Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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The features of Cockayne syndrome include dwarfism, cataracts, optic atrophy, intellectual disability, an unusual facies and body habitus, hearing loss, a peculiar form of fine pigmentary retinitis without the typical spicules seen in retinitis pigmentosa, and some similarities to the condition progeria. This condition can be caused by two gene mutations, CNK1 (ERCC8 or CSA) and ERCC6 (CSB), located on the 5 and 10 chromosomes respectively, causing two variations: Cockayne syndrome type A, secondary to an ERCC8 mutation, and Cockayne syndrome type B with ERCC6 mutation. The latter causes hypersensitivity to ultraviolet light, secondary to a DNA repair defect. The syndrome is also associated with mutations of the XPB, XPD, and XPG genes. Cockayne syndrome is extremely rare, with approximately 200 cases in the literature. Death generally occurs by the age of 30 years, secondary to inanition or infection. Current management focuses on symptomatic therapy, although the possibility of gene therapy is under investigation.
• Cockayne syndrome is an autosomal recessive multisystem disorder, predominantly characterized by neurologic and sensory impairment, cachectic dwarfism, and photosensitivity.
• Although the most typical form is known as Cockayne syndrome type I, a severe form seen at birth is known as Cockayne syndrome type II (known as cerebro-oculo-facial-skeletal syndrome or Pena-Shokeir syndrome type II). A much milder form is known as Cockayne syndrome type III. In addition, an entity known as xeroderma pigmentosum-Cockayne syndrome is recognized.
• Diagnosis is made on clinical grounds and, when needed, molecular genetic testing.
• Treatment consists of purely supportive care.
• Molecular prenatal diagnosis of Cockayne syndrome type A has been successful. Carrier detection (50% chance of being an asymptomatic carrier) is available once the mutations have been identified in the proband.
• Cockayne syndrome is characterized by a deficiency in the transcription-couple DNA repair pathway caused by mutations mainly in the Cockayne syndrome group B gene (ERCC6 or CSB).
Cockayne syndrome, or Cockayne-Neill-Dingwall syndrome, was first reported by Cockayne in 1936 in a brother and sister with dwarfism and retinal atrophy (14). He made a follow-up report in 1946, at which time he reported that the children were markedly different than at first presentation (15). The features of the condition included the postnatal onset of dwarfism, cataracts, optic atrophy, mental retardation, an unusual facies and body habitus, hearing loss, and a peculiar form of fine pigmentary retinitis without the typical spicules seen in retinitis pigmentosa. Neill and Dingwall later reported on another child and commented on some similarities to the condition progeria (61). Macdonald and colleagues reported three additional patients in a family (51). They saw a clear and sharp distinction between Cockayne syndrome and progeria, a point that has been clearly borne out by the discovery of the underlying pathogenesis in Cockayne syndrome.
Cockayne syndrome can be caused by two gene mutations, CNK1 (ERCC8 or CSA) and ERCC6, located on the 5 and 10 chromosomes respectively, causing two variations: Cockayne syndrome type A, secondary to an ERCC8 mutation, and Cockayne syndrome type B with ERCC6 (or CSB) mutation. The latter causes hypersensitivity to ultraviolet light, secondary to a DNA repair defect. The syndrome is also associated with mutations of the XPB, XPD, and XPG genes.
Cockayne syndrome is a genetic condition characterized by short stature, microcephaly, mental retardation, characteristic senile appearance, retinopathy, sensorineural hearing loss, and the development of a leukodystrophy that results from a defect in the repair mechanism of actively transcribed DNA (46). The growth failure is typically of postnatal onset, children usually having been born with normal birth weight and length. Growth slows in the first year of life so that by early childhood they are two standard deviations below the mean (57). The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood (69).
The facial appearance as patients with Cockayne syndrome grow older is distinctive. A loss of subcutaneous periorbital fat of the face occurs as they mature, giving a wizened look. The eyes are sunken. The ears and nose are prominent. The ears are cupped and large, the nose long and angulated. The teeth are carious (14; 15; 61; 51; 57).
