Lakshminarayan Ranganath - Academia.edu (original) (raw)

Papers by Lakshminarayan Ranganath

Research paper thumbnail of Metabolomic analysis of bone resorption in vitro provides new insights into osteoclastic action and reveals novel biomarkers

Research paper thumbnail of Knockdown of cathepsin Z by siRNAs is associated with reduced cell invasion in osteosarcoma cells

Research paper thumbnail of New Lessons From An Old Disease - What Alkaptonuria Teaches Us About Cartilage and Bone Remodelling

Research paper thumbnail of Cathepsin Z as a novel potential biomarker for osteoporosis

Scientific Reports, 2019

Osteoporosis, one of the most prevalent chronic ageing-related bone diseases, often goes undetect... more Osteoporosis, one of the most prevalent chronic ageing-related bone diseases, often goes undetected until the first fragility fracture occurs, causing patient suffering and cost to health/social care services. Osteoporosis arises from imbalanced activity of osteoclasts and osteoblasts. Since these cell lineages produce the protease, cathepsin Z, the aim of this study was to investigate whether altered cathepsin Z mRNA levels are associated with osteoporosis in clinical samples. Cathepsin Z mRNA in human peripheral blood mononuclear cells was significantly differentially-expressed among non-osteoporotic controls, osteopenia and osteoporosis patients (p < 0.0001) and in female osteoporosis patients over the age of 50 years (P = 0.0016). Cathepsin Z mRNA level strongly correlated with low bone mineral density (BMD) (g/cm2), lumbar spine L2-L4 and femoral neck (T-scores) (P = 0.0149, 0.0002 and 0.0139, respectively). Importantly, cathepsin Z mRNA was significantly associated with fra...

Research paper thumbnail of Reduction of frontal plane knee load caused by lateral trunk lean depends on step width

Gait & posture, 2018

The internal knee abduction moment (KAM) in osteoarthritis is reduced by increased lateral trunk ... more The internal knee abduction moment (KAM) in osteoarthritis is reduced by increased lateral trunk lean (TL). Mechanistically, this occurs as the Centre of Mass (COM) moves further over the stance leg. Since the size of the base of support constrains the COM, an associated increase in step width (SW) would be expected to maintain stability. This study tested the effects of TL on SW and KAM in healthy participants (n = 21) who performed normal and 6° TL walks. The latter was controlled via audio-visual biofeedback. We found two distinct gait strategies in TL walk: widening the step width substantially (>50%) to permit an increase in the COM displacement (WSW, n = 13), or maintaining a baseline SW and minimally displacing the COM by moving the hip/pelvic complex in the opposite direction (NSW, n = 8). WSW doubled SW (11.3 ± 2.4 v. 24.7 ± 5.5 cm, p < .0001), NSW did not change SW (12.2 ± 2.8 v. 13.7 ± 4.7 cm, p > .05). These two distinct gait strategies resulted in unique patter...

Research paper thumbnail of Identification of high density mineralised protrusions in human knees ex-vivo and in-situ by clinical scanning techniques

Osteoarthritis and Cartilage, 2016

Research paper thumbnail of Circulating microRNAs as Potential Diagnostic Biomarkers and Therapeutic Targets in Gastric Cancer: Current Status and Future Perspectives

Current Medicinal Chemistry, 2016

Research paper thumbnail of Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on ‘black bone disease’ in Italy

European Journal of Human Genetics, 2015

Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-di... more Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T4A), Slovakia (c.500C4T) and France (c.440T4C), three in patients from India (c.469+6T4C, c.650-85A4G, c.158G4A), and six in patients from Italy (c.742A4G, c.614G4A, c.1057A4C, c.752G4A, c.119A4C, c.926G4T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.

