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Neurogenetic Self-Assessment
John K. Fink, M.D.,
Professor, Department of Neurology, University of Michigan
Feb. 24, 2009
Movement disorders: Parkinson’s, Huntingtons, Dystonia, Wilson’s
Ataxia: SCAs, Friedreich’s, et al.
Motor sensory neuropathies
Motor neuron disorders: Kennedy syndrome, ALSs, HSPs, PLS, SMA, DHMN
Dementias: CJD,GSS, FFI, Tau, PS1, PS2, APP, APOE,
Metabolic: Lysosomal storage, Urea cycle, Amino acidurias, Mucopolysacharideoses, Glycogen storage
diseases, Mucolipidoses
Mitochondrial: MERRF, NARP, Leighs, et al.
Phakomatoses: Tuberous sclerosis, Neurofibromatosis I & II, Sturge Weber, Von Hipple Lindau, Fabry
Stroke: heritable coagulaopathies
Myopathies
Periodic paralyses
Epilepsy
Sleep disorders
Behavioral disorders
The following questions are intended as a screening, self-assessment of knowledge of neurogenetic
topics.
Suggestion: Take this exam as a timed, 60-minute exercise to identify those areas in which greater
familiarity is needed.
Request: Comments and suggestions are welcome ([email protected]) !
2.
Match each disorder with its abnormality:
1. Gaucher disease
2. Krabbe disease
3
Tay Sach’s disease
4. Fabry disease
5. Metachromatic leukodystrophy
6. Niemann-Pick disease, Type A
7. Niemann-Pick disease, Type B
8. Niemann-Pick disease, Type C
9. Adrenoleukodystrophy
10. Pelizeaus-Merzbacher disease
11. Sandhoff’s disease
Hexosaminidase A and B (beta subunit mutation)
Cholesterol esterification deficiency
-galactocerebrosidase deficiency
-galactocerebroside galactosidase
Sphingomyelinase deficiency
Hexosaminadase A deficiency (alpha subunit mutation)
Increased long chain fatty acids
Arylsulfatase A deficiency
Glucocerebrosidase
None of the above
Proteolipid protein mutation
Peroxisome disorder
2.
Match each disorder with its abnormality:
1.
2.
3
4.
5.
6.
Gaucher disease
Krabbe disease
Tay Sach’s disease
Fabry disease
Metachromatic leukodystrophy
Niemann-Pick disease, Type A
Glucocerebrosidase deficiency
-galactocerebroside galactosidase
Hexosaminadase A deficiency (alpha subunit mutation)
-galactocerebrosidase deficiency
Arylsulfatase A deficiency
Sphingomyelinase deficiency
7.
8.
Niemann-Pick disease, Type B
Niemann-Pick disease, Type C
Sphingomyelinase deficiency
Cholesterol esterification deficiency
9.
Adrenoleukodystrophy
Peroxisome disorder: Increased ratio (not absolute
amount) of C27 to C22 fatty acids
Proteolipid protein gene mutation
Hexosaminidase A and B (beta subunit mutation)
10. Pelizeaus-Merzbacher disease
11. Sandhoff’s disease
Increased long chain fatty acids: does not apply.
1. Which of the following statements are true?
1. Huntington’s chorea exhibits genetic
anticipation.
2. The gene for Huntington’s chorea is
expressed almost exclusively in the brain.
3. Many patients with Huntington’s chorea
have no family history of the disorder.
4. The juvenile dystonic form of Huntington’s
chorea is usually inherited from the
mother.
1. Which of the following statements are true?
1. Huntington’s chorea exhibits genetic
anticipation.
2. The gene for Huntington’s chorea is
expressed almost exclusively in the brain.
3. Many patients with Huntington’s chorea
have no family history of the disorder.
4. The juvenile dystonic form of Huntington’s
chorea is usually inherited from the
mother.
2. Major diagnostic criteria for neurofibromatosis
include:
1.
2.
3.
4.
Plexiform neurofibroma.
Lisch nodules.
Freckles under the arm.
A first-degree relative with
neurofibromatosis.
2. Major diagnostic criteria for neurofibromatosis
include:
1.
2.
3.
4.
Plexiform neurofibroma.
Lisch nodules.
Freckles under the arm.
A first-degree relative with
neurofibromatosis.
Leukodystrophy
•
15 yo male with dementia, progressive
spasticity, muscle weakness. Had
brother who died at 4yo. Mother has
mild spastic gait. MRI of another
patient with similar condition is shown.
What is the most likely diagnosis?
•
24 yo female with juvenile cataracts,
dementia and progressive spastic gait.
Diagnostic test? Treatment?
Leukodystrophy: keywords (“handles”)
•
15 yo male with dementia, progressive
spasticity, and muscle weakness. Had
brother who died at 4yo. Mother is c/o
mild spastic gait. MRI of another patient
with similar condition is shown. What is
the most likely diagnosis?
