Diagnosis Of Alkaptonuria Research Articles

Every Dark Urine is Not Hematuria – A Novel Mutation Associated with Alkaptonuria

A 3-year-old boy came to our outpatient department with complaints of dark urine noticed by the mother since birth. On examination, the child had dysmorphic facies, synophrys, hypertelorism, micrognathia, prominent lashes, and difficulty in vision. The weight and height were below the third centile. Urinalysis showed glucosuria; tandem mass spectrometry and gas chromatography–mass spectrometry showed high levels of homogentisic acid and glycerol-3-phosphate. Exome sequencing revealed a missense homozygous variant in the gene encoding homogentisate 1,2-dioxygenase. A diagnosis of alkaptonuria was made and the patient was started on a low-protein diet and ascorbic acid.

PSAT182 Dilemmas in the Diagnosis and Management of Osteoporosis in a patient with Alkaptonuria: Successful Treatment with Teriparatide

Abstract Introduction Diagnosis and management of osteoporosis in patients with alkaptonuria can be challenging. Coexisting arthritis involving the lumbar spine (LS) and hips can falsely elevate bone density making DXA interpretation difficult. We report a patient with alkaptonuria who was successfully treated with teriparatide in addition to bisphosphonate therapy. Case History A 69-year-old female presented for evaluation of osteoporosis. She was diagnosed with alkaptonuria at age 29 when she reported bilateral conjunctival hyperpigmentation. She was also diagnosed with arthritis requiring left knee joint replacement at the age of 57 years. Subsequently, she underwent left hip, right knee, right hip, and left shoulder joint replacement surgeries. She also sustained fragility fractures in the foot and a 2-inches height loss. Physical examination: normal vital signs. Examination of eyes and ears: bluish black discoloration of the conjunctiva and ear lobes. Heart examination showed normal S1, split S2, and IV/VI systolic murmur over the right parasternal border; the rest of the physical examination revealed limited joint movements of thoracic and lumbar spines, wrists, ankles, knees and hip joints. Laboratory: serum PTH 33 pg./mL, 25-OH vitamins 28 ng/mL, 1,25 (OH)2 vitamin D 43 pg/mL, osteocalcin 11.6 mg/mL (ref 9.4-47.4), collagen cross-linked C-telopeptide 318 pg/mL (ref 104-1008), tyrosine 79.1 umol/L (ref 31.1-118.1), 24 hours urine homogentisic acid 4.2 gms (ref 20-30 mg). Genetic testing: compound heterozygous mutation for the HGD C. 496T2T>C and HGD C.1102A < G (p.mev368Va) variants, consistent with a diagnosis of alkaptonuria. DXA scan done at the age of 56 years showed osteoporosis (T score -2.7 femoral neck, 1.8 total hip, 2.5 LS). Patient was started on alendronate 70mg PO weekly for 5 years in addition to nitisinone. While on alendronate, she sustained fragility fractures of the right radius and left ankle. After 5 years of alendronate, the patient was transitioned to teriparatide 20-mcg subcutaneously (SC) daily for 2 years followed by annual intravenous zoledronic acid. For the subsequent 7 years, the patient led a healthy, active life with no fractures. Follow-up DXA showed improvement to the osteopenic range at the radius site as degenerative arthritis made interpretation of other sites impossible.This case illustrates the challenges in the diagnosis and treatment of osteoporosis in patients with alkaptonuria. DXA can be ineffective in this condition due to the hip and LS arthritis. Measurement of trabecular bone scoreS and CT of the LS may be better alternate choices. Bisphosphonates alone are typically not effective in preventing fragility fractures in this population but use of teriparatide may be an effective treatment. Further studies are needed to assess the effectiveness of teriparatide in this population but our case shows promise that this treatment result in BMD improvement and fracture prevention. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

A rare case of metabolic disorder- Alkaptonuria

Alkaptonuria is a rare genetic disorder of tyrosine metabolism, due to deficiency of the enzyme homogentisate 1, 2 dioxygenase. This results in characteristic features like blackish urine discoloration, ochronosis, arthropathy, cardiac valve deterioration. In this paper, the authors presenta case report of a 4-month-old boy who was brought by his mother to the well-baby clinic, with a chief complaint of black staining of nappy, a few hours after voiding. A qualitative examination of urine after an hour of the collection showed dark black discoloration, Quantitative examination reveals the presence of homogentisic acid to the extent of200mg/dl. The Diagnosis of Alkaptonuria was confirmed and the infant was started on Vitamin C and put under regular follow-up.

