ABSTRACT
Joubert syndrome (JS) is a genetic neurodevelopmental disorder characterized by lower brainstem dysplasia and cerebellar vermis agenesis termed molar tooth sign (MTS), psychomotor retardation, abnormal respiratory pattern in infancy, and oculomotor abnormalities. Arima syndrome (AS), which is a severe form of JS, is characterized by severe psychomotor retardation, congenital visual impairment, progressive renal dysfunction, and lower brainstem dysplasia from early infancy. Numerous patients with AS expire in early childhood. Recently, c.6012-12T> A in the CEP290 gene was reported as a specific variant of AS. Herein, we report the cases of two siblings showing a phenotype of JS with compound heterozygous mutations (c.6012-12T > A / c.5924delT) in the CEP290 gene. The older sister (aged 19 years) had hypotonia, hypertelorism, and anteverted nares since birth. As a neonate, she developed a transient abnormal respiratory pattern and nystagmus, and brain magnetic resonance imaging (MRI) showed MTS. The younger sister (aged 13 years) exhibited mild hypotonia and pendular nystagmus as a neonate; MRI revealed MTS. Both sisters had psychomotor retardation, oculomotor dysfunction, and bilateral renal cysts with normal renal function. They can walk and have simple conversation. They do not meet the diagnostic criteria for AS, and their symptoms were milder than those of previously reported cases with this specific mutation. This report indicates the expanding spectrum of the CEP290 variant.
Subject(s)
Abnormalities, Multiple , Eye Abnormalities , Polycystic Kidney Diseases , Child, Preschool , Female , Humans , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/genetics , Antigens, Neoplasm/genetics , Cell Cycle Proteins/genetics , Cerebellum/pathology , Cytoskeletal Proteins/genetics , Eye Abnormalities/diagnostic imaging , Eye Abnormalities/genetics , Muscle Hypotonia , Phenotype , Polycystic Kidney Diseases/pathology , Retina/abnormalities , SiblingsABSTRACT
BACKGROUND: Very low-birth-weight infants (VLBWI) are at high risk for adverse neurodevelopmental outcomes. A new, feasible and practical classification system for white matter injury has been reported by Martinez-Biarge et al. Therefore, we investigated the relationship between white matter injury and neurodevelopmental outcomes using this system. MATERIALS AND METHODS: We enrolled a consecutive series of VLBWI birth weights <1500 g between 2012 and 2015. Two radiologists evaluated the brain MRI obtained in the VLBWI at term-equivalent age. MRI findings were classified into six Grades (Grade 0, Ia, Ib, II, III, IV). The frequency of abnormalities in each Grade was examined. The neurodevelopmental outcome of the VLBWI was assessed at two years or older, and we investigated the presence of cerebral palsy (CP) and intellectual disability (ID), and other serious outcomes. We also calculated the simple kappa value before the raters were matched. RESULTS: Among 167 VLBWI, 131 met the eligibility criteria. 114 was Grade 0 (87%), 11 was Grade I (8.4%), 3 was Grade II (2.3%), 1 was Grade III (0.8%), and 2 was Grade IV (1.5%). The frequency of any abnormalities of intelligence in Grade 0 was 24%. The frequency of CP in Grade I was 18%. All Grade III and Grade IV cases had mild CP and an ID. The simple kappa value was 0.95. CONCLUSION: The prognostic value of the MRI scoring tool was limited. However, all Grade III and Grade IV cases had mild CP and ID. The results demonstrated an excellent inter-rater correlation.
