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Disease Biochemical defect and pathogenesis Laboratory findings Clinical Manifestations Treatment
Alkaptonuria It is caused by a defect in the enzyme Homogentisic acid oxidase.Due to deficiency Homogentisic acid remains in the body and slowly and progressively get deposited in bones and cartilages where it turns into a pigmented polymeric material. 

These polymerised Homogentisic acid products are excreted in large amounts in urine and impart the black color to urine.


This blue-black discoloration of connective tissue (including bone, cartilage, and skin) is caused by deposits of yellow or ochre-colored pigment and  is called Ochronosis.



Diagnosis can be confirmed by demonstrating the presence of Homogentisic acid in the urine.This may be done by paper chromatography  or Thin-layer chromatography.  The earliest signs is thickening of the ear cartilage, skin turns a blue-black colour,Bones and cartilage of the lower back, knees, shoulders and hips are most affected, Deposits around the trachea, larynx and bronchi may cause shortness of breath and difficulty in breathing deposits around the heart and blood vessels can calcify and lead to atherosclerotic plaques,  

Urine exposed to air can become dark; this is useful for diagnosing young children using diapers.


Sclera becomes pigmented but this does not affect the vision.


Reducing intake of the amino acids phenylalanine and tyrosine to the minimum .Vitamin C has been found to slow down the conversion of Homogentisic acid to the polymeric deposits in cartilage and bone.
Albinism Albinism is a defect of melanin production that results in little or no color (pigment) in the skin, hair, and eyes.There are three  main categories of albinism in humans:In oculo cutaneous albinism pigment is lacking in the eyes, skin and hair.In ocular albinism, only the eyes lack pigment.

 People who have ocular albinism have generally normal skin and hair color.

In patchy albinism– patches of depigmentation  are there on skin and hair


The diagnosis of the condition is based on the appearance of skin, hair, and eyes.Genetic testing offers the most accurate way to diagnose albinism and its type. Absence of coloring from the hair, skin, or iris of the eye, Long-term sun exposure greatly increases the risk of skin damage and skin cancers, including an aggressive form of skin cancer called melanoma, in people with this condition. Symptomatic treatment. Sun screen lotions and sun glasses are very helpful.Genetic counseling is  recommended  if the disease runs in families.
Phenylketonuria (PKU) Deficiency of the enzyme phenylalanine hydroxylase or of its cofactor tetrahydrobiopterin causes accumulation of phenylalanine in body fluids and the central nervous system (CNS).


In classic PKU, levels may range from 6 to 80mg/dl, but are usually greater than 30mg/dl. Identification and measurement of phenylketones in the urine has no place in any screening program.


Identification of phenylketones in the urine by ferric chloride may offer a simple test for diagnosis of infants with developmental and neurologic abnormalities.

CLASSICAL    PKU- The infants are normal at birth, Mental retardation may develop gradually, Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an early symptom. Older untreated children become hyperactive with purposeless movements. On physical examination these infants are fairer in their complexion than unaffected siblings. About 25% of children have seizures, and more than 50% have electroencephalographic abnormalities.

Microcephaly, prominent maxilla with widely spaced teeth, enamel hypoplasia, and growth retardation are other common findings in untreated children.



The goal of PKU treatment is to maintain the blood level of phenylalanine between 2 and 10 mg/dl.Some phenylalanine is needed for normal growth.This requires a diet that has some phenylalanine but in much lower amounts than normal.Because phenylalanine is not synthesized by the body, “over treatment” may lead to phenylalanine deficiency manifested by lethargy, failure to thrive, anorexia, anemia, rashes, diarrhea, and even death; moreover, tyrosine becomes an essential amino acid in this disorder and its adequate intake must be ensured.

Oral administration of the cofactor (BH4 ) to patients with milder forms of hyperphenylalaninemia from phenylalanine hydroxylase deficiency may produce significant reductions.