Assessment of disability in patients with alkaptonuria

Background. Alkaptonuria is an orphan, autosomal recessive disease in which clinical symptoms debut in adulthood and are characterized by progressive degenerative changes in large joints (knee, hip, shoulder) and the spine, often leading to the need for joint replacement. Developing changes often lead to persistent disability.
 The purpose of this study was to evaluate disability among adult patients with alkaptonuria.
 Materials and methods. The study included 46 adult patients (31 m 67.4% and 15 w 32.6%) with a reliable diagnosis of alkaptonuria at the age of 20 to 76 years (avg age 56.83 10.52). The assessment of the presence of a disability group at the time of patients treatment to a rheumatologist was carried out.
 Results. It turned out that disability was determined in 34 (75.6%) patients, there were no signs of persistent disability in 11 patients (24.4%). Among the patients who had signs of persistent disability, most often during the survey period, group 2 disability was established (61.8%), the differences between this and other groups were statistically significant (p 0.05). For the first time, disability in the study cohort of patients was established at the age of 31 to 59 years (the average age was 50.83 5.5 years).
 Conclusions. It is important to note that in the vast majority of cases, persistent disability occurs in patients who were of working age, which underscores the importance of alkaptonuria as a medical and social problem.

Ear, nose, and throat manifestations of alkaptonuria patients from Jordan

Objective: Alkaptonuria (AKU) is a rare inborn error of metabolism that is characterized as a multisystem disease with specific ear, nose, and throat (ENT) manifestations. The present study reports ENT findings in pediatric and adult AKU patients from Jordan. Materials and Methods: A full ENT examination and audiological assessment were conducted among the patients attending the AKU Research Office in our University. Results: The results showed that 88% of both pediatrics and adult patients had ENT signs or symptoms; while, the pediatric age group had only one sign that is the discoloration of the cerumen. The adult group had more than one sign, including the discoloration of cerumen and pinna, hearing loss, and discoloration of the gum and teeth. Conclusion: Discoloration of the cerumen is a common sign in pediatric patients; therefore, it is considered as an important early clinical sign for the diagnosis of AKU. Annual follow-up of pediatric patients with audiological assessment is needed to clarify the association between AKU and hearing loss. Otolaryngologist should be aware of these signs for early diagnosis and provide patients early treatment with nitisinone.

Nuclear medicine techniques in the assessment of alkaptonuria

Alkaptonuria is a rare autosomal recessive disorder due to a lack of the enzyme homogentisate dioxygenase, leading to ochronosis, a process of accumulation of a melanin-like polymer of homogentisic acid in cartilage and other collagenous structures. Patients develop severe osteoarthropathy that resembles osteoarthritis. Although the diagnosis of alkaptonuria is not particularly challenging in view of the blue-black discolouration of visible connective tissue and the presence of homogentisic acid in urine, the natural history of alkaptonuria remains poorly understood. Patients would benefit immensely from an objective assessment of their disease status and from a clearer understanding of the pathophysiology and associated physical changes. Isotope bone scans, which are commonly used to identify the extent of involvement of bones in cancerous processes, have also been increasingly used for characterizing the extent of arthropathy in conditions such as osteoarthritis and rheumatoid arthritis. Semiquantitative scores based on the extent of involvement of joints have been used to describe the involvement of large joints in the context of symptomatic treatment for osteoarthritis. A similar semiquantitative isotope bone scan score depending on the involvement of the number of large joints in patients with alkaptonuria can be formulated and validated in a suitable cohort of patients. Bone densitometry measurement using dual-energy X-ray absorptiometry scanning is an internationally accepted tool to assess the risk and extent of osteoporosis, and is increasingly used to assess the additional fracture risk in patients with arthropathy. We believe that, currently, nuclear medicine techniques can provide useful information, which can be incorporated into disease severity scores for alkaptonuria. Once the biological basis for alkaptonuria is better understood, it is feasible that nuclear medicine techniques of even greater sensitivity and specificity can be developed, thereby taking advantage of the vast advances in the fields of radiochemistry, radiopharmacy, positron emission tomography-computed tomography and positron emission tomography-magnetic resonance imaging scanning.