Because of the impaired ability to repair DNA damage resulting from ultraviolet exposure, the skin is extremely sensitive to sunlight, often burning even after a trivial exposure. This photosensitivity has been reported in three fourths of affected individuals (57). There may be secondary reaction by the skin to this photosensitivity, but there is no increase in skin malignancy. This stands in contrast to the related condition xeroderma pigmentosa. Other skin manifestations include dry, scaly skin and thin hair; diminished subcutaneous tissue; dry, scaly skin; and occasionally anhidrosis (57). Sonmez and colleagues reported six patients with Cockayne syndrome type B without photosensitivity. They are all from the same inbred family and exhibit variable clinical features, including progressive encephalopathy, intracranial calcification and white-matter lesions, dwarfism without growth hormone deficiency, senile appearance, mental and motor retardation, atrophy of subcutaneous fat tissue, severe pectus carinatus, and spasticity. Clinical photosensitivity was not observed in any patient. Other clinical findings include cataract, pigmentary retinopathy, and peripheral neuropathy. The onset of the disease was between three and six months of age. Molecular genetic analyses in the family established linkage to ERCC6, confirming the clinical diagnosis, Cockayne syndrome type B (77).
Eye involvement includes retinopathy, enophthalmos, strabismus, amblyopia, and cataract (81). The pigmentary changes in the retina are fine, involve the periphery, and are progressive. Studies utilizing electroretinogram and retinography in older patients show diffuse pigmentary retinopathy and macular atrophy (23). Bone spicules have been seen in older patients. Retinal dystrophy is seen in 60% of patients (57). Cockayne's original patients had cataracts, a feature seen in only 15% of patients (81). Visual acuity may be preserved in spite of significant retinal changes and optic atrophy. Other ophthalmological involvements have been optic atrophy, nystagmus, corneal lesions, band keratopathy, recurrent erosions, and poor pupillary response to dilating agents (81).
Sensorineural hearing loss occurs in over half of the individuals, with involvement ranging from mild to severe (57). Cellular degeneration of multiple components of the temporal bone has been reported (30). As with other features in this condition, the onset may be delayed and not apparent until late childhood or adolescence.
The coexistence of impairment of hearing and vision make cognitive ability difficult to evaluate but, with few exceptions, individuals are moderately to severely impaired. Milestones in the first year of life may be near normal, but later, delays become evident. Many speak, although language is often reported as immature. There may be surprisingly good social interaction and ability to make interpersonal contact (51).
The development of a leukodystrophy results in progressive neurologic deterioration. Often spasticity, ataxia, or choreoathetosis are experienced. Tremor may be prominent. The demyelination is both central and peripheral, with the peripheral neuropathy demonstrated by muscle weakness and wasting (57). Young patients may manifest epilepsy (27).
Contractures of the large joints result in a stooped posture with splayed legs. A bow-legged or horse-riding stance and a peculiar gait can be seen in those who walk (51). The limbs themselves are long, with large hands and feet, and may be held in flexion (27). Kyphoscoliosis is often present.
Arenas-Sordo and colleagues observed congenital absence of 14, 23, and 24 teeth, and mandibular hypoplasia in the x-ray. In addition, they found deficient hygiene, gingivitis, cervical caries, enamel hypoplasia, abnormal position of the upper and inferior lateral incisors, and macrodontia of the upper central teeth (Arenas-Sordo et al 2006).
Other features that have been associated include functional renal abnormalities and signs of endocrine dysfunction, including undescended testes, micropenis, and irregular menses (57). In one study, renal disease was identified in 69% of patients, with reduced glomerular filtration rate; proteinuria, sometimes with full-blown nephrotic syndrome; and hyperuricemia common findings (79). Funaki and colleagues described Cockayne syndrome with recurrent acute tubulointerstitial nephritis, suggesting that rapid deterioration of the renal function in Cockayne syndrome patients might be the result of acute tubulointerstitial nephritis (25). The nephrotic syndrome in their patient seemed to be accompanied by acute tubulointerstitial nephritis, as in other reports. Variability in the renal findings of siblings indicates that no obvious genotype-phenotype correlation exists; some renal changes may be related to premature aging (05).
