Genetics/Metabolics Flashcards
What is Sturge Weber syndrome?
Neurocutaneous disorder including:
- Port wine stain (facial angioma) usually in V1/V2 distribution
- Leptomeningeal angiomas (tram track appearance on CT)
- Seizures
- Glaucoma
- Stroke-like episodes
- Intellectual disability
- Hemiparesis
What is the genetic inheritance of Sturge Weber syndrome?
Most common vascular malformation
1:1 sex ratio
Sporadic
Cases of RASA1 gene mutations
What is Lesch-Nyhan syndrome?
- X-linked recessive inherited disorder
- Enzyme defect in HPRT leading to increased production of uric acid
- Presentation:
- Motor delays more significant followed by GDD starting at 4 to 8 months
- Gout, nephrolithiasis leading to renal failure
- Choreoathetosis, spasticity, dystonia
- Megaloblastic anemia, self injurious behaviours (particularly peri-oral)
Treatment:
- Allopurinol and restraints/tooth extraction for behaviour
What is alpha-1 antitrypsin deficiency?
- A1AT enzyme inhibits neutrophil proteases (break down other proteins) and elastase (breaks down elastin)
- In infection neutrophils are activated and produce protease and elastase to break down bacteria but then can also go on and break the elastin in alveoli which gives elasticity and strength thus get dilated alveoli which leads to emphysema, chronic bronchitis, bronchiectasis, COPD
- Autosomal codominant inheritance
- Multiple phenotypes (serpina 1 gene on chromosome 14 leads to production of alpha-1 antitrypsin)
- MM is the normal phenotype
- MS, SS and MZ are associated with mild to moderate deficiency
- ZZ and SZ are associated with severe deficiency
- Mutations leads to A1AT protein misfolding accumulation in liver cells
- Get stuck in endoplasmic reticulum of hepatocytes because are misfolded and this leads to liver disease
What is Incontinentia pigmenti?
- Genetic ectodermal dysplasia affecting the skin
- X-linked dominant disease due to a NF-kappa-essential modulator (NEMO) gene mutation
- Lethal in males (results in miscarriage or still born)
- Four cutaneous stages:
- Vesicular stage: vesicles arranged in linear/whorled streaks that resolve by 6 weeks of age
- Verrucous stage: thickened hyperkeratotic linear plaques that typically resolve by 2 years of age
- Hyperpigmented: linear/whorled hyper pigmented patches that resolve by adolescence
- Hypopigmented: hypo pigmented linear streaks with decreased hair density
- Other cutaneous symptoms include patchy scarring alopecia and absent or peg-shaped teeth and nail dystrophy
What is Denys-Drash syndrome?
Characterized by the development of nephropathy, Wilms tumour and gonadal dysgenesis
DDS is characterized by diffuse mesangial sclerosis (leads to end stage renal disease in adolescence) and gonadal dysgenesis due to mutations in WT1
AD inheritance
Diagnosis made through molecular sequencing of WT1
Surveillance for Wilms tumour necessary because this affects up to 90% of individuals
Renal transplant is routine for management to avoid renal failure and potential tumour development
Males with DDS are infertile
What is adrenoleukodystrophy?
- Inherited disorder (most commonly x-linked) that results in impaired B-oxidation of very long chain fatty acids in peroxisomes and subsequent accumulation in body tissues and fluids
- The result is an adrenocortical deficiency and CNS demyelination and neurodegeneration
- Classic presentation is late childhood (age 7 usually) onset of subtle neurologic symptoms (commonly diagnosed as ADHD) and progressive deterioration (ie: dementia, vison/hearing loss) associated with adrenal insufficiency
What is Ataxia Telangiectasia?
- Autosomal recessive disorder
- Defect in ATM gene involved in DNA repair
Clinical Presentation
- At first, infants appear normal - may learn to walk on time
- By age 2 to 3 years ataxia appears and then progresses, typically requiring wheelchair by age 15 years
- Oculomotor apraxia: patient cannot make fast voluntary eye movements so he or she turns head instead
- Other systemic manifestations:
- Telangiectasia - on eye and skin, typically appear after age 3 years
- Immunodeficiency - frequent upper and lower respiratory tract infections with decreased levels of Ig and T-cell dysfunction
- Malignancy - increased risk of cancer (often leukemia or lymphoma)
- Progressive pulmonary disease: infection, interstitial lung disease
Evaluation * Serum alpha fetoprotein (AFP): elevated * Serum IgA: reduced * Genetic testing Treatment * Supportive Prognosis * Median age of death in mid-20s
What is Friedrich ataxia?
Most common hereditary ataxia
Usually autosomal recessive or sporadic
Loss of function mutations in the frataxin gene, usually due to expansion of a GAA-trinucleotide repeat
Atrophy of spinal cord and medulla
Clinical Presentation Typically presents in adolescence Progressive ataxia of all extremities Dysarthria is common Sensory loss, particularly vibration and proprioception Eventual loss of DTRs Other systemic manifestations: Hypertrophic cardiomyopathy Kyphoscoliosis Diabetes mellitus
Evaluation
Neuroimaging of brain and spinal cord to exclude other causes
Genetic testing
Treatment
Supportive, no disease modifying therapy is available
Age of death usually in 30s from cardiac complications
What is the best genetic test for Turner Syndrome?
Karyotype
What is the best genetic test for DiGeorge Syndrome?
Microarray
What is the best genetic test for fragile X?
PCR, trinucleotide CGG repeats (full mutation is >200 repeat)
What is the best genetic test for Prader Will syndrome?
DNA methylation analysis. 70% can be picked up by microarray but 30% are due to imprinting and methylation studies pick up all of them
What is PHACE syndrome?
PHACE Association P - posterior fossa abnormalities (dandy walker malformation) H - hemangioma (large facial IH >5cm) A - arterial/aortic abnormalities C - cardiac anomalies E - eye abnormalities
What is William’s syndrome?
7q11.23 deletion
Facies: periorbital fullness, stellate irides (starry pattern of the eyes), long philtre, thick lips, wide mouth
CVS: any artery may be narrowed
PPS, Supravalvular aortic stenosis (75%)
Hernias, bowel/bladder diverticula, lax skin
Within the realm of connective tissue disorders
ID (mild to severe)
Specific cognitive profile: strengths in STM and language, weakness in visuospatial skills
Personality: over friendly, anxiety, phobias
FTT, short stature
Hypercalcemia