Hart Nup Disease It is caused by impaired neutral (i.e., monoaminomonocarboxylic) amino acid transport in the apical brush border membrane of the small intestine and the proximal tubules of the kidney. Excessive amounts of amino acids, such as Tryptophan, are excreted in the urine.The body is thus left with inadequate amounts of amino acids. Urine Analysis –   Neutral amino acids, Tryptophan, Indole derivatives and Tryptophan degradation products are present in urine. Patients present with pellagra like skin eruptions, cerebellar ataxia,, nystagmus , tremor, failure to thrive, photosensitivity,  and gross aminoaciduria.Symptoms may be triggered by sunlight, fever, drugs, emotional or physical stress. A high-protein diet can overcome the deficient transport of neutral amino acids in most patients. Avoiding excessive exposure to sunlight, wearing protective clothing, and using physical and chemical sunscreens are mandatory, daily supplementation with nicotinic acid or nicotinamide reduces both number and severity of attacks.
Maple syrup urine disease MSUD is caused by a deficiency of the branched-chain alpha-Keto acid dehydrogenase complex (BCKDH), leading to a buildup of the branched-chain amino acids (leucine, Isoleucine, and Valine) and their toxic by-products in the blood and urine. Blood and urine in this disease have elevated levels of branched amino acids and their keto derivatives. The keto derivatives cause acidosis. Poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, Ketoacidosis, opisthotonus, pancreatitis, coma and neurological decline. The disease is characterized in an infant by the presence of sweet-smelling urine, with an odor similar to that of maple syrup. Infants with this disease seem healthy at birth but if left untreated suffer severe brain damage, and eventually die.  A diet with minimal levels of the amino acids leucine, Isoleucine, and Valine must be maintained in order to prevent neurological damage.As these three amino acids are required for proper metabolic functions, specialized protein preparations containing substitutes and adjusted levels of the amino acids have been synthesized and tested, allowing MSUD patients to meet normal nutritional requirements without causing harm.
Cystinuria The amino acid transporter for cystine and other amino acids like Arginine, ornithine and Lysine, is defective both in the intestine and in PCT of nephron. This leads to retention of cystine and other amino acids in urine. Cystine gets precipitated in acidic pH 1)Sodium cyanide nitroprusside test. in the presence of cystine a purple-red colour is observed.2) Flat x-ray of the kidney, ureters and bladder (KUB), is undertaken to visualize the stones.3) Microscopic examination  of urine  reveals flat hexagonal crystals of cystine.  Recurrent nephrolithiasis. Possible complications include obstruction of the urinary tract, which can predispose to infection of the urine ,fever may be apparent, and white blood cells are noted in the urine. Unrelieved obstruction leads to renal dysfunction, renal failure and the need for dialysis are quite rare. Medical therapy is directed toward dissolution of existing calculi and prevention of new stone formation.Increasing urine volume by generous oral fluid intake is beneficial.Cystine solubility can be improved by urinary alkalinization and where necessary by the administration of thiol chelators, particularly D-penicillamine or mercaptopropionyl glycine.


Carcinoid syndrome Carcinoid syndrome refers to the array of symptoms that occur secondary to Carcinoid tumors. Many of the symptoms of carcinoid syndrome are produced by serotonin or its metabolites. 24 hour urine levels of 5-HIAA (5-hydroxyindoleacetic acid), a breakdown product of serotonin. Patients with carcinoid syndrome usually excrete >25 mg of 5-HIAA per day. For localization of both primary lesions and metastasis, the initial imaging method is Octreoscan,  Flushing ,pellagra like rash, Secretory diarrhea and abdominal cramps are also characteristic features of the syndrome. When the diarrhea is intensive it may lead to electrolyte disturbance and dehydration. Other associated symptoms are nausea, and vomiting. About 50% of patients have cardiac abnormalities, caused by serotonin-induced fibrosis of the tricuspid and pulmonary valves. Symptomatic treatment,.octreotide (a somatostatin analogue that neutralizes serotonin and decreases urinary 5-HIAA),methysergide maleate (antiserotonin agent but not used because of serious side effect of retroperitoneal fibrosis),cyproheptadine (an antihistamine drug).Surgical resection of tumor and chemotherapy (5-FU and doxorubicin) are the alternative treatments. 
Homocystinuria (Homocysteinemia).



Three major forms of homocysteinemia and Homocystinuria have been identified :1) Homocystinuria due to Cystathionine beta Synthetase deficiency,(Classical Homocystinuria),2)  The other forms can be caused by defective Methionine synthase or reduced availability of two essential cofactors, 5-methyltetrahydrofolate and Methylcobalamine (methyl-vitamin B12).


Elevations of both Methionine and homocystine in body fluids are the diagnostic laboratory findings.Total plasma homocysteine is extremely elevated (usually >100 M). 

Cystine is low or absent in plasma.


The diagnosis may be established by assay of the enzyme in liver biopsy specimens, cultured fibroblasts.


Failure to thrive and developmental delay. Subluxation of the ocular lens (ectopia lentis) occurs. This causes severe myopia and iridodonesis (quivering of the iris), Astigmatism, glaucoma, cataracts, retinal detachment, and optic atrophy may develop later in life.  

Progressive mental retardation is common, skeletal abnormalities resemble those of Marfan syndrome;

Patients usually have fair complexions, blue eyes, and a peculiar malar flush.

Generalized osteoporosis, especially of the spine, is the main radiographic finding.


Thromboembolic episodes involving both large and small vessels, especially those of the brain, are common and may occur at any age.




Supplementation with pyridoxine, folic acid, B12 or trimethylglycine (betaine) reduces the concentration of homocysteine considerably in the blood stream. Those who do not respond require a low Methionine diet.
Cystinosis Cystinosis occurs due to a mutation in the gene CTNS, located on chromosome 17, which codes for cystinosin, the lysosomal cystine transporter. The accumulation is caused by abnormal transport of Cystine from lysosomes, resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alter apoptosis in such a way that cells die inappropriately, leading to loss of renal epithelial cells. This results in renal Fanconi syndrome and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.  Definitive diagnosis and treatment monitoring are most often performed through measurement of white blood cell cystine level using tandem mass spectrometry.



Symptoms are first seen at about 3 to 18 months of age with profound polyuria (excessive urination), followed by poor growth, photophobia, and ultimately kidney failure by age 6 years in the nephropathic form. The other forms are Intermediate cystinosis (Juvenile) and Non-nephropathic or ocular cystinosis (Adult) forms. The drug cysteamine slows the progression of cystinosis by removing the cystine from cells, but for the drug treatment to be effective, it must be taken every six hours. Without specific treatment, these children progress to end-stage renal failure by an average age of nine years. Cystinosis is a common cause of the Fanconi Syndrome, a renal tubular disease.  









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