A case of dilated cardiomyopathy has been reported, but cardiac involvement in general, has not been described in Cockayne syndrome patients. Ovaert and colleagues report one patient in whom marked ascending aorta dilatation was observed together with mild aortic regurgitation (62).
The disease is progressive, although it often remains at a plateau for years. Many of the individuals die in late childhood or early adulthood of inanition, infection, or atherosclerosis. Rarely, and for unexplained reasons, the course for some patients with Cockayne syndrome is slower than usual, resulting in survival into adulthood. Rapin and colleagues report the clinical course and pathology of a man with Cockayne syndrome group A who died at the age of 31-and-a-half years with 15 adequately documented other adults with Cockayne syndrome and five with xeroderma pigmentosum-Cockayne syndrome complex (69).
A group of children with congenital abnormalities but who appear to have the main features of Cockayne syndrome has been described (50; 49). This group with the more severe phenotype has been labeled as Cockayne syndrome type II to differentiate them from type I and has a poorer prognosis (49). Tinsa and colleagues describe a rare case of Cockayne syndrome that started in early infancy and presented with no photosensitivity (80).
Death generally occurs by the age of 30, secondary to inanition or infection.
Cockayne syndrome is an autosomal recessive condition that results from a defect in repair of transcriptionally active genes. It is considered to be a heterogeneous condition (29; 73) based on complementation in cell fusion studies, with two major forms, namely Cockayne syndrome type A and Cockayne syndrome type B. CKN1 is the gene responsible for type A, whose mutations disrupt the transcription-coupled repair system of the actively transcribed DNA. Bertola and colleagues reported five novel mutations in their study of mutation analysis of the CKN1 gene in eight typical Cockayne syndrome type A Brazilian patients from six families, showing a gene alteration in all of them. However, they found no obvious genotype-phenotype correlation across the mutational spectrum (06). Progeroid syndromes, including Cockayne syndrome, constitute a group of disorders characterized by clinical features mimicking physiological aging at an early age. All the characterized progeroid syndromes enter in the field of rare monogenic disorders, and several causative genes have been identified. These can be separated in subcategories corresponding to: (1) genes encoding DNA repair factors, in particular, DNA helicases; and (2) genes affecting the structure or post-translational maturation of lamin A, a major nuclear component (59).
The reason patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known. Some 43 patients with the rare xeroderma pigmentosum-Cockayne syndrome complex have been summarized (58).
Cleaver and colleagues posit that the complex symptoms of Cockayne syndrome may be due to multiple, independent, downstream targets of the E3 ubiquitylation system that result in increased DNA damage, reduced transcription coupled repair, and inhibition of cell cycle progression and growth (13). They have found that the Cockayne syndrome type B defect results in altered expression of anti-angiogenic and cell cycle genes and proteins at the level of both gene expression and protein lifetime. They also find an overabundance of p21 due to reduced protein turnover, possibly due to the loss of activity of the Cockayne syndrome type A/type B E3 ubiquitylation pathway (13). Increased levels of p21 are thought to result in growth inhibition, reduced repair from the p21-PCNA interaction, and increased generation of reactive oxygen.
Cockayne syndrome is characterized by a deficiency in the transcription-couple DNA repair pathway caused by mutations mainly in the Cockayne syndrome group B (CSB) gene (ERCC6 or CSB). In their study, Andrade and colleagues reveal that the induced pluripotent stem cells from CSB skin fibroblasts they generated, modulated by CSB, exhibited elevated cell death rate and higher reactive oxygen species production accompanied by an up-regulation of TXNIP and TP53 transcriptional expression (02). This offers some evidence for premature aging due to oxidative stress in induced pluripotent stem cells from Cockayne syndrome. Further evidence for this comes from the recognition that XPD-mutated cell lines are also sensitive to oxidative stress (47).
