Day 7, Lecture 1 (Aug 30): Genetics X: Disorders with Mendelian Inheritance

Question 1

Common Mendelian Disorder

Answer 1

• AR
  
  • PKU
  • Hurler Syndrome
  • Sickle Cell Disease
  • Cystic Fibrosis
• AD
  
  • Neurofibromatosis
  • Achondroplasia
• XLR
  
  • Duchenne Muscular Dystrophy

Question 2

Phenylketonuria (PKU)

Answer 2

• Deficiency of phenylalanine hydroxylase (PAH)
• Cytogenetic location fo PAH:
  
  • 12q23.2
• Relatively common disorder, prevalence at birth:
  
  • about 1/10,000-1/20,000
• Pathophysiology
  
  • Untreated, PKU leads to:
    
    • Phenylalanine accumulation
    • Tyrosine deficiency
  • Main pathogenicity is increased phenylalanine accumulation in the brain, resulting in severe intellectual disability
  • Other features, if untreated, are:
    
    • Fair hair
    • Pale skin, blue eyes
    • Microcephaly
    • Eczematous skin rashes
    • Musty/mousy odor (phenylketones in urine and sweat)
• Not all mutations totally ‘destroy’ PAH activity and some just cause hypoinsufficiency thus some patients have a milder form of the disease
• Management of PKU
  
  • Early identification
    
    • newborn screening
  • Early confirmatory testing
  • Early intervention
    
    • Metabolic formula, with phe
  • later in life, continued phe frequent monitoring
  • In adolescence and adulthood, compliance with diet, with phe control, and increasing problem function (note that in adults you can get a reversible situation and go back to the diet restriction with limited permanent effects but this is not the issue in children)
  • Another problem is the ‘infant of PKU mother’
    
    • The infant can have the symptoms of PKU without having the disease do to the mothers elevated levels
• Novel (experimental) therapies
  
  • PAL: Phenylalanine amonia lyase
    
    • This is a plant enzyme
    • converts L-Phe to trans-cinnamic acid
• Genetic counseling
  
  • Parents heterozygous, asymptomatic carriers
    
    • recurrence risk is 25%
  • Prenatal testing is possible
    
    • best if molecular diagnosis in proband known
      
      • not commonly done

Question 3

Novel (experiemental) therpy for PKU

Answer 3

Question 4

Hurler Syndrome

Answer 4

• Deficiency of alpha-L-iduronidase
• Cytogenetic location of IDUA:
  
  • 4p16.3
• Rare disorder, there are milder forms as well
  
  • Hurler-Scheie syndrome, Scheie syndrome
• Dr. Gerturd Hurler first described in 1919
• Typical features:
  
  • Dwarfism
  • Kyphosis
  • Coarse face
  • Intellectual disability
  • Clouding of the cornea
  • Sensorineural deafness
  • Hepatosplenomegaly
  • Decreased joint mobility
  • (note that these symptoms are often not seen at birth and develope in the first year of life)
• Diagnosis:
  
  • Newborn screening possible and considered, but not (yet) implemented
  • Typically suspected based on physical findings
    
    • usually 6-18 monthes of age in severe forms
  • confirmed by metabolic and molecular genetics studies
    
    • IDUA activity, and Sanger sequencing of IDUA gene
• Treatment:
  
  • Without treatment, fatal within a few years
    
    • progressive organ dysfunction, including dementia
  • Supportive care:
    
    • Heart, joints, eyes, ears, development
  • Treatment options:
    
    • Enzyme replacement therapy
      
      • Does not cross blood-brain barrier
      • Requires a port-a-cath
      • Usually done in infusion center, weekly, over 4 hours
    • Stem cell transplantation
      
      • Definitive treatment
      • Does not reverse pre-transplant
      • Limited long-term outcome data
• Genetic counseling
  
  • Parents heterozygous, Asymptomatic carriers
    
    • Recurrence risk is 25%
  • Prenatal testing is possible
    
    • Best if molcular diagnosis in proband known

Question 5

Neurofibromatosis Type I (NF1)

Answer 5

• Autosomal Dominant
• Cytogenetic location of NF1:
  
  • 17q11.2
• 1/3,000 to 1/4,000 individuals
• Protein:
  
  • Neurofibromin
    
    • a protein predominantly expressed in neurons
    • regulates several intracellular processes, including the RAS-cyclic AMP pathway, and hence controls cell division
• NF1 is caused by heterozygous loss-of-function mutation in NF1
  
  • Loss of the other copy of NF1, due to another insult, leads to uncontrolled cell proliferation, resulting in local tumors
  • Hence named ‘tumor suppressor disorder’
    
    • All cells have loss of 1 copy of NF1 (germline mutation)
    • Tumors have clonal loss (different for individual tumors) of the other NF1 allele (often small deletions)
• Diagnosis:
  
  • Two or more of the following findings:
    
