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M B Delatycki

Publications and source records attributed to M B Delatycki.

34 records · Page 2Linked to original sources
PubMed2002

Sleep disturbance in mucopolysaccharidosis type III (Sanfilippo syndrome): a survey of managing clinicians.

Sanfilippo syndrome (mucopolysaccharidosis type III) is the commonest mucoploysaccharidosis. It causes neurodegeneration with often profound sleep and behavioral disturbance. Management of the sleep disturbance is difficult and inconsistent. In this study, we surveyed clinicians with particular expertise in the management of individuals with mucopolysaccharidoses. We found that sleep problems are almost universal in this patient population and that no one treatment is consistently viewed as beneficial. Among the clinicians surveyed, melatonin is reported as the medication most likely to be of benefit. Benzodiazepines, chloral hydrate, antihistamines and antipsychotic agents are overall reported as less efficacious. The major side-effect of the medications as a group was reported to be daytime somnolence. Based on this study, recommendations are given regarding the approach to sleep disturbance in Sanfilippo syndrome.

Behavior Therapy↗
PubMed2001

New variant of familial cerebellar ataxia with hypergonadotropic hypogonadism and sensorineural deafness.

Cerebellar ataxia and hypergonadotropic hypogonadism comprise a rare and presumably heterogeneous association. Inheritance in most cases appears to be autosomal recessive, and associated features include deafness, intellectual impairment, and neuropathy. Typically, onset of ataxia is in the first decade and hypogonadism results in primary amenorrhoea in females. We describe two sisters with a previously undescribed pattern of adult onset progressive cerebellar ataxia and secondary amenorrhoea due to hypergonadotropic hypogonadism. Sensorineural deafness with vestibular hypofunction and peripheral sensory impairment were also present, and intellect was normal. Onset of neurological symptoms was in the third decade, with secondary amenorrhoea occurring at the ages of 16 and 32 years, respectively. The association of ataxia and hypergonadotropic hypergonadism has been classified both as a variant of Holmes type ataxia and as a variant of Perrault syndrome, but we suggest the use of a separate category of ataxia with hypergonadotropic hypogonadism.

Adolescent↗
PubMed2001

Genetic factors in athetoid cerebral palsy.

Within the cerebral palsy syndromes, athetosis is most commonly causally associated with serious perinatal complications. Genetic factors are thought to play a lesser role, although the risk of recurrence in siblings has been suggested to be as high as 10%. We have conducted a clinical study of 22 subjects with a diagnosis of athetoid cerebral palsy and a review of the literature aiming to identify instances of familial recurrence of athetoid cerebral palsy. The birth history, family history, and previous investigations of subjects with athetoid cerebral palsy were studied and subjects were clinically examined for evidence of an underlying genetic etiology. Factors suggesting a genetic cause were specifically sought, such as advanced paternal age, progression of symptoms, and associated congenital abnormalities. No subjects in the study group had similarly affected relatives, and additional features suggesting a genetic cause were not observed. A literature search identified 16 instances of familial recurrence of athetoid cerebral palsy. Familial cases were typically associated with significant spasticity, microcephaly, intellectual disability, seizures, and a lack of history of birth asphyxia, and most could be explained by either autosomal-recessive or X-linked-recessive inheritance. The genetic contribution to athetoid cerebral palsy is small, with an overall risk of recurrence in siblings of about 1%. This risk is lower than previously suggested in the literature.

Adolescent↗
PubMed2000

Friedreich ataxia: an overview.

Friedreich ataxia, an autosomal recessive neurodegenerative disease, is the most common of the inherited ataxias. The recent discovery of the gene that is mutated in this condition, FRDA, has led to rapid advances in the understanding of the pathogenesis of Friedreich ataxia. About 98% of mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of the gene. This leads to reduced levels of the protein, frataxin. There is mounting evidence to suggest that Friedreich ataxia is the result of accumulation of iron in mitochondria leading to excess production of free radicals, which then results in cellular damage and death. Currently there is no known treatment that alters the natural course of the disease. The discovery of the FRDA gene and its possible function has raised hope that rational therapeutic strategies will be developed.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Clinical and genetic study of Friedreich ataxia in an Australian population.

Friedreich ataxia is an autosomal recessive disorder caused by mutations in the FRDA gene that encodes a 210-amino acid protein called frataxin. An expansion of a GAA trinucleotide repeat in intron 1 of the gene is present in more than 95% of mutant alleles. Of the 83 people we studied who have mutations in FRDA, 78 are homozygous for an expanded GAA repeat; the other five patients have an expansion in one allele and a point mutation in the other. Here we present a detailed clinical and genetic study of a subset of 51 patients homozygous for an expansion of the GAA repeat. We found a correlation between the size of the smaller of the two expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity. There was no significant correlation between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms. The larger allele size correlated with bladder symptoms and the presence of foot deformity. The duration of disease is correlated with wheelchair use and the presence of diabetes, scoliosis, bladder symptoms and impaired proprioception, and vibration sense but no other complications studied.

Adolescent↗
PubMed1999

Persistent truncus arteriosus in monozygotic twins: case report and literature review.

We report on a pair of monozygotic twins with persistent truncus arteriosus. They had no evident clinical signs of DiGeorge syndrome. Pathologic examination of the placenta and DNA analysis in chromosomes 7, 8, and 15 was consistent with monozygosity. Fluorescence in situ hybridization test was negative for chromosome 22q11 microdeletion. Family history revealed a female cousin with tetralogy of Fallot. The isolated presence of this conotruncal abnormality in monozygotic twins is extremely rare. The genetic considerations are discussed.

Diseases in Twins↗
PubMed1999

G130V, a common FRDA point mutation, appears to have arisen from a common founder.

