Medical Genetics 3

Front 1

Allelic heterogeneity (compound heterozygotes)

Back 1

Having one mutation on one allele, and a different mutation which causes the same disease on the other allele. The phenotype is an affected person.

Front 2

AR Congenital Deafness (DFNB1)
DeaFNess, autosoimal recessive=B)

Sx. Gene and protein. Dx.

Back 2

Sx: non-progressive deafness. No other problems (non-syndromic)

Gene and protein: GJB2 (codes for connexin 26), and GJB6 (connexin 30) cause DFNB1. Locus heterogeneity!

Dx is made using molecular genetic testing (can identify >99%)

Front 3

Is cochlear implants successful for Deaf people with DFNB1?

Back 3

Yes.

Front 4

Alpha 1-AntiTrypsin Deficiency (AATD)

What is the function of AAT? Clinical findings. Age of onset in non-smokers vs. smokers. DX

Back 4

Alpha 1-AntiTrypsin coats the lungs, protecting it from neutrophils. It's a protease inhibitor.

Clinical findings: COPD include emphysema, asthma, airflow obstruction, and chronic bronchitis. Can include liver diseases such as jaundice.

Age of onset in non-smokers is approximately 60yo, vs 40yo in smokers.

Dx: low plasma levels of alpha 1-antitrypsin.

Front 5

Heteroplasmic DNA

Back 5

More than one genotype in a cell. Mt has heteroplasmic DNA.

Front 6

Kearns-Sayre Syndrome.

Classification. Etiology. Subtype (localized to eyes).

Sx

Back 6

Mitochondrial deletion syndrome. Etiology: usually sporadic (unlike point mutatiosn which are uaually maternally inherited.

Progressive External Ophthalmoplegia (PEO) is a KSS version localized to the eyes. (ophthalmoplegia= paralysis of one or more external ocular muscles). In PEO, deletions are primarily in the muscles.

Sx: short stature, hearing loss, mental retardation or dementia, and endocrinopathy.

Front 7

LHON (Leber's Hereditary Optic Neuropathy).

Classification? What structure is mutated? Sx.

Back 7

Mitochondrial point mutation. Mutation is in complex I subunit. Most mutations are homoplasmic, but some are heteroplasmic.

Sx: inflammation of optic nerve. Blindness due to optic nerve degeneration.

Front 8

Leigh Syndrome

Classification. Sx.

Back 8

Classification: Mt point mutation.

Sx: mild forms show NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa).
More severe cases show more devastating sx in brain and basal ganglia.

Front 9

What is MARP

Back 9

Mt ATP Production Rate

Front 10

Compound heterozygocity vs double heterozygocity vs digenic inheritance.

Back 10

Compound heterozygocity: having two heterogeneous recessive alleles which cause disease (so the pt will have the disease phenotype despite being a heterozygote). Occurs in diseases that have allelic heterogeneity.

Double heterozygocity: The condition of having two mutant alleles on two different loci, resulting in diseased phenotype. Occurs in diseases that have locus heterogeneity. This is also called digenic inheritance (double heterozygote with resultant disease)

Front 11

What are some of the downstream diseases caused by reduced energy production by Mt?

Back 11

Alzheimer's, Parkinson's, diabetes, cancer, psychiatric diseases, cardiomyopathies, neuropathies ALS, and MS)

Front 12

Parkinson's Disease (PD)

Classification. List some genes involved.

Back 12

PD is a mitochondrial disease.

Genes involved: TFAM, PARKIN, PINK1, DJ, and others.

Front 13

Multiple Sclerosis (MS)

Describe. Possible causes.

Back 13

An acquired demyelination of the CNS.

Causes: there is growing evidence that mt function and energy metabolism play an important role.

Front 14

Diabetes Mellitus

Which type of mitochondrial genetic mutations contribute/cause it? (mtDNA or nuclear?)

Back 14

Several percent cause by frank mtDNA mutatation. Also, some nuclear mt gene mutations are observed in other individuals.

Front 15

Direct vs indirect analysis of genetic mutation

Back 15

Direct analysis: requires knowledge of normal gene sequence to identofy mutants.