Research paper thumbnail of Identification of an extraordinary bone phenotype in a patient with alkaptonuria

Frontiers in Endocrinology, 2011

Research paper thumbnail of Nutrient Regulation of Post-Heparin Lipoprotein Lipase Activity in Obese Subjects

Hormone and Metabolic Research, 2001

This study examines the immediate effect of ingestion of oral carbohydrate and fat on lipoprotein... more This study examines the immediate effect of ingestion of oral carbohydrate and fat on lipoprotein lipase (LPL) activity post-heparin in six lean and six obese age-matched women. Subjects were given, on two separate occasions, 340 kcal carbohydrate or an equicaloric amount of fat, both in 300 ml of water. Post-heparin LPL activity (10,000 U) was measured on each occasion 120 minutes after ingestion of the meal. Following oral carbohydrate postprandial plasma insulin levels were significantly higher in obese subjects than in lean (p &lt; 0.01). Impaired glucose tolerance was seen in the obese group. GIP secretion was similar in lean and obese subjects both during oral fat and carbohydrate ingestion. GLP-1 secretion post-carbohydrate was lower in obese subjects. Total LPL activity unadjusted for body weight was similar in the two groups after carbohydrate administration but was significantly lower when adjusted per kg body weight. Total LPL activity was lower in the lean group at 130 minutes after fat administration (p &lt; 0.02). Fasting serum triglycerides were higher in the obese group and were inversely related to the post-carbohydrate LPL activity (r = - 0.65, p &lt; 0.02). Intraluminal lipoprotein lipase activity is not increased in established obesity. Fat and carbohydrate nutrients may affect LPL activity differently in lean and obese subjects.

Research paper thumbnail of A patient survey on the impact of alkaptonuria symptoms as perceived by the patients and their experiences of receiving diagnosis and care

JIMD Reports, 2020

BackgroundAlkaptonuria (AKU) is an ultrarare and multifaceted disease characterized by the absenc... more BackgroundAlkaptonuria (AKU) is an ultrarare and multifaceted disease characterized by the absence of functional homogentisate 1,2‐dioxygenase activity, the enzyme responsible for breakdown of homogentisic acid—a tyrosine‐degradation product. The presymptomatic phase of the disease makes diagnosis difficult, with many patients unidentified or diagnosed late in life.ObjectiveTo date, no study has analyzed the perceived impact of different symptoms or the experiences of individuals through the patient journey in the context of AKU. This study aimed to examine patients' perceptions of AKU symptoms and their impact on quality of life as well as patients' experiences of being diagnosed and living with the disease.MethodsData for this study were collected using a quantitative self‐report questionnaire administered online to people with AKU.ResultsData from 45 participants indicate that symptoms with the highest impact for patients are those related to pain and ruptures, disability...

Research paper thumbnail of Analysis of cartilage biomarkers of aging and turnover in the osteoarthropathy of alkaptonuria

Osteoarthritis and Cartilage, 2015

Research paper thumbnail of Recent advances in understanding the pathogenesis of ochronosis

Reumatologia, 2012

Alkaptonuria (AKU) is an iconic disease caused by deficiency of the enzyme homogentisate 1,2-diox... more Alkaptonuria (AKU) is an iconic disease caused by deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD). Deficiency results in an increase in the circulating concentration of homogentisic acid (HGA), which over time is deposited as pigmented polymers in tissues including sclera, heart valves and cartilage, a process described as ochronosis. Joint ochronosis causes severe, early onset osteoarthritis. Studies on ex vivo tissue samples, in vitro cell cultures and mouse models of AKU indicate that tissues are initially resistant to ochronosis and become susceptible possibly following mechanical or oxidative damage and/or local metabolic changes. There is a lack of effective biomarkers to monitor the progression of ochronosis and response to potential therapies but a disease severity index for AKU has recently been developed. Current studies are evaluating the efficacy of the potential therapy nitisinone in AKU. Research on ochronosis has led to the identification of several previ...

