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Martin B Delatycki

Publications and source records attributed to Martin B Delatycki.

At least 19 recordsLinked to original sources
PubMed2026

Elucidating the Role of SET as a Key Contributor to Neurodevelopmental Disability Within the 9q34.11 Deletion Syndrome Interval.

The 9q34.11 chromosomal region contains multiple neurodevelopmental genes involved in synaptic transmission, axonal structure and neuronal maturation. Pathogenic microdeletions, duplications and single nucleotide variants in numerous genes were previously linked with neurodevelopmental disorders (NDDs). Amongst them, SET has recently been implicated in a rare NDD with speech delay and facial dysmorphism. This study reports a female with a heterozygous de novo deletion impacting SET but not other NDD-associated genes at 9q34.11. The proband was initially diagnosed with atypical Rett syndrome with overlapping clinical features of SET haploinsufficiency. The deletion was confirmed using microarray and long-read sequencing. Subsequent quantitative proteomic evaluation identified a significant decrease of SET protein in patient-derived fibroblasts compared to control lines. This study provides insights into the proband's clinical course over their 28 year diagnostic odyssey, and emphasises the benefits of early speech therapy interventions. The proband had no functional speech, but regained the capacity to meaningfully communicate and articulate a limited vocabulary in adulthood, concordant with other reported non-paediatric cases of SET-NDD. This study expands current knowledge on the genotypic and phenotypic spectra of SET-NDD, and pinpoints a smaller 9q34.11 critical region excluding upstream NDD-associated genes, STXBP1 and SPTAN1, implicating SET as a significant NDD-associated gene.

Humans↗
PubMed2024

Offering complex genomic screening in acute pediatric settings: Family decision-making and outcomes.

PURPOSE: Families of children in pediatric acute care who are offered ultrarapid genomic sequencing are making complex decisions during a high-stress period. To reduce complexity for families and clinicians, we offered genomic screening for the child and parents after the completion of diagnostic testing. We evaluated uptake, understanding, and service delivery preferences. METHODS: A cohort of 235 families who had completed ultrarapid diagnostic genomic sequencing at 17 Australian hospitals were offered up to 3 screens on their genomic data: pediatric-onset, adult-onset, and expanded couple carrier screening. We investigated decision making, understanding, and service delivery preferences using surveys at 3 time points (pre counseling, post counseling, and post result) and performed inductive content analysis of pretest genetic counseling transcripts. RESULTS: A total of 119 families (51%) attended genetic counseling with 115 (49%) accepting genomic screening. Survey respondents were more likely to find decisions about couple carrier screening easy (87%) compared with adult (68%; P = .002) or pediatric (71%; P = .01) screening decisions. All respondents with newly detected pathogenic variants accurately recalled this 1 month later. A delayed offer of screening was acceptable to most respondents (78%). CONCLUSION: Separating genomic screening from the stressful diagnostic period is supported by families who demonstrate good knowledge and recall. Our results suggest delaying genomic screening should be trialed more widely.

Humans↗
PubMed2006

Towards an understanding of cognitive function in Friedreich ataxia.

There is limited documentation regarding cognitive function in individuals with Friedreich ataxia (FRDA), possibly because FRDA is widely held to predominantly affect the spinal cord, peripheral sensory nerves and cerebellum and not to affect cognition. Traditionally, the cerebellum has been thought to coordinate voluntary movement and motor tone, posture and gait. However, recent studies have implicated the cerebellum in a range of cognitive functions including executive function, visuospatial organisation and memory. We review the available data on cognitive function and neuroimaging in FRDA and the role of the cerebellum in cognitive function. We conclude with recommendations for future research including correlating cognitive function in individuals with FRDA with possible determinants of disease severity, such as age of onset and the causative genetic mutation.

Cerebellum↗
PubMed2006

It's "back to school" for genetic screening.

