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Biomedical subjects

J Christodoulou

Publications and source records attributed to J Christodoulou.

At least 19 recordsLinked to original sources
PubMed2006

Early progressive encephalopathy in boys and MECP2 mutations.

MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.

Cerebral Cortex↗
PubMed2006

Lesch-Nyhan disease in a 20-year- old man incorrectly described as developing 'cerebral palsy' after general anaesthesia in infancy.

Lesch-Nyhan disease (LND) is a rare X-linked recessive genetic disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The classic clinical condition is characterized by cognitive impairment, hypotonia at rest, choreoathetosis, hyperuricaemia and the hallmark symptom of severe and involuntary self-mutilation. We describe a man with LND who was initially thought to have suffered from a dyskinetic cerebral palsy after an uncomplicated inguinal herniorrhaphy under general anaesthesia at 5 1/2 months of age. In the absence of overt self-injurious behaviour, the diagnosis was not considered for nearly two decades. The diagnosis of LND was established at 20 years of age through clinical review, biochemical examinations and molecular analysis. HPRT haemolysate activity was 7.6% of the normal control, suggesting that he had a milder variant of the disease. Mutation analysis of the HPRT gene revealed a novel missense mutation, c.449T > G in exon 6 (p.V150G). Cascade testing of family members revealed that the mother was heterozygous for the mutation but two siblings (a brother and a sister) did not carry the sequence mutation. Whether the onset of neurological abnormalities in this particular case can be attributed to the general anaesthesia is discussed.

Adult↗
PubMed2005

Lost in translation: translational interference from a recurrent mutation in exon 1 of MECP2.

BACKGROUND: Rett syndrome (RTT) is an X linked neuro-developmental disorder affecting mostly girls. Mutations in the coding region of MECP2 are found in 80% of classic RTT patients. Until recently, the region encoding MECP2 was believed to comprise exons 2, 3, and 4 with the ATG start site located at the end of exon 2 (MeCP2_e2). METHODS: Recent reports of another mRNA transcript transcribed from exon 1 (MeCP2_e1) prompted us to screen exon 1 among RNA samples from 20 females with classic or atypical RTT. RESULTS: A previously reported 11 base pair deletion in exon 1 was detected in one subject with a milder phenotype. Although RNA expression for both protein isoforms was detected from the mutant allele, evaluation of MeCP2 protein in uncultured patient lymphocytes by immunocytochemistry revealed that MeCP2 protein production was restricted to only 74-76% of lymphocytes. X chromosome inactivation studies of genomic DNA revealed similar XCI ratios at the HUMARA locus (73:27 with HpaII and 74:26 with McrBC). We have demonstrated that translation but not transcription of the MeCP2_e2 isoform is ablated by the 11 nucleotide deletion, 103 nucleotides upstream of the e2 translation start site. CONCLUSIONS: These findings reveal that nucleotides within the deleted sequence in the 5'-UTR of the MeCP2_e2 transcript, while not required for transcription, are essential for translation.

Adolescent↗
PubMed2005

OPA3 mutation screening in patients with unexplained 3-methylglutaconic aciduria.

We have screened 13 patients with neurological abnormalities and 3-methylglutaconic aciduria (3MGA) for mutations in the OPA3 gene, which are known to be the cause of Costeff syndrome (optic atrophy, chorea and spasticity; type III 3MGA). We aimed to explore whether mutations in the OPA3 gene are present in patients with 3MGA but without classic Costeff syndrome. OPA3 mutations (IVS1-1G>C) were identified in 2 patients with the classic phenotype of type III 3MGA, but not in the other 11 patients with differing non-Costeff phenotypes associated with developmental delay and neurological signs and symptoms as described. We identified a previously described sequence variation in the OPA3 gene (c.231T>C) in 12/13 patients. The alteration was homozygous in 8/12 and heterozygous in 4/12. This alteration was also found in 60 of 98 normal control alleles. In a single patient, a novel sequence variation in the 5' UTR was identified, (c.-38A>G). Our studies suggest that the c.231T>C sequence variation is of no clinical significance, whereas the significance of the 5' UTR sequence variation remains open to speculation. Our study of the OPA3 gene in patients with 3MGA without Costeff syndrome suggests that mutations in OPA3 are not a common cause of 3MGA in the absence of signs of Costeff syndrome.

5' Untranslated Regions↗
PubMed2005

Rett syndrome: clinical review and genetic update.

