MSK - Genetics - Neurocutaneous, Mitochondrial, & Lysosomal Disorders Flashcards
What is the simplified pathophysiology of tuberous sclerosis complex?
Mutation in genes coding for tumor suppressor proteins
–> potential mix of benign tumor growth in several organs
(e.g. kidneys, heart, liver, eyes, lungs, and skin)
Does tuberous sclerosis typically result in benign or malignant tumors?
Benign
What are some of the organs most commonly affected by tuberous sclerosis?
Skin, brain, kidney, heart, lung
85% of individuals with tuberous sclerosis will show a mutation in one of what two genes?
TSC2 (69%);
TSC1 (31%)
As far as tuberous sclerosis diagnoses go, describe the constellation of signs/symptoms that would indicate each the following in separate patients:
definite TS complex
probable TS complex
possible TS complex
Definite
2 major features or 1 major + 2 minor
Probable
1 major + 1 minor
Possible
1 major or 2 minor
Between major and minor features of tuberous sclerosis complex, what constellation is needed for definitive diagnosis?
2 major features
OR
1 major + 2 minor features
Name three skin lesions commonly associated with tuberous sclerosis.
Hypomelanotic (ash leaf) macules (87-100% of cases)
Facial angiofibromas (47-90% of cases)
Shagreen (coast of Maine) patches (20-80% of cases)
Name two brain lesions commonly associated with tuberous sclerosis.
Name two signs or symptoms of brain lesions commonly associated with tuberous sclerosis.
Subependymal nodules (SENs; 90% of cases)
Cortical tubers (70% of cases);
Seizures (80% of cases)
Intellectual Disability (50% of cases)
Tuberous sclerosis is associated with mutations in what two genes (85% of cases involving one of these genes)?
What two proteins are coded for by these two genes, respectively?
TSC1 - hamartin;
TSC2 - tuberin
What is the leading cause of increased morbidity and mortality in tuberous sclerosis?
What is the 2nd leading cause of increased morbidity and mortality in tuberous sclerosis?
CNS tumors / intellectual disability;
renal disease
What is the most common renal lesion in tuberous sclerosis?
What is the 2nd most common renal lesion in tuberous sclerosis?
Benign angiomyolipomas (70% of cases)
epithelial cysts (30% of cases)
True/False.
Tuberous sclerosis complex has a fairly high association with autism spectrum disorder?
True (~0.4)
What mode of inheritance does tuberous sclerosis show?
Autosomal dominant
(with variable expressivity)
What is the purpose of the proteins hamartin and tuberin?
What disease is associated with mutations in the genes coding for these proteins?
What are the genes?
Tumor suppression;
tuberous sclerosis;
TSC1 (hamartin) and TSC2 (tuberin)
Name some of the major features of tuberous sclerosis that are present in the majority of cases (bolded).
Name a few features that aren’t necessarily present in the majority of cases (italicized).
- Subependymal nodule (SEN) (90%)
- Hypomelanotic (ash leaf) macule (87-100%)
- Facial angiofibroma (47-90%)
- Cortical tuber (70%)
- Shagreen (coast of Maine) patch (connective tissue nevus) (20-80%)
- Cardiac rhabdomyoma (47-67%)
- Renal angiomyolipoma (typically benign)
- Multiple retinal hamartoma
- Lymphangiomyomatosi (LAM) (30%)
- Subependymal Giant Cell Astrocytoma (SEGA) (6-14%)
What is a defining feature of tuberous sclerosis autosomal dominant inheritance?
Variable expressivity
What mode of inheritance does tuberous sclerosis display?
What may be responsible for its variable expressivity?
Autosomal dominant;
the ‘two-hit’ hypothesis / random nature of second hit (TSC1, TSC2 genes)
True/False.
The majority of cases of tuberous sclerorsis develop malignant renal angiomyolipomas.
False (<3%);
70% show benign renal angiomyolipomas
Define the medical term proband.
An individual who presents with a genetic disorder
(must warrant investigation of the individual’s family)
What percentage of tuberous sclerosis probands (new cases) have an affected parent?
What percentage do not?
1/3;
2/3 (de novo mutations)
An individual with tuberous sclerosis complex has what likelihood of passing it on to their progeny?
(Note: meaning the likelihood of a single birth where one parent is affected resulting in a child with the disease)
50%
(autosomal dominant)
A child is born with tuberous sclerosis. Neither of her parents are affected. What risk do her future siblings have?
1-2%
(possible germline mosaicism)
What dermatological lesion is here shown?
With what neurocutaneous disorder is it associated?
A shagreen patch;
tuberous sclerosis complex
What dermatological lesions are here shown?
With what neurocutaneous disorder is it associated?
Hypomelanotic macules;
tuberous sclerosis complex
What dermatological lesions are here shown?
With what neurocutaneous disorder is it associated?
Similar wart-like projects and bumps are sometimes associated with this disorder and found where on the body?
Facial angiofibromas;
tuberous sclerosis complex;
skin around nail folds (periungal fibromas)
A seven-year-old male is brought in by his concerned parents for your evaluation after experiencing a short seizure of undetermined type and origin.
Upon physical exam, you notice the child has several near-white macules on his hips, back, and shoulders. You also notice some roughened skin on his face in a malar distribution.
The child is mentally disabled.
What syndrome is at the top of your differential?
It is associated with mutations in what gene(s)?