Cockayne syndrome is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair that is responsible for the removal of photodamage from actively transcribed genes. Because cells from Cockayne syndrome patients have a defect in transcription-coupled nucleotide excision repair (TC-NER), Cockayne syndrome is typically considered to be a DNA repair disorder. It appears, though, that defects in base excision DNA repair and certain mitochondrial functions may also be important (37). UV-sensitive, NER-deficient xeroderma pigmentosum patients mimic the sun-sensitive phenotype of Cockayne syndrome, but these patients do not suffer from the neurologic and other abnormalities that Cockayne syndrome patients do. Brooks proposes that the defects in transcription by both RNA polymerases I and II that have been documented in Cockayne syndrome cells provide a better explanation for many of the severe growth and neurodevelopmental defects in Cockayne syndrome patients than defective DNA repair (10).
Cockayne syndrome results from a specific defect in the DNA repair system. Cellular studies in fibroblasts from patients with Cockayne syndrome have shown hypersensitivity to the lethal effects of ultraviolet radiation. After irradiation, RNA synthesis is depressed in both normal and Cockayne syndrome cells. However, RNA synthesis recovers rapidly in normal cells, but fails to do so in cells from patients with Cockayne syndrome. This rapid recovery in normal cells is due to the preferential repair of DNA in transcribed regions, which does not occur in Cockayne syndrome (46). Ultraviolet (genotoxic) stress stops transcription of about 70% of both genes (21).
The repair of DNA lesions is an extremely important process for the integrity of the cell. Although several mechanisms exist for DNA repair, the most important is nucleotide excision repair. Nucleotide excision repair removes all types of lesions from DNA and is carried out by the coordinated action of eight to 10 protein subunits (20). Much of what has been learned about the nucleotide excision system in humans has come from the study of Cockayne syndrome and xeroderma pigmentosum. Xeroderma pigmentosum is a heterogeneous group (seven complementation groups identified) characterized by defects in DNA repair with the common clinical problem of photosensitivity and a predisposition for skin cancer. Although xeroderma pigmentosum is defective in repairing all ultraviolet-induced damage, Cockayne syndrome patients are unable to perform gene-specific repair (20).
Using complementation analysis, two complementation groups, Cockayne syndrome complementation group A and Cockayne syndrome complementation group B, have been identified. Stefanini and colleagues analyzed complementation as defined by restoration of normal RNA synthesis rates in ultraviolet-irradiated heterokaryons. They studied cell cultures from 22 patients with Cockayne syndrome. Cultures from five patients were assigned to complementation group A and the remaining 17 were assigned to complementation group B. There were no distinctions in terms of race, clinical presentation, or cellular characteristics between the two complementation groups (78).
The genes for both complementation groups, Cockayne syndrome complementation group A (or Cockayne syndrome A) and Cockayne syndrome complementation B (Cockayne syndrome B), have been identified. The gene for Cockayne syndrome B has been identified as one of the excision repair genes. Originally referred to as ERCC6, it is now called CSB. This gene encodes a 160 kd protein that is essential for nucleotide excision repair and the relief of oxidative stress. Without CSB, cells accumulate oxidative DNA lesions. Mutations in the gene encoding the CSB protein are responsible for most cases of Cockayne syndrome (08). The specific role of this protein is still under investigation. The gene for Cockayne syndrome A encodes a polypeptide of 396 amino acids with a calculated molecular mass of approximately 44 kd (33). The predicted structure of the putative protein indicates that it is a WD repeat protein, and is associated with a variety of cellular regulatory functions. This group has the potential for interaction with other proteins and many are components of multiprotein complexes. Like CSB, CSA is involved in DNA repair and offers protection from senescence for keratinocytes (18). Although CSA and CSB share certain functions, they appear to act at different times during the DNA repair process (64).
From the study of these conditions as well as mutations in bacteria and yeast, it has been determined that transcription, RNA synthesis, and DNA repair are coupled. When the transcription enzymes encounter a DNA lesion such as a bulky pyrimidine dimer, they will stall and transcription ceases. This interferes with the smooth reading and transcription of active genes.
