-
Metabolites Oct 2022Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different...
Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different variants of this gene have been reported. The metabolic disorder in AKU leads to the accumulation of homogentisic acid (HGA), resulting in ochronosis (pigmentation of the connective tissues) and severe ochronotic spondylo-arthropathy, which usually manifests in the mid-thirties. An earlier genotype−phenotype correlation study showed no differences in serum HGA levels, absolute urinary excretion of HGA, or in the clinical symptoms between patients carrying HGD variants leading to 1% or >30% residual HGD activity. Still, as reported previously, the variance of the excretion of the HGA was smaller within affected siblings that share a common genotype. The present study is the first ever to systematically analyze the baseline clinical data of 24 AKU sibling pairs/groups collected in the SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) study to evaluate phenotypical differences between patients carrying the same HGD genetic variants. We show that even between siblings there was considerable variability in the disease severity. This indicates that some other yet unidentified genetic, biomechanical, or environmental modifying factors may contribute to accelerated pigmentation and connective tissue damage observed in some patients.
PubMed: 36295892
DOI: 10.3390/metabo12100990 -
JIMD Reports Sep 2020Increased homogentisic acid (HGA) causes ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the ochronosis progression.
BACKGROUND
Increased homogentisic acid (HGA) causes ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the ochronosis progression.
METHODS
Photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at V-1 (pre-baseline visit), V0 (baseline visit when 2 mg nitisinone was commenced), and yearly at V1, V2, and V3 visits. Photographs were inspected for evolution of ochronotic pigment and also scored categorically to derive eye, ear, and combined ochronosis scores. An ear cartilage biopsy was also carried out at V0 and one year after V3 (V4) and ochronotic pigment was assessed and quantitated. Visits were compared for changes in pigment. Fasting blood and 24-hour urine samples were collected for measurement of HGA.
RESULTS
There were 80 AKU patients at V0, and 52, 47, and 40 at V1, V2, and V3 in the group with variable numbers (VAR Group) respectively; 23 patients attended once before V0, in the V-1 visit. Photographs of patients show increase in eye pigment between V-1 and V0, followed by decrease post-nitisinone at V1, V2, and V3. Ear and combined ochronosis semiquantitative scoring showed an increase between V-1 and V0 ( < .01), followed by a decrease at V1, V2, and V3, in the VAR group ( < .01). Ochronotic pigment in ear biopsy between V0 and V4 showed a 19.1% decrease ( < .05).
CONCLUSIONS
Nitisinone decreases HGA and partially reverses ochronosis.
PubMed: 32904992
DOI: 10.1002/jmd2.12137 -
Cureus Nov 2023Exogenous ochronosis (EO) results as a complication of long-term usage of skin lightening creams containing hydroquinone or other bleaching agents. Duration of use and...
Exogenous ochronosis (EO) results as a complication of long-term usage of skin lightening creams containing hydroquinone or other bleaching agents. Duration of use and concentration of hydroquinone in the product are noted to be key factors that decide the occurrence of EO. With more cases being reported globally, current classification systems lack practical applicability and may not be adequate for detecting early cases. Dermoscopy and clinicopathological correlation are very important for early diagnosis of EO to avoid undue overuse of hydroquinone leading to further deterioration of pigmentation. We report a series of six patients in one year with EO with the minimum duration of use of hydroquinone being three months to the development of ochronosis. The most common strength of hydroquinone used was 2%, documented in 5/6 cases. Three out of six patients (50%) had discordant findings according to the Dogliotti classification, while four out of six patients (66.7%) had discordant findings according to the Phillips classification. Our findings suggest that EO can occur with a shorter duration of hydroquinone use, even at lower percentage strengths. We propose that it may be more useful to accept the clinical presentation supported by dermoscopic features as adequate actionable findings, consider all the histopathological stages as warning signs of ochronosis or impending ochronosis, and terminate the use of hydroquinone in such patients.
PubMed: 38161945
DOI: 10.7759/cureus.49620 -
Journal of Medical Case Reports Oct 2022We present this report of a new ophthalmic finding in a patient with ochronosis.
BACKGROUND
We present this report of a new ophthalmic finding in a patient with ochronosis.
CASE PRESENTATION
An 85-year-old Caucasian male patient with bilateral dark temporal and nasal pigmentation of conjunctiva and sclera was referred to our hospital owing to low visual acuity. On biomicroscopic examination, bilateral horizontal Descemet's membrane folds were observed. Corneal tomography revealed irregular and asymmetric "against-the-rule" astigmatism in both eyes. Anterior segment optical coherence tomography demonstrated numerous central Descemet's without edema or other corneal structure alterations.
CONCLUSION
This is the first report of Descemet's membrane folds in ochronosis. These corneal findings suggest that the accumulation of homogentisic acid in the sclera leads to thickening and stiffness of this region. These alterations could remarkably decrease visual acuity owing to topographic corneal curvature alterations, especially in elderly patients.
