Syndromes: Neurologic

Question 1

Microcephaly vera

Answer 1

ASPM, WDR62

Question 2

Periventricular heterotopia (AD)

Answer 2

FLNA

Question 3

Periventricular heterotopia (AR)

Answer 3

ARFGEF2

Question 4

Band heterotopia (XD)

Answer 4

DCX

Question 5

Band heterotopia (XR)

Answer 5

ARX

Question 6

Lissencephaly (AD)

Answer 6

LIS1, TUBA1A

Question 7

Lissencephaly (XL)

Answer 7

DCX, ARX

Question 8

Posterior lissencephaly

Answer 8

DYNC1H1, CEP85L

Question 9

Lissencephaly with cerebellar hypoplasia (AR)

Answer 9

RELN, VLDLR

Question 10

Type 2 Lissencephaly/Walker-Warburg

Answer 10

POMT1/2, Fukutin

Question 11

Type 2 Lissencephaly/Muscle-Eye-Brain disease

Answer 11

POMGnT1

Question 12

Polymicrogyria + macrocephaly

Answer 12

mTOR pathway (PIK3CA, PIK3R, mTOR, AKT3, CCND2)

Question 13

Polymicrogyria + microcephaly

Answer 13

ASPM, WDR62, RAP3GAP2

Question 14

Polymicrogyria + normocephaly

Answer 14

Tubulinopathies (TUBB2B), ion channels (SCN3A)…

Question 15

Order of myelination

Answer 15

Projection before association, peripheral before central, sensory before motor (proprioception, vision, then auditory). Pyramidal tract myelination occurs with developmental milestones.

Question 16

0-6mo with hyperirritability, arching, hyporeflexia. Rapid decline to seizures and death. MRI: Posterior demyelination without contrast enhancement.

Answer 16

Classic infantile Globoid cell leukodystrophy/Krabbe disease; GALC

Question 17

3-8yo with spasticity, abnormal gait with frequent falls, rarely ocular abnormalities. MRI: posterior demyelination without contrast enhancement.

Answer 17

Juvenile onset Globoid cell leukodystrophy/Krabbe disease; GALC

Question 18

<18mo, progressive macrocephaly, poor head control, delayed sitting, hypotonia, nystagmus. MRI: edematous white matter esp. basal ganglia demyelination & subcortical U-fibers, high NAA on MRS.

Answer 18

Canavan disease: N-acetylaspartoacylase

Question 19

Newborn with respiratory distress, poor feeding, fluctuation in tone, and refractory seizures. MRI: cavitation of posterior white matter.

Answer 19

Sulfite oxidase deficiency; detectable with + urine sulfite dipstick or elevated urine thiosulfate and sulfocysteine

Question 20

6-15mo with arrest in development, pain with minimal passive movement of limbs. Diffuse (butterfly) demyelination with sparing of subcortical U-fibers.

Answer 20

Late infantile onset Metachromatic leukodystrophy: ARSA/arylsulfatase A

Question 21

3-8yo behavioral changes, tremor, gait difficulties, and seizures. MRI: diffuse (butterfly) demyelination with sparing of subcortical U fibers.

Answer 21

Juvenile onset Metachromatic leukodystrophy: ARSA/arylsulfatase A

Question 22

Infant <2yo w/macrocephaly, regressions seizures

Answer 22

Alexander Disease: GFAP

Question 23

Child with headache, vomiting, symmetric brainstem lesions

Answer 23

Juvenile-onset Alexander Disease: GFAP

Question 24

Episodic dramatic declines (motor milestones, ataxia; eventually mental status) triggered by fevers head trauma; no seizures.

Answer 24

Vanishing white matter disease: eIF2B (initiation factor for translation)

Question 25

Boy with hyperactivity, inattention, gait difficulties --> nonambulatory and nonverbal within months.

Answer 25

Childhood cerebral adrenoleukodystrophy (ABCD1), X-ALD

Question 26

Adult male with slowly progressive spastic paraparesis, bladder/bowel problems, intact cognition for the most part.

Answer 26

Adrenomyeloneuropathy (ABCD1), X-ALD; spinal cord involvement mostly although do remain at risk for demyelination of brain

Question 27

Cataracts, chronic diarrhea, coordination difficulty, dementia

Answer 27

Cerebrotendinous xanthosis: CYP27A1. Treat with chenodeoxycholic acid

Question 28

Sudden loss of motor function, cystic changes in brain MRI after head trauma in adult

Answer 28

Adult vanishing white matter disease: eIF2B5

Question 29

Adult with personality/behavioral changes, dementia, depression, epilepsy, eventual motor dysfunction. White matter degeneration/demyelination on brain MRI.