Subject(s)
Brain Injuries , Cerebral Palsy , Intellectual Disability , Cerebral Palsy/diagnostic imaging , Humans , Infant , Infant, Newborn , Infant, Very Low Birth Weight , Intelligence , Magnetic Resonance Imaging/methodsABSTRACT
BACKGROUND: Diffusion-weighted imaging performed shortly after brain injury has been shown to facilitate visualization of acute corticospinal tract injury known as "pre-Wallerian degeneration." OBJECTIVE: The aim of this study was to determine whether diffusion restriction in the corticospinal tract and corpus callosum occurs within the first 2 weeks after birth in neonates with neonatal hypoxic-ischemic encephalopathy. MATERIALS AND METHODS: We enrolled a consecutive series of 66 infants diagnosed with hypoxic-ischemic encephalopathy who underwent MRI. We evaluated diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) values to assess the presence of restricted diffusion in the corticospinal tract and corpus callosum. Next, we compared ADC values in the corticospinal tract and in the splenium and genu of the corpus callosum of infants with abnormal pattern on MRI with those of control infants, who showed a normal pattern on MRI. We attempted to follow all infants with hypoxic-ischemic encephalopathy until 18 months of age and assess them using a standardized neurologic examination. RESULTS: After exclusions, we recruited 25 infants with abnormal MRI and 20 with normal MRI (controls). Among these 45 neonates, pre-Wallerian degeneration was visualized in the corticospinal tract in 10 neonates and in the corpus callosum in 12. The ADC values in the corticospinal tract in the first week were significantly lower than they were in the second week. Infants with pre-Wallerian degeneration in the corticospinal tract showed an unfavorable outcome. CONCLUSION: Pre-Wallerian degeneration was visualized in the corticospinal tract and corpus callosum and was associated with extensive brain injury caused by hypoxic-ischemic encephalopathy. The changes in signal were observed to evolve over time within the first 2 weeks. The clinical outcome of infants having pre-Wallerian degeneration in the corticospinal tract was unfavorable.
Subject(s)
Brain Injuries , Hypoxia-Ischemia, Brain , Corpus Callosum/diagnostic imaging , Corpus Callosum/pathology , Diffusion Magnetic Resonance Imaging/methods , Humans , Hypoxia-Ischemia, Brain/diagnostic imaging , Hypoxia-Ischemia, Brain/pathology , Infant , Infant, Newborn , Pyramidal Tracts/diagnostic imaging , Wallerian Degeneration/complications , Wallerian Degeneration/pathologyABSTRACT
We performed a retrospective survey and verification of the medical records of death cases of children (and adolescents; aged <18 years) between 2014 and 2016 in pediatric specialty training facilities in Japan. Of the 2,827 registered cases at 163 facilities, 2,348 cases were included. The rate of identified deaths compared with the demographic survey, was 18.2%-21.0% by age group. The breakdown of deaths was determined as follows: 638 cases (27.2%) were due to external factors or unknown causes, 118 (5.0%) were suspected to involve child maltreatment, 932 (39.7%) were of moderate or high preventability or were indeterminable. Further detailed verification was required for 1,333 cases (56.8%). Comparison of the three prefectures with high rates of identified deaths in Japan revealed no significant differences, such as in the distribution of diseases, suggesting that there was little selection bias. The autopsy rate of deaths of unknown cause was 43.4%, indicating a high ratio of forensic autopsies. However, sufficient clinical information was not collected; therefore, thorough evaluations were difficult to perform. Cases with a moderate or high possibility of involvement of child maltreatment accounted for 5%, similar to previous studies. However, more objective evaluation is necessary. Preventable death cases including potentially preventable deaths accounted for 25%, indicating that proposals need to be made for specific preventive measures. Individual primary verification followed by secondary verification by multiple organizations is effective. It is anticipated that a child death review (CDR) system with such a multi-layered structure will be established; however, the following challenges were revealed: The subjects of CDR are all child deaths. Even if natural death cases are entrusted to medical organizations, and complicated cases to other special panels, the numbers are very high. Procedures need to be established to sufficiently verify these cases. Although demographic statistics are useful for identifying all deaths, care must be taken when interpreting such data. Detailed verification of the cause of death will affect the determination of subsequent preventability. Verification based only on clinical information is difficult, so a procedure that collates non-medical information sources should be established. It is necessary to organize the procedures to evaluate the involvement of child maltreatment objectively and raise awareness among practitioners. To propose specific preventive measures, a mechanism to ensure multiprofessional diverse perspectives is crucial, in addition to fostering the foundation of individual practitioners. To implement the proposed measures, it is also necessary to discuss the responsibilities and authority of each organization. Once the CDR system is implemented, verification of the system should be repeated. Efforts to learn from child deaths and prevent deaths that are preventable as much as possible are essential duties of pediatricians. Pediatricians are expected to undertake the identified challenges and promote and lead the implementation of the CDR system. This is a word-for-word translation of the report in J. Jpn. Pediatr. Soc. 2019; 123 (11): 1736-1750, which is available only in the Japanese language.