Topics: Aged; Aged, 80 and over; Cornea; Descemet Membrane; Homogentisic Acid; Humans; Male; Ochronosis; Visual Acuity
PubMed: 36183119
DOI: 10.1186/s13256-022-03599-x -
Calcified Tissue International Feb 2021Alkaptonuria (AKU) is characterised by increased circulating homogentisic acid and deposition of ochronotic pigment in collagen-rich connective tissues (ochronosis),...
Alkaptonuria (AKU) is characterised by increased circulating homogentisic acid and deposition of ochronotic pigment in collagen-rich connective tissues (ochronosis), stiffening the tissue. This process over many years leads to a painful and severe osteoarthropathy, particularly affecting the cartilage of the spine and large weight bearing joints. Evidence in human AKU tissue suggests that pigment binds to collagen. The exposed collagen hypothesis suggests that collagen is initially protected from ochronosis, and that ageing and mechanical loading causes loss of protective molecules, allowing pigment binding. Schmorl's staining has previously demonstrated knee joint ochronosis in AKU mice. This study documents more comprehensively the anatomical distribution of ochronosis in two AKU mouse models (BALB/c Hgd, Hgd tm1a), using Schmorl's staining. Progression of knee joint pigmentation with age in the two AKU mouse models was comparable. Within the knee, hip, shoulder, elbow and wrist joints, pigmentation was associated with chondrons of calcified cartilage. Pigmented chondrons were identified in calcified endplates of intervertebral discs and the calcified knee joint meniscus, suggesting that calcified tissues are more susceptible to pigmentation. There were significantly more pigmented chondrons in lumbar versus tail intervertebral disc endplates (p = 0.002) and clusters of pigmented chondrons were observed at the insertions of ligaments and tendons. These observations suggest that loading/strain may be associated with increased pigmentation but needs further experimental investigation. The calcified cartilage may be the first joint tissue to acquire matrix damage, most likely to collagen, through normal ageing and physiological loading, as it is the first to become susceptible to pigmentation.
Topics: Alkaptonuria; Animals; Cartilage; Chondrocytes; Female; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Ochronosis; Pigmentation
PubMed: 33057760
DOI: 10.1007/s00223-020-00764-6 -
Turk Gogus Kalp Damar Cerrahisi Dergisi Jan 2022Alkaptonuria is a rare inherited metabolic disease caused by homogentisic acid oxidase enzyme deficiency. Homogentisic acid formed during phenylalanine and tyrosine...
Alkaptonuria is a rare inherited metabolic disease caused by homogentisic acid oxidase enzyme deficiency. Homogentisic acid formed during phenylalanine and tyrosine metabolism cannot be further metabolized and accumulates due to this enzyme deficiency. Some of the homogentisic acid that cannot be removed by metabolism is excreted with urine, some of it causes this accumulation known as ochronosis, which is characterized by dark pigmented color change in tissues. The classic clinical triad of the disease is darkening of the urine color, degenerative arthritis in the joints and dark colored pigmentation in the connective tissue. Herein, we present a case of ochronosis detected incidentally during aortic valve replacement with the diagnosis of aortic insufficiency.
PubMed: 35444851
DOI: 10.5606/tgkdc.dergisi.2022.20909 -
Journal of Orthopaedic Case Reports Jul 2021Ochronotic arthropathy in patients with alkaptonuria is a rare hereditary disorder. The altered metabolism causes the homogentesic acid derivatives to deposit in various...
INTRODUCTION
Ochronotic arthropathy in patients with alkaptonuria is a rare hereditary disorder. The altered metabolism causes the homogentesic acid derivatives to deposit in various connective tissues causing characteristic pigmentation. Due to the close clinical resemblance to that of a degenerative disorder, diagnosis of ochronotic arthropathy usually occurs intraoperatively. We report arthroscopic findings of a 50-year-old female with ochronotic arthropathy.
CASE REPORT
A 50-year-old woman came with complaints of pain and swelling in the left knee. Clinical examination and MRI findings were correlated to reveal a tear of lateral meniscus. On arthroscopic examination, the blackish pigmentation of the meniscus and the articular cartilage led to the diagnosis of ochronotic arthropathy.
CONCLUSION
Arthroscopy plays an important role in diagnosis and treatment of patients with ochronotic arthropathy. The characteristic arthroscopic finding may aid diagnosis even in patients who do not have other systemic manifestations. Timely arthroscopic intervention can help delay the disease progression.
PubMed: 34790614
DOI: 10.13107/jocr.2021.v11.i07.2334 -
Journal of Cutaneous and Aesthetic... 2024Facial pigmentation is a common presentation of patients attending dermatology out patient department (OPD) and is of great concern to patients. Facial pigmentation may...
INTRODUCTION
Facial pigmentation is a common presentation of patients attending dermatology out patient department (OPD) and is of great concern to patients. Facial pigmentation may be multifactorial and is only rarely diagnosed accurately by a detailed history and clinical examination. Pigmentary disorders cause psychological distress and negatively impact the quality of life of an individual.