Rett syndrome (RS) is a severe neurodevelopmental disorder that contributes significantly to severe intellectual disability in females worldwide. It is caused by mutations in MECP2 in the majority of cases, but a proportion of atypical cases may result from mutations in CDKL5, particularly the early onset seizure variant. The relationship between MECP2 and CDKL5, and whether they cause RS through the same or different mechanisms is unknown, but is worthy of investigation. Mutations in MECP2 appear to give a growth disadvantage to both neuronal and lymphoblast cells, often resulting in skewing of X inactivation that may contribute to the large degree of phenotypic variation. MeCP2 was originally thought to be a global transcriptional repressor, but recent evidence suggests that it may have a role in regulating neuronal activity dependent expression of specific genes such as Hairy2a in Xenopus and Bdnf in mouse and rat.

Animals↗
PubMed2004

Trisomy 21 and Rett syndrome: a double burden.

Rett syndrome is a severe neurodevelopmental disorder generally affecting girls. Affected individuals are apparently normal at birth but later pass through a period of regression with loss of hand and communication skills and the development of hand stereotypies and dyspraxia. Mutations in the methyl-CpG binding protein 2 (MECP2) gene, have now been found to cause Rett syndrome in up to 80% of classical cases. We report a girl with Down syndrome, one of three children with birth defects in a family of five. From the age of 18 months she developed symptomatology considered by her primary physician to be very characteristic of Rett syndrome. However, this remained a clinical diagnosis till the age of 12 years. Laboratory confirmation of the dual diagnosis, which includes a R168X mutation in the MECP2 gene in addition to trisomy 21, has now been possible. The presence of one neurological or developmental disorder does not necessarily preclude a diagnosis of Rett syndrome.

Child↗
PubMed2003

Myelodysplastic syndrome (RARS) with +i(12p) abnormality in a patient 10 months after diagnosis and successful treatment of a mediastinal germ cell tumor (MGCT).

We report on a 21-year-old man with a mediastinal germ cell tumor (MGCT) who developed a myelodysplastic syndrome (MDS) (refractory anemia with ringed sideroblasts, RARS) 10 months after the start of successful treatment with cisplatin, etoposide, ifosfamide, and paclitaxel. A very rare early occurrence of a therapy-related MDS was suspected. Cytogenetic analysis of the bone marrow revealed an aberrant karyotype, showing a deletion in 12p, an isochromosome 5p, as well as gain of an isochromosome 12p. Isochromosome 12p is a specific aberration frequently observed in MGCT. It also was described in patients who developed hematological transformation of a mediastinal germ cell tumor. In this report the association between mediastinal germ cell tumors and hematological malignancies including the possibility of a common genetic origin is discussed.

Adult↗
PubMed2003

Describing the phenotype in Rett syndrome using a population database.

BACKGROUND: Mutations in the MECP2 gene have been recently identified as the cause of Rett syndrome, prompting research into genotype-phenotype relations. However, despite these genetic advances there has been little descriptive epidemiology of the full range of phenotypes. AIMS: To describe the variation in phenotype in Rett syndrome using four different scales, by means of a population database. METHODS: Using multiple sources of ascertainment including the Australian Paediatric Surveillance Unit, the development of an Australian cohort of Rett syndrome cases born since 1976 has provided the first genetically characterised population based study of Rett syndrome. Follow up questionnaires were administered in 2000 to families and used to provide responses for items in four different severity scales. RESULTS: A total of 199 verified cases of Rett syndrome were reported between January 1993 and July 2000; 152 families provided information for the follow up study. The mean score using the Kerr scale was 22.9 (SD 4.8) and ranged from 20.5 in those under 7 years to 24.2 in those over 17 years. The mean Percy score was 24.9 (SD 6.6) and also increased with age group from 23.0 to 26.9. The mean Pineda score was 16.3 (SD 4.5) and did not differ by age group. The mean WeeFIM was 29.0 (SD 11.9), indicating extreme dependence, and ranged from 18 to 75. CONCLUSION: We have expanded on the descriptive epidemiology of Rett syndrome and shown different patterns according to the severity scale selected. Although all affected children are severely functionally dependent, it is still possible to identify some variation in ability, even in children with identified MECP2 mutations.

Adolescent↗
PubMed2002

Clinical approach to inborn errors of metabolism presenting in the newborn period.

Inborn errors of metabolism are individually rare, but collectively are responsible for significant levels of paediatric morbidity and mortality. More than 400 biochemically diverse inborn errors of metabolism have been identified. Recent advances in the diagnosis and treatment of these disorders have substantially improved the prognosis for many of them. Paediatricians and neonatologists play a vital role in identifying which patients need to be investigated. The diagnosis of an inborn error of metabolism often needs to be established quickly in order to prevent death or permanent neurological sequelae, and this should be carried out in collaboration with a specialized unit. The present review provides a practical approach to the recognition and investigation of neonates in whom an inborn error may be present. We also provide guidelines for the stabilization and initial management of infants at high risk of a metabolic disorder.