Subject(s)
Child Abuse , Child Mortality , Adolescent , Child , Humans , Infant , Japan/epidemiology , Retrospective Studies , Autopsy , Cause of DeathABSTRACT
BACKGROUND: The morphological changes in the pons and cerebellum of neonates experiencing profound asphyxia in the early period of life remain to be clarified. PURPOSE: To assess the changes in the size of the pons and cerebellum during the first two weeks of life in term neonates with pontine and cerebellar injury caused by hypoxic-ischemic encephalopathy in comparison with a control group. MATERIAL AND METHODS: Two groups were investigated: a group with pontine/cerebellar injury (PCI) (n = 10) demonstrated by magnetic resonance imaging (MRI) diffusion-weighted imaging; and a control group without PCI - focal-multifocal white matter injury and a normal pattern (n = 24). The anteroposterior diameter (APD) and height of the pons and cerebellar vermis, and the transverse width of the cerebellum were measured twice in the first and second weeks of life. Differences between the groups were analyzed statistically using paired and unpaired Student's t-test at a significance level of P < 0.05. RESULTS: In the PCI group, the pontine APD and cerebellar vermian height were significantly decreased in the second week. An increase of pons and cerebellar size was evident during the first two weeks of life in the control groups. CONCLUSION: Infants with PCI and profound asphyxia show rapid decreases in pontine APD and cerebellar vermian height within the first two weeks of life.
Subject(s)
Asphyxia , Pons , Asphyxia/pathology , Cerebellum/diagnostic imaging , Cerebellum/pathology , Diffusion Magnetic Resonance Imaging , Humans , Infant , Infant, Newborn , Magnetic Resonance Imaging , Pons/diagnostic imaging , Pons/pathologyABSTRACT
OBJECTIVE: There has been no previous report of diffusion restriction in the optic radiation of term neonates with hypoxic-ischemic encephalopathy. Here, using diffusion-weighted magnetic resonance imaging (MRI), we assessed diffusion restriction in the optic radiation within the first 2 weeks of life and estimated signal changes and the apparent diffusion coefficient in the optic radiation and lateral geniculate body using T1-weighted MRI. MATERIALS AND METHODS: Forty-five term neonates with hypoxic-ischemic encephalopathy underwent MRI twice during the first 2 weeks of life. Diffusion-weighted imaging and apparent diffusion coefficient were used to evaluate the presence of diffusion restriction in the optic radiation and lateral geniculate body. Apparent diffusion coefficient and T1 signal changes in the optic radiation and lateral geniculate body were also compared with those in 11 control neonates showing a normal pattern on MRI. RESULTS: Diffusion restriction in the optic radiation was observed in 29% (13/45) of the hypoxic-ischemic encephalopathy neonates at a median age of 3.5 days (range: 1-9 days). The apparent diffusion coefficient in the optic radiation of affected neonates was significantly reduced in comparison with the controls. In all neonates with optic radiation involvement, increased T1 signal intensity was observed in the optic radiation in the second week, and was also evident in in lateral geniculate body in 8 of those neonates. CONCLUSION: Diffusion restriction in the optic radiation is not rare among term neonates with hypoxic-ischemic encephalopathy, being visualized by diffusion-weighted imaging in the first week of life and also high-intensity T1 signal changes in the second week. This diffusion restriction in the optic radiation might be due to transsynaptic neuronal degeneration.