AIMS AND OBJECTIVES
(1) To study different dermoscopic patterns in facial melanosis. (2) To estimate the frequency of different dermoscopic patterns.
MATERIALS AND METHODS
Patients with facial hyperpigmentation attending the dermatology OPD were recruited after taking their written consent. A detailed history was taken to collect demographic data. Clinical examination and dermoscopy were done in all patients. Biopsy was done as and when required. Descriptive statistics has been used to describe the quantitative data. Qualitative data were presented as frequency and percentage for clinical and dermoscopic patterns.
RESULTS
The study included 100 patients with 15 different facial melanoses. The most common age group affected was 21-40 years in 53 (53%) cases. The female-to-male ratio was 1.63:1. Melasma was reported as the most common cause of facial melanosis constituting 49 (49%) of the total cases. Out of the total melasma cases, epidermal melasma constituted 22 (45%) cases, dermal melasma constituted four (4%) cases and mixed melasma constituted 23 (47%) cases. Other cases included were lichen planus pigmentosus (14; 14%), facial acanthosis nigricans (14; 14%), periorbital hyperpigmentation (7; 7%), post-inflammatory hyperpigmentation (4; 4%), exogenous ochronosis (2; 2%), lentigines (2; 2%), frictional melanosis (2;2%), and one case each of Becker's nevus, nevus of Ota, olanzapine-induced hyperpigmentation, Riehl's melanosis, macular amyloidosis, and tanning.
CONCLUSIONS
Melasma was reported as the most common cause of facial melanosis. The most common dermoscopic feature was accentuated pseudopigment network. The study is beneficial in understanding the different clinical and dermoscopic patterns of facial melanosis, thus helping the physician to effectively manage the conditions and reduce the need of biopsy.
LIMITATIONS
(1) A small sample size. (2) Histopathological correlation was not done in all cases.
PubMed: 38800811
DOI: 10.4103/JCAS.JCAS_48_23 -
BioMed Research International 2021Metabolic disorder alkaptonuria is an autosomal recessive disorder caused by mutations in the gene, and a deficiency HGD enzyme activity results in an accumulation of...
BACKGROUND
Metabolic disorder alkaptonuria is an autosomal recessive disorder caused by mutations in the gene, and a deficiency HGD enzyme activity results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue.
METHODS
We clinically evaluated 18 alkaptonuria patients (age range, 3 to 60 years) from four unrelated families. Furthermore, 11 out of 18 alkaptonuria patients and 7 unaffected members were enrolled for molecular investigations by utilizing Sanger sequencing to identify variants of the 14 exons of gene.
RESULTS
We found that the seven patients from the 4 unrelated families carried a recurrent pathogenic missense variant (c.365C>T, p. Ala122Val) in exon 6 of gene. The variant was fully segregated with the disease in affected family members while the other unaffected family members were heterozygous carriers for this variant. Additionally, the clinical features were fully predicted with alkaptonuria disorder.
CONCLUSION
In this study, we confirmed that the most common variants in Jordanian AKU patients was c.365C>T, p. Ala122Val in exon 6 of gene. Additionally, we correlated the clinical and genetic features of AKU patients at various ages (3-60 years).
Topics: Adolescent; Adult; Alkaptonuria; Child; Child, Preschool; Exons; Family Health; Female; Founder Effect; Genes, Recessive; Genetic Variation; Heterozygote; Homogentisate 1,2-Dioxygenase; Homogentisic Acid; Humans; Jordan; Male; Middle Aged; Mutation, Missense; Ochronosis; Oligonucleotides; Pedigree; Sequence Analysis, DNA; Young Adult
PubMed: 34235214
DOI: 10.1155/2021/1515641 -
World Journal of Clinical Cases Jan 2023Ochronosis, also known as alkaptonuria, is a rare autosomal recessive self-metabolic disease arising from deficiency of homogentisate 1,2 dioxygenase enzyme. It affects...
BACKGROUND
Ochronosis, also known as alkaptonuria, is a rare autosomal recessive self-metabolic disease arising from deficiency of homogentisate 1,2 dioxygenase enzyme. It affects several organs and muscoskeletal structures. We herein report a case of a patient who presented with severe hip arthropathy complicated with late stage ochronosis.
CASE SUMMARY
A 56-year-old male patient was admitted in our department in 2019 with complaints of chronic low backache and left hip pain. After the required investigations were done, lumbar disc herniation and severe hip arthritis were the initial diagnosis. A total left hip arthroplasty was performed. Ochronotic osteoarthritis was only obtained post-surgery as confirmatory diagnosis. He was again admitted mid 2022 with the same complaints on the right hip. Subsequently, he underwent a total right hip arthroplasty. Post-operative recovery and follow-ups were deemed very satisfactory.
CONCLUSION
Ochronosis is an unusual diagnosis for a patient who presents with typical hip arthritis. Thus, unless meticulous history taking and advanced laboratory tests, the diagnosis can easily be missed by surgeons.
PubMed: 36687193
DOI: 10.12998/wjcc.v11.i1.210