The role of the Cockayne syndrome A and Cockayne syndrome B proteins in transcription and repair is understood incompletely. Although it has been postulated that the senile aging of the skin, retinal degeneration, and nervous system degeneration are the result of failure of DNA repair of active genes and resultant senescence or “genosenium” (29; 48), other evidence suggests a primary transcription defect (33; 24).
The Cockayne syndrome B protein is involved in ultraviolet-induced transcription coupled repair, base excision repair, and general transcription. Cockayne syndrome B also has a DNA-dependent ATPase activity that may play a role in remodeling chromatin in vivo. Muftuoglu and colleagues report the novel finding that Cockayne syndrome B catalyzes the annealing of complementary single-stranded DNA molecules with high efficiency and has strand exchange activity (56). The rate of Cockayne syndrome B-catalyzed annealing of complementary single-strand DNA is 25-fold faster than the rate of spontaneous single-strand DNA annealing under identical in vitro conditions, and the reaction occurs with a high specificity in the presence of excess non-homologous single-strand DNA. The specificity and intrinsic nature of the reaction is also confirmed by the observation that it is stimulated by dephosphorylation of Cockayne syndrome B, which occurs after ultraviolet-induced DNA damage, and is inhibited in the presence of ATP[gamma]S. Falik-Zaccai and colleagues have identified six Cockayne syndrome patients in one large, highly consanguineous, Druze kindred who descended from a single ancestor; all six patients presented with the congenital severe phenotype of the syndrome (22). They had no language skills, could not sit or walk independently, and died by the age of five years. Cellular studies of the fibroblasts from three patients showed a significant defect in transcription-coupled DNA repair (TCR) and a marked correction of the abnormal cellular phenotype with a plasmid containing the cDNA of the ERCC6 gene. Molecular studies led to identification of a novel insertion mutation, c.1034-1035insT in exon 5 of the ERCC6 gene (p.Lys345Asnfs*24). This mutation was identified in one in 15 healthy individuals from the same village, indicating an extremely high carrier frequency. The authors feel that identification of the causative mutation enables comprehensive genetic counseling among the population at risk from this village.
The neuropathology involves both the central and peripheral nervous system and is characterized by striking atrophy, demyelination, and the presence of mineralization (53; 72; 76). The brain at autopsy is very small for the age of the patient, consistent with the marked microcephaly in life. The skull is thickened. Atrophy of the cerebrum and cerebellum occurs, along with a reduction in the white matter with dilatation of the ventricles. Demyelination is patchy with a tigroid pattern of involvement. This pattern is also seen in Pelizaeus-Merzbacher disease and is not specific (53). The arcuate fibers are not spared and no evidence is seen of inflammation. The demyelination has been seen throughout the nervous system, including brainstem, spinal cord, and peripheral nerve (72). Mineralization surrounding the vasculature is present. These widespread encrustations are positive for both calcium and iron and occasionally can form sizable brain stones in the basal ganglia (72).
Microscopically, ferruginated neurons are seen and others may contain lipofuscin pigment. Unusual astroglial cells, some multinucleated, have been reported (76). Macroglial cells are hyperchromatic and demyelination is patchy (86). In the cerebellum, severe atrophy of the internal granular layer and Purkinje cells occurs (72; 76). The inner layer of the retina is also gliotic, with the outer retina relatively spared (72). Using the TUNEL staining method and other immunohistochemical methods, it has been demonstrated that cerebellar granule cells undergo apoptotic cell death (42). Arteriosclerosis in the brain and subdural hemorrhage have been reported in a few Cockayne syndrome cases. By performing elastica van Gieson (EVG) staining and immunohistochemistry for collagen type IV, CD34, and aquaporin 4 in autopsy cases of Cockayne syndrome, Hayashi and colleagues showed an increase in the small arteries without arteriosclerosis in the subarachnoid space, in addition to string vessels (twisted capillaries) in the cerebral white matter and increased density of CD34-immunoreactive vessels (31). They speculate that the increased subarachnoid artery space may be the cause of subdural hemorrhage in Cockayne syndrome.
