Physical, oral, and swallowing functions of three patients with type a xeroderma pigmentosum: a report of three cases.

BACKGROUND: Xeroderma pigmentosum (XP) is an extremely rare and severe form of photosensitivity. It is classified into types A-G or V according to the gene responsible for the disease. The progression and severity of symptoms vary depending on the type. Although dysphagia caused by decreased swallowing function and dental malposition due to stenosis of the dentition in the facial and oral regions is common, it has not been reported in detail. We report three cases of type A XP, in which central and peripheral neurological symptoms appeared early on and progressed rapidly. We describe the oral function of these patients, focusing on the swallowing function and dentition malposition. CASE PRESENTATION: Two males (27 and 25 years old) and one female (28 years old) presented with diverse neurological symptoms. We focused on the relationship between the changes in swallowing and oral functions and conditions due to decline in physical function. Some effects were observed by addressing the decline in swallowing and oral functions. In particular, a dental approach to manage the narrowing of the dentition, which was observed in all three patients, improved the swallowing and oral functions and maintained the current status of these functions. CONCLUSIONS: In type A XP, early decline in oral and swallowing functions is caused by the early decline in physical function, and it is necessary to monitor the condition at an early stage.

Long-Term Evaluation of Low-Dose Betamethasone for Ataxia Telangiectasia.

BACKGROUND: Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia. METHODS: Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period. RESULTS: Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases. CONCLUSIONS: Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.

Circadian Rhythms of Oxidative Stress Markers and Melatonin Metabolite in Patients with Xeroderma Pigmentosum Group A.

Xeroderma pigmentosum group A (XPA) is a genetic disorder in DNA nucleotide excision repair (NER) with severe neurological disorders, in which oxidative stress and disturbed melatonin metabolism may be involved. Herein we confirmed the diurnal variation of melatonin metabolites, oxidative stress markers, and antioxidant power in urine of patients with XPA and age-matched controls, using enzyme-linked immunosorbent assay (ELISA). The peak of 6-sulfatoxymelatonin, a metabolite of melatonin, was seen at 6:00 in both the XPA patients and controls, though the peak value is lower, specifically in the younger age group of XPA patients. The older XPA patients demonstrated an increase in the urinary levels of 8-hydroxy-2'-deoxyguanosine and hexanoyl-lysine, a marker of oxidative DNA damage and lipid peroxidation, having a robust peak at 6:00 and 18:00, respectively. In addition, the urinary level of total antioxidant power was decreased in the older XPA patients. Recently, it is speculated that oxidative stress and antioxidant properties may have a diurnal variation, and the circadian rhythm is likely to influence the NER itself. We believe that the administration of melatonin has the possibility of ameliorating the augmented oxidative stress in neurodegeneration, especially in the older XPA patients, modulating the melatonin metabolism and the circadian rhythm.

The Role of ARX in Human Pancreatic Endocrine Specification.

The in vitro differentiation of human embryonic stem cells (hESCs) offers a model system to explore human development. Humans with mutations in the transcription factor Aristaless Related Homeobox (ARX) often suffer from the syndrome X-linked lissencephaly with ambiguous genitalia (XLAG), affecting many cell types including those of the pancreas. Indeed, XLAG pancreatic islets lack glucagon and pancreatic polypeptide-positive cells but retain somatostatin, insulin, and ghrelin-positive cells. To further examine the role of ARX in human pancreatic endocrine development, we utilized genomic editing in hESCs to generate deletions in ARX. ARX knockout hESCs retained pancreatic differentiation capacity and ARX knockout endocrine cells were biased toward somatostatin-positive cells (94% of endocrine cells) with reduced pancreatic polypeptide (rarely detected), glucagon (90% reduced) and insulin-positive (65% reduced) lineages. ARX knockout somatostatin-positive cells shared expression patterns with human fetal and adult δ-cells. Differentiated ARX knockout cells upregulated PAX4, NKX2.2, ISL1, HHEX, PCSK1, PCSK2 expression while downregulating PAX6 and IRX2. Re-expression of ARX in ARX knockout pancreatic progenitors reduced HHEX and increased PAX6 and insulin expression following differentiation. Taken together these data suggest that ARX plays a key role in pancreatic endocrine fate specification of pancreatic polypeptide, somatostatin, glucagon and insulin positive cells from hESCs.

Cerebrospinal fluid oxidative stress marker levels and cytokine concentrations in a neonate with incontinentia pigmenti.

BACKGROUND: Some children with incontinentia pigmenti exhibit encephalopathic features with severe seizures and disturbed consciousness, from the neonatal through the early infantile period. However, the pathological mechanism of brain lesion development is not fully understood. METHODS: We measured the cerebrospinal fluid levels of cytokines and oxidative stress markers (8-hydroxy-2-deoxyguanosine and the hexanoyl-lysine adduct) in a young girl with incontinentia pigmenti complicated by an encephalopathic event that occurred on her first day of life. Magnetic resonance imaging revealed widespread reduction of water diffusion in the basal ganglia, the periventricular and subcortical white matter, and the corpus callosum. RESULTS: Oxidative stress markers were elevated at 4 days of age but decreased mildly by 25 days of age. Elevated levels of soluble tumor necrosis factor receptor 1 were observed at both 4 and 25 days of age, although tumor necrosis factor-α levels were below the limit of detection. No other cytokine levels were elevated, except for those of interleukin-10 at 25 days of age. CONCLUSIONS: Tumor necrosis factor-α expression and oxidative stress are involved in the pathogenesis of brain lesions in children with incontinentia pigmenti, and elevated cerebrospinal fluid cytokine levels may not be apparent during encephalopathic events.

