Term
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Definition
Presence of multiple alleles at a locus
Could be due to
Allele with residual function
Ex: congenital absence of vas deferens and CFTR
Specific sub function of a protein more affected
Hb Kempsey and β-thalasemia
Unpredictable nature
α1-antitrypsin deficiency and liver disease |
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Term
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Definition
| Association of more than one locus with a specific clinical condition |
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Term
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Definition
Other disease causing alleles, polymorphisms or rare benign variants modulate severity of the disease
Ex: severity of disease in β –thalassemia homozyotes who also inherit an α-thalassemia allele, ApoE on Alzheimer’s disease
Cystic fibrosis -severity of pulmonary fibrosis(TGFB1 locus) |
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Term
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Definition
| Mutations in genes for enzymes |
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Term
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Definition
| With few exceptions, enzymopathies are inherited as ________ recessive disorders. |
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Term
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Definition
| Enzyme deficiencies of _____ ____are exceptions and are inherited in an autosomal dominant fashion |
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Term
| Tetrahydrobiopterin - BH4 |
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Definition
Deficiencies of multiple enzymes may occur simultaneously
Deficiency of the common cofactor or coenzyme. give an example of this disease |
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Term
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Definition
Mutation in the common subunit, activator or processing protein
Give an example of this |
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Term
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Definition
Enzymes processed by a common enzyme that is deficient
Give an example of this |
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Term
| peroxisomal disorders (e.g. Zellweger syndrome) |
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Definition
| Abnormality in organelles. give an example of this |
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Term
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Definition
The pathological effect of an enzyme deficiency
Is confined to the tissue in which the substrate accumulates IF The substrate cannot diffuse out of the cell or organelle
Give an example |
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Term
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Definition
| The pathological effect of an enzyme deficiency may be wide spread, involving many different organs and tissues IF The substrate is a diffusible small molecule. Give an example |
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Term
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Definition
| Partial deficiency of HPRT causes this |
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Term
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Definition
| Complete HPRT deficiency causes this syndrome |
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Term
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Definition
Illustrates almost every principle of biochemical genetics relating to enzyme deficiencies, hence termed as “the epitome of inborn errors of metabolism”
Most common deficiency of an enzyme of amino acid metabolism
Name comes from the excretion of phenylpyruvic acid, a phenylketone, in the urine
Over 170 mutations reported
I = 1/5000 to 1/16,000 (av. 1/10,000) in Caucasian populations
less frequent in other ethnic groups
AR
Deficiency of phenylalanine hydroxylase
Characterized by elevated levels of plasma phenylalanine
Neurological damage may be avoided by dietary modifications prevent phenylalanine accumulation
Normal plasma phenylalanine level < 1mM
Levels in PKU 2-3mM |
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Term
| Phenylalanine Hydroxylase |
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Definition
Catalyzes conversion of phenylalanine to Tyrosine
Requires BH4 (Tetrahydrobiopterin) as a coenzyme
BH4 level is maintained through recycling and de novo synthesis |
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Term
| dihydropteridine reductase |
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Definition
| BH4 is recycled by the enzyme |
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Term
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Definition
| Level of BH4 is also maintained through de novo synthesis from |
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Term
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Definition
| is also required as a coenzyme for tyrosine hydroxylase and tryptophan hydroxylase synthesis of catecholamine (NE, E) and serotonin respectively |
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Term
| 408 Arg →Trp (Arg408Trp; R408W) |
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Definition
| what is the most common mutation (31%), causing classic PKU |
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Term
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Definition
Neurotoxic effects due to elevated level of phenylalanine damaging the developing central nervous system in early childhood
developmental delay (apparent in infancy), microcephaly, seizures, hyperactivity, behavioral disturbances, profound mental retardation, if untreated
Underpigmentation because of tyrosine deficiency and competitive inhibition of tyrosinase Light color of skin and blue eyes
Infants have a mousy or musty odor resulting from ketoacid metabolites of phenylalanine |
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Term
| The Guthrie card bacterial inhibition assay (BIA), |
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Definition
| what is the test used for neonatal diagnosis of PKU |
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Term
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Definition
| If the woman has high plasma phenyl alanine concentrations during pregnancy this could lead to a |
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Term
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Definition
| Children most likely will have congenital heart malformations, intrauterine and postnatal growth retardation, microcephaly, and mental retardation in the presence of |