Subject(s)
Hypoxia-Ischemia, Brain/diagnostic imaging , Hypoxia-Ischemia, Brain/pathology , Magnetic Resonance Imaging/methods , Visual Pathways/diagnostic imaging , Brain/diagnostic imaging , Brain/pathology , Diffusion Magnetic Resonance Imaging/methods , Female , Humans , Infant, Newborn , Male , Retrospective StudiesABSTRACT
BACKGROUND: Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of death and disability in infants. Magnetic resonance imaging (MRI) is valuable for predicting the outcome in high-risk neonates. The relationship of pontine and cerebellar injury to outcome has not been explored sufficiently. PURPOSE: To characterize MRI features of pontine and cerebellar injury and to assess the clinical outcomes of these neonates. MATERIAL AND METHODS: The retrospective study included 59 term neonates (25 girls) examined by MRI using 1.5-T scanner in the first two weeks of life between 2008 and 2017. Involvement of the pons and cerebellum was judged as a high signal intensity on diffusion-weighted image (DWI) and a restricted diffusion on an apparent diffusion coefficient (ADC) map. RESULTS: Pontine involvement was observed in the dorsal portion of pons in eight neonates and cerebellar involvement was observed in dentate nucleus (n = 8), cerebellar vermis (n = 3), and hemisphere (n = 1) in 11 neonates. Combined pontine and cerebellar involvement was observed in eight neonates and only cerebellar involvement in three. The pontine and cerebellar injuries were always associated with very severe brain injury including a basal ganglia/thalamus injury pattern and a total brain injury pattern. In terms of clinical outcome, all but four lost to follow-up, had severe cerebral palsy. CONCLUSION: Pontine and cerebellar involvement occurred in the dorsal portion of pons and mostly dentate nucleus and was always associated with a more severe brain injury pattern as well as being predictive of major disability.
Subject(s)
Cerebellum/diagnostic imaging , Hypoxia-Ischemia, Brain/diagnostic imaging , Magnetic Resonance Imaging/methods , Pons/diagnostic imaging , Cerebellum/pathology , Diffusion Magnetic Resonance Imaging , Female , Humans , Hypoxia-Ischemia, Brain/pathology , Infant, Newborn , Male , Pons/pathologyABSTRACT
BACKGROUND: The mitochondrial DNA MT-ATP6 gene encodes the ATP6 subunit of the mitochondrial ATP synthase. The m.9185â¯Tâ¯>â¯C variant in MT-ATP6 has been reported to cause various neurological disorders including late-onset Leigh syndrome (LS). To our knowledge, there has been no reported case of infantile-onset LS associated with the m.9185â¯Tâ¯>â¯C variant. Herein, we report a patient with early-onset LS complicated with infantile spasms who exhibited profound developmental delay. CASE REPORT: A 3-month-old Japanese girl presented with focal seizures. Brain magnetic resonance imaging (MRI) revealed bilateral lesions in the basal ganglia and cerebral peduncle. Laboratory evaluation demonstrated marked elevations of lactate and pyruvate in both venous blood and cerebrospinal fluid. At 6â¯months, she developed infantile spasms, which were ceased by adrenocorticotropic hormone therapy. At 2â¯years of age, she was bedridden due to hypotonic quadriplegia and was unable to make eye contact. Whole-exome sequencing identified apparently de novo homoplasmic m.9185â¯Tâ¯>â¯C variant in her blood. CONCLUSION: This is the first case report describing early infantile-onset LS associated with the m.9185â¯Tâ¯>â¯C variant, and thereby broadens the phenotypic spectrum of m.9185â¯Tâ¯>â¯C-related disorders.
Subject(s)
Leigh Disease/genetics , Mitochondrial Proton-Translocating ATPases/genetics , Spasms, Infantile/genetics , Female , Humans , Infant , MutationABSTRACT
BACKGROUND: Citrin (mitochondrial aspartate-glutamate transporter) deficiency causes the failures in both carbohydrate-energy metabolism and the urea cycle, and the alterations in the serum levels of several amino acids in the stages of newborn (NICCD) and adult (CTLN2). However, the clinical manifestations are resolved between the NICCD and CTLN2, but the reasons are still unclear. This study evaluated the serum amino acid profile in citrin-deficient children during the healthy stage. METHODS: Using HPLC-MS/MS analysis, serum amino acids were evaluated among 20 citrin-deficient children aged 5-13 years exhibiting normal liver function and 35 age-matched healthy controls. RESULTS: The alterations in serum amino acids characterized in the NICCD and CTLN2 stages were not observed in the citrin-deficient children. Amino acids involved in the urea cycle, including arginine, ornithine, citrulline, and aspartate, were comparable in the citrin-deficient children to the respective control levels, but serum urea was twofold higher, suggestive of a functional urea cycle. The blood sugar level was normal, but glucogenic amino acids and glutamine were significantly decreased in the citrin-deficient children compared to those in the controls. In addition, significant increases of ketogenic amino acids, branched-chain amino acids (BCAAs), a valine intermediate 3-hydroxyisobutyrate, and ß-alanine were also found in the citrin-deficient children. CONCLUSION: The profile of serum amino acids in the citrin-deficient children during the healthy stage showed different characteristics from the NICCD and CTLN2 stages, suggesting that the failures in both urea cycle function and energy metabolism might be compensated by amino acid metabolism. SYNOPSIS: In the citrin-deficient children during the healthy stage, the characteristics of serum amino acids, including decrease of glucogenic amino acids, and increase of ketogenic amino acids, BCAAs, valine intermediate, and ß-alanine, were found by comparison to the age-matched healthy control children, and it suggested that the characteristic alteration of serum amino acids may be resulted from compensation for energy metabolism and ammonia detoxification.