Hounsfield unit values of retropharyngeal abscess-like lesions seen in Kawasaki disease.

CONCLUSIONS: Retropharyngeal abscess-like lesions are occasionally seen in computed tomography (CT) imaging of patients with Kawasaki disease (KD) and these patients often undergo unnecessary surgery. We could distinguish the lesions from true abscesses by measuring their Hounsfield unit values (HUs). OBJECTIVE: To distinguish the retropharyngeal abscess-like lesions from true abscesses without any surgical procedure. METHODS: We investigated six cases of KD showing such lesions on CTs, both with and without contrast enhancement (CE). We measured the HUs of those lesions and compared them with those of 10 true abscesses as controls. RESULTS: Abscess-like lesions of KD were well enhanced by CE, whereas abscesses showed virtually no enhancement. The mean HU in the six KD cases was 20.0 ± 4.65 (mean ± SD) on plain CTs and 35.6 ± 4.49 on contrast CTs. In abscesses, it was 30.3 ± 4.42 on plain CTs and 30.3 ± 3.57 on contrast CTs. The difference in HU values [(HU on contrast CT) - (HU on plain CT)] was defined as ΔHU. The mean ΔHU was 15.6 ± 5.36 in the six KD lesions and 0.0 ± 2.93 in abscesses, with statistical significance of p < 0.0001 by Student's t test. Thus, ΔHU value may potentially be a useful parameter for their distinction.

Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.

Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart.

Oxidative stress in developmental brain disorders.

In order to examine the involvement of oxidative stress in developmental brain disorders, we have performed immunohistochemistry in autopsy brains and enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid and urines of patients. Here, we review our data on the hereditary DNA repair disorders, congenital metabolic errors and childhood-onset neurodegenerative disorders. First, in our studies on hereditary DNA repair disorders, increased oxidative DNA damage and lipid peroxidation were carried out in the degeneration of basal ganglia, intracerebral calcification and cerebellar degeneration in patients with xeroderma pigmentosum, Cockayne syndrome and ataxia-telangiectasia-like disorder, respectively. Next, congenital metabolic errors, apoptosis due to lipid peroxidation seemed to cause neuronal damage in neuronal ceroid-lipofuscinosis. Oxidative stress of DNA combined with reduced expression of antioxidant enzymes occurred in the lesion of the cerebral cortex in mucopolysaccharidoses and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. In childhood-onset neurodegenerative disorders, increased oxidative DNA damage and lipid peroxidation may lead to motor neuron death in spinal muscular atrophy like in amyotrophic lateral sclerosis. In patients with dentatorubral-pallidoluysian atrophy, a triplet repeat disease, deposition of oxidative products of nucleosides and reduced expression of antioxidant enzymes were found in the lenticular nucleus. In contrast, the involvement of oxidative stress is not definite in patients with Lafora disease. Rett syndrome patients showed changes of oxidative stress markers and antioxidant power in urines, although the changes may be related to systemic complications.

Partial loss of pancreas endocrine and exocrine cells of human ARX-null mutation: consideration of pancreas differentiation.

Aristaless-related homeobox gene (ARX) mutation leads to several neurological disorders including X-linked lissencephaly with abnormal genitalia (XLAG), West syndrome and Partington syndrome, with XLAG being the most severe form. Although some of the brain pathologies of XLAG have already been described, the crucial extra-brain symptoms are severe growth retardation, transient hyperglycemia and intractable diarrhea. Since ARX expresses in the islets of Langerhans during the embryonic stage, these visceral phenotypes may be related to a loss of ARX function, which develops endocrine cells in the pancreas. We investigated the abnormal pancreatic development of XLAG patients with ARX-null mutation. We performed immunohistochemistry of XLAG pancreases, using the antibodies against glucagon, insulin, somatostatin, pancreatic polypeptide, ghrelin, Brn4, Nkx2.2, Mash1, amylase and pancreatic lipase. As the results, the glucagon- and pancreatic polypeptide-producing cells were found to be completely deficient in the islets of Langerhans. We also discovered marked interstitial fibrosis, small exocrine cells with loss of amylase-producing cells and an enlargement of the central lumen of the glandular acini. These pathological findings indicate that ARX contributes not only to endocrine development, but also to exocrine development of the human pancreas, and its deficiency may lead to the severe phenotypes of XLAG patients.

Low-dose levodopa is effective for laryngeal dystonia in xeroderma pigmentosum group A.

