-
Orphanet Journal of Rare Diseases Aug 2021Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are...
Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are joint problems, cardiac valve abnormalities and renal problems. Landmark intervention studies with nitisinone 10 mg daily, suppressing an upstream enzyme activity, demonstrated its beneficial effects in AKU patients with established complications, which usually start to develop in the fourth decade. Lower dose of nitisinone in the range of 0.2-2 mg daily will already reduce urinary homogentisic acid (uHGA) excretion by > 90%, which may prevent AKU-related complications earlier in the course of the disease while limiting the possibility of side-effects related to the increase of plasma tyrosine levels caused by nitisinone. Future preventive studies should establish the lowest possible dose for an individual patient, the best age to start treatment and also collect evidence to which level uHGA excretion should be reduced to prevent complications.
Topics: Alkaptonuria; Cyclohexanones; Humans; Nitrobenzoates; Tyrosine
PubMed: 34344451
DOI: 10.1186/s13023-021-01977-0 -
JIMD Reports Jan 2022Outcomes from studies employing nitisinone 10 mg and 2 mg in alkaptonuria were compared.
BACKGROUND
Outcomes from studies employing nitisinone 10 mg and 2 mg in alkaptonuria were compared.
PATIENTS AND METHODS
Sixty-nine patients in each of the nitisinone (10 mg daily) and controls of suitability of nitisinone in alkaptonuria 2 (SONIA 2), as well as 37 and 23 in nitisinone (2 mg daily) and control cohorts at the National Alkaptonuria Centre (NAC), respectively, were followed up for 4 years. Severity of alkaptonuria (AKU) was assessed by the AKU Severity Score Index (AKUSSI). 24-h urine homogentisic acid (uHGA), serum HGA (sHGA), serum tyrosine (sTYR) and serum nitisinone (sNIT) were also analysed at each time point. Dietetic support was used in the NAC, but not in SONIA 2. Safety outcomes were also compared. All statistical analyses were post hoc.
RESULTS
The slope of the AKUSSI was 0.55, 0.19, 0.30, and 0.06 per month in the control NAC, nitisinone NAC, control SONIA 2, and nitisinone SONIA 2 cohorts, respectively. The intersection of the slopes on the -axis was -132, -411, -295, and - 1460 months, respectively. The control and nitisinone slope comparisons were statistically significant both in the NAC ( < 0.001) and the SONIA 2 ( < 0.001). Corneal keratopathy occurred in 3 and 10 patients in the NAC and SONIA 2, respectively.
DISCUSSION
The nitisinone 10 mg dose decreased disease progression more than the 2 mg dose although the incidence of corneal keratopathy was 14.5% and 4.9%, respectively.
CONCLUSION
Nitisinone 10 mg decreased urine and serum HGA, increased serum tyrosine, and decreased disease progression more than 2 mg. Low-protein dietetic support may be needed to mitigate tyrosinaemia following nitisinone.
HIGHLIGHTS
Nitisinone 10 mg apparently slows alkaptonuria disease progression more than 2 mg in adults.Corneal keratopathy during nitisinone therapy was more common in men.Serum nitisinone concentrations increased significantly over time.Nitisinone may inhibit cytochrome P450 self catabolism.
PubMed: 35028273
DOI: 10.1002/jmd2.12261 -
Proceedings of the Royal Society of... May 1969
Topics: Adult; Alkaptonuria; Chromatography, Gas; Humans; Male; Phenylacetates
PubMed: 5770593
DOI: No ID Found -
Clinical Case Reports Apr 2022Blue discoloration of the skin and cartilage, or ochronosis, is a rare physical examination finding. We present two cases of childhood onset ochronosis, one exogenous...
Blue discoloration of the skin and cartilage, or ochronosis, is a rare physical examination finding. We present two cases of childhood onset ochronosis, one exogenous and one endogenous in etiology. The first was caused by minocycline use for severe acne, and the second was caused by congenital alkaptonuria.
PubMed: 35441025
DOI: 10.1002/ccr3.5717 -
TheScientificWorldJournal Aug 2010Alkaptonuria is a rare, autosomal-recessive disease of tyrosine degradation resulting from accumulation of homogentisic acid (HGA) within the body due to deficiency of...
Alkaptonuria is a rare, autosomal-recessive disease of tyrosine degradation resulting from accumulation of homogentisic acid (HGA) within the body due to deficiency of the hepatic enzyme homogentisate 1,2-dioxygenase[1]. HGD is the gene encoding homogentisate 1,2-dioxygenase and is the only gene known to be associated with alkaptonuria. In this patient the disease also manifested itself with symmetric blue-gray discoloration on the helix cartilage of his ears. The initial diagnosis of alkaptonuria was made some 20 years earlier because of the appearance of low back pain and dark urine. HGA is responsible for the black color of urine and is deposited in the cartilage of the body, including ears.