Research paper thumbnail of Recent advances in understanding the pathogenesis of ochronosis : Najnowsze postępy w zrozumieniu patogenezy ochronozy

Alkaptonuria (AKU) is an iconic disease caused by deficiency of the enzyme homogentisate 1,2-diox... more Alkaptonuria (AKU) is an iconic disease caused by deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD). Deficiency results in an increase in the circulating concentration of homogentisic acid (HGA), which over time is deposited as pigmented polymers in tissues including sclera, heart valves and cartilage, a process described as ochronosis. Joint ochronosis causes severe, early onset osteoarthritis. Studies on ex vivo tissue samples, in vitro cell cultures and mouse models of AKU indicate that tissues are initially resistant to ochronosis and become susceptible possibly following mechanical or oxidative damage and/or local metabolic changes. There is a lack of effective biomarkers to monitor the progression of ochronosis and response to potential therapies but a disease severity index for AKU has recently been developed. Current studies are evaluating the efficacy of the potential therapy nitisinone in AKU. Research on ochronosis has led to the identification of several previ...

Research paper thumbnail of Adipocytic Templating of Bone Matrix Deposition in Osteoarthropathies

The FASEB Journal, 2015

Alkaptonuria (AKU), the first human disorder recognised to conform to Mendelian inheritance, is a... more Alkaptonuria (AKU), the first human disorder recognised to conform to Mendelian inheritance, is accompanied by early onset, rapidly progressing osteoarthropathy. Novel anatomical and microanatomica...

Research paper thumbnail of Alkaptonuria Severity Score Index Revisited: Analysing the AKUSSI and Its Subcomponent Features

JIMD Reports

BACKGROUND Alkaptonuria (AKU) is a rare disorder with no licensed treatment; nitisinone may reduc... more BACKGROUND Alkaptonuria (AKU) is a rare disorder with no licensed treatment; nitisinone may reduce symptoms and progression. The All Alkaptonuria Severity Score Index (AKUSSI) measures disease severity in clinical, joint and spine domains, with 57 subcomponent feature scores. Our primary aim was to assess tools for validating scores such as the AKUSSI by detecting relationships between features both before and during nitisinone treatment. METHODS AKUSSI measurements from nitisinone-treated patients visiting the National AKU Centre between 01-Jun-2012 and 31-May-2016 were analysed pre-treatment, at first treatment and annually to Year 3 post-treatment. Principal component analysis (PCA) and redundancy analysis assessed whether any AKUSSI features contributed little information to the overall score. RESULTS 65 AKU patients were included: 17 with a pre-treatment AKUSSI measurement (10 later received nitisinone) and 48 with a first measurement at their first treatment visit. In PCA, the first four principal components (PC1-PC4) explained ≥50% of AKUSSI variance at all visits (54.1-87.3%). Some features regularly dominated their domain's PC1: ears, aortic sclerosis, and nasal/temporal eye scores (clinical), pain-related scores (joint) and cervical, lumbar and thoracic spine scores (spine). Only the right-hand/wrist score was consistently redundant. Right eye (nasal) and left ear scores were redundant pre-treatment, potentially correlating with other dominant clinical PC1 features. CONCLUSIONS PCA and redundancy analysis supported the AKUSSI as a robust AKU disease severity measure, although some AKUSSI features could be removed for simplicity. For small patient populations and rare diseases, PCA and redundancy analysis together can aid validation of disease severity metrics.

Research paper thumbnail of Vitiligo, alkaptonuria, and nitisinone—A report of three families and review of the literature

JIMD Reports

Four patients, from three families, with alkaptonuria receiving 4‐hydroxyphenylpyruvate dioxygena... more Four patients, from three families, with alkaptonuria receiving 4‐hydroxyphenylpyruvate dioxygenase‐inhibiting nitisinone therapy, which lowers homogentisic acid and increases tyrosine, developed vitiligo. Three of the four patients were receiving nitisinone 2 mg daily, while the fourth was on 10 mg daily. All four patients were either receiving or had received transiently proton‐pump inhibitors as therapy for dyspepsia. The ages of the patients were 35, 42, 40, and 67 years, respectively. Three patients were men and one was a woman. All four patients were either taking a proton‐pump inhibitor or had been taking one at some point. Three of the four were of South Asian and one of Caucasian background. The three patients with South Asian background also had either a personal or family history of autoimmune disease. Distressing vitiligo, initially in an acrofacial distribution, developed unexpectedly in these four patients, before then progressing to involve other parts of the body. Potential factors in the appearance of vitiligo in this setting, including nitisinone and other drug therapy, are explored and responses to the appearance of vitiligo are discussed.

