An autosomal recessive pedigree

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An autosomal recessive pedigree
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Autosomal recessive inheritance

• Affected individuals in a family usually are seen
  only within a sibship, not in their parents,
  offspring or other relatives, i.e. horizontal
  rather than vertical clustering of the condition
  in the family pedigree.
• The risk to each sib of an affected individual of
  showing the phenotype is 25 .
• Consanguinity significantly increases the risk of
  manifesting a recessive phenotype.
• Males and females are equally likely to be
  affected.
• Ethnicity and geographic isolation may affect the
  frequency of recessive conditions in a population

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Calculating the probabilities

• Probability
• Where
• Nnumber of children
• Snumber of normal children in family
• Tnumber of affected children
• Pprobability of being affected
• Qprobability of being normal
• Example 1 affected, 2 normal children
• Probability

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Heterozygous parents infrequently have more than
one affected child (with three total kids)
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Population genetics and carrier frequency
calculation

• The Hardy Weinberg equation
• Applies to a simple two allele system (I.e. two
  variants of a gene)
• p and q are the frequencies of two alleles in a
  stable population
• p2 frequency of diseased individuals
• 2pq carrier frequency

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The heterozygous state may be advantageous

• Sickle cell and thalassemia traits (heterozygous
  state, probably confer resistance to malaria)
• Cystic fibrosis carriers may be more resistant to
  dysentery

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Cystic fibrosis

• Clinical
• Dysfunction of mucous producing glands in gut,
  bronchioles, pancreatic exocrine dysfunction and
  sweat gland dysfunction
• Malabsorption, intestinal obstruction
• Frequent pulmonary obstruction and infections
• Abnormal vas deferens development ? male
  sterility
• Death usually by 20s from pulmonary
  complications
• Sweat chloride elevated

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Cystic fibrosis

• Prevalence
• Affects 1/2500 Caucasian births, carrier
  frequency 1/25
• Cystic fibrosis transmembrane regulator (CFTR)
  gene mutated.
• Large gene on 7q31
• Many different mutations described, but deletion
  of 3 bases at codon 508 occur in about 90 of CF
  patients of Northern European heritage. Ashkenazi
  Jewish CF patients have a different mutation as a
  rule.
• Large size of gene and variety of mutations (over
  400 known) makes screening difficult. Screening
  for the more common mutations can detect about 95
  of mutations in Caucasians, but only 50 of
  mutations affecting African Americans

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Cystic fibrosis transmembrane regulator
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Cystic fibrosis

• Management
• Treatment of ileus surgically may be necessary
• Pancreatic enzyme replacement
• Good pulmonary therapy
• DNAse inhaler to reduce viscosity of airway
  secretions
• ?Gene therapy, e.g. adenovirus vector mediated
  delivery of CF gene to bronchiolar epithelium
• Lung transplantation
• Genetic counseling

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Congenital bilateral absence of the vas deferens

• Occurs in males who are compound heterozygotes
  they have one severe CFTR allele and one mild
  CFTR allele
• They only have absent vas deferens no pulmonary
  or gastrointestinal problems
• Males present at infertility clinics
• May conceive using sperm aspirated from
  epididymal remnant
• Need appropriate genetic counseling
• Partners should be screened for CFTR mutations

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Sickle cell trait and anemia

• First genetic disease to be characterized at
  molecular level Protein sequence abnormality
  found before gene was isolated
• Mutation causes a valine substitution for the
  normal glutamate at the sixth amino acid position
  of ?-globin
• Under conditions of low oxygen tension,
  hemoglobin tetramers self associate to form rigid
  hemoglobin polymers that distort the RBCs which
  are fragile and can clog capillaries, resulting
  in a crisis.

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Sickle cell

• Sickle trait (the presence of any HbS) is
  dominant, but is generally asymptomatic unless
  extremely hypoxic (e.g. unpressurized at high
  altitude)
• Sickle cell anemia is recessive
• Clinical syndrome
• Painful abdominal and bone crises brought out
  especially by hypoxia, but often unpredictable
• Complications include infarcts of internal organs
  and joints
• May autosplenectomize, leading to predisposition
  to infections

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Sickle cell anemia
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Sickle cell mutation
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Pathogenesis of sickle cell disease
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Sickle cell

• Prevalence
• 1/500 births among African Americans
• Carrier frequency (i.e. prevalence of trait) 8
  of African Americans
• Screening readily accomplished by direct protein
  analysis
• Trait provides resistance to malaria

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Sickle cell

• Management
• Crises
• Oxygen
• Analgesia
• May need transfusions
• Long term
• Hydroxyurea, probably helps prevent
  polymerization of hemoglobin (should not be used
  in pregnant women)
• ? fetal bone marrow transplantation if detected
  in utero
• Gene therapy
• Pneumovax (patients often autosplenectomize)

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Autosomal recessive, 1 carrier, 1 affected parent
2 carriers 2 affected homozygotes (pseudodominant
pattern)
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Autosomal recessive, 1 normal and 1 affected
parent
4 heterozygous carriers
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Ethnic background and consanguinity are important

• Examples
• Tay-Sachs disease (hexosaminidase A deficiency)
• Severe, infantile onset neurodegenerative
  disorder
• Cherry red macula
• Fatal in first few years of life
• Most often seen in those of Ashkenazi (Eastern
  European) Jewish background
• Ataxia with vitamin E deficiency (AVED)
• First recognized in Middle East, where first
  cousin marriages are more common
• Caused by mutations in protein needed in gut for
  vitamin E absorption
• Treatable by high doses of vitamin E