Implementation of population genetic screening programmes requires consideration of strategies for reaching the greatest proportion of the target population in order to achieve maximum awareness. This article reviews the current strategy of school-based population genetic screening programmes. The school environment is an ideal setting for offering relevant genetic screening programmes as it provides an opportunity to engage people at a time when they are exposed to a range of educational experiences and are sufficiently mature to be involved in decision-making processes. Such programmes allow all students, not only those studying biology, an opportunity to be educated and experience genetic screening in a supportive environment, ultimately increasing understanding and empowering students. While the major form of genetic screening in schools has been for reproductive health information (eg carrier screening for TaySachs disease and cystic fibrosis), genetic screening in schools for other conditions may be a timely proposition.

Australia↗
PubMed2006

Fifteen years of experience in predictive testing for Huntington disease at a single testing center in Victoria, Australia.

PURPOSE: This retrospective study describes 15 years of experience in predictive testing for Huntington disease at a single center in Victoria, Australia. METHOD: Data collected on 756 participants included age, gender, family history, prior risk and the age at which this risk became known, exposure to Huntington disease, number of children, and proximity to the testing center. RESULTS: Some 57.8% of participants were female, and 88.8% had a 50% risk of developing Huntington disease. The mean age at entry was 40.4 years and was gender-independent. Of all completed tests (n = 648), 37.5% gave high-risk results, and 3.2% were in the zone of reduced penetrance. The 14.3% who withdrew from testing tended to be younger and childless, lacked exposure to severe Huntington disease, and more often at 25% or less risk. Some 32.4% of candidates presented for testing within 1 year of becoming aware of their risk, and most of these individuals had little or no exposure to severe Huntington disease. Those whose exposure was considerable waited on average for more than 13 years. Among the most inexperienced candidates were a group of "adoptees" (raised away from their biological family). Maternal transmission was the source of risk for 19 of 20 adoptees. CONCLUSION: This study illustrates the significance of exposure to Huntington disease and its impact on the timing of testing.

Adolescent↗
PubMed2006

Long-term survival in a child with severe congenital contractural arachnodactyly, autism and severe intellectual disability.

The severe form of congenital contractural arachnodactyly is usually associated with early mortality due to multisystem complications. Here, we report a 9-year-old male child with severe skeletal manifestations of congenital contractural arachnodactyly. He had none of the cardiovascular or gastrointestinal features that have been described in severe congenital contractural arachnodactyly. He had profound intellectual disability with autism. All exons of FBN2, the gene associated with congenital contractural arachnodactyly, were sequenced and no disease-causing mutation was found. When severe congenital contractural arachnodactyly is diagnosed in the newborn period, parents need to be aware that long-term survival is possible, particularly if no significant extraskeletal complications are present, and that significant neurodevelopmental delay may occur.

Arachnodactyly↗
PubMed2005

A de novo, apparently balanced reciprocal translocation in a child with developmental delay whose mother was being treated with low-dose methotrexate at the time of conception.

BACKGROUND: Methotrexate is a proven teratogen and its use periconceptually is strongly advised against. Concerns about possible chromosomal effects in the offspring of women treated with this agent have been raised, but they have not been reported. In vivo and in vitro studies have supported this possibility, however. CASE: A 32-year-old primigravida was treated with low-dose methotrexate for rheumatoid arthritis from prior to conception until six weeks postconception. Her child was born without congenital malformations but subsequently developed seizures and was diagnosed with developmental delay. He was found to have a de novo, apparently balanced, reciprocal translocation between chromosomes 5 and 20 (46,XY,t(5:20)(q15;p12)). Other investigations failed to reveal another cause for his developmental delay. CONCLUSIONS: The possible association between maternal methotrexate exposure and a de novo chromosomal anomaly in an offspring supports the recommendation that women should be advised to cease taking this drug for at least six months prior to conception.

Adult↗
PubMed2005

Surgery for equinovarus deformity in Friedreich's ataxia improves mobility and independence.