Research paper thumbnail of The contribution of mouse models in the rare disease alkaptonuria

Drug Discovery Today: Disease Models

Alkaptonuria is an ultra-rare autosomal recessive disorder of tyrosine metabolism, whereby the ho... more Alkaptonuria is an ultra-rare autosomal recessive disorder of tyrosine metabolism, whereby the homogentisate 1,2-dioxygenase (HGD) enzyme is deficient, causing an elevation of its substrate homogentisic acid (HGA). Overtime, elevated HGA causes connective tissue ochronosis, leading to a severe and early onset osteoarthropathy. The use of HGD deficient mouse models in this metabolic bone disease have provided the opportunity to investigate AKU pathophysiology and potential treatments. An ENU mutagenesis AKU mouse model (BALB/c Hgd−/−) provided the means to explore the onset of pigmentation in cartilage and treatment of AKU with nitisinone, an inhibitor of the upstream enzyme forming HGA. This work provided evidence that nitisinone could not only lower circulating HGA, but could also prevent ochronosis and halt disease progression, leading to its off-label use at the National Alkaptonuria Centre (Liverpool, UK) and its subsequent testing in human clinical trials (DevelopAKUre). Recently, a new targeted AKU mouse model (Hgd tm1a−/−, C57BL/6) has been established, offering a LacZ reporter gene for localising gene expression and LoxP and FRT sites that enabled generation of an inducible and liver-specific HGD knockout model (Hgd tm1d MxCre+/−). This conditional model determined the importance of the liver as a target organ for future gene/enzyme replacement therapies in AKU. The contribution of AKU mouse models has clearly accelerated the treatment and knowledge of this rare disease, and will continue to be used.

Research paper thumbnail of Initiation and progression of ochronotic osteoarthropathy in alkaptonuric mice

Osteoarthritis and Cartilage, 2013

Research paper thumbnail of WITHDRAWN: A protective effect in females with alkaptonuria: Relationships between gait deviations and ochronosis

Research paper thumbnail of Metabolomic analysis of bone resorption in vitro provides new insights into osteoclastic action and reveals novel biomarkers

Research paper thumbnail of Knockdown of cathepsin Z by siRNAs is associated with reduced cell invasion in osteosarcoma cells

Research paper thumbnail of New Lessons From An Old Disease - What Alkaptonuria Teaches Us About Cartilage and Bone Remodelling

Research paper thumbnail of Cathepsin Z as a novel potential biomarker for osteoporosis

Scientific Reports, 2019

Osteoporosis, one of the most prevalent chronic ageing-related bone diseases, often goes undetect... more Osteoporosis, one of the most prevalent chronic ageing-related bone diseases, often goes undetected until the first fragility fracture occurs, causing patient suffering and cost to health/social care services. Osteoporosis arises from imbalanced activity of osteoclasts and osteoblasts. Since these cell lineages produce the protease, cathepsin Z, the aim of this study was to investigate whether altered cathepsin Z mRNA levels are associated with osteoporosis in clinical samples. Cathepsin Z mRNA in human peripheral blood mononuclear cells was significantly differentially-expressed among non-osteoporotic controls, osteopenia and osteoporosis patients (p < 0.0001) and in female osteoporosis patients over the age of 50 years (P = 0.0016). Cathepsin Z mRNA level strongly correlated with low bone mineral density (BMD) (g/cm2), lumbar spine L2-L4 and femoral neck (T-scores) (P = 0.0149, 0.0002 and 0.0139, respectively). Importantly, cathepsin Z mRNA was significantly associated with fra...