Subject(s)
Abdominal Abscess/surgery , Drainage/methods , Laparoscopy/methods , Salmonella Infections/complications , Splenic Diseases/surgery , Abdominal Abscess/drug therapy , Anti-Bacterial Agents/therapeutic use , Child , Female , Humans , Salmonella/isolation & purification , Salmonella Infections/drug therapy , Salmonella Infections/surgery , Spleen/pathology , Splenectomy , Splenic Diseases/drug therapy , Tomography, X-Ray ComputedABSTRACT
Context: Citrin-deficient infants present neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), which resolves at 12 months. Thereafter, they have normal liver function associated with hypercholesterolemia, and a preference for lipid-rich carbohydrate-restricted diets. However, some develop adult-onset type II citrullinemia, which is associated with metabolic abnormalities. Objectives: To identify the causes of hypercholesterolemia in citrin-deficient children post-NICCD. Design and Setting: We determined the concentrations of sterol markers of cholesterol synthesis, absorption, and catabolism by liquid chromatography-electrospray ionization-tandem mass spectrometry and evaluated serum lipoprotein profiles. Subjects: Twenty citrin-deficient children aged 5 to 13 years and 37 age-matched healthy children. Intervention: None. Main Outcome Measures: Relationship between serum lipoproteins and sterol markers of cholesterol metabolism. Results: The citrin-deficient group had a significantly higher high-density lipoprotein cholesterol (HDL-C) concentration than did the control group (78 ± 11 mg/dL vs 62 ± 14 mg/dL, P < 0.001), whereas the two groups had similar low-density lipoprotein cholesterol and triglyceride concentrations. The concentrations of markers of cholesterol synthesis (lathosterol and 7-dehydrocholesterol) and bile acids synthesis (7α-hydroxycholesterol and 27-hydroxycholesterol) were 1.5- to 2.8-fold and 1.5- to 3.9-fold, respectively, higher in the citrin-deficient group than in the control group. The concentration of 24S-hydroxycholesterol, a marker of cholesterol catabolism in the brain, was 2.5-fold higher in the citrin-deficient group. In both groups, the HDL-C concentration was significantly positively correlated with that of 27-hydroxycholesterol, the first product of the alternative bile acid synthesis pathway. Conclusions: HDL-C and sterol marker concentrations are elevated in citrin-deficient children post-NICCD. Moreover, cholesterol synthesis and elimination are markedly enhanced in the liver and brain of citrin-deficient children.