Humans↗
PubMed2001

Guidelines for reporting clinical features in cases with MECP2 mutations.

An international group recommends that papers relating phenotypes to genotypes involving mutations in the X chromosome gene MECP2 should provide a minimum data set reporting the range of disturbances frequently encountered in Rett Syndrome. A simple scoring system is suggested which will facilitate comparison among the various clinical profiles. Features are described which should prompt screening for MECP2 mutations.

Chromosomal Proteins, Non-Histone↗
PubMed2001

Medium-term open label trial of L-carnitine in Rett syndrome.

Treatment strategies in Rett syndrome so far have been essentially symptomatic and supportive. In order to establish the medium-term effects of L-carnitine, an open label trial was performed in a cohort of 21 Rett syndrome females, with a control group of 62 Rett syndrome females of a similar age, for a 6-month period. Compared with the Rett syndrome controls, treatment with L-carnitine led to significant improvements in sleep efficiency (P=0.027), especially in the subjects with a baseline sleep efficiency less than 90%, energy level (P<0.005) and communication skills (P=0.004). There was no significant difference in the subject's level of physical activity, hand function or in the quality of life of the subject's parents. In addition, before and after comparisons of the treatment group showed improvements in expressive speech (P=0.011). Treatment with L-carnitine seems to be of significant benefit in a subgroup of girls with Rett syndrome. In these girls, small but discernible improvements may be of considerable importance to their parents and carers.

Adolescent↗
PubMed2001

Sleep dysfunction in Rett syndrome: lack of age related decrease in sleep duration.

The sleep patterns of a cohort of 83 Rett syndrome females were characterized using a sleep diary for 7 consecutive days and nights and compared with normative sleep data. The mean total sleep time of the cohort was 10.75 h, daytime sleep 0.77 h, sleep efficiency 89.7%, and sleep latency 0.52 h. When subjects were categorized according to age and Rett syndrome classification, there was no significant difference in their sleep characteristics. There was a significant difference in the percentage predicted total sleep time (P<0.001) and Z scores for total sleep time (P<0.001), when subjects were categorized according to age and compared with normal children. The Rett syndrome subjects in this study did not show the age related decrease in total and daytime sleep time seen in normal children. The immature sleep pattern demonstrated in this cohort, may be a consequence of arrested brain development.

Adolescent↗
PubMed2001

Spinocerebellar ataxia type 7: a distinctive form of autosomal dominant cerebellar ataxia with retinopathy and marked genetic anticipation.

When a child presents with progressive ataxia, there is a broad differential diagnosis and a very long list of potential investigations. Spinocerebellar ataxia type 7 presenting in infancy is a rare condition where a presumptive diagnosis can be made based on the clinical features alone. These include rapidly progressive ataxia, retinopathy and autosomal dominant inheritance with marked genetic anticipation of paternal origin. The father of the infant may manifest minimal symptoms at a time when the infant is severely affected. Diagnosis is confirmed by the demonstration of an expansion of a CAG repeat in the coding region of the gene on chromosome 3p. We present a case to illustrate the diagnostic difficulties. Antenatal diagnosis was performed in two subsequent pregnancies.

Fatal Outcome↗
PubMed2001

A case of multiple congenital anomalies in association with Rett syndrome confirmed by MECP2 mutation screening.

Rett syndrome (RTT) is a severe neurodevelopmental disorder. Apparently normal at birth, girls with RTT undergo developmental regression and acquire a neurological and behavioural phenotype that has been used to define clinical diagnostic criteria for the disorder. Recently mutations in the methyl-CpG binding protein 2 gene (MECP2), located on Xq28 have been identified in females with RTT. We report a girl whose clinical course was complicated by congenital abnormalities of the respiratory tract and gastrointestinal system. In addition neurological abnormalities were evident in the newborn period. By the age of 3 years she had developed a phenotype very suggestive of RTT, but had not demonstrated deceleration of head growth and the development of expressive language was prevented by the presence of the tracheostomy. The clinical impression of RTT was confirmed by the recent finding of a mutation in the MECP2 gene. This case report highlights the importance of considering the clinical diagnosis of RTT even in the presence of other conditions and emphasises that girls with RTT may not be normal from birth.

Abnormalities, Multiple↗