Research paper thumbnail of Reduction of frontal plane knee load caused by lateral trunk lean depends on step width

Gait & posture, 2018

The internal knee abduction moment (KAM) in osteoarthritis is reduced by increased lateral trunk ... more The internal knee abduction moment (KAM) in osteoarthritis is reduced by increased lateral trunk lean (TL). Mechanistically, this occurs as the Centre of Mass (COM) moves further over the stance leg. Since the size of the base of support constrains the COM, an associated increase in step width (SW) would be expected to maintain stability. This study tested the effects of TL on SW and KAM in healthy participants (n = 21) who performed normal and 6° TL walks. The latter was controlled via audio-visual biofeedback. We found two distinct gait strategies in TL walk: widening the step width substantially (>50%) to permit an increase in the COM displacement (WSW, n = 13), or maintaining a baseline SW and minimally displacing the COM by moving the hip/pelvic complex in the opposite direction (NSW, n = 8). WSW doubled SW (11.3 ± 2.4 v. 24.7 ± 5.5 cm, p < .0001), NSW did not change SW (12.2 ± 2.8 v. 13.7 ± 4.7 cm, p > .05). These two distinct gait strategies resulted in unique patter...

Research paper thumbnail of Identification of high density mineralised protrusions in human knees ex-vivo and in-situ by clinical scanning techniques

Osteoarthritis and Cartilage, 2016

Research paper thumbnail of Circulating microRNAs as Potential Diagnostic Biomarkers and Therapeutic Targets in Gastric Cancer: Current Status and Future Perspectives

Current Medicinal Chemistry, 2016

Research paper thumbnail of Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on ‘black bone disease’ in Italy

European Journal of Human Genetics, 2015

Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-di... more Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T4A), Slovakia (c.500C4T) and France (c.440T4C), three in patients from India (c.469+6T4C, c.650-85A4G, c.158G4A), and six in patients from Italy (c.742A4G, c.614G4A, c.1057A4C, c.752G4A, c.119A4C, c.926G4T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.

Research paper thumbnail of Identification of an extraordinary bone phenotype in a patient with alkaptonuria

Frontiers in Endocrinology, 2011

Research paper thumbnail of Nutrient Regulation of Post-Heparin Lipoprotein Lipase Activity in Obese Subjects

Hormone and Metabolic Research, 2001

This study examines the immediate effect of ingestion of oral carbohydrate and fat on lipoprotein... more This study examines the immediate effect of ingestion of oral carbohydrate and fat on lipoprotein lipase (LPL) activity post-heparin in six lean and six obese age-matched women. Subjects were given, on two separate occasions, 340 kcal carbohydrate or an equicaloric amount of fat, both in 300 ml of water. Post-heparin LPL activity (10,000 U) was measured on each occasion 120 minutes after ingestion of the meal. Following oral carbohydrate postprandial plasma insulin levels were significantly higher in obese subjects than in lean (p &lt; 0.01). Impaired glucose tolerance was seen in the obese group. GIP secretion was similar in lean and obese subjects both during oral fat and carbohydrate ingestion. GLP-1 secretion post-carbohydrate was lower in obese subjects. Total LPL activity unadjusted for body weight was similar in the two groups after carbohydrate administration but was significantly lower when adjusted per kg body weight. Total LPL activity was lower in the lean group at 130 minutes after fat administration (p &lt; 0.02). Fasting serum triglycerides were higher in the obese group and were inversely related to the post-carbohydrate LPL activity (r = - 0.65, p &lt; 0.02). Intraluminal lipoprotein lipase activity is not increased in established obesity. Fat and carbohydrate nutrients may affect LPL activity differently in lean and obese subjects.

Research paper thumbnail of A patient survey on the impact of alkaptonuria symptoms as perceived by the patients and their experiences of receiving diagnosis and care

JIMD Reports, 2020

BackgroundAlkaptonuria (AKU) is an ultrarare and multifaceted disease characterized by the absenc... more BackgroundAlkaptonuria (AKU) is an ultrarare and multifaceted disease characterized by the absence of functional homogentisate 1,2‐dioxygenase activity, the enzyme responsible for breakdown of homogentisic acid—a tyrosine‐degradation product. The presymptomatic phase of the disease makes diagnosis difficult, with many patients unidentified or diagnosed late in life.ObjectiveTo date, no study has analyzed the perceived impact of different symptoms or the experiences of individuals through the patient journey in the context of AKU. This study aimed to examine patients' perceptions of AKU symptoms and their impact on quality of life as well as patients' experiences of being diagnosed and living with the disease.MethodsData for this study were collected using a quantitative self‐report questionnaire administered online to people with AKU.ResultsData from 45 participants indicate that symptoms with the highest impact for patients are those related to pain and ruptures, disability...

