Lecture4 - amino acid storage disorders

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Most amino acids are

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“tied up” in protein

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small pools of amino acids exist and are in equilibrium with

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reservoirs in plasma, cerebrospinal fluid, lumina of GIT and kidney

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Physiologically: not only building blocks for proteins
Also have roles as

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• neurotransmitters: glycine, glutamate, γ-aminobutyric acid
• precursors of hormones, coenzymes, pigments etc: phenylalanine, tyrosine, tryptophan, glycine
• Each has its unique degradative pathway, providing the carbon and nitrogen to the synthesis of other amino acids, carbohydrates or lipids, or ATP

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> 70 disorders of amino acid metabolism are known

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Each of the disorders is relatively rare (1:10 000-1:200 000)
Collectively however 1:500 to 1:1000 (standard integrated tests)

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Almost all are

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autosomal recessive traits

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Naming:

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according to the compound that accumulates highest
In blood (-emia) or urine (-uria)

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Amino acid condition:

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aminoacidopathy
Parent amino acid accumulates vs the products of the metabolic pathway

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Pathway dynamics:

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Role of the site of the enzymatic block, reversibility of reactions proximal to lesion, flux through the pathway, metabolic “run off” pathways

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For some, eg branched chain amino acids, defects at each step of pathway

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High degree of biochemical and genetic heterogeneity:

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4 forms of hyperphenylalaninemia, 7 homocystinuria (enzyme activities)

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Manifestations differ widely:

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hyperprolinemia –> no clinical side effects vs complete deficiency of branched-chain keto acid dehydrogenase –> lethal in untreated neonate

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Common (more than half of the disorders):

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developmental retardation, CNS dysfunction, seizures, behavioral disturbances
Hyperammonemia (toxic), vomiting, neurologic dysfunction (urea cycle)
Metabolic ketoacidosis and hyperammonemia, liver disease or renal failure, cutaneous abnormalities, ocular lesions

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Clinical manifestations in many conditions can be prevented or mitigated IF diagnosed early
Dietary protein or amino acid restriction, vitamin supplementation
Routine screen in newborns

Prenatal amniotic fluid analysis

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Hyperphenylalaninemia definition

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autosomal recessive disorder in phenylalanine metabolism –> accumulation in blood and urine (as phenylbenzoic acid)

• 1:10 000, male/female equally

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Hyperphenylalaninemia
Pathophysiology:

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Highly decreased or non existent phenylalanine hydroxylase activity (hepatic), >300 mutations in PAH gene identified!
Increased accumulation inhibits other amino acid transport mechanisms (eg tryptophan), including transport across blood brain barrier
Synthesis dysfunction for: neurotransmitters (serotonin, noradrenalin), myelin, melanin

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Hyperphenylalaninemia
Clinically

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3 months post birth first signs
“mousy” piercing odor (phenylacetate in sweat and urine)
Eczema
5th month onwards: neurological dysfunction: spasms, rigor, tremor, hyperactivity, psychomotoric retarded, microencephaly in exceptional cases, light skin, blond hair (melanin deficiency)

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Hyperphenylalaninemia
Diagnosis

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5th day post birth, test (Guthrie)
EEG, phenylalanine challenge

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Hyperphenylalaninemia
Therapy:

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immediate: lifelong phenylalanine free diet, essential amino acid substitution
If late diagnosis: still diet, to reduce epileptic fits

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Hyperphenylalaninemia
Prognosis

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if not treated: 75 % lethal before age 30, high degree of mental retardation, IQ<50
If treated immediately: normal mental and physical development (indicating compensation and role of impaired transport as principal disturbances)

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Hyperphenylalaninemia is quite common in people of

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Scandinavian descent

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Hyperphenylalaninemia
Maternal PKU

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teratogene effects, congenital abnormalities, mental retardation

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Benign hyperphenylalaninemia

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(partial deficiency)
10% of variant forms: eg dihydropteridine reductase deficiency (here treatment with dietary restriction is not possible)

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Alkaptonuria
Definition and epidemiology:

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Disorder of tyrosine catabolism,
autosomal recessive (first human disease shown in this mode)
Deficiency of homogentisade 1,2 dioxygenase (liver, kidney)
Excretion of large amounts - homogentisic acid
1:200 000, more men affected
445 amino acid protein, HGD gene

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Alkaptonuria
Pathophysiology

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Accumulation of homogentisic acid as oxidised homogentisic acid pigment in tissues
Degenerative disease of joints, inflammatory changes at heart valves, vessels and joints

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Alkaptonuria
Clinically

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black/blue pigmentation (ochronosis) of sclera, skin, eyelid, ear, nose, sweat, cerumen
Polymerization of homogentisic acid interacting with connective tissue
Inner ear –> hearing disability

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Alkaptonuria
Diagnosis

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change of colour urine black
Skin pigmentations
Calcification and degeneration of joints and spinal column

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Alkaptonuria
Therapy:

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symptomatic treatment for joint degeneration

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Alkaptonuria
Prognosis

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Usually normal life expectancy
In age: myocardial valve disease, infarction, aneurisma

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Maple Syrup urine disease

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Maple Syrup urine disease
Severe forms

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Infants develop seizures and coma during first day of life and can die within days to weeks
Treatment with dialysis

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Maple Syrup urine disease
Milder forms

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children initially appear normal
during infection, physical stress, surgery etc: vomiting, staggering, confusion and coma
Treatment with Vit B1 injections, diet

Newborns screened routinely since 2007 in US

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Thinking points
What are common denominators (metabolically, physiologically, clinically) in amino acid storage disorders?

Why are these conditions mostly fatal if not treated? Use an example to explain.