Topics: Alkaptonuria; Ear; Genetic Predisposition to Disease; Homogentisate 1,2-Dioxygenase; Homogentisic Acid; Humans; Male; Middle Aged; Pigmentation Disorders
PubMed: 20694448
DOI: 10.1100/tsw.2010.147 -
JIMD Reports Sep 2021Four patients, from three families, with alkaptonuria receiving 4-hydroxyphenylpyruvate dioxygenase-inhibiting nitisinone therapy, which lowers homogentisic acid and...
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.
PubMed: 34485014
DOI: 10.1002/jmd2.12225 -
The Yale Journal of Biology and Medicine 1978In normal individuals, the main route for tyrosine degradation is the hepatic pathway tyrosine→4-hydroxyphenylpyruvic acid→homogentisic acid→CO(2). Quantitatively... (Review)
Review
In normal individuals, the main route for tyrosine degradation is the hepatic pathway tyrosine→4-hydroxyphenylpyruvic acid→homogentisic acid→CO(2). Quantitatively minor pathways, in large part extrahepatic, are: tyrosine→tyramine→octopamine and tyrosine→dopa→catecholamines.In cirrhosis, the main hepatic pathway is blocked to varying degrees at the first three stages. This appears to be due to lack of activity of the enzymes tyrosine transaminase, PHPA oxidase, and HGA oxidase, the first step being rate limiting. Hypertyrosinemia and tyrosine intolerance result.With the main hepatic pathway partially blocked, an abnormally large amount of tyrosine passes into the normally minor extrahepatic pathway leading to the false neurotransmitters tyramine and octopamine. Overproduction of these amines ensues and they accumulate in the body fluid.The false neurotransmitters can displace catecholamines from their storage sites in the peripheral and central nervous system, and thereby disrupt adrenergic processes in arterioles, kidneys, and brain. Their accumulation in cirrhotic patients may play a role in the pathogenesis of hepatic encephalopathy, hepatorenal syndrome, and hyperdynamic circulation.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Alkaptonuria; Amino Acid Metabolism, Inborn Errors; Catecholamines; Homogentisic Acid; Humans; Liver Cirrhosis; Male; Middle Aged; Models, Biological; Octopamine; Oxygenases; Phenylketonurias; Tyramine; Tyrosine; Tyrosine Transaminase
PubMed: 36717
DOI: No ID Found -
Metabolites Aug 2022Nitisinone (NIT) causes tyrosinaemia and corneal keratopathy (KP), especially in men. However, the adaptation within the phenylalanine (PHE)/tyrosine (TYR) catabolic...
Comparing the Phenylalanine/Tyrosine Pathway and Related Factors between Keratopathy and No-Keratopathy Groups as Well as between Genders in Alkaptonuria during Nitisinone Treatment.
Nitisinone (NIT) causes tyrosinaemia and corneal keratopathy (KP), especially in men. However, the adaptation within the phenylalanine (PHE)/tyrosine (TYR) catabolic pathway during KP is not understood. The objective of this study is to assess potential differences in the PHE/TYR pathway during KP and the influence of gender in NIT-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24 h urine collected from patients treated with NIT during a 4-year randomized study in NIT vs. no-treatment controls (SONIA 2; Suitability Of Nitisinone In Alkaptonuria 2; EudraCT no. 2013-001633-41) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), TYR, PHE, hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine in the NIT-group. All statistical analyses were post hoc. Keratopathy occurred in 10 out of 69 AKU patients, eight of them male. Thirty-five sampling points (serum and 24 h urine) were analysed in patients experiencing KP and 272 in those with no-KP (NKP) during NIT therapy. The KP group had a lower HPLA/TYR ratio and a higher TYR/PHE ratio compared with the NKP group (p < 0.05 for both). There were 24, 45, 100 and 207 sampling points (serum and 24 h urine) in the NIT group which were pre-NIT female, pre-NIT male, NIT female and NIT male, respectively. The PHE/TYR ratio and the HPLA/TYR ratio were lower in males (p < 0.001 and p < 0.01, respectively). In the KP group and in the male group during NIT therapy, adaptive responses to minimise TYR formation were impaired compared to NKP group and females, respectively.
PubMed: 36005644
DOI: 10.3390/metabo12080772 -
Organogenesis Oct 2021Osteopenia is common in phenylalanine hydroxylase deficient phenylketonuria (PKU). PKU is managed by limiting dietary phenylalanine. Osteopenia in PKU might reflect a...
