CME INDIA Case Presentation by Prof. (Dr.) Abhay Narain Rai, Founder CCDSI, Gaya.
CME INDIA Case Study
How Presented?
- 3-year-old child present to OPD of AIIMS-Gaya.
- Mother complains… Whenever child passes urine, after few hours turns black.
- No clear family history traced.
- RFT, LFT, CBC, Cardiac evaluation, Urine analysis… All normal.
Spot the diagnosis
CME INDIA Responses
Dr. Ashutosh Ojha, Pune: Phenylketonuria.
Dr. Surendra Kr. Goyal, Kota: Alkaptonuria.
Dr. Rajkamal Chaudhary, Asso. Prof. Med., Bhagalpur: Alkaptonuria.
Dr. Dharmendra Kumar, Sr. Consult, TMH, Jamshedpur: Porphyria.
Dr. Anil Kumar, Ranchi: Acute intermittent porphyria.
Dr. Navin Burnwal, Nephrologist, Ranchi: Alkaptonuria.
Dr. Sangeeta, Varanasi: Alkaptonuria.
Dr. K. N. Jayachandran, TN: Alkaptonuria.
Dr. Venkatesh Molio, Maregoan, Goa: Alkaptonuria.
Dr. Leelavathy: Alkaptonuria.
Dr. Swati Srivastava, Sr. Prof. SMSMC, Jaipur:
- Alkaptonuria
- Rare genetic disorder of protein metabolism
- Urine test for homogentisic acid
- D/D: Porphyria?
Dr. Deepak Gupta, Card, Ranchi: R/O AKU.
Urine Test
CME INDIA Learning Points
- Alkaptonuria is a rare genetic inborn error of protein metabolism.
- It is the result of the deficiency of an enzyme (homogentisate 1,2 dioxygenase – HGD), leading to the accumulation of homogentisic acid in connective tissue leading to ochronosis.
- Most of the time, diagnosis is delayed as the patient remains asymptomatic during childhood.
- Remember characteristic early clinical presentation.
- Observation that urine darkens on standing.
- This is the only symptom seen in the paediatric age group.
The triad of alkaptonuria
| Ochronosis |
| Homogenistic aciduria |
| Ochronotic osteoarthropathy |
The clinical features are secondary to ochronosis:
| General | Grey pigmentation in the ear cartilage or the sclerae, also skin discoloration. |
| Bone & Joints | Lumbar pain (ankylosis), arthritis leading to joint effusions, decreased joint mobility, impaired spinal, and thoracic mobility may lead to disability. There is also an increase in the prevalence of fractures secondary to osteopenia. |
| Respiratory | Decreased respiratory reserve and restrictive lung disease. |
| Cardiac | Valvular heart disease like aortic stenosis (more common), aortic regurgitation, mitral valve stenosis; cardiac arrhythmias; heart failure, and an increase in the incidence of coronary artery disease. |
| Neurological | Peripheral neuropathy, tinnitus, diplopia, and an increase in the incidence of stroke. |
| Metabolic | Increase in the incidence of renal, gallbladder, and prostatic stones. |
Laboratory Diagnosis
| The urine test for HGA is the gold-standard test to diagnose alkaptonuria. The amount of homogentisic acid in the 24-hour urine is detected via gas chromatography-mass spectrometry (GC-MS) analysis. The amount of HGA excreted each day in patients with AKU is usually between 1 and 8 grams. The change in urine color is non-specific. |
| Molecular genetic testing It can identify the biallelic abnormalities in HGD and other mutations that can help in family counselling. |
| CT scan or MRI help in assessing the severity of joint involvement. |
| 2D-Echocardiography can detect valvular abnormalities. |
| CT Angiogram can detect calcification of coronary vessels. |
It is not Phenylketonuria
- A musty odor to skin and urine can raise suspicion, it was not found with this case
- Signs and symptoms of the disease that become more pronounced when untreated include delayed developmental milestones, microcephaly, hypopigmentation, hyperactivity/behaviour problems, seizures, and a musty odor to skin and urine.
It is not Acute Intermittent Porphyria
- Abdominal pain with a relatively unremarkable physical examination is the most common neurovisceral manifestation of acute hepatic porphyria.
- Three groups of symptoms, abdominal pain, central nervous system abnormalities, and peripheral neuropathy, are described as a “classic triad” that should suggest acute porphyria.