Tuberous sclerosis;
TSC1 (hamartin protein), TSC2 (tuberin protein)
What is the treatment for a patient with tuberous sclerosis that has a subependymal giant cell astrocytoma?
What is the treatment for a patient with tuberous sclerosis that has a renal angiomyolipoma?
What is the treatment for a patient with tuberous sclerosis that is experiencing somewhat frequent seizures?
mTOR (mammalian target of rapamycin) inhibitors;
renal artery embolization / surgery (renal sparing);
normal epileptical / seizure control
What disorder has a similar pathophysiology as tuberous sclerosis complex (mutations in tumor suppressor genes/proteins) but is mainly characterized by benign tumors of the nervous system?
Neurofibromatosis
What are the two types of neurofibromatosis called?
Some sources include what as a third type?
Neurofibromatosis type I and type II;
Schwannomatosis
Neurofibromatosis type I is associated with what tumor suppressor gene on what chromosome? What is its inheritance pattern?
Neurofibromatosis type II is associated with what tumor suppressor gene on what chromosome? What is its inheritance pattern?
NF-1, chromosome 17, autosomal dominant;
NF-2, chromosome 22, autosomal dominant
Describe the inheritance pattern of both types of neurofibromatosis.
(E.g. inheritance type, expressivity, penetrance, mutation rate)
Autosomal dominant;
nearly 100% penetrant;
high level of variance in expressivity;
high mutation rate (50% of cases are new cases)
What is the hallmark feature of neurofibromatosis type I?
What is the hallmark feature of neurofibromatosis type II?
Cafe au lait spoits;
acoustic neuromas
What is the hallmark feature of neurofibromatosis type I?
Cafe au lait spots
What is the hallmark feature of neurofibromatosis type II?
Acoustic neuromas
Why is the diagnosis of neurofibromatosis so difficult?
High variance in expressivity
Dianosis of neurofibromatosis type I is made if a person has two or more of what signs and symptoms?
≥ 6 café au lait spots (> 5 mm in diameter in pre-pubertal persons and > 15 mm in post-pubertals)
≥ 2 neurofibromas of any type
Freckling in the axillary or inguinal regions
Optic glioma
≥ 2 Lisch nodules
A distinct osseous lesion
A first degree relative with NF-1 (by the above criteria)
What is the most common CNS tumor of neurofibromatosis type I?
Optic gliomas
Chromosome 17 produces a protein that is involved in maintaining the balance between cell proliferation and differentiation.
What protein is it and a deficiency in it is associated what disease?
Neurofibromin;
neurofibromatosis type I
Diagnosis of neurofibromatosis type II requires 2 or more of what clinical features?
Either
Bilateral auditory canal masses;
OR
an affected first-degree relative and a unilateral auditory mass
What dermatological lesions are here shown?
This is indicative of what disorder?
It is associated with a mutation of what chromosome?
Cafe au Lait (also known as coast of Maine) spots;
neurofibromatosis type I;
chromosome 17
What is the pathophysiology of Huntington’s disease?
Neuronal death due to Huntingtin protein amyloidosis
What is the genetic cause of Huntington disease pathology?
CAG trinucleotide repeats on chromosome 4
Less than how many CAG repeats on chromosome 4 is normal?
Greater than how many CAG repeats on chromosome 4 is associated with severe Huntington’s disease?
< 26;
≥ 40
What is the inheritance pattern of Huntington’s disease?
It usually presents at what age?
Autosomal dominant’
30 - 40 (can be as low as 10 and as high as 60)
The increased severity of Huntington’s disease is associated with transmission from which parent?
Paternal transmission
Name the major signs and symptoms of Huntington’s disease.
Progressive chorea, rigidity, psychiatric symptoms, and dementia
What is the most common form of inherited cognitive impairment?
Fragile X syndrome
(spectrum of ADHD vs. mild impairment vs. autism vs. severe intellectual disability)
What disorder is associated with trinucleotide CGG repeats on the X chromosome?
What number of repeats is considered normal?
What number is considered pathological?
Fragile X syndrome;
5 - 44;
> 200
Fragile X syndrome is generally more severe in which sex?
Males
Some cells have 100s of _________.
Highly active cells can have 1000s of _________.
Mitochondria;
mitochondria
What organelle is the major source of reactive oxygen species (ROSs)?
What organelle regulates apoptosis?
Mitochondria;
mitochondria
What is homoplasmy?
What is heteroplasmy?
A cell contains only one type of mtDNA (DNAmitochondrial);
a cell contains both normal and mutant mtDNA
What is difficult about the pleiotropic nature of many disorders of the mitochondrial genome?
Different organs can be affected in different patients with the same mutation
Disorders of the mitochondrial genome are often pleitotropic and show variable ___________, making them difficult to both diagnose and also track through generations.
Expressivity
True/False.
A mutant gene must show effects on multiple phenotypic characteristics simultaneously in order to be considered an example of pleiotropy.
False.
(the same pleiotropic gene can show different effects in differing individuals)
If a woman is homoplasmic for a certain mutation, how many of her children are likely to receive that mutation?
If a man is homoplasmic for a certain mutation, how many of his children are likely to receive that mutation?
All of them;
none of them
A woman who is heteroplasmic for a point mutation or duplication will pass it on to how many of her children?
(What will the effect be like?)
All of them
(however, there will be varying severity of phenotypic manifestation as the fraction of mutant mitochondria in the offspring may vary significantly)