    • Six or more light brown spots on the skin (often called ‘cafe-au-lait’ spots)
    • Two or more neurofibromas, or one plexiform neurofibroma (a neurofibroma that involves many nerves)
    • Freckling in the area of the armpit or the groin
    • Two or more growths on the iris of the eye (known as Lisch nodules or iris hemartomas)
    • Tumor on the optic nerve (called an optic nerve glioma)
    • Abnormal development of the spine (scoliosis), the temple (sphenoid) bone the skull, or the tibia (one of the long bones of the shin)
    • A first degree relative (parent, sibling, or child) with NF1
• Treatment
  
  • Currently, limited options
    
    • Monitoring of optic nerve
    • Avoid surgery as much possible
    • Treatment for neurofibromas that become malignant may include surgery, radiation, or chemotherapy
    • There are experimental drug trials, aimed at interrupting the signaling defect
• Genetic counseling
  
  • often inherited from an affected parent
    
    • recurrence risk is 50%
  • Sometimes NF1 is due to ‘de novo’ mutation
    
    • in that case, recurrence risk is usually quoted as 1-2% per subsequent pregnancy

Question 6

Achondroplasia

Answer 6

• Autosomal dominant
• heterozygous mutation in the fibroblast growth factor receptor-3 gene- FGFR3
• Cytogenetic location:
  
  • 4p16.3F
• Increased signaling through the FGFR3 receptor (always on) due to gain-of-function mutation
• Diagnosis
  
  • Often diagnosed prenatally, as limbs are short on prenatal US
  • Affected individuals have:
    
    • shart stature caused by shortening of the limbs
    • Characteristic face with frontal bossing and mid-face hypoplasia
    • Other skeletal issues, as exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand
    • Normal intelligence
  • Confirmatory test:
    
    • FGFR3
      
      • (in 99% of cases the disease is caused by replacing a glycine with an arginine)
• Treatment:
  
  • Currently limited options
  • Maintain good skeltal health and mobility
  • monitor for hydrocephalus, due to narrow foramen magnum-surgery if needed (laminectomy)
  • Adjust living conditions for optimal independence
  • Therapeutic trials are underway in Europe: a Phase 2, open label, sequential cohort dose-escalation study of BMN 111 in children with achondroplasia
    
    • A version of the natural human C-type natriurtic peptide (CNP) named BMN-111
    • CNP has a receptor in the growth plate, which along with the fibroblast growth factor receptor 3 (FGFR3) regulates normal bone growth
    • BMN-111 has the potential for improving some of the bone related medical complications of achondroplasia, and increasing bone growth
    • Daily subcutaneous injections of BMN-111 have previously been tested in mouse models of achondroplasia, with benefits
• Genetic Counseling
  
  • If parents are of normal height, all cases of achondroplasia are ‘de novo’
    
    • Recurrence risk is usually quoted as 1-2% per subsequent pregnancies
    • Otherwise recurrence risk is 50%
    • Sometimes 2 parents have achondroplasia
      
      • the homozygous state for the common FGFR3 mutation is incompatible with life

Question 7

What is the consequence if 2 parents have achondroplasia

Answer 7

• The disease is autosomal dominant btu the homozygous state for the common FGFR3 mutation is incompatible with life so the recurrence risk is 2/3.

Question 8

Duschenne muscular dystrophy (DMD)

Answer 8

• XLR
• Duchenne muscular dystrophy is caused by hemizygous mutation in the Duchenne muscular dystrophy gene DMD
• Cytogenetic location:
  
  • Xp21.2-p21.1
• Most mutations are multi-exonic out-of-frame deletions, some are non-sense/splice mutations
• Causes severe lack (absence) of dystrophin
  
  • A ‘milder’ form is named Becker muscular dystrophy
    
    • in Becker, some dystrophin production is preserved
• Presentation:
  
  • Usually fairly normal infancy
  • many boys however, never learn to walk, while some learn to walk, but lose this ability gradually due to progressive lower extremity weakness
  • often leads to life in wheelchair, typically around age 12
  • Eventually weakness also affects respiratory muscles, often resulting in death in late teenage years
  • Grower maneuver:
    
    • This is a maneuver that patients with muscular dystrophy use to get up off the floor unassisted. They will use there hand to push up and then walk there legs up to there hands then they can push off the floor and lean up.
• Diagnosis:
  
  • Often suspected clinically, even in ‘simplex’ cases
  • In combination with clinical picture, markedly elevated creatine kinase (CK) in blood is highly suggestive
  • Confirmatory test:
    
    • DMD testing, typically
      
      1. looking if all exons are prestne (exon array, MLPA)
      2. Sequencing
    • DMD is very large gene (2.6 Mb, 97exons), testing is expensive
• Therapy:
  
  • Traditionally, supportive
  • New therapies are being developed, and trials have started
  • Mostly focused on addressing out-of frame exonic deletions, trying to bring bakc the ‘normal’ reading frame
• Genetic counseling
  
  • If there are maternal relatives with DMD, mother is obligate carrier
    
    • if simplex case, mother is still at 2/3 risk of bing a carrier
    • GC in eith case is strongly recommended
      
      • especially since there may be more carrier females who are unaware of their status
    • Prenatal testing is possible if mutation known

Question 9

Duscheen vs. Becker Muscular dystrophy

Answer 9