Answer 29

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): CSF1R (microglial gene)

Question 30

Infant with nystagmus, hypotonia -> motor delay, prominent ataxia -> spastic paresis. Slow improvement until puberty, then variable decline.

Answer 30

Pelizaeus-Merzbacher disease: proteolipid protein 1 PLP1 (myelin protein), XL

Question 31

3-5mo with weakness and decreased responsiveness, exaggerated startle, myoclonic jerks, seizures, cherry red macula, loss of motor milestones, HSM.

Answer 31

Infantile GM2 gangliosidosis: Tay-Sachs/ HEXA, Sandhoff/HEXA or B

Question 32

Adolescent or adult w/cognitive impairment, poor coordination w/loss of ability to walk. Normal myelination.

Answer 32

Juvenile or adult-onset GM2 gangliosidosis: HEXA or HEXB

Question 33

High arches, hammer toes, demyelination

Answer 33

Charcot-Marie-Tooth: AD, most common PMP22 dup (and HNPP deletion w/non-homologous recombination); X-linked GJP1 (1/3 affected like males)

Question 34

Spontaneous foot-drop, wrist-drop

Answer 34

Hereditary neuropathy w/pressure palsies: loss of HNPP

Question 35

Fragile X repeat

Answer 35

CGG in 5' UTR

Question 36

SCA repeats

Answer 36

CAG, usually exonic.

Question 37

Huntington disease repeats

Answer 37

CAG (polyQ) in exon

Question 38

Friederich ataxia repeats

Answer 38

GAA in intron

Question 39

Myotonic dystrophy repeats

Answer 39

CTG (CUG) in 3' UTR -- missed by exome sequencing, RAN translation -> toxic products

Question 40

Progressive myoclonus epilepsy repeat

Answer 40

Long repeat in promoter

Question 41

Proximal weakness, myotonia w/percussion or cold, arrhythmias/conductive block, myopathic facies, diabetes, hypogonadism, GI pseudoobstruction

Answer 41

Myotonic dystrophy

Question 42

Expansion from maternal allele

Question 43

Expansion from paternal allele

Question 44

Adult w/progressive cerebellar ataxia and intention tremor, memory loss, cognitive decline, peripheral neuropathy, autonomic dysfunction

Answer 44

Fragile-X ataxia syndrome -- from permutation (55-200 CGG repeats) increasing rate with age

Question 45

High risk ApoE alleles for AD

Answer 45

E4/E4 highest risk (clearance and oligomerization of APP)

Question 46

Parkinson plus other symptoms

Answer 46

Progressive supranuclear palsy or multiple system atrophy (motor failure), poor response to levodopa

Question 47

AD Parkinson genes

Answer 47

SCNA (alpha synuclein)/PARK1 or LRRK2/PARK8 (incomplete penetrance)

Question 48

Other loci associated with Parkinson disease

Answer 48

MAPT (microtubule-associated Tau), Glucocerebrosidase (Gaucher disease), some other very rare AR genes

Question 49

SMA genetic basis

Answer 49

Homozygous deletion of exon 7 in SMN1, # of copies of SMN2 determines how much functional protein gets made (1-2 copies = never sit, 3-4 progress more). 5% have compound heterozygosity for SMN1 (e.g. deletion/mutation). Normal individuals have 2-3 copies of SMN1 and 0-3 of SMN2; carriers have only 1 copy SMN1.

Question 50

Floppy baby (most never sit), tongue fasciculations, expressive face

Answer 50

SMA (loss of anterior horn cells)

Question 51

Medications to increase SMN2 production in SMA

Answer 51

Intrathecal ASO Nusinersen, oral SMN2 splicing modifier Risdiplam (approved)

Question 52

Limb-girdle weakness w/elevated CK, onset before age 5. Cardiomyopathy, cognitive impairment, lose ability to walk after age 12, death in 20s-30s.

Answer 52

Duchenne muscular dystrophy

Question 53

Limb-girdle weakness w/elevated CK, progressive onset after age 5, cardiomyopathy, respiratory failure in 40s.

Answer 53

Becker muscular dystrophy

Question 54

Treatment for DMD

Answer 54

ASOs that skip exons 51 or 53 --> BMD, AAV therapy with "microdystrophin" small version of gene