Amino Acid Disorders — Phenylketonuria, Alkaptonuria, Maple Syrup Urine Disease, Homocystinuria, Albinism and Tyrosinaemia

An inborn error of amino acid metabolism is an inherited defect of one enzyme (or its cofactor) in the breakdown of an amino acid. Two things then go wrong: the substrate builds up and can be toxic, and the product becomes deficient. Almost all the classic examples are autosomal recessive, so consanguinity and affected siblings are common clues.

Exam questions cluster around the phenylalanine–tyrosine pathway (PKU, tyrosinaemias, alkaptonuria, albinism), the branched-chain amino acids (maple syrup urine disease) and the sulphur amino acids (homocystinuria). Learn each disorder as a chain: enzyme → what accumulates → signature sign → treatment.

Phenylketonuria (PKU) is deficiency of phenylalanine hydroxylase (PAH), the enzyme that converts the essential amino acid phenylalanine to tyrosine. The PAH gene is on chromosome 12q23.2, and inheritance is autosomal recessive. PAH needs tetrahydrobiopterin (BH4) as a cofactor; BH4 deficiencies cause only 1–2% of hyperphenylalaninaemia but also block neurotransmitter synthesis.

High phenylalanine competes with other large neutral amino acids for transport into the brain, so brain levels of their precursors fall and synthesis of dopamine, noradrenaline, adrenaline and serotonin is impaired. Tyrosine becomes deficient, so melanin falls too. Babies look normal at birth; untreated, over months they develop:

• Musty or mousy odour of skin and urine — from phenylacetic acid.
• Hypopigmentation (fair skin and hair) and eczema.
• Irritability, tremors, seizures, acquired microcephaly and intellectual disability.

PKU founded newborn screening. In the early 1960s Robert Guthrie developed a bacterial inhibition assay that detected high phenylalanine in dried blood spots (the Guthrie test). Today the heel-prick dried blood spot, taken at about 24–48 hours of life, is analysed by tandem mass spectrometry for phenylalanine and the phenylalanine-to-tyrosine ratio.

• Diet (mainstay, lifelong): avoid high-protein foods (meat, fish, eggs, dairy, soy, nuts) and aspartame, measure the small allowance of natural protein, and use phenylalanine-free medical formula.
• Sapropterin — synthetic BH4 — boosts residual PAH activity in BH4-responsive patients and lets them eat a more varied diet.
• Pegvaliase — PEGylated phenylalanine ammonia lyase, a daily subcutaneous injection for adults — breaks down phenylalanine without needing PAH.
• Large neutral amino acids can be used as an adjunct in adolescents and adults, because phenylalanine competes with them (for example tyrosine and tryptophan) for entry across the blood–brain barrier.

Alkaptonuria is autosomal recessive deficiency of homogentisate 1,2-dioxygenase (HGD), gene on chromosome 3q13.33. Homogentisic acid (HGA) builds up; patients excrete about 1–8 g a day in urine. Its three major features are urine that turns dark on standing, ochronosis and arthritis of the spine and large joints. It is rare — about 1 in 250,000 to 1 in 1,000,000 births in the US.

• Childhood: often the only sign is dark urine or dark stains on the nappy, from oxidation and polymerisation of HGA. Many patients never notice black urine, so it is unreliable.
• Ochronosis (named by Virchow in 1866 for the ochre colour under the microscope): bluish-black pigment in connective tissue — sclera, ear cartilage, skin of the hands. It usually appears after 30 years; arthritis often starts in the third decade.
• Spine: radiographs showing flattened, calcified intervertebral discs are pathognomonic; kyphoscoliosis, spinal stenosis and myelopathy follow.
• Other: aortic stenosis (most common cardiac lesion) and valve calcification, renal, prostatic and gallbladder stones, tendon and ligament ruptures.

Treatment: nitisinone blocks the step that makes HGA and has been shown to slow progression; the European Medicines Agency has approved it for alkaptonuria (the US FDA has not). Restricting phenylalanine and tyrosine in the diet has not proved effective and is impractical long term.

Maple syrup urine disease (MSUD) is deficiency of the mitochondrial branched-chain α-ketoacid dehydrogenase (BCKAD) complex, made of three catalytic subunits (E1, E2 and E3). The branched-chain amino acids — leucine, isoleucine and valine — and their ketoacids accumulate. Worldwide incidence is about 1 in 185,000 live births.

• Classic MSUD presents in the neonatal period: poor feeding, lethargy, irritability, and a maple syrup odour noticed first in the ear wax (cerumen) and then urine.
• The odour comes from sotolone, a metabolite of isoleucine.
• Leucine is the neurotoxic one: its product α-ketoisocaproic acid drives the encephalopathy; cerebral oedema is a cause of death.
• Diagnosis: raised plasma BCAAs and alloisoleucine; a clearly raised alloisoleucine is highly sensitive and specific and is considered pathognomonic (it may not be detectable until about day 6 of life).
• Treatment: restrict BCAAs, especially leucine, while supplementing valine and isoleucine; check thiamine responsiveness (a thiamine-responsive variant exists); liver transplantation for classic MSUD that diet cannot control.

Classic homocystinuria is deficiency of cystathionine β-synthase (CBS), which normally moves homocysteine on to cystathionine. Methionine and homocysteine accumulate. Four systems are involved:

• Eye: ectopia lentis and/or severe myopia — lens dislocation in nearly 90%, bilateral, inferonasal in about 60%.
• Skeleton: tall stature, long limbs, arachnodactyly, scoliosis, pectus deformity — a marfanoid habitus — but with osteoporosis.
• Vessels: thromboembolism — an apparently healthy adult may present with a stroke or other clot as the first sign.
• CNS: developmental delay, intellectual disability, seizures, psychiatric problems and dystonia.

Treatment: a trial of vitamin B6 (pyridoxine), the CBS cofactor — though almost all babies picked up by newborn screening are B6-non-responsive; a methionine-restricted diet; folic acid and B12 as needed; and betaine. Homocysteine metabolism also links to megaloblastic anaemia.

Albinism: tyrosinase catalyses the first, rate-limiting step of melanin synthesis (tyrosine → DOPA). In oculocutaneous albinism type 1A loss of tyrosinase abolishes eumelanin. Melanin also guides development of the fovea and optic pathways, so albinism causes nystagmus and misrouted optic fibres. Without melanin's photoprotection the skin is prone to sun damage and squamous cell carcinoma, so lifelong sun protection and skin checks are needed. Melanocytes sit in the basal layer of the epidermis.

Hartnup disease is an autosomal recessive defect of absorption of neutral amino acids from the gut and the renal tubule. The gene is SLC6A19 (short arm of chromosome 5), which encodes the apical transporter B0AT1 of the small intestine and proximal convoluted tubule; ACE2 (gut) and collectrin (kidney) are needed to bring it to the cell surface.

• PKU with normal PAH but progressive neurology despite diet → think BH4 deficiency.
• Dark urine on standing + back stiffness in a 40-year-old → alkaptonuria; X-ray shows calcified discs.
• Ear-wax smell in a sick neonate → MSUD; the toxic amino acid is leucine, the odour is from isoleucine (sotolone).
• Tall child, downward lens dislocation, DVT or stroke → homocystinuria, not Marfan syndrome.
• Child with absent pigment and nystagmus from birth → albinism (tyrosinase), not PKU — PKU babies look normal at birth.
• Infant with liver failure and rickets-like bone disease, raised succinylacetone → tyrosinaemia type I (see rickets).

Biochemistry past papers are in the NEET PG Biochemistry PYQs; chromosomal causes of intellectual disability are on the chromosomal syndromes page.