Osteopenia is common in phenylalanine hydroxylase deficient phenylketonuria (PKU). PKU is managed by limiting dietary phenylalanine. Osteopenia in PKU might reflect a therapeutic diet, with reduced bone forming materials. However, osteopenia occurs in patients who never received dietary therapy or following short-term therapy. Humans and animal studies find no correlation between bone loss, plasma hyperphenylalaninemia, bone formation, and resorption markers. Work in the Pah mouse recently showed a mesenchymal stem cell (MSC) developmental defect in the osteoblast pathway. Specifically, Pah MSCs are affected by energy dysregulation and oxidative stress. In PKU, MSCs oximetry and respirometry show mitochondrial respiratory-chain complex 1 deficit and over-representation of superoxide, producing reactive oxygen species affecting mitochondrial function. Similar mechanisms are involved in aging bone and other rare defects including alkaptonuria and homocysteinemia. Novel interventions to support energy and reduce oxidative stress may restore bone formation PKU patients, and in metabolic diseases with related mechanisms.
Topics: Animals; Bone Diseases, Metabolic; Disease Models, Animal; Humans; Mice; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias
PubMed: 34432558
DOI: 10.1080/15476278.2021.1949865 -
JAMA Network Open Mar 2020Alkaptonuria is an autosomal recessive disorder caused by pathogenic variants in the HGD gene. Deficiency of the HGD enzyme leads to tissue deposition of homogentisic...
IMPORTANCE
Alkaptonuria is an autosomal recessive disorder caused by pathogenic variants in the HGD gene. Deficiency of the HGD enzyme leads to tissue deposition of homogentisic acid (HGA), causing severe osteoarthropathies and cardiac valve degeneration. Although HGD is vital for the catabolism of tyrosine, which provides the basis for thyroid hormone synthesis, the prevalence of thyroid dysfunction in alkaptonuria is unknown.
OBJECTIVE
To assess thyroid structure and function in patients with alkaptonuria.
DESIGN, SETTING, AND PARTICIPANTS
A single-center cohort study was conducted in a tertiary referral center including patients with alkaptonuria followed up for a median of 93 (interquartile range, 48-150) months between February 1, 2000, and December 31, 2018. The alkaptonuria diagnosis was based on clinical presentation and elevated urine HGA levels. A total of 130 patients were considered for participation.
MAIN OUTCOMES AND MEASURES
Prevalence of thyroid dysfunction in adults with alkaptonuria compared with the general population. Thyrotropin and free thyroxine levels were measured by immunoassay and repeated in each patient a median of 3 (interquartile range, 2-22) times. Neck ultrasonographic scans were analyzed in a subset of participants. Logistic regression was used to test the association of thyroid dysfunction with age, sex, thyroid peroxidase (TPO) antibodies, serum tyrosine levels, and urine HGA levels.
RESULTS
Of the 130 patients, 5 were excluded owing to thyroidectomy as the cause of hypothyroidism. The study cohort consisted of 125 patients; the median age was 45 (interquartile range, 35-51) years. Most of the patients were men (72 [57.6%]). The prevalence of primary hyperthyroidism was 0.8% (1 of 125 patients), similar to 0.5% observed in the general population (difference, 0.003; 95% CI, -0.001 to 0.04; P = .88). The prevalence of primary hypothyroidism was 16.0% (20 of 125 patients), which is significantly higher than 3.7% reported in the general population (difference, 0.12; 95% CI, 0.10-0.24; P < .001). Women were more likely to have primary hypothyroidism than men (odds ratio, 10.99; 95% CI, 3.13-38.66; P < .001). Patients with TPO antibodies had a higher likelihood of primary hypothyroidism than those without TPO antibodies (odds ratio, 7.36; 95% CI, 1.89-28.62; P = .004). There was no significant difference in the prevalence of thyroid nodules between patients in this study (29 of 49 [59.2%]) vs the general population (68%) (difference, 0.088; 95% CI, -0.44 to 0.73; P = .20) or of cancer (7% vs 5%; difference, 0.01; 95% CI, -0.01 to 0.17; P = .86).
CONCLUSIONS AND RELEVANCE
The high prevalence of primary hypothyroidism noted in patients with alkaptonuria in this study suggests that serial screening in this population should be considered and prioritized.
Topics: Adult; Alkaptonuria; Autoantibodies; Autoantigens; Cohort Studies; Female; Homogentisic Acid; Humans; Hyperthyroidism; Hypothyroidism; Iodide Peroxidase; Iron-Binding Proteins; Logistic Models; Male; Middle Aged; Prevalence; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyroxine; Tyrosine
PubMed: 32202644
DOI: 10.1001/jamanetworkopen.2020.1357