Possible Relationship Between Infertility and Alkaptonuria

Alkaptonuria is a rare metabolic disease which is not known to cause infertility up to now. Reported manifestations are mainly darkening of urine, ochronotic pigmentation of skin and various musculoskeletal symptoms. We aimed to report a family having many members affected with alkaptonuria and infertility. For the couple first we met from this family, after diagnosis of alkaptonuria, noticed them to have infertility. Infertility test including hysterosalpingography and sperm analysis are performed. After detailed investigation we noticed coexistence of infertility and alkaptonuria in three of eight couples. All three couples have desired to have children and asked medical help in the past. Hereby, presentation of close relation between alkaptonuria and infertility was pointed out.

Ashy Ears

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.

ACUTE EXACERBATION AS PRESENTING OR COMPLICATING FEATURE OF IDIOPATHIC PULMONARY FIBROSIS

A 68-year-old white man was evaluated for failure to wean from mechanical ventilation after cardiac surgery. Bronchoscopy performed prior to percutaneous dilatational tracheotomy revealed circumferential strikingly dark-colored airways, most prominent in the trachea and mainstem bronchi, extending distally into all airways with overlying desiccated black secretions. Histologic examination of bronchial mucosal biopsy samples and the desiccated secretions showed acute bronchitis and necrotic debris, respectively. This finding and the patient's history led to testing for plasma homogentisic acid, which was found to be elevated at 12.6 mug/mL, establishing the first diagnosis of alkaptonuria made using flexible bronchoscopy.

Minocycline‐induced hyperpigmentation masquerading as alkaptonuria in individuals with joint pain

Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of alkaptonuria. We present 5 such cases. Eighty-eight patients with a possible diagnosis of alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods. Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of alkaptonuria.

The success of dietary protein restriction in alkaptonuria patients is age-dependent.

Alkaptonuria is characterized by an increased urinary excretion of homogentisic acid, pigmentation of cartilage and connective tissues, and ultimately the development of inflammatory arthropathy. Various diets low in protein have been designed to decrease homogentisic acid excretion and to prevent the ochronotic pigmentation and arthritic lesions. However, limited information is available on the long-term beneficial effects of these diets. We reviewed the medical records of 16 patients aged 3-27 years (4 > 18 years) to ascertain the age of diagnosis, growth, development, social behaviour, signs of complications and longitudinal dietary compliance. The diagnosis of alkaptonuria was made at an average age of 1.4 years (2 months-4 years); following the diagnosis all patients were prescribed a diet with a protein content of 1.5 g/kg per day. All patients showed normal growth and development, and no major complications of the disease. Behavioural problems associated with poor dietary compliance emerged as the main problem. Dietary compliance decreased progressively with age. The effect of dietary protein restriction in homogentisic acid excretion was studied by fixing the amounts of protein in the diet at 1 g/kg per day and 3.5-5 g/kg per day during 8 days. Twelve patients, aged 4-27 years, participated in the investigation. Protein restriction resulted in a significantly lower excretion of homogentisic acid in the urine of children younger than 12 years (p < 0.01), whereas this effect was less obvious for adolescent and adult patients. The results suggest that restriction of protein intake may have a beneficial effect on alkaptonuric children; but continuation of this regimen to older age seems questionable and not practical.

Alkaptonuria: report of 12 cases.

Excerpt From 1927 to 1953, inclusive, a period of 26 years, the diagnosis of alkaptonuria was made in only 12 cases at the Mayo Clinic. Moreover, the medical literature of the last 370 years contai...