- Urine: Urine porphobilinogen (PBG) is the most important first-line screening test, which is both highly sensitive and highly specific.
- Hepatic porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), aminolevulinic acid dehydratase deficiency porphyria (ALAD), hereditary coproporphyria (HCP), and porphyria cutanea tarda (PCT).
Each feature of AKU present at various stages in life, the earliest being detection of HGA in urine.
A. The passing of black urine is the only manifestation of the condition known in pediatrics, leading to 21% of patients being diagnosed with AKU before 1 year of age.
The darkening of urine occurs because the HGA pigment oxidizes to Benzoquinone acetate (BQA), which forms a melanin-like polymer that slowly turns urine black.
B. Ochronosis develops as the BQA accumulates both intra- and extra-cellularly in connective tissue. This feature is commonly observed in the third through to fifth decades of life.
C. The development of ochronotic arthropathy is the result of deposition of the HGA polymer within hyaline articular cartilage. Pigmentation is widespread, with all tissues of the joint organ being affected. The affected tissues often become weak, brittle, and prone to chipping, fracturing, and cracking, causing rapid joint degeneration, which means that patients can be left profoundly disabled at a young age. If treatment also delays, it leads to severe deformity of joints, spine, and organ dysfunction. Early diagnosis is the key to managing alkaptonuria effectively.
Does it affect Life expectancy?
No. It does not reduce life expectancy but it significantly affects quality of life.
Do we have any drug to cure?
Management:
There is currently no approved cure for AKU.
| Ascorbic acid | Efficacy unproven, increases HGA production, may exacerbate condition |
| Low protein diet | Efficacy in adults unproven, compliance difficult |
| Pain Control | Widely used, incompletely effective |
| HGA lowering therapy: Nitisinone | Not shown to alter outcomes, increases tyrosine |
| Palliative surgery | Effective but invasive |
| Enzyme replacement | Not available |
| Gene replacement | Not available |
CME INDIA Tail Piece
- It was Garrod who used AKU in the Croonian lectures brought the condition into the spotlight in 1908.
- Documentation of the condition began in the 16th and 17th centuries.
- The earliest clinical case of AKU was found in the Egyptian mummy Harwa, which is believed to date back as far as 1500 BC.
- The name Alkaptonuria is derived from the Arabic word “alkali” (meaning alkali) and the Greek word meaning “to suck up oxygen greedily in alkali.”
- The name was created by Boedeker in 1859 after he discovered unusual reducing properties in the urine of a patient.
- Ochronosis was first described and named by Virchow in 1866, because under microscopy the HGA pigment appeared to be ochre (yellow/brown) in color.
- In 1891 HGA was identified as the causative component.
- By 1995 the genetic defect was discovered, cloned, and mapped to chromosome 3q21-q23.
References:
- Mistry JB, Bukhari M, Taylor AM. Alkaptonuria. Rare Dis. 2013 Dec 18;1:e27475. doi: 10.4161/rdis.27475. PMID: 25003018; PMCID: PMC3978898.
- Garrod AE, Oxon MD. The incidence of alkaptonuria: a study in chemical individuality. 1902. Mol Med 1996; 2:274 – 82; PMID: 8784780
- O’Brien WM, La Du BN, Bunim JJ. Biochemical, pathologic and clinical aspects of alkaptonuria, ochronosis and ochronotic arthropathy. Am J Med 1963; 34:813 – 38; http://dx.doi.org/10.1016/0002-9343(63)90089-5
- Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A. Biochemical identification of homogentisic acid pigment in an ochronotic egyptian mummy. Science 1977; 197:566 – 8; http://dx.doi.org/10.1126/science.327549; PMID: 327549
- Zatkova A (December 2011). “An update on molecular genetics of Alkaptonuria (AKU)”. J. Inherit. Metab. Dis. 34 (6): 1127–36.
- Garrod AE (1902). “The incidence of alkaptonuria: a study in clinical individuality”. Lancet. 2 (4137): 1616–20. doi:10.1016/S0140-6736(01)41972-6. PMC 2230159. PMID 8784780. Reproduced in Garrod AE (2002). “The incidence of alkaptonuria: a study in chemical individuality. 1902 classical article”. Yale Journal of Biology and Medicine. 75 (4): 221–31. PMC 2588790. PMID 12784973
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