Neurology Board Review - Genetics And Metabolic Disorders

Front 1

Metachromatic Leukodystrophy

Back 1

- AR
- Arylsulfatase A deficiency
- Increased urine sulfatides

Front 2

Tay Sach's Disease

Back 2

- AR
- Hexosaminidase A
- Ashkenazi jews and french canadians
- GM-2 ganglioside accumulation

Front 3

Niemann-Pick Disease

Back 3

- AR
- Sphingomyelinase deficiency
- More common among ashkenazi jews
- Foam cells on bone marrow biopsy

Front 4

Congenital myasthenia gravis

Back 4

- Mutation in either Rapsyn (later onset)
- Mutation in AchR episilon subunit (predominantly ocular)

Front 5

PKAN
(Neurodegeneration with brain iron accumulation type 1)
Genetics

Back 5

- AR
- PANK2 gene
- Chromosome 20

Front 6

GEFS+

Back 6

- Voltage gated sodium channel Beta-1 subunit (SCN1B or SCN1A)
- Chromosome 19

Front 7

NF-1

Back 7

- AD
- Chromosome 17
- neurofibromin

Front 8

NF-2

Back 8

- AD
- Chromosome 22
- merlin

Front 9

Friedrich's Ataxia

Back 9

- AR
- Frataxin gene on chromosome 9
- GAA repeat

Front 10

Alzheimer's Disease genetics

Back 10

Autosomal Dominant:
- Presenilin 1 (chr 14) - most common
- Presenilin 2 (chr 1)
- Amyloid precursor protein on chromosome 21 - also common
Sporadic:
- APOe4 strongest association with late onset sporadic AD
- APOe2 protective

Front 11

Hypokalemic periodic paralysis

Back 11

- AD
- Primary defect is in a calcium channel, not potassium channel

Front 12

Anderson-Tawill syndrome

Back 12

- AD
- Potassium channelopathy
- Episodic weakness and long QT syndrome

Front 13

Myotonia congenita

Back 13

- Chloride channel
- AD or AR
- CLCN1 gene

Front 14

Paramytonia congenita

Back 14

- AD
- Paradoxical myotonia or induced by cold
- SCN4A mutation
- Sodium channelopathy

Front 15

Huntington's Disease

Back 15

- AD
- CAG trinucleotide repeat in exonic DNA
- Chromosome 4
- Need more than 39 repeats to become symptomatic
- 36 to 39 are indeterminate

Front 16

Oculopharyngeal muscular dystrophy

Back 16

- AD
- CGC repeats
- PABN 1 gene
- Chr 14

Front 17

Fragile X

Back 17

- X-linked recessive
- CGG

Front 18

Myotonic dystrophy type 2

Back 18

- AD
- CCTG repeat
- Chr 3

Front 19

Spinocerebellar ataxia 12

Back 19

- CAG repeat on 5' untranslated region

Front 20

Tuberous Sclerosis (genetics)

Back 20

- AD
- TSC1 (Hamartin) on Chr 9
- TSC2 (Tuberin) on Chr 16

Front 21

Rett's disease

Back 21

- X chromosome
- MECP-2
- Mutation is fatal in boys

Front 22

Familial parkinsonism

Back 22

- Alpha synuclein
- Chromosome 4

Front 23

Charcot-Marie-Tooth Type 1A

Back 23

- Duplications in peripheral myelin protein 22 (PMP22)
- AD

Front 24

Charcot-Marie-Tooth Type 1B

Back 24

- Myelin Protein zero (MPZ)
- AD

Front 25

Hereditary neuropathy and liability to pressure palsies

Back 25

- Deletions in PMP22
- AD
- Chr 17

Front 26

McArdle's disease

Back 26

- Type V glycogen storage disease
- Enzyme is myophosphorylase
- Causes glycogen accumulation