Indirect analysis (linkae analysis): identification of specific sequence change close to gene of interest. Used when specific gene is yet UNIDENTIFIED. DOES NOT detect causative mutation within a specific gene.

Front 16

What are SNP's clinically useful for?

Back 16

Detection of CNV's, and copy neutral absense of heterozygocity (AOH) associated with uniparental disomy and consanguinity. Also, loss of heterozygocity in tumor cells.

Front 17

Fragile X Syndrome

Dx testing

Back 17

Dx of syndrome Sx.
Dx of FXTAS (Fragile X Ataxia Syndrome).
Dx of Premature Ovarian Illness.

Front 18

Inherited thrombophilia disorders (factor V Leiden)

Describe. Pregnancy effect. Penetrance. Increases risk for what?

Back 18

Increased risk of venous thrombosis. Pregnancy is an "aquired" risk factor, i.e. it increases coaglation and decreases fibrinolysis.

Not all carriers will develop the disease.

Increases risk for preeclampsia, stillbirth, abruptio placentae, and perhaps fetal growth retardation.

Front 19

Phenylketonuria (PKU)

Mode of inheritance. Cause of disease.

Back 19

Mode of inheritance: autosomal recessive.

Cause of disease: mutatiopn in gene coding phenylalanine hydroxylase which converts phenylalanine to tyrosine. This leads to increased plasma phe. Accumulation of PRODUCT interfers with CNS.
Accumulation of ALTERNATIVE product (phenylpyruvic acid) also causes toxicity.
DEFICIENCY of product: deficiency of tyrosine leads to neurotransmitter deficiency.

Front 20

PKU

Sx. Dx. Tx

Back 20

Sx: severe mental retardation, dry skin, seizures, and autism. Phe is a teratogen.
Sx are preventable!

Dx: elevated plasma phe levels, and low tyrosine levels.

Tx: lifelong dietary modification. Supplementation with ynthetic BH4 (a cofactor).

Front 21

Galactosemia

Mutation. Sx. Dx. Tx. Prognosis.

Back 21

Mutation in gal-1-phosphate uridyltransferase.

Sx start with milk feeding. Vomit and diarrhea, lethargy, hypotonia, jaundice, enlarged liver, susceptibility to Gram - bacterial infections. Mental retardation. Early menopause.

Dx: elevated plasma or urine galactose.

Tx: dietary restriction (no milk or dairy).

Prognosis: good general health as long as tx is followed.

Front 22

Fatty Acids oxidation disorders.

How do they present?

Back 22

They present as hypoketotic hypoglycemia, which can lead to seizures and coma.

Front 23

Medium chain Acyl-CoA Dehydrogenase Deficiency.

Mode of inheritance. Sx. Dx. Tx. Prognosis.

Back 23

Autosomal recessive. Most common fatty acid oxidation disorder.

Sx: previously healtjhy child presents with hypoketotic hypoglycemia, vomiting, lethargy. Will progress to coma and death if untreated.

Dx: based on Sx, and also plasma acylcarnitine.

Tx: avoidance of fasting, and speedy treatment of illnesses.

Prognosis: excellent once dx is established.

Front 24

Lysosomal storage diseases

What is the one uniform clinical sx? Describe the progression of disease in individuals. Mode of inheritance.

Examples.

Back 24

Unrelenting progression.

Pt's appear normal at birth, but as material accumulates there is plateau then regression.

Modr of inheritance is usually autosomal recessive, except Hunter syndrome which is X-linked recessive.

Examples: Tay-Sachs disease, and mucopolysacccharidosis.

Front 25

Tay Sachs Disease.

Causes. Sx.

Back 25

Caused by inability to degrade the sphingolipid GM2, due to deficiency in enzyme hex A.

Sx: impact is almost solely on the brain. Gradual neurological deterioration in infants who previosly appeared healthy. Loss of milestones, weakness, increased sensitivity to noises, seizures, blindness, and spacticity. Cherry-red spot on retina in ophthalmologic exams. Death occurs at 2-5yo.