– Posteriorly affected white
matter abnormalities.
– Possibility of X-linked
disorder
– Adrenoleukodystrophy.
•
24 yo female with dementia and
progressive spastic gait. History of
cataract (7yo). Her lower extremities are
shown. What would you choose as a
single lab test to add clue to her
diagnosis?
– Xanthomas
– Consider cerebrotendinous
xanthomatosis (with a history
of cataract)
– Cholestanol
3. Neurofibromatosis affects the CNS by
1. Spinal nerve compression
2. Optic nerve gliomas typically lead to
blindness
3. Deafness
4. Intracerebral tumors are frequently
malignant.
3. Neurofibromatosis affects the CNS by
1. Spinal nerve compression
2. Optic nerve gliomas typically lead to
blindness
3. Deafness
4. Intracerebral tumors are frequently
malignant.
•
•
•
•
•
Which of the following single gene mutations cause Alzheimer’s
disease?
1. Presenilin 1 and Presenilin 2
2. ApoE
3. Amyloid precursor protein
4. Tau
• Which of the following single gene mutations cause
Alzheimer’s disease?
• 1. Presenilin 1 and Presenilin 2
• 2. ApoE
• 3. Amyloid precursor protein
• 4. Tau
7 Parkinson’s disease:
1. Risk of Parkinson’s disease is significantly increased in first-degree
relatives of subjects with Parkinson’s disease.
2. -synuclein and LRRK2 mutations cause Autos. Dom PD
3. The concordance rate for Parkinson’s disease in monozygotic twins
greatly exceeds that for dizygotic twins
4. PINK1, Parkin2, and DJ-1 cause Autos. Recessive PD.
7 Parkinson’s disease:
1. Risk of Parkinson’s disease is significantly increased in first-degree
relatives of subjects with Parkinson’s disease.
2. -synuclein and LRRK2 mutations cause Autos. Dom PD
3. The concordance rate for Parkinson’s disease in monozygotic twins
greatly exceeds that for dizygotic twins
4. PINK1, Parkin2, and DJ-1 cause Autos. Recessive PD.
8. Dopa-responsive dystonia:
1. Is usually less severe in the morning
2. Usually is evident in infancy
3. May be autosomal dominant (GTP-CH) or
autosomal recessive (TH).
4. Eventually becomes unresponsive to
levodopa-carbidopa.
8. Dopa-responsive dystonia:
1. Is usually less severe in the morning
2. Usually is evident in infancy
3. May be autosomal dominant (GTP-CH) or
autosomal recessive (TH).
4. Eventually becomes unresponsive to
levodopa-carbidopa.
9. Prion Protein gene mutations
1.
2.
3.
4.
Cause fatal familial insomnia
Are associated with transplant-related CJD
Cause familial CJD
Cause dominantly inherited ataxia.
9. Prion Protein gene mutations
1. Cause fatal familial insomnia
2. Are associated with transplant-related CJD (PrP
129Met/Val polymorphism)
3. Cause familial CJD
4. Cause dominantly inherited ataxia (GerstmannStraussler-Scheinker).
10.
Wilson’s disease:
1. Absence of family history argues against Wilson’s
disease
2. Dysarthria and behavioral disturbance are the
most common presenting neurologic symptoms
3. Is characterized by high serum ceruloplasmin and
low urine copper excretion.
4. Both Wilson’s disease and Menke’s disease are
due to copper ATPase transporter genes.
10.
Wilson’s disease:
1. Absence of family history argues against Wilson’s
disease
2. Dysarthria and behavioral disturbance are the
most common presenting neurologic symptoms
3. Is characterized by high serum ceruloplasmin and
low urine copper excretion.
4. Both Wilson’s disease and Menke’s disease are
due to copper ATPase transporter genes.
12.
Expanded trinucleotide repeats (such as
CAGn):
1. Greater repeat length  earlier symptom
onset
2. Are unstable during meiosis.
3. Cause myotonic dystrophy, Huntington’s
chorea, Machado-Joseph disease, and
spinocerebellar ataxia type I and II.
4. Do not cause X-linked or autosomal
recessive disease.
12.
Expanded trinucleotide repeats (such as
CAGn):
1. Greater repeat length  earlier symptom
onset and more severe symptoms
2. Are unstable during meiosis.
3. Cause myotonic dystrophy, Huntington’s
chorea, Machado-Joseph disease, and
spinocerebellar ataxia type I and II.
4. Do not cause X-linked or autosomal
recessive disease
13.
Friedreich’s ataxia:
1. The Friedreich’s ataxia gene mutation is in
an intron.
2. Is due to an expanded trinucleotide repeat.
3. Cardiac conduction disturbance and
peripheral neuropathy are common.
4. Is a mitochondrial disorder
13.
Friedreich’s ataxia:
1. The Friedreich’s ataxia gene mutation is in
an intron.
2. Is due to an expanded trinucleotide repeat.
3. Cardiac conduction disturbance and
peripheral neuropathy are common.