Front 27

Holoprosencephaly

Back 27

- Sonic hedgehog
- Trisomy 13
- Associated with cyclopea, ethmocephaly (proboscis)
- Developmental delays, seizures, swallowing difficulties

Front 28

Zellweger's syndrome

Back 28

- AR
- PEX 3
- Peroxysomal storage disorder (increased VLCFA)
- Liver, kidneys, brain
- hepatomegaly, renal failure, hypotonia, elevated serum iron and copper, vision disturbance
- Abn gyral patterns, impaired myelination, periventricular pseudocysts

Front 29

X-linked lissencephaly

Back 29

Doublecortin
- In males, this gene causes lissencephaly
- In females in causes cortical band heterotopia

Front 30

Heterotopias

Back 30

- laminin (band like)
- filamin (nodular)

Front 31

Hartnup's disease

Back 31

- AR
- Metabolic disorder of absorption of neutral amino acids
- These are typically converted to serotonin, melatonin, niacin
- Need niacin repletion

Front 32

CACH (childhood ataxia with central hypomyelination)

Back 32

- AR
- Mutation in eukaryotic initiation factor (eIF) 2B
- A leukodystrophy
- Present before age 6, rapid progression
- On path, cystic WM degeneration

Front 33

Fabry's disease

Back 33

- X-linked lysosomal storage disorder
- Decreased alpha galactosidase A activity
- Lipid laden macrophages in bone marrow
- Enzyme replacement available

Front 34

Sandhoff's disease

Back 34

- Hexosaminidase B deficiency

Front 35

Canavan's disease, genetics

Back 35

- AR, more common in jewish descent
- Aspartoacylase deficiency
- High NAA

Front 36

Pompe's Disease

Back 36

- Alpha 1,4 glucosidase deficiency (also called acid maltase)
- A glycogen storage disorder (lysosomal)
- Enlarged tongue, hypotonia, cardiomegaly with shortened PR interval
- Replace enzyme or death within first year of life

Front 37

Glycogen storage diseases

Back 37

0 - glycogen synthase deficiency
Ia - von Gierke's disease (glucose-6-phosphotase)
II - Pompe's disease (acid maltase or alpha 1,4 glucosidase)
III - Forbes-Cori disease (debranching enzyme)
IV - Anderson's disease, amylopectinosis (Translucosidase)
V - McArdle's disease (myophosphorylase)
VI - Hers disease (Phosphorylase)
VII - Tauri disease (phosphofructokinase deficiency)

Front 38

Refsum's disease (genetics)

Back 38

- AR, peroxisomal disorder
- phytanic acid oxidase (phytanoyl coA hydroxylase) mutation

Front 39

Episodic ataxia I

Back 39

- AD
- K+ channel
- Attack minutes to hours
- EMG shows myokymia
- Normal MRI
- Associated with epilepsy
- Attacks improve with age
- Treat with acetazolamide

Front 40

Episodic ataxia II

Back 40

- AD
- Ca2+ channel
- Attacks last hours to days
- No EMG findings
- MRI shows cerebellar atrophy
- Associated with migraine
- Progressive course of disease
- Treat with acetazolamide

Front 41

PKU

Back 41

- AR
- Defect in phenylalanine hydroxylation to tyrosine in liver
- Mousy urine odor
- Restrict phenylalanine

Front 42

Homocystinuria

Back 42

- AR
- deficiency in cystathione B-synthase
- Accumulation of homocysteine in serum and urine
- Enhanced reconversion to methionine
- Marfanoid habitus
- Mental retardation
- Thromboses
- Treat with folate and pyridoxine

Front 43

Maple Syrup urine disease

Back 43

- AR
- branched chain ketoaciduria
- deficiency in decarboxylase that initiates degradation of leucine/valine
- Can cause seizures, lethargy, opisthotonus
- 10-14 days