Front 26

Mucopolysaccharidosis (MPS)

What are mucopolysaccharides? What is MPS? Mode of inheritance.

Back 26

Mucopolysaccharides are polysaccharides synthesized by CT.

MPS are a group of heterogenous diseases in which mucopolysaccharides accumulate in lysosomes (lysosome storage disease).

Mode of inheritance: all is autosomal recessive, except Hunter Syndrome, which is X-linked recessive. Hurler syndrome is the prototype MPS disease.

Front 27

Hurler Syndrome

What type of metabolic genetic disease is this? What is the mode of inheritance?

Sx. Dx. Tx.

Back 27

A mucopolysaccharidosis (MPS) disease, which is a lysosomal storage disease.

Mode of inheritance: autosomal recessive.

Sx: normal infant at birth, then typical regression of lysosomal storage diseases (unrelenting progression, increased mass of affected tissue).

Dx: Enzyme assay, and non-degraded mucopolysaccharides in urine.

Tx: bone marrow transplant at an early stage may may slow progression. Enzyme therapy can ameliorate some of the sx, but because enzymes don't cross BBB mental retardation will still occur.

Front 28

What are two examples of co-enzyme deficiencies?

Back 28

Methylmalonic acidemia, and biotinidase dificiency.

Front 29

Methylmalonic acidemia.

What causes it? Sx. Dx. Tx.

Back 29

Caused by failure to convert methylmalonyl CoA to succinyl CoA by the enzyme methylmalonyl CoA mutase.
The former is an intermediate in BCAA metabolism.
Disease can be due to mutation in the coenzyme itself, or the cofactor (vit B12)

Sx: metabolic acidosis and neurologic sx (seizures, poor muscle tone, profound mental retardation).

Dx: enzyme assay and and elevated urine methylmalonic acid.

Tx: pt's having a cofactor deficiency may be vit B12 responsive. For pt's with the enzyme deficiency itself, tx is difficult and involves protein reduction but acidosis invariably occurs and can give cobalamine.

Front 30

Biotinidase Deficiency.

What causes it? Mode of inheritance. Sx. Dx. Tx.

Back 30

Caused by defect in recycling of the vitamin biotin, a cofactor required for all carboxylase enzymes.

Mode of inheritance: autosomal recessive.

Sx: metabolic acidosis, neurologic abnormalities, and eczema-like skin rash, and alopecia. Can result in coma and death.

Dx: urine organic acids. COnfirmed by enzyme assays.

Tx: very simple. Biotin supplemetation will prevent most sx. However, if if specific enzyme is deficient, tx is difficult.

Front 31

What are the acute neonatal sx of IEM?

Back 31

persistent or recurrent vomiting.
Poor feeding, or failure to gain normal weight.
Abnormal breating rate (apnea or increased respiratory rate).
Jaundice or enlarged liver.
Irritability.
Letahrgy.
Seizures.
Coma.
Unusual odors.
Unexplained clinical deterioration.

Front 32

What are some diseases caused by mutations in genes encoding tRNA?

What is the characteristic Sx in each?

Back 32

Myoclonic Epilepsy with Ragged Red Fibers (MERRF). Characteristic Sx: seizures.
Mitochondrial encephalopathy, lactic acidosis, and stroke-like symptoms (MELAS). Characteristic Sx: stroke.

In both cases, mutations are heteroplasmic (families may have asymptomatic individuals)

Other diseases are maternal myopathy and cardiomyopathy.

Front 33

Which gene is a mutation hotspot in Mt?

Back 33

Gene encoding Leu tRNA. Mutations in this gene support the idea that Mt genes may have more than one function because different mutations produce different Sx.

Front 34

What is the mechanism of genetic drift and gene flow?

Back 34

The mechanism of genetic drift is chance (usually happens in small population).

The mechanism of gene flow is migration and inter-racial matings.

Front 35

Multifactorial vs. pylogenic traits

Back 35

Multifactorial: multiple genes at different loci have additive effects; plus environmental factors contribute to the etiology.

Pylogenic: involves the additive effect of multiple genes, but NO ENVIRONMENTAL factors.