Research paper thumbnail of Analysis of cartilage biomarkers of aging and turnover in the osteoarthropathy of alkaptonuria

Osteoarthritis and Cartilage, 2015

Research paper thumbnail of Recent advances in understanding the pathogenesis of ochronosis

Reumatologia, 2012

Alkaptonuria (AKU) is an iconic disease caused by deficiency of the enzyme homogentisate 1,2-diox... more Alkaptonuria (AKU) is an iconic disease caused by deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD). Deficiency results in an increase in the circulating concentration of homogentisic acid (HGA), which over time is deposited as pigmented polymers in tissues including sclera, heart valves and cartilage, a process described as ochronosis. Joint ochronosis causes severe, early onset osteoarthritis. Studies on ex vivo tissue samples, in vitro cell cultures and mouse models of AKU indicate that tissues are initially resistant to ochronosis and become susceptible possibly following mechanical or oxidative damage and/or local metabolic changes. There is a lack of effective biomarkers to monitor the progression of ochronosis and response to potential therapies but a disease severity index for AKU has recently been developed. Current studies are evaluating the efficacy of the potential therapy nitisinone in AKU. Research on ochronosis has led to the identification of several previ...

Research paper thumbnail of Recent advances in understanding the pathogenesis of ochronosis : Najnowsze postępy w zrozumieniu patogenezy ochronozy

Alkaptonuria (AKU) is an iconic disease caused by deficiency of the enzyme homogentisate 1,2-diox... more Alkaptonuria (AKU) is an iconic disease caused by deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD). Deficiency results in an increase in the circulating concentration of homogentisic acid (HGA), which over time is deposited as pigmented polymers in tissues including sclera, heart valves and cartilage, a process described as ochronosis. Joint ochronosis causes severe, early onset osteoarthritis. Studies on ex vivo tissue samples, in vitro cell cultures and mouse models of AKU indicate that tissues are initially resistant to ochronosis and become susceptible possibly following mechanical or oxidative damage and/or local metabolic changes. There is a lack of effective biomarkers to monitor the progression of ochronosis and response to potential therapies but a disease severity index for AKU has recently been developed. Current studies are evaluating the efficacy of the potential therapy nitisinone in AKU. Research on ochronosis has led to the identification of several previ...

Research paper thumbnail of Adipocytic Templating of Bone Matrix Deposition in Osteoarthropathies

The FASEB Journal, 2015

Alkaptonuria (AKU), the first human disorder recognised to conform to Mendelian inheritance, is a... more Alkaptonuria (AKU), the first human disorder recognised to conform to Mendelian inheritance, is accompanied by early onset, rapidly progressing osteoarthropathy. Novel anatomical and microanatomica...

Research paper thumbnail of Alkaptonuria Severity Score Index Revisited: Analysing the AKUSSI and Its Subcomponent Features

JIMD Reports

BACKGROUND Alkaptonuria (AKU) is a rare disorder with no licensed treatment; nitisinone may reduc... more BACKGROUND Alkaptonuria (AKU) is a rare disorder with no licensed treatment; nitisinone may reduce symptoms and progression. The All Alkaptonuria Severity Score Index (AKUSSI) measures disease severity in clinical, joint and spine domains, with 57 subcomponent feature scores. Our primary aim was to assess tools for validating scores such as the AKUSSI by detecting relationships between features both before and during nitisinone treatment. METHODS AKUSSI measurements from nitisinone-treated patients visiting the National AKU Centre between 01-Jun-2012 and 31-May-2016 were analysed pre-treatment, at first treatment and annually to Year 3 post-treatment. Principal component analysis (PCA) and redundancy analysis assessed whether any AKUSSI features contributed little information to the overall score. RESULTS 65 AKU patients were included: 17 with a pre-treatment AKUSSI measurement (10 later received nitisinone) and 48 with a first measurement at their first treatment visit. In PCA, the first four principal components (PC1-PC4) explained ≥50% of AKUSSI variance at all visits (54.1-87.3%). Some features regularly dominated their domain's PC1: ears, aortic sclerosis, and nasal/temporal eye scores (clinical), pain-related scores (joint) and cervical, lumbar and thoracic spine scores (spine). Only the right-hand/wrist score was consistently redundant. Right eye (nasal) and left ear scores were redundant pre-treatment, potentially correlating with other dominant clinical PC1 features. CONCLUSIONS PCA and redundancy analysis supported the AKUSSI as a robust AKU disease severity measure, although some AKUSSI features could be removed for simplicity. For small patient populations and rare diseases, PCA and redundancy analysis together can aid validation of disease severity metrics.