Front 44

Organic acidurias

Back 44

- Methylmalonic acidemia, propionic acidemia, isovaleric acidemia
- Acidosis, hyperammonemia, hyperglycemia
- treatment to stop catabolism: give glucose, not protein
- Supplement with carnitine
- At risk for basal ganglia infarction during acute metabolic decompensation

Front 45

Urea cycle defects

Back 45

- X-linked recessive
- most common is OTC deficiency
- Hyperammonemia and orotic acid in urine
- Treat with protein restriction

Front 46

Nonketotic hyperglycinemia

Back 46

- AR
- neonatal CNS deterioration, seizures, respiratory depression
- Test simultaneous glycine in plasma and CSF

Front 47

Biotinidase deficiency

Back 47

- AR
- Seizures prominent, hypotonia, alopecia, skin rash, acidosis, immunodeficiency
- Supplement with biotin

Front 48

Glutaric aciduria I

Back 48

- Macrocephaly, dystonia, acidosis, idiopathic subdurals may occur
- Treat with low protein diet, riboflavin, depakote, baclofen (increase GABA)

Front 49

Glutaric aciduria II

Back 49

- Electron transport chain defect
- AR

Front 50

Adrenoleukodystrophy

Back 50

- X-linked
- Defect of B-oxidation, accumulation of VLCFA
- Childhood most common, 4-8 years
- Learning disabilities, cognitive and behavioral problems, blindness, quadriparesis, seizures in 20%
- Adrenal insufficiency, hyperpigmented skin
- VLCFA are increased
- Demyelination on MRI (posterior) with peripheral enhancement
- no good treatment (bone marrow transplant)

Front 51

Adrenomyeloneuropathy

Back 51

- Presents in adult males between 20-40
- Spinal cord dysfunction with progressive stiffness and weakness of legs. May present as progressive cerebellar disorder

Front 52

Lysosomal storage disorders (mucopolysaccharidoses) type I

Back 52

I - Hurler's (iduronidase), corneal clouding, MR, dysostosis multiplex, bone marrow transplant

Front 53

MPS

Back 53

II - Hunter's (X linked recessive), iduronate 2 sulfatase, no corneal opacities, profound MR
Others not likely to show on exam?

Front 54

Lysosomal storage disorders

Back 54

Type I Gaucher's disease
Type A Niemann-Pick
type B Niemann-Pick
Type C Niemann-Pick
Tay -Sachs
Metachromatic leukodystrophy
Fabry's disease
Krabbe's disease

Front 55

Krabbe's disease

Back 55

- B-galatosidase deficiency
- Four forms, infantile, late infantile, juvenile, and adult
- FTT, optic atrophy, blindness, hyperiritability, CNS degeneration, seizures, decerebrate posturing late
- Diffuse atrophy on MRI, decrease NC velocity, increase CSF protein

Front 56

Menke's disease

Back 56

- X-linked disorder of copper transport
- CTP7A -> copper deficiency
- 2-3 months of age
- hypotonia, seizures, FTT, changes in hair, autonomic dysfunction
- Death by age 3, but can inject copper before 10 days of age

Front 57

Alexander's disease

Back 57

- AD but most are de novo mutations
- Infantile most common but also juvenile and adult
- Birth to early childhood, with regression, macrocephaly, spasticity, seizure
- Death by age 2
- Progressive leukodystrophy affecting deep white matter, spares periventricular region, frontal predominance
- Mutation in GFAP

Front 58

Vanishing white matter disease

Back 58

- Leukodystrophy
- AR, variable age of onset
- Head trauma or infection followed by rapid deterioration
- Cerebellar ataxia, spasticity, seizures
- MRI showed WM disease and cystic degenerative changes. Spares the temporal lobes
- eIF2B

Front 59

Pelizaeus-Merzbacher disease, genetics

Back 59

- X-linked
- PLP gene (Xq22)
- The same gene causes C-linked spastic paraplegia

Front 60

CCM (cerebral cavernous malformations)