In peripheral nerve, mixed axonal and demyelinating neuropathy is seen. The density of myelinated fibers is diminished. Chronic demyelination and remyelination with onion-bulb formation is seen. These changes are age-dependent, being most pronounced in older individuals (75). Membrane-bound inclusions of polymorphous material have been seen in Schwann cells (26; 87).
Jaarsma and colleagues conclude that Cockayne syndrome mouse models mice develop a range of Cockayne syndrome phenotypes and open promising perspectives for testing interventional approaches (36). Mice deficient for CS-A or CS-B genetically mimic Cockayne syndrome in humans, and develop mild Cockayne syndrome symptoms including reduced fat tissue, photoreceptor cell loss, and mild but characteristic nervous system pathology. These mild Cockayne syndrome models are converted into severe Cockayne syndrome models with short life span, progressive nervous system degeneration, and cachectic dwarfism after simultaneous complete inactivation of global genome NER. A spectrum of mild-to-severe Cockayne syndrome-like symptoms occurs in Xpb, Xpd, and Xpg mice that genetically mimic patients with a disorder that combines Cockayne syndrome symptoms with another NER syndrome, xeroderma pigmentosum. Cockayne syndrome is caused by mutations in CSA and CSB genes and is a hallmark feature of CSB patients is neurodegeneration. The precise molecular cause continues to remain elusive, but it has been suggested that damage to mitochondria could be involved, either as part of the accelerated aging that is manifest in Cockayne syndrome or accumulated damages that are part of normal aging (74). Altered ribosomal biogenesis may lead to stressed endoplasmic reticulum and apoptosis (66). By using the human neural progenitor cells that have self-renewal and differentiation capabilities, Ciaffardini and colleagues have shown that stable CSB knockdown dramatically reduced the differentiation potential of human neural progenitor cells revealing a key role for CSB in neurogenesis (11). In addition, neurite outgrowth, a characteristic feature of differentiated neurons, was also greatly abolished in CSB-suppressed cells. Based on the data, they conclude that CSB has a crucial role in coordinated regulation of transcription and chromatin remodeling activities that are required during neurogenesis. In Cockayne syndrome, the encoded ERCC6 protein is more commonly referred to as Cockayne syndrome B protein (CSB). Vessoni and colleagues successfully derived functional Cockayne syndrome neural networks from human Cockayne syndrome induced pluripotent stem cells (iPSCs), providing a new tool to facilitate studying this disease (85). They identified dysregulation of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway, as well as pathways related to synapse formation, maintenance, and neuronal differentiation in CSB-neurons using unbiased RNA-seq gene expression analyses. Also, when compared to unaffected controls, CSB-deficient neural networks displayed altered electrophysiological activity, including decreased synchrony and reduced synapse density, suggesting that CSB is required for normal neuronal function.
Cockayne syndrome is extremely rare, with at least 200 cases in the literature (57). Laboratory diagnosis for DNA repair diseases, the combined data from the DNA repair diagnostic centers in France, (West) Germany, Italy, the Netherlands, and the United Kingdom, have established the incidence for Cockayne syndrome (including xeroderma pigmentosum-Cockayne syndrome complex) at 2.7 per million. In Japan, the same incidence is reported, with 90% represented by classic Cockayne syndrome (54). As immigrant populations were disproportionately represented in the patients' groups, incidences were also established for the autochthonic western European population at 1.8 per million for Cockayne syndrome (38).
Prenatal detection is possible in a fetus at risk.
Hereditary diseases characterized by genetic defects of DNA repair include ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. They share many clinical features such as growth retardation; neurologic disorders; premature aging; skin alterations including abnormal pigmentation; telangiectasia; xerosis cutis; pathological wound healing; as well as an increased risk of developing different types of cancer (40).