UNLABELLED: Friedreich's ataxia results in morbidity because of many factors; progressive equinovarus deformity is one of these. We studied the risk factors and incidence of this deformity. We sought to assess whether surgical management of fixed equinovarus deformity leads to functional improvement. Thirty-six patients with Friedrich's ataxia were assessed for this deformity. These patients were treated by splinting, botulinum toxin Type A injection, and surgery, as indicated by the severity, followed by an ongoing rehabilitation program. The effect of surgery was assessed using subscales of the Barthel index and functional independence measure. Severe foot deformities in which either surgery or botulinum toxin injection was recommended correlated with current age, years since disease onset, and years that the patient required a wheelchair for mobility, but not with the GAA repeat size or age at disease onset. Function and mobility were improved after surgery compared with a similar period before surgery. Three of seven patients who had surgery had significant complications. Aggressive management of foot deformities should be considered, and active measures to prevent permanent foot deformities should be pursued to maximize quality of life and independence of patients with Friedreich's ataxia. LEVEL OF EVIDENCE: Therapeutic study, Level IV (case series-no, or historical control group).

Activities of Daily Living↗
PubMed2005

Novel ophthalmological features in hereditary endotheliopathy with retinopathy, nephropathy and stroke syndrome.

The ophthalmic features are reported of a member of an Australian pedigree with three affected individuals spanning two generations with a hereditary endotheliopathy syndrome resulting in retinopathy, leukoencephalopathy and nephropathy. The index case initially presented with asymptomatic retinopathy, cerebral microvascular disease, nephropathy and raised inflammatory markers. The clinical, neuro-radiological, biochemical and histopathological findings in this patient are consistent with a diagnosis of hereditary endotheliopathy, retinopathy, nephropathy and stroke (HERNS). Linkage analysis has identified a locus for HERNS on chromosome 3p21.1-p21.3. This locus is shared with two other diseases: hereditary vascular retinopathy (HVR) and cerebroretinal vasculopathy (CRV). Although peripheral retinal involvement is a feature of HVR, it has not previously been described in HERNS. This case represents a novel phenotype of HERNS, and serves to blur the distinction between the vasculopathies mapping to chromosome 3p21. Although previously thought to be distinct clinical entities, it is possible that HERNS, HVR and CRV simply represent different phenotypes of the same disease. This will only be clarified with the identification of the gene or genes. This case also raises the question of how best to manage rare forms of vascular retinopathy.

Adult↗
PubMed2004

Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia.

Friedreich ataxia is caused by the expansion of a polymorphic and unstable GAA triplet repeat in the FRDA gene, but the mechanisms for its instability are poorly understood. Replication of (GAA*TTC)n sequences (9-105 triplets) in plasmids propagated in Escherichia coli displayed length- and orientation-dependent instability. There were small length variations upon replication in both orientations, but large contractions were frequently observed when GAA was the lagging strand template. DNA replication was also significantly slower in this orientation. To evaluate the physiological relevance of our findings, we analyzed peripheral leukocytes from human subjects carrying repeats of similar length (8-107 triplets). Analysis of 9400 somatic FRDA molecules using small-pool PCR revealed a similar mutational spectrum, including large contractions. The threshold length for the initiation of somatic instability in vivo was between 40 and 44 triplets, corresponding to the length of a eukaryotic Okazaki fragment. Consistent with the stabilization of premutation alleles during germline transmission, we also found that instability of somatic cells in vivo and repeats propagated in E.coli were abrogated by (GAGGAA)n hexanucleotide interruptions. Our data demonstrate that the GAA triplet repeat mutation in Friedreich ataxia is destabilized, frequently undergoing large contractions, during DNA replication.

DNA↗
PubMed2004

Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation.

Nonsyndromic X-linked mental retardation (NSXLMR) is a very heterogeneous condition, and most of the underlying gene defects are still unknown. Recently, we have shown that approximately 30% of these genes cluster on the proximal Xp, which prompted us to perform systematic mutation screening in brain-expressed genes from this region. Here, we report on a novel NSXLMR gene, FTSJ1, which harbors mutations in three unrelated families--one with a splicing defect, one with a nonsense mutation, and one with a deletion of one nucleotide. In two families, subsequent expression studies showed complete absence or significant reduction of mutant FTSJ1 transcripts. FTSJ1 protein is a homolog of Escherichia coli RNA methyltransferase FtsJ/RrmJ and may play a role in the regulation of translation. Further studies aim to elucidate the function of human FTSJ1 and its role during brain development.