Subject(s)
Brain/metabolism , Cholesterol, HDL/metabolism , Cholesterol, LDL/metabolism , Citrullinemia/metabolism , Hypercholesterolemia/etiology , Liver/metabolism , Adolescent , Bile Acids and Salts/biosynthesis , Biomarkers/blood , Case-Control Studies , Child , Child, Preschool , Cholesterol/blood , Citrullinemia/complications , Dehydrocholesterols/blood , Female , Humans , Hydroxycholesterols/blood , Male , Triglycerides/bloodABSTRACT
BACKGROUND: Silver-Russell syndrome (SRS) is a rare congenital disorder characterized by pre- and postnatal growth failure and dysmorphic features. Recently, pathogenic copy number variations (PCNVs) and imprinting defects other than hypomethylation of the H19-differentially methylated region (DMR) and maternal uniparental disomy chromosome 7 have been reported in patients with the SRS phenotype. This study aimed to clarify the frequency and clinical features of patients with SRS phenotype caused by PCNVs. METHODS: We performed array comparative genomic hybridization analysis using a catalog array for 54 patients satisfying the Netchine-Harbison clinical scoring system (NH-CSS) (SRS-compatible) and for 28 patients presenting with three NH-CSS items together with triangular face and/or fifth finger clinodactyly and/or brachydactyly (SRS-like) without abnormal methylation levels of 9 DMRs related to known imprinting disorders. We then investigated the clinical features of patients with PCNVs. RESULTS: Three of the 54 SRS-compatible patients (5.6%) and 2 of the 28 SRS-like patients (7.1%) had PCNVs. We detected 3.5 Mb deletion in 4p16.3, mosaic trisomy 18, and 3.77-4.00 Mb deletion in 19q13.11-12 in SRS-compatible patients, and 1.41-1.97 Mb deletion in 7q11.23 in both SRS-like patients. Congenital heart diseases (CHDs) were identified in two patients and moderate to severe global developmental delay was observed in four patients. CONCLUSIONS: Of the patients in our study, 5.6% of SRS-compatible and 7.1% of SRS-like patients had PCNVs. All PCNVs have been previously reported for genetic causes of contiguous deletion syndromes or mosaic trisomy 18. Our study suggests patients with PCNVs, who have a phenotype resembling SRS, show a high tendency towards CHDs and/or apparent developmental delay.
Subject(s)
Comparative Genomic Hybridization/methods , DNA Copy Number Variations , Developmental Disabilities/genetics , Heart Diseases/congenital , Silver-Russell Syndrome/genetics , Child , Child, Preschool , DNA Methylation , Developmental Disabilities/diagnosis , Epigenesis, Genetic , Female , Genetic Heterogeneity , Genomic Imprinting , Heart Diseases/diagnosis , Heart Diseases/genetics , Humans , Infant , Male , Young AdultABSTRACT
Citrin deficiency causes adult-onset type II citrullinemia (CTLN-2), which later manifests as severe liver steatosis and life-threatening encephalopathy. Long-standing energy deficit of the liver and brain may predispose ones to CTLN-2. Here, we compared the energy-driving tricarboxylic acid (TCA) cycle and fatty acid ß-oxidation cycle between 22 citrin-deficient children (age, 3-13years) with normal liver functions and 37 healthy controls (age, 5-13years). TCA cycle analysis showed that basal plasma citrate and α-ketoglutarate levels were significantly higher in the affected than the control group (p<0.01). Conversely, basal plasma fumarate and malate levels were significantly lower than those for the control (p<0.001). The plasma level of 3-OH-butyrate derived from fatty acid ß-oxidation was significantly higher in the affected group (p<0.01). Ten patients underwent sodium pyruvate therapy. However, this therapy did not correct or attenuate such deviations in both cycles. Sodium pyruvate therapy significantly increased fasting insulin secretion (p<0.01); the fasting sugar level remained unchanged. Our results suggest that citrin-deficient children show considerable deviations of TCA cycle metabolite profiles that are resistant to sodium pyruvate treatment. Thus, long-standing and considerable TCA cycle dysfunction might be a pivotal metabolic background of CTLN-2 development.
Subject(s)
Citric Acid Cycle , Citrullinemia/drug therapy , Citrullinemia/metabolism , Fatty Acids/metabolism , Pyruvates/administration & dosage , Adolescent , Child , Child, Preschool , Citric Acid/blood , Citric Acid Cycle/drug effects , Female , Fumarates/blood , Humans , Ketoglutaric Acids/blood , Malates/blood , Male , Oxidative Stress/drug effects , Pyruvates/pharmacology , Treatment OutcomeABSTRACT
Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.