4. Is a mitochondrial disorder
14.
Adrenoleukodystrophy:
1. Abnormal peroxisomes.
2. Increased ratio of plasma C27:C22 fatty
acids.
3. Is etiologically related to
adrenomyeloneuropathy.
4. Does not affect females
14.
Adrenoleukodystrophy:
1. Abnormal peroxisomes.
2. Increased ratio of plasma C27:C22 fatty
acids.
3. Is etiologically related to
adrenomyeloneuropathy.
4. Does not affect females
15.
Rett’s syndrome:
1. MECP2 mutation
2. Hyperventilation and apnea
3. DNA methylation abnormality
4. Chromosome fragility disorder
15.
Rett’s syndrome:
1. MECP2 mutation
2. Hyperventilation and apnea
3. DNA methylation abnormality
4. Chromosome fragility disorder
16.
Ataxia telangactasia:
1. Progressive chorea and dystonia
2. Defective DNA repair
3. Lymphoreticular malignancy and
immunological deficiency.
4. Increased serum alphafetoprotein and
increased fibroblast sensitivity to Xirradiation damage are diagnostic tests.
16.
Ataxia telangactasia:
1. Progressive chorea and dystonia
2. Defective DNA repair
3. Lymphoreticular malignancy and
immunological deficiency.
4. Increased serum alphafetoprotein and
increased fibroblast sensitivity to Xirradiation damage are diagnostic tests.
16.
Ataxia telangactasia:
1. Progressive chorea and dystonia
2. Defective DNA repair
3. Lymphoreticular malignancy and
immunological deficiency.
4. Increased serum alphafetoprotein and
increased fibroblast sensitivity to Xirradiation damage are diagnostic tests.
20.
Myotonic dystrophy:
1. Testicular atrophy and diabetes
2. DM-2 tetranucleotide repeat expansion
3. Infantile form is characterized by
respiratory distress, poor feeding and
ptosis
4. DM-1: Trinucleotide repeat leads to
polyGlutamine expansion
20.
Myotonic dystrophy:
1. Testicular atrophy and diabetes
2. DM-2 tetranucleotide repeat expansion
3. Infantile form is characterized by
respiratory distress, poor feeding and
ptosis
4. DM-1: Trinucleotide repeat leads to
polyGlutamine expansion
23.
Mitochondrial disorders:
1. Are due to mitochondrial gene mutation.
2. Are due to mutations in nuclear encoded
genes.
3. Syndromes include neuropathy, myopathy,
blindness, and multiple strokes.
4. There is roughly the same proportion of
abnormal mitochondria in each tissue.
23.
Mitochondrial disorders:
1. Are due to mitochondrial gene mutation.
2. Are due to mutations in nuclear encoded
genes.
3. Syndromes include neuropathy, myopathy,
optic atrophy, and multiple strokes, and
retinitis.
4. There is roughly the same proportion of
abnormal mitochondria in each tissue.
24.
Fragile X syndrome:
1. Is the most common inherited cause of
mental retardation.
2. Affects boys and girls.
3. Causes hypergonadism.
4. Causes ataxia.
24.
Fragile X syndrome:
1. Is the most common inherited cause of
mental retardation.
2. Affects boys and girls.
3. Causes hypergonadism.
4. Causes ataxia.
26.
1.
2.
3.
4.
Cataracts occur in:
Hyperlipidemia type III
Cerebrotendinous xanthamatosis.
Galactosidase deficiency.
Wilson’s disease.
26.
1.
2.
3.
4.
Cataracts occur in:
Hyperlipidemia type III
Cerebrotendinous xanthamatosis.
Galactosidase deficiency.
Wilson’s disease.
Match each of the following disorders with their
molecular basis:
36.
Episodic ataxia with myokemia (EA1):
37.
Episodic ataxia without myokemia
(EA2)
Hyperkalemic period paralysis and
paramyotonia congenita
Spinocerebellar ataxia type 6.
38.
39.
40.
41.
A.
B.
C.
D.
Dominant (Thomson) and recessive
(Becker) myotonia congenita
Andersen-Tawil syndrome
Calcium channel gene mutation
Sodium channel gene mutation
Potassium channel gene mutation
Chloride channel gene mutation
Match each of the following disorders with their molecular basis:
36. Episodic ataxia with myokemia (EA1):
Potassium channel gene (KCNA1)
37. Episodic ataxia without myokemia (EA2)
Calcium channel gene (CACNA1A)
38. Hyperkalemic period paralysis and
Sodium channel gene (SCN4A)
paramyotonia congenita
39. Spinocerebellar ataxia type 6.
40. Dominant (Thomson) and recessive
(Becker) myotonia congenita
41. Andersen-Tawil syndrome
Calcium channel gene (CACNL1A4)
Chloride Channel gene
(CLCN1)
Potassium channel gene
(KCNJ2)