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Thalassemias

• A group of hemoglobinopathies primarily
  characterized by abnormal levels of a particular
  globin chain
• More prevalent in malaria endemic regions trait
  may provide resistance to malaria
• ?-thalassemias Reduced levels of ?-globin
• 2 ?-globin genes on chromosome 16, therefore
  normally 4 ?-globin genes in human genome
• When 2 ?-globin genes are inactive ?-thalassemia
  trait
• When 3 ?-globin genes are inactive detectable ?4
  (HbH), with significant but non-lethal anemia
• When all 4 ?-globin genes are inactive ?4
  (Hemoglobin Barts) predominates leading to
  hydrops fetalis, neonatal or fetal lethal anemia
  with widespread tissue necrosis

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Thalassemias

• ?-thalassemias Reduced levels of ?-globin
• ?-globin gene lies on chromosome 11
• Huge range of mutation types, leading to reduced
  levels of ?-globin gene expression from affected
  chromosome
• Heterozygotes unaffected
• Homozygous state First year of life relatively
  normal since fetal hemoglobin still present, as
  fetal globin declines and attempts to make adult
  globin commence, anemia develops with massive
  hepatosplenomegaly, marrow space enlargement
• Management
• Transfusions, but must combine with iron
  chelation to prevent iron deposition and
  hemochromatosis
• ?Bone marrow transplantation

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Partial map of beta globin mutations
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Most enzymatic pathway diseases are recessive
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Metachromatic leukodystrophy

• Clinical
• Autosomal recessive
• Variable onset developmental delay after initial
  normal early development
• Spastic paraparesis/quadriparesis
• Seizures
• Peripheral neuropathy
• Fatal by age 5 in most severe form
• Laboratory
• Abnormal white matter on MRI scan, typically
  frontal predominance
• Relative to absolute deficiency of arylsulfatase
  A, a lysosomal enzyme needed for degradation of
  sulfatides, an important class of myelin lipid
• Pseudodeficiency of ARSA occurs as in vitro
  artifact where enzyme activity is low in test
  tubes, but sulfatide metabolism is normal when
  measured in cultured living cells from these
  patients.

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Sulfo-lipids
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Metachromatic leukodystrophy T2w MRI
Normal
MLD patient
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Metachromatic leukodystrophy

• Genetics
• Mutation of ARSA gene
• Chromosome 22q13.31 qter
• Multiple alleles allelic heterogeneity
• Clinical severity varies with degree of residual
  enzyme activity (worse with lower levels of
  activity)
• Onset ranges from infancy to adulthood, the
  latter may present with behavioral and cognitive
  abnormalities before motor deficits appear
• Locus heterogeneity
• Mutations of prosaposin, a cofactor for ARSA,
  produce clinically similar disease
• Limited success with bone marrow transplantation

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Ataxia telangiectasia (Louis-Bar syndrome)

• Clinical features
• Ataxia
• Begins during infancy
• Incoordination, dysarthria, nystagmus
• Telangiectases
• Appear during childhood. Easiest to see in bulbar
  conjunctivae
• Immunodeficiency
• Affects both B and T cell function
• Frequent infections
• Predisposition to malignancy
• Second most common cause of death
• Extremely sensitive to radiation (e.g. diagnostic
  X-rays)

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Ataxia-Telangiectasia II

• Prevalence of 1/40,000, carrier frequency 1 in
  US
• Carriers have 5 fold increase in breast cancer
  and other malignancies. More sensitive to
  radiation
• Ataxia telangiectasia gene (ATM) on 11q22 encodes
  a probable regulatory protein kinase probably
  regulates activity of genes involved in cell
  cycle control, DNA repair and tumor suppresser
  genes such as p53

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Ataxia telangiectasia
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Ataxia-telangiectasia elbow telangiectasias
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Friedreich ataxia

• The most common hereditary ataxia in US and
  Europe ( 50 )
• Prevalence 2 4/100,000, Carrier frequency 1/60
  1/100
• Progressive limb and gait ataxia usually
  beginning before age 25
• Absent tendon reflexes
• Babinski signs
• Pes cavus often present
• Sensory peripheral neuropathy with primarily
  axonal degeneration

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Friedreich ataxia an autosomal recessive disease
that affects mitochondria

• Clinical features
• Progressive gait and limb ataxia
• Absent reflexes
• Onset before age 20 - 25
• Dysarthria
• Autosomal recessive
• Sensory peripheral neuropathy
• Non neurologic features
• Cardiomyopathy (most severe complication of
  disease), deafness, diabetes

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Friedreich ataxia genetics

• Highly variable GAA trinucleotide repeat
  expansions in frataxin gene (9q13) intron 1
• Expansions show intergenerational and somatic
  variability
• Expansions interfere with gene expression and/or
  splicing
• Rough correlation between expansion length and
  disease severity
• Some patients have point mutations in frataxin
  gene

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Functional genomics Gene homologs in surprising
places

• Frataxin is homologous to a yeast protein
  involved in mitochondrial iron transport and
  homeostasis
• Mutations in yeast frataxin homolog result in
  accumulation of iron in mitochondria, leading to
  increased toxic free radicals and reduced
  mitochondrial function
• Idebenone, an antioxidant similar to coenzyme
  Q10, protects mitochondrial membranes and enzymes
  from damage and clinically helps prevent
  cardiomyopathy in FA patients

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Reduced ATP synthesis in FALodi et al. PNAS
9611492, 1999
Normal
FA
Postexcercise
30 s rest
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Reduced rate of ATP synthesis in FA
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GAA repeat size is inversely correlated with ATP
synthesis rate
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Friedreich ataxia pathogenesis defect in
intracellular iron homeostasis
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Frataxin an example of a nuclear gene involved
in mitochondrial function

• At least 1000 proteins in mitochondria
• mtDNA (16,569 bp)codes for
• Only 13 proteins
• 22 tRNA genes
• 12S and 16 S rRNA