Subject(s)
Adrenal Insufficiency/genetics , Chromosomes, Human, Pair 7/genetics , Growth Disorders/genetics , Mutation/genetics , Myelodysplastic Syndromes/genetics , Proteins/genetics , Adolescent , Adrenal Insufficiency/pathology , Child , Endosomes/metabolism , ErbB Receptors/genetics , Female , Genotype , Growth Disorders/pathology , Humans , Hypoadrenocorticism, Familial , Infant , Infant, Newborn , Intracellular Signaling Peptides and Proteins , Male , Middle Aged , Myelodysplastic Syndromes/pathology , Pedigree , PhenotypeABSTRACT
We report the first case of Leigh syndrome (LS) with Fukuyama congenital muscular dystrophy (FCMD). A neonate suffered from lactic acidosis and subsequently presented with poor feeding, muscle weakness, hypotonia, cardiopulmonary dysfunction, and hydrocephalus. He died at 17 months. The findings of brain magnetic resonance imaging indicated some specific features of both LS and FCMD, and FCMD gene mutation was detected. Decreased mitochondrial respiratory complex I and II activity was noted. Mitochondrial DNA sequencing showed no pathogenic mutation. A case with complex I+II deficiency has rarely been reported, suggesting a nuclear gene mutation.
Subject(s)
Leigh Disease/complications , Leigh Disease/diagnosis , Walker-Warburg Syndrome/complications , Walker-Warburg Syndrome/diagnosis , Brain/pathology , Humans , Infant, Newborn , Leigh Disease/pathology , Magnetic Resonance Imaging , Male , Walker-Warburg Syndrome/metabolism , Walker-Warburg Syndrome/pathologyABSTRACT
OBJECTIVE: To determine the HLA-DRB1, DQB1, DPB1, A, C, and B genotypes among Japanese children with autoimmune type 1 diabetes. METHODS: Four hundred and thirty patients who were GADAb and/or IA-2Ab-positive (Type 1A) were recruited from 37 medical centers as part of a nationwide multicenter collaborative study. DNA samples from 83 siblings of the children with Type 1A diabetes and 149 parent-child trios were also analyzed. A case-control study and a transmission disequilibrium test (TDT) were then performed. RESULTS: The susceptible and protective DRB1 and DQB1 alleles and haplotypes were confirmed. DPB1 alleles unique to the Japanese population and those common to multiple ethnic groups were also present. A linkage disequilibrium (LD) analysis showed both susceptible and protective haplotypes. The TDT did not reveal any alleles that were transmitted preferentially from the mother or father to children with Type 1A. Homozygosity for DRB1-09:01-DQB1-03:03 and heterozygosity for DRB1-04:05-DQB1-04:01 and DRB1-08:02-DQB1-03:02 were associated with an extremely high risk of Type 1A. A comparison of children with Type 1A and their parents and siblings suggested a dose effect of susceptible DRB1-DQB1 haplotypes and an effect of protective alleles on immunological pathogenesis. DRB1-09:01 appeared to be strongly associated with an early onset in preschool children with Type 1A diabetes. CONCLUSIONS: This study demonstrated the characteristic association of HLA-class II and class I genes with Type 1A diabetes among Japanese children. A TDT did not reveal the genomic imprinting of HLA-class II and class I genes in Type 1A diabetes.
Subject(s)
Asian People/genetics , Diabetes Mellitus, Type 1/genetics , Family , Genes, MHC Class II/genetics , Genes, MHC Class I/genetics , Adolescent , Asian People/statistics & numerical data , Child , Child, Preschool , DNA Mutational Analysis , Diabetes Mellitus, Type 1/classification , Diabetes Mellitus, Type 1/ethnology , Female , Genotype , Humans , Infant , Infant, Newborn , MaleABSTRACT
BACKGROUND: The relationship between oxygen and retinopathy of prematurity (ROP) has been studied frequently, and a pulse oximeter has the potential to facilitate the control of oxygen fluctuation in neonates. The objective of the present study was to compare the incidence of threshold ROP (stage 3 requiring laser treatment and stage 4) in infants of <33 weeks gestation after implementing a new clinical O(2) management practice. METHODS: A retrospective study of data from the Kyoto First Red Cross Hospital neonatal intensive care unit (NICU) from 1 July 2004 to 31 October 2007 (closed 1 December 2006-30 March 2007 for reconstruction). A reduced oxygen protocol was implemented to maintain oxygen saturation (SpO(2)) values using a pulse oximeter between 88% and 92%. The incidence of threshold ROP in the earlier period (1 July 2004-31 December 2005) and the later period (1 January 2006-31 October 2007) were compared. RESULTS: The incidence of threshold ROP significantly decreased from 32.2% to 16.7%, after changing to the reduced oxygen protocol (P < 0.05). CONCLUSION: A significant decrease in the rate of threshold ROP in infants of <33 weeks gestation was observed after implementation of the new clinical O(2) management practice.
