Nayana Lahiri

St George's University Hospitals NHS Foundation Trust & St. George's University, London · Clinical Genetics

Objective: We sought to evaluate outcomes for clinical management following a genetic diagnosis from the Deciphering Developmental Disorders (DDD) Study. Design: Individuals in the DDD study who had a pathogenic/likely pathogenic genotype in the DECIPHER database were selected for inclusion (n=5010). Clinical notes from regional clinical genetics s...

Background Both promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown. Methods We presen...

The association between vascular Ehlers-Danlos Syndrome (vEDS) and amniotic band sequence (ABS) has been previously reported in the literature, mostly in single patient case reports. Here, we aim to extend the current knowledge of this association through a case series of five unrelated individuals with ABS in association with molecularly confirmed...

Background Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in chi...

Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by café-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associate...

Sotos syndrome is an overgrowth‐intellectual disability (OGID) syndrome caused by NSD1 pathogenic variants and characterized by a distinctive facial appearance, an intellectual disability, tall stature and/or macrocephaly. Other associated clinical features include scoliosis, seizures, renal anomalies, and cardiac anomalies. However, many of the pu...

Split-hand–split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500–25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked...

Background Although intermediate alleles (27–35 CAG repeats) do not fall within the range to cause Huntington’s Disease (HD), they are susceptible to paternal germline instability, and so may expand into the reduced penetrance or full mutation range upon transmission to the next generation. The risk of IAs expanding into the HD disease causing rang...

A consistent feature of predictive testing guidelines for Huntington's disease (HD) is the recommendation not to undertake predictive tests on those < 18 years. Exceptions are made but the extent of, and reasons for, deviation from the guidelines are unknown. The UK Huntington's Prediction Consortium has collected data annually on predictive tests...

Background: In Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline...

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and...

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify...

Background Huntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat within the Huntingin gene, with affected individuals inheriting >36 CAG repeats. Intermediate alleles (IAs) are classed as 27–35 CAG repeats. Although IAs do not fall within the disease causing range, they are susceptible to paternal germline instability, and so...

Background A consistent feature of predictive testing guidelines for HD has been recommendations not to undertake predictive tests on those <18 years. However, it is known that exceptions are made. Since 1989 a UK HD Prediction Consortium (UKHPC) has been established to collect data annually on the number of predictive tests which have been underta...

Previous studies have shown activation of the immune system and altered immune response in Huntington's disease (HD) gene carriers. Here, we hypothesized that peripheral and central immune responses could be concurrent pathophysiological events and represent a global innate immune response to the toxic effects of mutant huntingtin in HD gene carrie...

Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding sit...

Background The South West Thames Regional Genetics Service was established at St. George’s Hospital in 1986 and has expanded greatly over the last 25 years. The Regional Genetics Service serves a population of over 3.1 million. The HD service has been provided through monthly specialist clinics at St. George’s and ad-hoc in a number of local distri...

“Genetic counselling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease” (NSGC, 2006). In the 20 years since the discovery of the HD gene, guidelines for predictive testing in Huntington’s disease have become a model for genetic counselling across a wide...

Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by a combination of motor abnormalities (chorea, dystonia, hypokinesia), cognitive impairment and neuropsychiatric symptoms, including depression, irritability and apathy. The age at onset is typically 35–45 years but it can present in juveniles and the elderly.1 The...

Huntington's disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system contributes to Huntington's disease pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant huntingtin expression...

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Both central and peripheral innate immune activation have been described as features of the disease. Isolated human HD monocytes have been shown to produce more cytokines upon LPS stimulation compared to control monocy...

Huntington’s Disease is a progressive, adult onset, neurodegenerative disease. It is inherited in an autosomal dominant fashion and is caused by a trinucleotide repeat expansion in huntingtin, which encodes the protein huntingtin. The length of the expanded trinucleotide repeats accounts for some, but not all of the age of onset of the condition. D...

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophag...

Background: Huntington's Disease (HD) is a hereditary, progressive neurodegenerative disorder characterised by both neurological and systemic symptoms. In HD, immune changes can be observed before the onset of overt clinical features raising the possibility that inflammatory markers in plasma could be used to track disease progression. It has previ...

Background: Huntington's disease is a neurodegenerative disorder characterized by transcriptional alterations both in central and peripheral tissues. Therefore, the identification of a transcriptional signature in an accessible tissue can meaningfully complement current efforts in clinical biomarker development. Gene expression normalization repre...

Background Therapeutic approaches to treat Huntington's disease by lowering mutant (m)HTT levels are expected to proceed to human trials, yet non-invasive quantification of mHTT is not currently possible. The peripheral immune system in neurodegenerative disease is becoming increasingly recognised as important and peripheral immune cells have been...

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Therapeutic approaches to lower mutant HTT (mHTT) levels are expected to proceed to human trials, but noninvasive quantification of mHTT is not currently possible. The importance of the peripheral immune...

Background Huntington's Disease (HD) is a progressive neurodegenerative genetic disorder characterised by motor dysfunction, cognitive decline and psychiatric disturbance. Although HD is not traditionally thought of as an inflammatory disorder, it has been shown that there is a parallel immune activation in CNS and the periphery that can be seen th...