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Term
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Definition
AR
Deficient enzyme: Homogentisate oxidase
Catalyzes conversion of homogentisic acid to maleylacetoacetate in the catabolic pathway for tyrosine
Homogentisic acid accumulates and auto-oxidizes polymerizes to form a dark-colored pigment deposited in connective tissue (alkaptan bodies) normally transparent tissues become slate blue
Onset: fourth decade of life - external signs of pigment deposition ochronosis, begin to appear discoloration of sclerae and ear cartilage
Hips, knees, and intervertebral joints affected most commonly degenerative arthritis
Treatment high doses of vitamin C |
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Term
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Definition
AR
Enzyme deficiency: Classic OCA, Tyrosinase
Tyrosine ____Tyrosinase__→ Melanin (pigment)
Mutations in other loci may also be involved
Pathology/ clinical features
lack of pigment in skin, hair, iris, ocular fundus
poor visual acuity, nystagmus (pendular eye movement)
underdevelopment of retinal fovea
impaired projection of the visual pathways to optical cortex |
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Term
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Definition
AR
Deficient enzyme: cystathioneine β-synthetase
also could be caused by deficiency of
methionine synthase,
coenzyme deficiencies
pyridoxal phosphate (Vitamin B6) (cytathionine β-synthetase),
folate and vitamin B12 (methionine synthase) |
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Term
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Definition
Deficiency of Glucose 6-phosphatase
Affects liver, kidney and intestinal mucosa
Accumulation of Glycogen of normal structure
Clinical features
Growth retardation, hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia & hyperlipidemia
Treatment nocturnal nasogastric administration of glucose or oral uncooked starch |
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Term
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Definition
| Lysosomal storage disorder |
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Term
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Definition
Deficiency of debranching enzyme
Accumulation of glycogen with structure resembling limit dextrin (glycogen with short outer chains)
Affects glycogen metabolism but not gluconeogenesis
Clinical features in childhood – hepatomegaly and hypoglycemia; symptoms improve with age and disappear after puberty |
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Term
| Type IV – Andersen’s disease |
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Definition
Deficiency of branching enzyme
Accumulation of glycogen with long, unbranched outer chains
Presents in first year of life with hepatosplenomegaly and failure to thrive
Progressive liver cirrhosis death by 5 years |
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Term
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Definition
Deficiency of muscle phosphorylase
Symptoms in adulthood exercise intolerance, muscle cramps and myoglobinuria |
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Term
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Definition
Deficiency of liver phosphorylase
Similar to von Gierke’s disease but milder symptoms |
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Term
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Definition
HGPRT deficiency)
X-linked recessive inheritance
Absolute deficiency of HGPRT (hypoxanthine guanine phosphoribosyltransferase)
HGPRT –participates in Salvage pathway of Purines
Symptoms:
Hyperuricemia Nephrolithiasis with renal failure, gouty arthritis, and tophi.
Neurological disability extra pyramidal signs (dystonia, choreoathetosis) & pyramidal signs( spasticity and hyperreflexia) possibly due to purine imbalance
Behavioral problems cognitive dysfunction and aggressive and impulsive behaviors & self mutilation
Present at 3-12 months with delayed motor development
"orange sand" in the diapers uric acid crystalluria and microhematuria. |
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Term
| Alpha 1 antitrypsin deficiency |
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Definition
Autosomal recessive inheritance
Associated with high risk of chronic obstructive lung disease and cirrhosis of liver
Belongs to the family of serine protease inhibitors ( serpins)
Chief role is to bind and inhibit elastase particularly neutrophil elastase from lower respiratory tract
Deficiency
In Caucasian population 1 in 5000 incidence and 2% are carriers |
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Term
| methionine 358 (at active site) |
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Definition
| Nicotine metabolites oxidise |
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Term
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Definition
| Lung disease with z/z phenotype, survival after 60 years in non-smokers is __ and in smokers it is __ |
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Term
| Acute intermittent porphyria |
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Definition
Autosomal dominant disorder
Associated with intermittent neurological dysfunction
Due to deficiency of porphobilinogen deaminase an enzyme in Heme biosynthetic pathway
Catalyzes cyclization of single pyrrole (PBG) into first tetrapyrrole (Uroporphyrinogen I) in the pathway of heme synthesis
Clinical features can be precipitated by events that induce Cytochrome P450 system |
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Term
| negative feedback control |
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Definition
| Synthesis of ALA synthase upregulated due to loss of ___ ____ ____ |
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Term
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Definition
| residues bind to specific receptors on the inner surface of the Golgi membrane |
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Term
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Definition
| metabolic turnover of intracellular organelles |
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Term
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Definition
| extra-cellular substrates acquired by phagocytosis |
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Term
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Definition
degraded in lysosomes by acid hydrolases
Any hereditary defect in one of these enzymes results in a Sphingolipid storage disease
Substrate of the missing enzyme accumulates with disastrous consequences |
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