Back 60

- KRIT-1 in hispanics

Front 61

Melas

Back 61

- Mitochondrial
- tRNA leucine

Front 62

Atypical teratoid/rhabdoid tumors

Back 62

- Chromosome 22
- INI1 gene

Front 63

Neuroacanthocytosis

Back 63

- Chromosome 9
- AR
- abnormality in membrane lipids
- orofacial dystonia, chorea, tics, motor neuropathy

Front 64

PARK 1,4

Back 64

- AD
- Chromosome 4
- alpha synuclein
- Usually de novo

Front 65

PARK 3

Back 65

- AD
- Chromosome 2
- Unknown function

Front 66

PARK 5

Back 66

- AD
- Chromosome 4
- Ubiquitin C-terminal hydrolase L1

Front 67

PARK 2

Back 67

- AR
- Chromosome 6
- Parkin (E3 ubiquitin ligase with alpha synuclein as a substrate)
- Onset 20-40 years of age

Front 68

PARK 6

Back 68

- AR
- Chromosome 1
- PINK-1

Front 69

PARK 7

Back 69

- AR
- Chromosome 1
- DJ-1

Front 70

PARK8

Back 70

- LRRK2 (codes for dardarin protein)

Front 71

Early onset dystonia

Back 71

- AD
- Torsin A
- GAG deletion
- Childhood onset

Front 72

Segawa syndrome (dopa responsive dystonia)

Back 72

- AR
- Tyrosine hydroxylase mutation

Front 73

DOPA responsive dystonia-parkinsonism

Back 73

- AD
- GTP cyclohydrolase (synthesizes cofactor for DA synthesis)

Front 74

Myoclonic dystonia

Back 74

- AD
- E Sarcoglycan gene.
(note sarcoglycans also mutated in AR limb girdle musculodystrophy)

Front 75

PSP

Back 75

- 90% homozygous for H1 allele of tau gene but 60% of normal population is too.

Front 76

H1 haplotype

Back 76

- PSP, CBGD

Front 77

H2 haplotype

Back 77

- FTD

Front 78

FTD familial

Back 78

- Chromosome 17 (tau gene)

Front 79

HSP

Back 79

- SPG genes, multiple chromosomes
- Spastin, atlastin, seipin, paraplegin, L1CAM, PLP

Front 80

SCA-1, 2, and 3, also 7

Back 80

- AD
- CAG trinucleotide repeat in ataxin 1, 2, or 3, 7 (ataxin degrades ubiquitin)
- 3 is machado joseph (German or Portuguese)

Front 81

SCA-6

Back 81

- CACNA1A (p/q type ca channel)
- This gene also causes episodic ataxia type 2 and familial hemiplegic migraine
- Onset greater than 50 years of age

Front 82

SCA-10

Back 82

- Pentanucleotide repeat
- Seizures
- Mexicans

Front 83

Ataxia-telangectasia

Back 83

- ATM gene (Tumor suppressor)
- 7->14 chromosomal translocation
- Reduced Ig except IgM, increased alpha fetoprotein
- Cerebellum atrophic

Front 84

Myotonic distrophy Type I

Back 84

- AD
- CTG repeat
- Chr 19

Front 85

Fascio-scapular-humeral muscular dystrophy

Back 85

- AD
- Chr 4

Front 86

Duchenne's and Becker's genetics

Back 86

- X-linked recessive
- Dystrophin

Front 87

Emery Dreifuss MD (genetics)

Back 87

- X linked recessive
- Emerin (nuclear membrane prot)
- Lamin A/C in type 2 (note also in LGMD type 1 and CMT 2a

Front 88

LGMD type 1

Back 88

- AD
- Lamin A/C (note also mutated in CMT 2a, E-D type 2), caveolin-3, myotilin

Front 89

LGMD tyle 2

Back 89

- AR
- Calpain 3, dysferlin, sarcoglycans

Front 90

Williams syndrome

Back 90

- Chromosome 7 deletion
- Happy, trusting children