neurogenetic self-assessment john k. fink, m.d., professor, department of neurology, university of...

Neurogenetic Self-Assessment

John K. Fink, M.D., Professor, Department of Neurology, University of MichiganFeb. 24, 2009

Movement disorders: Parkinson’s, Huntingtons, Dystonia, Wilson’s Ataxia: SCAs, Friedreich’s, et al.Motor sensory neuropathiesMotor neuron disorders: Kennedy syndrome, ALSs, HSPs, PLS, SMA, DHMNDementias: CJD,GSS, FFI, Tau, PS1, PS2, APP, APOE, Metabolic: Lysosomal storage, Urea cycle, Amino acidurias, Mucopolysacharideoses, Glycogen storage

diseases, MucolipidosesMitochondrial: MERRF, NARP, Leighs, et al.Phakomatoses: Tuberous sclerosis, Neurofibromatosis I & II, Sturge Weber, Von Hipple Lindau, FabryStroke: heritable coagulaopathiesMyopathiesPeriodic paralysesEpilepsySleep disordersBehavioral 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 (jkfink@umich.edu) !

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. Gaucher disease Glucocerebrosidase deficiency 2. Krabbe disease -galactocerebroside galactosidase 3 Tay Sach’s disease Hexosaminadase A deficiency (alpha subunit mutation) 4. Fabry disease -galactocerebrosidase deficiency 5. Metachromatic leukodystrophy Arylsulfatase A deficiency 6. Niemann-Pick disease, Type A Sphingomyelinase deficiency

7. Niemann-Pick disease, Type B Sphingomyelinase deficiency 8. Niemann-Pick disease, Type C Cholesterol esterification deficiency 9. Adrenoleukodystrophy Peroxisome disorder: Increased ratio (not absolute

amount) of C27 to C22 fatty acids 10. Pelizeaus-Merzbacher disease Proteolipid protein gene mutation 11. Sandhoff’s disease Hexosaminidase A and B (beta subunit mutation)

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. Plexiform neurofibroma. 2. Lisch nodules. 3. Freckles under the arm. 4. A first-degree relative with

neurofibromatosis.

2. Major diagnostic criteria for neurofibromatosis include:

1. Plexiform neurofibroma. 2. Lisch nodules. 3. Freckles under the arm. 4. 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 PD3. The concordance rate for Parkinson’s disease in monozygotic twins

greatly exceeds that for dizygotic twins4. 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 PD3. The concordance rate for Parkinson’s disease in monozygotic twins

greatly exceeds that for dizygotic twins4. 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. Cause fatal familial insomnia 2. Are associated with transplant-related CJD 3. Cause familial CJD 4. 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 (Gerstmann-

Straussler-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 X-irradiation 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 X-irradiation 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 X-irradiation 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. Cataracts occur in: 1. Hyperlipidemia type III 2. Cerebrotendinous xanthamatosis. 3. Galactosidase deficiency. 4. Wilson’s disease.

26. Cataracts occur in: 1. Hyperlipidemia type III 2. Cerebrotendinous xanthamatosis. 3. Galactosidase deficiency. 4. 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)

38. Hyperkalemic period paralysis and paramyotonia congenita

39. Spinocerebellar ataxia type 6. 40. Dominant (Thomson) and recessive

(Becker) myotonia congenita 41. Andersen-Tawil syndrome

A. Calcium channel gene mutation B. Sodium channel gene mutation C. Potassium channel gene mutation D. 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 paramyotonia congenita

Sodium channel gene (SCN4A)

39. Spinocerebellar ataxia type 6. Calcium channel gene (CACNL1A4)

40. Dominant (Thomson) and recessive (Becker) myotonia congenita

Chloride Channel gene (CLCN1)

41. Andersen-Tawil syndrome Potassium channel gene (KCNJ2)