Cockayne syndrome is distinctive, especially in older individuals, but may overlap with xeroderma pigmentosum. Xeroderma pigmentosum is generally distinguished from Cockayne syndrome by the increased incidence of skin neoplasms in xeroderma pigmentosum. There have now been at least three forms of xeroderma pigmentosum determined by complementation where the individual has had some features of Cockayne syndrome. There have also been reports of two patients with the features of DeSanctis-Cacchione syndrome, a subtype of xeroderma pigmentosum with complementation studies consistent with a defect in Cockayne syndrome type B, or ERCC6, indicating some degree of phenotype heterogeneity (35). The difference in incidence of cancer may be due to the fact that UV exposure in Cockayne syndrome results in cell lethality but not mutagenesis (70).
As a leukodystrophy, the tigroid pattern of involvement needs to be distinguished from the connatal form of Pelizaeus-Merzbacher. However, the other clinical features should allow discernment.
When cardinal features are lacking, the diagnosis of Cockayne syndrome should be considered if presented with growth retardation, microcephaly, and one of the suggesting features, such as enophthalmia, limb ataxia, abnormal auditory evoked responses, or increased ventricular size on cerebral imaging (65).
The hallmark of Cockayne syndrome is the failure of RNA synthesis to recover after ultraviolet irradiation. After irradiation, RNA synthesis is depressed in both normal and Cockayne syndrome cells but recovers rapidly in normal cells. It fails to do so in cells with the biochemical defect of Cockayne syndrome. This rapid recovery in normal cells is due to the preferential repair of DNA in transcribed regions, which does not occur in Cockayne syndrome (45).
Additional studies that aid in the diagnosis include ophthalmological examination for cataracts and retinopathy (81); nerve conduction velocity or nerve biopsy examining for peripheral neuropathy (75; 26; 87); electromyography for the identification of demyelinating peripheral myopathy (07); CT scan for cerebral calcifications (19); MRI showing abnormalities of myelination (09); and skeletal radiographs showing thickened skull, intracranial calcifications, marble epiphyses in the terminal phalanges of the hands, protrusion of the anterior aspect of the vertebral bodies, and hypoplasia of the iliac wings (12).
Adachi and colleagues describe MRI findings of small patchy subcortical lesions visualized as areas of high intensity on diffusion-weighted images and low intensity on FLAIR images, suggestive of active demyelinating lesions (01). Koob and colleagues describe the neuroimaging characteristics of Cockayne syndrome (43). Hypomyelination was more severe in early onset disease than the late onset, though the latter also showed less cerebral atrophy. Atrophy involves the supratentorial white matter, cerebellum, corpus callosum, and brain stem. Calcifications seen were characteristically in the sulcal depths of the cortex. Putamen and dentate nuclei calcifications can occur as well. SPECT scans revealed presence of lactate and decreased choline and NAA ratios. Diffusion tensor imaging with volumetric analysis has been used to quantify atrophy and white matter abnormalities (44).
Kleijer and colleagues evaluated the results of 29 prenatal diagnoses for Cockayne syndrome in a consecutive series. They conclude that reliable prenatal diagnosis of the Cockayne syndrome can be made by the demonstration of a strongly reduced recovery of DNA-synthesis in ultraviolet-irradiated cultured chorionic villus cells or amniocytes (39). Assessment of the recovery of RNA-synthesis was needed as an adjunctive method in rare cases of poor cell growth and DNA-synthesis. Performing immunohistochemistry in autopsy brains and ELISA in the cerebrospinal fluid and urine of patients with hereditary DNA repair disorders, Hayashi and colleagues report that increased oxidative DNA damage and lipid peroxidation were noted in the presence of degeneration of basal ganglia, intracerebral calcification, and cerebellar degeneration in patients with xeroderma pigmentosum, Cockayne syndrome, and ataxia-telangiectasia-like disorder, respectively (32).
Genetic counseling. Genetic counseling is an integral part of patient care in those with this syndrome or those suspected of having it. Cockayne syndrome is inherited in an autosomal recessive manner. Reproduction has not been reported in any individual with Cockayne syndrome. Atypical cases may require molecular genetic testing. The two genes responsible for Cockayne syndrome are ERCC6 for 65% to 75% of individuals (82) and ERCC8 for 25% to 35% of individuals (33; 63). Sequence analysis for both genes is clinically available. Prenatal testing is available through laboratories offering custom prenatal testing. Carrier detection (50% chance of being an asymptomatic carrier) is available once the mutations have been identified in the proband.