Subject(s)
Oxygen Inhalation Therapy/methods , Retinopathy of Prematurity/prevention & control , Birth Weight , Cross-Sectional Studies , Female , Gestational Age , Humans , Infant, Newborn , Intensive Care Units, Neonatal , Male , Oximetry , Retinopathy of Prematurity/blood , Retinopathy of Prematurity/diagnosis , Retinopathy of Prematurity/epidemiology , Retrospective StudiesABSTRACT
Recent studies have shown that cells from bone marrow (BM) can give rise to differentiated skeletal muscle fibers. However, the mechanisms and identities of the cell types involved remain unknown. We performed BM transplantation in acid alpha-glucosidase (GAA) knockout mice, a model of glycogen storage disease type II, and our observations suggested that the BM cells contribute to skeletal muscle fiber formation. Furthermore, we showed that most CD45+:Sca1+ cells have a donor character in regenerating muscle of recipient mice. Based on these findings, CD45+:Sca1+ cells were sorted from regenerating muscles. The cell number was increased with granulocyte colony-stimulating factor after cardiotoxin injury, and the cells were transplanted directly into the tibialis anterior (TA) muscles of GAA knockout mice. Sections of the TA muscles stained with anti-laminin-alpha2 antibody showed that the number of CD45+:Sca1+ cells contributing to muscle fiber formation and glycogen levels were decreased in transplanted muscles. Our results indicated that hematopoietic stem cells, such as CD45+:Sca1+ cells, are involved in skeletal muscle regeneration.
Subject(s)
Hematopoietic Stem Cells/physiology , Muscle, Skeletal/physiology , Regeneration , alpha-Glucosidases/genetics , Animals , Antigens, Ly/metabolism , Glycogen/metabolism , Hematopoietic Stem Cell Transplantation , Leukocyte Common Antigens/metabolism , Membrane Proteins/metabolism , Mice , Mice, Knockout , Nerve Fibers/physiologyABSTRACT
BACKGROUND: Evidence is accumulating that the promoter region of the insulin-like growth factor I (IGF-I) gene polymorphism and low levels of IGF-I are associated with type 2 diabetes, cardiovascular disease and birth weight; however, the number of wild-type alleles is different in each country. OBJECTIVES: This study aimed to examine the 737/738 marker, a cytosine-adenine repeat in the promoter region of the IGF-I gene polymorphism, and plasma IGF-I levels in Japanese infants and analyze the genetic background. METHODS: Data were collected for 15 months in Kyoto Prefectural University of Medicine. The body composition parameters of all infants were determined at birth. At 5 days after birth, we took blood samples to measure the product size of the promoter region of the IGF-I gene polymorphism and plasma IGF-I. RESULTS: In a population-based sample of 160 subjects, 6 different alleles and 16 genotypes were identified in the promoter region of the IGF-I gene polymorphism. The existence of a 196-bp allele has proved to result in a low plasma IGF-I level, a small head and chest circumference (p < 0.05) and no significant for premature birth, short-birth height and low-birth weight. CONCLUSIONS: This is the first study showing the role of the promoter region of the IGF-I gene polymorphism and the level of plasma IGF-I and body composition parameters in Japanese infants. Our results suggest genetical influence on prenatal growth and serum IGF-I levels.
Subject(s)
Genetic Markers , Genetic Predisposition to Disease/genetics , Genetic Testing , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor I/genetics , Polymorphism, Genetic , Body Size , Female , Genetic Predisposition to Disease/epidemiology , Genotype , Hospitals, University , Humans , Infant, Newborn , Japan/epidemiology , Male , Promoter Regions, Genetic/geneticsABSTRACT
In neonatal-onset nonketotic hyperglycinemia, severe psychomotor retardation is the expected uniform outcome. We report two patients with typical neonatal presentation who showed far better developmental outcomes. The in vitro expression analysis of the identified GLDC mutations revealed considerable residual enzyme activity, suggesting prognostic and enzymatic heterogeneity even in neonatal-onset nonketotic hyperglycinemia.