Friedreich ataxia (FRDA) is the most common inherited ataxia. About 98% of mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of the affected gene, FRDA. The other 2% are point mutations. Of the 17 point mutations so far described, three appear to be more common. One of these is the G130V mutation in exon 4 of FRDA. G130V, when present with an expanded GAA repeat on the other allele, is associated with an atypical FRDA phenotype. Haplotype analysis was undertaken on the four families who have been described with this mutation. The results suggest a common founder for this mutation. Although marked differences in extragenic marker haplotypes were seen in one family, similar intragenic haplotyping suggests the same mutation founder for this family with the differences explicable by two recombination events.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Directly inherited partial trisomy of chromosome 6p identified in a father and daughter by chromosome microdissection.

Cytogenetic analysis of a 4 year old girl with developmental delay and dysmorphic features showed extra chromosomal material of unknown origin on 20p (46,XX,add(20)(p13)). Familial chromosome studies showed direct inheritance of add(20)(p13) from the father, who had a similar, albeit milder, phenotype. Fibroblast chromosome studies of the father showed no karyotype mosaicism. The additional material could not be identified on the basis of the G banding pattern owing to its small size and ambiguous banding pattern. Chromosome microdissection of the unknown material was performed, the DNA was amplified and labelled using degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR) and reverse painted to the proband's cells to show the karyotype 46,XX,der(20)t(6;20) (p23;p13), conferring partial trisomy 6p and presumed partial monosomy for 20p. Chromosome microdissection has made possible the first reported case of directly inherited partial trisomy 6p.

Child, Preschool↗
PubMed1999

Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia.

Friedreich ataxia (FRDA) is due to mutations in the FRDA gene (FRDA). When the gene homologous to FRDA is knocked out in yeast, there is accumulation of iron in mitochondria and reduced respiratory function. So far, there is only indirect evidence to support the hypothesis that FRDA is due to accumulation of mitochondrial iron leading to increased production of free radicals. We show here that mitochondrial iron is significantly higher in fibroblasts from patients with FRDA than in control fibroblasts. This is the first direct evidence that the findings in yeast are reproducible in cells from patients with FRDA.

Fibroblasts↗
PubMed1998

Trisomy 13 mosaicism at prenatal diagnosis: dilemmas in interpretation.

We describe six cases of trisomy 13 mosaicism detected at prenatal diagnosis. Most level I and level II trisomy 13 mosaicism detected at prenatal diagnosis is pseudomosaicism or confined placental mosaicism. Rarely, low-level mosaicism at chorionic villus sampling or amniocentesis reflects a true fetal mosaicism. In this case, a normal phenotype is a possible, but not a certain, outcome. Genetic counselling is not straightforward.

Adult↗
PubMed1998

The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene.

Most cases of Friedreich ataxia (FRDA) are due to expansions of a GAA trinucleotide repeat sequence in the FRDA gene coding for frataxin, a protein of poorly understood function which may regulate mitochondrial iron transport. However, between 1% and 5% of mutations are single base changes in the sequence of the FRDA gene, causing missense, nonsense, or splicing mutations. We describe three new mutations, IVS4nt2 (T to G), R165C, and L182F, which occur in patients in association with GAA expansions. These cases, and a further five reported cases of point mutations causing FRDA, demonstrate that splicing, nonsense, or initiation codon mutations (which cause a complete absence of functional frataxin) are associated with a severe phenotype. Missense mutations, even in highly evolutionally conserved amino acids, may cause a mild or severe phenotype.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene.

Friedreich ataxia is usually caused by an expansion of a GAA trinucleotide repeat in intron 1 of the FRDA gene. Occasionally, a fully expanded allele has been found to arise from a premutation of 100 or less triplet repeats. We have examined the sperm DNA of a premutation carrier. This man's leucocyte DNA showed one normal allele and one allele of approximately 100 repeats. His sperm showed an expanded allele in a tight range centering on a size of approximately 320 trinucleotide repeats. His affected son has repeat sizes of 1040 and 540. These data suggest that expansion occurs in two stages, the first during meiosis followed by a second mitotic expansion. We also show that in all informative carrier father to affected child transmissions, with the notable exception of the premutation carrier, the expansion size decreases.

Adaptor Proteins, Signal Transducing↗
PubMed1997

A maternally transmitted lethal neonatal progeroid syndrome with prominent genitourinary and gastrointestinal features.

Twin brothers and their maternal uncle with a previously undescribed neonatal progeroid syndrome are presented. In addition to progeroid features, they had pseudo-obstruction of the urinary and gastrointestinal tracts, severe leucocytosis, liver dysfunction, and low complex III and IV in muscle but not in liver. Previously described neonatal progeroid syndromes and syndromes featuring pseudo-obstruction are discussed. The two most likely aetiological mechanisms are an X linked single gene disorder or a mitochondrial disorder. The evidence for these possibilities is presented.

Abnormalities, Multiple↗
PubMedDate not supplied

Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis.

HFE-associated hereditary haemochromatosis is a recessive, iron-overload disorder that affects about one in 200 north Europeans and that can be easily prevented. However, genetic screening for this disease is controversial, and so we assessed whether such screening was suitable for communities. Cheek-brush screening for the Cys282Tyr HFE mutation was offered to individuals in the workplace. Outcomes were assessed by questionnaires before and after testing. 11,307 individuals were screened. We recorded no increase in anxiety in individuals who were homozygous for the Cys282Tyr mutation or non-homozygous. Self-reported tiredness before testing was significantly higher in homozygous participants than in non-homozygous participants (chi2 test, p=0.029). Of the 47 homozygous individuals identified, 46 have taken steps to treat or prevent iron accumulation. Population genetic screening for HFE-associated hereditary haemochromatosis can be practicable and acceptable.

Adult↗