Background Altered innate immune responses are observed in HD, with hyper-reactive central and peripheral immune cells producing increased levels of pro-inflammatory cytokine in HD patients. Bone marrow transplantation studies and KMO inhibitor administration have both shown that the immune system is a modifier of HD progression. However, a mechani...

Hemoglobin released from damaged erythrocytes is a major pro-oxidant, generator of free radicals and inflammatory mediator. Huntington's disease is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities, in which oxidative stress has been suggested as a possible pathogenic mechanism. In the present wor...

Selection of papers about BDNF measure in plasma in different pathological conditions. (XLS)

A) Correlation between BDNF levels in preHD subjects and time to disease onset. B) and C) Semiquantitative RT-PCR analyses of human BDNF mRNA isoforms expression in adult human tissues. cDNA samples were amplified for (B) 35 and (C) 40 cycles. In blood (bl), transcripts were predominately detected from promoter IX, and at very low levels, from prom...

Selection of papers about BDNF measure in serum in different pathological conditions. (XLS)

BDNF ELISA interassay variability. (DOC)

Reduced Brain-Derived Neurotrophic Factor (BDNF) levels have been described in a number of patho-physiological conditions, most notably, in Huntington's disease (HD), a progressive neurodegenerative disorder. Since BDNF is also produced in blood, we have undertaken the measurement of its peripheral levels in the attempt to identify a possible link...

Movement artifacts and other sources of noise are a matter of concern particularly in the neuroimaging research of movement disorders such as Huntington's disease (HD). Using diffusion weighted imaging (DWI) and fractional anisotropy (FA) as a compound marker of white matter integrity, we investigated the effect of movement on HD specific changes i...

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. Immune activation is a well-established feature of the HD brain and we have previously demonstrated a widespread, progressive innate immune response detectable in plasma throughout the course of HD. In the present work...

Huntington's disease (HD) is a devastating, neurodegenerative condition, which lacks effective treatment. Normal Huntingtin (HTT) and mutant Huntingtin (mHTT) are expressed in multiple tissues and can alter transcription of microRNAs (miRs). Importantly, miRs are present in a bio-stable form in human peripheral blood plasma and have recently been s...

Background Huntington's disease (HD) is a fully penetrant dominantly inherited neurodegenerative disease. The aim of this study was to identify sensitive and reliable biomarkers in clinically premanifest HD gene carriers and early HD patients. Methods TRACK-HD is a multinational longitudinal observational study that uses an extensive battery of as...

Background We have previously described an aberrant innate immune response in Huntington's disease (HD) in which proinflammatory cytokines are increased in HD patient brain striatum, plasma and CSF, and mutant htt expressing myeloid cells produce increased interleukin 6 in response to lipopolysaccharide (LPS). This suggests that altered myeloid cel...

Background In previous work, we described an altered innate immune response in Huntington's disease (HD), demonstrating that proinflammatory cytokines such as interleukin (IL)-6 were significantly increased in the striatum and plasma of HD patients. We also reported altered peripheral and CNS myeloid cell function with elevated IL6 production in mu...

A selection of RNA from peripheral blood used in this study.

Protocol for EAR amplification in the human transcriptome.

We describe a novel strategy for mRNA normalization in quantitative real-time polymerase chain reaction (PCR) that is based on expressed Alu repeat amplification as a measure for the mRNA fraction. We show that expressed Alu repeat amplification is a fast, accurate normalization tool that can be successfully used for quantification of selected mRNA...

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean o...

A 56-year-old man with refractory gelastic epilepsy who began listening to Mozart regularly experienced improvement in seizure control.

Autosomal recessive Robinow syndrome is a form of mesomelic dwarfism with multiple rib and vertebral anomalies. Using autozygosity mapping we have identified a genetic locus (RBNW1) for this syndrome at chromosome 9q22 in seven consanguineous families from Oman. Our results indicate that the gene lies within a 4 cM region between markers D9S1836 an...

Autosomal recessive Robinow syndrome is a form of mesomelic dwarfism with multiple rib and vertebral anomalies. Using autozygosity mapping we have identified a genetic locus (RBNW1) for this syndrome at chromosome 9q22 in seven consanguineous families from Oman. Our results indicate that the gene lies within a 4 cM region between markers D9S1836 an...

Background Myocardial perfusion is widely used for risk stratification of patients with suspected or known coronary artery disease (CAD). Recent years have seen an increasing demand for screening of such patients. The value of a normal stress thallium-201 scanning is well established. The advent of technetium 99m-sestamibi single photon emission co...

Myocardial perfusion imaging with Tc-99m sestamibi (MIBI) SPECT is well established for the diagnosis and risk stratification of suspected coronary artery disease (CAD). However, the prognostic value of a negative MIBI scan is less well established. Although short term studies suggest a low incidence of adverse cardiac events in patients who have a...

Despite significant advances in therapy, coronary artery disease is still the leading cause of mortality in the western world. Since the Goteborg metoprolol trial [1], several others have confirmed the beneficial effects of β-blockers in acute myocardial infarction. These range from a 13% reduction in mortality in the first 24 h after early intrave...