Research paper thumbnail of Vitiligo, alkaptonuria, and nitisinone—A report of three families and review of the literature

JIMD Reports

Four patients, from three families, with alkaptonuria receiving 4‐hydroxyphenylpyruvate dioxygena... more Four patients, from three families, with alkaptonuria receiving 4‐hydroxyphenylpyruvate dioxygenase‐inhibiting nitisinone therapy, which lowers homogentisic acid and increases tyrosine, developed vitiligo. Three of the four patients were receiving nitisinone 2 mg daily, while the fourth was on 10 mg daily. All four patients were either receiving or had received transiently proton‐pump inhibitors as therapy for dyspepsia. The ages of the patients were 35, 42, 40, and 67 years, respectively. Three patients were men and one was a woman. All four patients were either taking a proton‐pump inhibitor or had been taking one at some point. Three of the four were of South Asian and one of Caucasian background. The three patients with South Asian background also had either a personal or family history of autoimmune disease. Distressing vitiligo, initially in an acrofacial distribution, developed unexpectedly in these four patients, before then progressing to involve other parts of the body. Potential factors in the appearance of vitiligo in this setting, including nitisinone and other drug therapy, are explored and responses to the appearance of vitiligo are discussed.

Research paper thumbnail of The contribution of mouse models in the rare disease alkaptonuria

Drug Discovery Today: Disease Models

Alkaptonuria is an ultra-rare autosomal recessive disorder of tyrosine metabolism, whereby the ho... more Alkaptonuria is an ultra-rare autosomal recessive disorder of tyrosine metabolism, whereby the homogentisate 1,2-dioxygenase (HGD) enzyme is deficient, causing an elevation of its substrate homogentisic acid (HGA). Overtime, elevated HGA causes connective tissue ochronosis, leading to a severe and early onset osteoarthropathy. The use of HGD deficient mouse models in this metabolic bone disease have provided the opportunity to investigate AKU pathophysiology and potential treatments. An ENU mutagenesis AKU mouse model (BALB/c Hgd−/−) provided the means to explore the onset of pigmentation in cartilage and treatment of AKU with nitisinone, an inhibitor of the upstream enzyme forming HGA. This work provided evidence that nitisinone could not only lower circulating HGA, but could also prevent ochronosis and halt disease progression, leading to its off-label use at the National Alkaptonuria Centre (Liverpool, UK) and its subsequent testing in human clinical trials (DevelopAKUre). Recently, a new targeted AKU mouse model (Hgd tm1a−/−, C57BL/6) has been established, offering a LacZ reporter gene for localising gene expression and LoxP and FRT sites that enabled generation of an inducible and liver-specific HGD knockout model (Hgd tm1d MxCre+/−). This conditional model determined the importance of the liver as a target organ for future gene/enzyme replacement therapies in AKU. The contribution of AKU mouse models has clearly accelerated the treatment and knowledge of this rare disease, and will continue to be used.

Research paper thumbnail of Initiation and progression of ochronotic osteoarthropathy in alkaptonuric mice

Osteoarthritis and Cartilage, 2013

Research paper thumbnail of WITHDRAWN: A protective effect in females with alkaptonuria: Relationships between gait deviations and ochronosis