Family support groups are an important adjunct and can be collaborative, assuming appropriate boundaries—ethical, professional, geographic, and other—are recognized (90).
Patients who receive the antibiotic metronidazole may suffer acute neurologic deficits within weeks of administration. However, of greater concern is hepatotoxicity, which can be lethal within days of administration (04). An exact mechanism has not been identified, although hepatic difficulties are recognized in Cockayne patients and could be exacerbated by the drug (89).
Standard treatment focuses largely on managing symptoms. Growth hormone has not improved stature (57). Some patients have required feeding tubes because of poor oral intake to avoid malnutrition. Individuals with photosensitivity should avoid direct sun and wear sunscreen. Patients should be monitored for treatable complications including progressive hearing and visual loss, hypertension, renal problems, and dental caries. Cochlear implants are successful in managing progressive hearing loss (84). Use of appropriate therapies, even with neurologic decline, optimizes the patient's well-being. Neilan and colleagues studied the effect of carbidopa-levodopa therapy in three patients with Cockayne syndrome (60). Main outcome measures included status of tremors, ability to perform daily tasks, serial physical examinations, and results of handwriting samples. They found that all three patients had a clear reduction in tremors and improvements in handwriting and manipulation of utensils and cups.
A significant proportion will require cataract extraction at an early age, which may present technical difficulties due to enophthalmos, which is a constant finding, with poor pupillary dilation and growth retardation. The fitting and assessment of aphakic contact lenses during the postoperative period also requires great skill. General anesthesia in these patients may be hazardous; in particular, difficulty with endotracheal intubation should be anticipated (52).
In the perioperative management of Cockayne syndrome, use of weight-appropriate rather than age-appropriate airway equipment must be a consideration. Because of premature aging, the “adult” plateau in development is often attained in early childhood in severe cases. Hence, in these patients’ recognition of advanced physiological age vis-à-vis their somatic appearance is essential for successful management (68). GPi-pallidal stimulation has been used to treat generalized dystonia in Cockayne syndrome (28). Horbelt reports that the dental care, procedures, and intervention offered to Cockayne syndrome patients do not differ much from that given to any other patient (34).
In their study, Motojima and colleagues evaluated the longitudinal changes in serum creatinine and serum cystatin C levels in three patients with Cockayne syndrome and found that the serum creatinine level in these Cockayne syndrome patients gradually exceeded the reference level from five to seven years of age, after correcting for body length (55). The cystatin C level of the Cockayne syndrome patients increased to above the reference level whereas their estimated glomerular filtration rate remained within stage 2 or 3, showing that serum creatinine level is useful for the evaluation of renal function in Cockayne syndrome, which further helps in clinical management of patients.
As more information regarding genetic mechanisms is obtained, molecular therapy may become available. A number of signaling pathways are involved in nucleotide excision repair and could be used in future therapies (41). One model for gene rescue has proven successful in Cockayne stem cells (88). Information gained from this approach could have ramifications, not only for Cockayne syndrome, but for general aging as well (37). Because CSB is often overexpressed in cancer cells, its clinically-induced downregulation may prove to be therapeutic (67).
Two successful deliveries by mothers with Cockayne syndrome have been reported (71). Spinal anesthesia is preferred, because of the variety of anomalies (eg, cardiorespiratory and neuromuscular) that may be present. Pregnancy with an affected fetus is normal. Conte and colleagues describe a molecular prenatal diagnosis of Cockayne syndrome type A for the first time (16).
Intubation can be difficult because of the small mandible, oral cavity, and larynx, compounded by the patient's mental retardation, blindness, and deafness (17). Electroencephalography has been used to ascertain anesthetic depth in the CNS and to titrate levels of anesthesia during dental surgery (83).
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.See Profile
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