors in the genome risks faulty transcription or replication. Its direct and indirect phenotypic consequences are rare, complex, dementing, lethal disorders of children with inadequately understood overlapping genotypes and variable severity. Mutations of CSA or CSB responsible for impaired transcription-coupled repair cause Cockayne syndrome (CS). Its characteristics are (1) profound growth deficiency affecting all tissues, including the brain, (2) premature aging marked by cachexia, vascular disease, exocrine deficiency, and osteopenia, but not cancer, and (3) a selective degenerative disorder of central and peripheral myelin and by neuronal loss in the retina and inner ear, and in the cerebellum and basal ganglia where it is associated with calcification. Xeroderma pigmentosum (XP) can arise from mutations of at least eight genes involved in global genomic repair. Severe XPA and XPC cause innumerable carcinomas and melanomas in light-exposed eyes and skin, and enhanced risk of visceral cancers. XPA and XPD and others can cause childhood XP neurological disease with widespread neuronal loss, axonal sensorimotor neuropathy, and dwarfing. Four genes, including XPD, can cause trichothiodystrophy (TTD) with sulfur-deficient, brittle, tiger-tail hair, and growth and developmental inadequacy. CSB or XPD can cause the severe congenital cerebro-oculofacioskeletal (COFS) CS-like syndrome with joint contractures, cataracts, and early death. Three XP genes can also cause XP/CS complex. Much more needs to be learned about these and other disorders of DNA repair to enable prevention and treatment.
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PMID:Disorders of nucleotide excision repair. 2362 85