Albinism

 Autosomal recessive
 Absence of colour pigmentation in skin, hair, iris
 Reduced pigmentation in iris ⇒ photosensitivity
 Reduced pigmentation in the skin ⇒ increased incidence of skin cancer
 In Type 1 albinism:
 Defects in metabolism of tyrosine
 Tyrosine tyrosinase melanin
Histidinaemia
 Autosomal recessive
 Half the cases are mentally retarded, speech defects
 Deficiency in histidinase, enzyme for normal metabolism of histidine
 Histidine → urocanate
Raised plasma and urine levels of histidine
Urocanate (normally present in sweat) is absent
Diagnosis:
Histidine and metabolite imidazole pyruvic acid present in urine
Add ferric chloride to urine
If urine turns green there is histidine

Cystinosis
 Rare, serious disorder of cystine metabolism
 Intracellular accumulation and storage of cystine within lysosomes in many
tissues: kidneys, thyroid, corneas
 Crystals in corneas ﾁ¨ blindness
 Renal tubular damage caused by cystine causes Fanconi’s Syndrome
Renal tubular acidosis: loss of nutrients, salts and minerals in urine

Long term damage occurs to glomeruli

Without treatment, kidneys eventually fail ⇒ dialysis or transplantation

 Autosomal recessive
 Must be distinguished from cystinuria
 Types of cystinosis:
 Infantile (nephropathic cystinosis)
 Late-onset cystinosis
♦ Late childhood or adult life
♦ Renal failure ⇒ transplantation
 Benign cystinosis
♦ Crystalline opacities of cornea and conjunctiva but no damage to retina
♦ No renal damage
 Treatment:
 Cysteamine reduces accumulation of cystine in cells
  ∴ reduce tissue damage
 Eye drops containing cysteamine reduce cornea damage

Homocystinuria
 Defect in enzyme cystathionine synthase
 Mechanism unclear
 Homocysteine cysteine
 Elevated levels of homocysteine ⇒ detected in urine
 Homocysteine methionine
 Methionine ↑↑ in serum
 Clinical presentation
 Dislocation of lens
 Mental retardation
 Skeletal and neurological problems

Maple Syrup Urine Disease (MSUD)

 General description:
 Caused by infant's inability to use several amino acids
 Infant's urine smells like maple syrup
 Disorder leads to mental retardation, seizures and usually death
 A special low protein diet to avoid many of these problems
 Autosomal recessive
 Block in degradation of 3 branched chain amino acids:
 Leucine
 Isoleucine
 Valine
 Raised concentration of these branched chain amino acids and their ketoic acids in
plasma and urine
 Detected by laboratory assays
 Disease presents during the first week of life
 Urine smells like maple syrup / burnt sugar
 Odour is derivative of isoleucine
 Untreated ⇒⇒ serious neurological lesion, mental retardation, respiratory failure,
death within weeks / months
 Dietary restriction of affected amino acids ﾁ¨ normal development possible
 Mandatory neonatal screening for MSUD
 Diagnosis:
 Raised plasma and urine concentrations of branched chain amino acids
 Demonstrate enzyme defect in leucocytes
 Treatment:
 Correcting metabolic imbalance ~ long-term dietary restriction
Inherited Disorders of Transport Mechanisms
 Chemically similar substances often transported by shared or interrelated
pathways
 Transport across cell membranes
 Defects often involve both the renal and the intestinal mucosa
 Affected: amino acid group pathways
 Dibasic amino acids (with two amino acid groups) cystine, ornithine, arginine,
and lysine (COAL) - Cystinuria
 Neutral amino acids (with one amino and one carboxyl group) - Hartnup disease
 Imino acids, proline, and hydroxyproline, which probably share a pathway with
glycine - Familial iminoglyciuria

Cystinuria
 Defect in amino acid transport
 Abnormality of tubular reabsorption
 Excessive urinary excretion of dibasic amino acids: cystine (and cystine stones),
ornithine, arginine, lysine
 Cystine is relatively insoluble
 Due to relatively high concentration in homozygotes: may precipitate and
form calculi in the renal tract
 Concentration not high enough to precipitate in heterozygotes
 Autosomal recessive
 Relatively harmless condition
 Diagnosis: demonstrate excessive urinary excretion of the characteristic amino
acids in urine
 Management:
 Prevent calculi formation by reducing urinary concentration
 Drink plenty of fluids 24/7, day & night
 Urine alkalinity ↑ cystine solubility ↑
 Should all fail, D-penicillinamine forms chelate which is more soluble than
cystine alone

Hartnup disease
 Named after the first patient described (by Baron et al. 1956)
 Clinical presentation resembles pellagra (red scaly rash on exposed area of skin),
aminoaciduria, cerebellar ataxia (reversible), mental confusion of variable degree
 The 3 D’s (of niacin deficiency):
 Diarrhea Dementia →Dermatitis
 Rare autosomal recessive
 Renal and intestinal transport defects involving neutral amino acids (e.g.
tryptophan) ¨¨ poor absorption and excess excretion
  Decreased intestinal absorption and increased urinary loss of tryptophan
 Tryptophan deficiency ﾁ¨ niacin deficiency
 Niacin = nicotinic acid = Vitamin B3
 Despite generalised defect of amino acid absorption, there is no protein
malnutrition
 Heterozygotes are normal
 Diagnosis of homozygotes:
 Demonstrating characteristic amino acid pattern in urine
 Most children with Hartnup defect remain asymptomatic
 Responds to nicotinamide administration

Familial iminoglycinuria
 Autosomal recessive trait
 Benign transport defect in renal tubular reabsorption of imino acids and glycine
 ∴ Increased urinary excretion of imino acids, proline and hydroxyproline, and
glycine
 Harmless, but must be differentiated from other more serious causes of
iminoglycinuria, such as defect of proline metabolism, hyperprolinaemia

Hyperammonemia
 Disorders of the urea cycle
 Defect ⇒ ammonia unable to enter urea cycle for elimination & excretion ⇒
ammonia ↑↑
 Incidence = 1:30,000 live births
 Associated with lack of protein / enzyme in urea cycle
 Clinical presentation: variety of neurologic imbalances, including mental
retardation
 Ornithine transcarbamylase deficiency (OTC)
 Argininosuccinate synthetase deficiency (citrullinemia)
 Arginase deficiency (hyperargininemia)
 Argininosuccinic aciduria
 Carbamyl phosphate synthetase (CPS) deficiency
 N-acetyl glutamate synthetase deficiency (NAGS)
 All but OTC are autosomal recessive disorders; OTC is X-linked
 Diagnosis:
 Elevated plasma ammonia level
 Aminoaciduria
 Low level of enzyme activity in liver

 Treatment:
 Dietary restriction of proteins
 Benzoic acid may facilitate ammonia elimination via alternative pathways
(hippuric acid production)
 Arginine supplementation necessary except in hyperargininemia