Xeroderma pigmentosum (XP), a genetic disorder in DNA nucleotide excision repair, is characterized by skin hypersensitivity to sunlight and progressive neurological impairment. Laryngeal dystonia and vocal cord paralysis are complications that can arise in older XP group A (XPA) patients. We report three patients with XPA being administered low-dose levodopa (0.3-1.5 mg/kg/day) for laryngeal dystonia. Patients were aged from 13 to 18 years, exhibited paroxysmal choking and inspiratory stridor, and were diagnosed with laryngeal dystonia. Two XPA patients responded to low-dose levodopa, and paroxysmal choking and involuntary movements resolved, although one of the two patients showed incomplete resolution due to suspected vocal cord paralysis. The other patient was unable to tolerate the medication because of a transient decrease of muscle tone in the extremities. We previously reported a decreased immunostaining of dopaminergic (DA) terminals in the basal ganglia of XPA patients, which may be involved in laryngeal dystonia. Low-dose levodopa has been reported to alleviate DA receptor supersensitivity in tic patients, while laryngeal dystonia occurs in patients with tardive dyskinesia caused by DA receptor supersensitivity. Thus, low-dose levodopa may improve laryngeal dystonia by alleviating DA receptor supersensitivity in XPA patients. We recommend that low-dose levodopa be used for treatment of paroxysmal respiratory disturbances and/or involuntary movements in XPA patients.

Analysis of the hypothalamus in a case of X-linked lissencephaly with abnormal genitalia (XLAG).

X-linked lissencephaly with abnormal genitalia (XLAG) is characterized by lissencephaly, absent corpus callosum and ambiguous genitalia. We examined hypothalamic dysfunctions in a XLAG case with a novel mutation of the ARX gene, and performed immunohistochemical evaluation of the diencephalons in autopsy brain. A 1-year-old boy showed intractable epilepsy, persistent diarrhea and disturbed temperature regulation. This case had abnormalities in circadian rhythms and pituitary hormone reserve test. He died of pneumonia. The globus pallidus and subthalamic nucleus was not identified, and the putamen and thalamus were dysplasic. The suprachiasmatic nucleus was absent. A few neurons immunoreactive for vasopressin seemed to form the ectopic supraoptic-like nucleus. The diencephalons were disturbed differently in each sub-region, and the changes may be related to various hypothalamic dysfunctions.

Oxidative stress as a biomarker of respiratory disturbance in patients with severe motor and intellectual disabilities.

Oxidative stress plays an important role in aging and various diseases such as cancer, cardiovascular diseases, diabetes mellitus and bronchial asthma. However, little is known about a potential role of oxidative stress in the pathogenesis of severe motor and intellectual disabilities (SMID) in terms of respiratory disturbance, which is the most common complication. In the present study, we examined the urinary levels of oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG), hexanoyl-lysine adduct (HEL) and acrolein-lysine adduct (ACR) in patients with SMID. The mean level of urinary 8-OHdG in SMID patients was significantly higher than that in normal controls (18.8 +/- 9.0 ng/mg Cre and 10.5 +/- 2.9 ng/mg Cre, respectively) (p < 0.01). There was no significant difference of the mean level of urinary HEL between patients with SMID and normal controls (81.9 +/- 40.3 pmol/mg Cre and 69.2 + /-37.7 pmol/mg Cre, respectively), while the mean level of ACR in patients with SMID was higher than that of normal controls (220.5 +/- 118.6 nmol/mg Cre and 144.9 +/- 62.0 nmol/mg Cre, respectively) (p < 0.05). In addition, the level of 8-OHdG was strongly correlated with the severity of respiratory disturbance evaluated as the respiratory disturbance score (RDS) (Spearman r = 0.73, n = 14, p < 0.01). In contrast, there was no correlation between the levels of these oxidative stress markers and age or medication of antiepileptic drugs. These results suggest that urinary 8-OHdG is a potentially useful biomarker for evaluating the severity of respiratory failure in patients with SMID.

Oxidative stress in neurodegeneration in dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is one of the CAG-repeat diseases, and is classified into juvenile and early adult types showing progressive myoclonus epilepsy (PME) in addition to late adult type. We immunohistochemically examined accumulation of oxidative products and expression of superoxide dismutase (SOD) in autopsy cases of DRPLA. Oxidative products to nucleosides, 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine, were accumulated in the lenticulate nucleus predominantly in DRPLA cases having PME. Neuronal accumulation of 4-hydroxy nonenal, a reactive lipid aldehyde, was found in the hippocampus, globus pallidus and cerebellar dentate nucleus in adult DRPLA cases and controls. Cytoplasmic immunoreactivity for Cu/ZnSOD was reduced in the external segment of globus pallidus, dentate nucleus and cerebellar cortex in DRPLA cases. Mitochondrial immunoreactivity for MnSOD was reduced in the lenticulate nucleus and cerebellum in DRPLA cases having PME. Some DRPLA cases showed reduced immunoreactivity for MnSOD in the cerebral cortex. Coexistence of reduced SOD expression and polyglutamine was observed in a few cases. It has been discussed in Huntington's disease that expanded polyglutamine can lead to oxidative neurodegeneration. It is likely that oxidative stress can be involved in DRPLA, although relationship with expanded polyglutamine remains to be elusive.