Adult↗
PubMed2004

Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles.

Friedreich ataxia patients are homozygous for expanded GAA triplet-repeats containing 66 to 1,700 triplets. We report two patients with delayed-onset, hyperreflexia and gradually progressive disease. Both were heterozygous for large expansions and also carried alleles with 44 and 66 triplet-repeats, respectively. Due to somatic instability, 15% (GAA-44) and 75% (GAA-66) of cells contained alleles with >/=66 triplet-repeats, constituting a plausible mechanism for their mild phenotype. A sibling with a stable GAA-37 allele and a large expansion was clinically normal. Instability of borderline alleles confers a risk for Friedreich ataxia, and the range of pathogenic alleles is broader than previously recognized.

Alleles↗
PubMed2004

Hereditary hemochromatosis genetic testing of at-risk children: what is the appropriate age?

The objective of this study was to consider the objective evidence and ethical arguments for the appropriate age to test children at risk of developing hereditary hemochromatosis. A literature search for information on iron overload in children, onset of disease expression for hemochromatosis, and recommendations for age of cascade screening was undertaken. We examined the objective evidence and arguments for testing in early childhood and those for delaying testing until later teenage years. Cascade testing of offspring of people with hemochromatosis is widely advocated because it is an easily preventable disease. The ideal age to test those offspring is a matter of debate. Some authorities advocate testing at a very young age whereas others recommend delaying testing until late teenage years. To date there has been no published overview of the objective evidence and arguments central to this debate. In children who are C282Y homozygous, iron overload is rare in the first two decades of life and associated morbidity has only been documented in 1 patient. In the cascade setting, genetic testing for hemochromatosis need not be offered until late teenage years.

Adolescent↗
PubMed2003

Friedreich ataxia-update on pathogenesis and possible therapies.

Friedreich ataxia is the most-common inherited ataxia. Since the causative genetic basis was described in 1996, much has been learnt about the pathogenesis from human, animal, and yeast studies. This has led to the development of rational therapeutic approaches. In this review, the current state of knowledge regarding the pathogenesis of Friedreich ataxia is presented and possible therapeutic strategies based on this knowledge are discussed.

Animals↗
PubMed2003

Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families.

CDMP-1, a cartilage-specific member of the TGFss superfamily of secreted signaling molecules, plays a key role in chondrogenesis, growth and patterning of the developing vertebrate skeleton. Homozygous CDMP-1 mutations cause Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia and DuPan syndrome in humans, as well as brachypodism in mice, while heterozygous mutations cause brachydactyly type C (BDC). We present clinical and radiographic data from three unrelated families in which 12 members share the same heterozygous CDMP-1 mutation, an insertion (insG206), resulting in a frameshift predicted to cause functional haploinsufficiency. Although eight mutation carriers display BDC, four have normal hands and feet, confirming nonpenetrance of BDC with CDMP-1 mutations. In addition, several carriers have other skeletal abnormalities, including severe bilateral vertical talus (in two), developmental hip dysplasia (in one), and short stature (in two, who are otherwise unaffected). Premature vertebral end-plate disease was observed in four mutation carriers and was associated with spondylolysis and spondylolisthesis in three of these. Axial skeletal involvement has not been previously reported in association with CDMP-1 mutations. This finding is consistent with CDMP-1 expression in human hypertrophic chondrocytes, which are present in the ring epiphyses of vertebral end plates. Phenotypic variation in BDC has previously been attributed either to locus heterogeneity or to the varied functional effects of different CDMP-1 mutations. The remarkable range of phenotypes caused by this identical CDMP-1 mutation in these families emphasizes the crucial role of genetic background, stochastic variation and/or environmental factors in modifying the observed phenotype. Our findings illustrate that nonpenetrance for the typical features of BDC can be appreciable and that atypical skeletal features that have been reported in some patients with BDC (i.e., clubfoot, short stature, spondylolysis) may also result from CDMP-1 mutation.

Bone Diseases↗