Pediatrics/Metab

Question 1

Zellweger’s Syndrome

Cause, symptoms

Answer 1

Peroxisome disorder (PEX1) - ^VLCFAs

Dysmorphic small face, cataracts, retinal dystrophy and hearing loss, severe hypotonia, severe ID, seizures

Question 2

Refsum Disease

Cause, symptoms?

Answer 2

Peroxisome disorder - ^Phytanic acid (PHYve senses)

• psychomotor slowing, hearing loss, blindness, anosmia, dysmorphism

Question 3

Fabry’s Disease

Cause, genetics, major symptoms

Answer 3

LSD - defect in alpha-galactosidase
X linked

Strokes + peripheral nerve disease and angiokeratomas

Question 4

Xeroderma Pigmentosum

Genetics, cause, major symptoms

Answer 4

AR disease of DNA repair

Skin cancers, sensitivity to light + hearing loss, cog dysfunction, chorea, neuropathy

Question 5

Neuronal Ceroid Lipofuscinosis

Causes, major symptoms?

Answer 5

AR mutations, mostly in CLN1 and CLN2

Blindness, seizures, ataxia, abnormal movements, and myoclonus in infantile and child forms.

Question 6

X-linked Adrenoleukodystrophy
Cause, symptoms, MRI and lab findings?

Answer 6

• ABCD1 gene for a peroxisome transporter
• ADHD, cognitive impairment, spasticity -> ataxia, bulbar involvement, adreal insufficiency
• MRI w/ T2 hyperintense in posterior brain, rim of enhancement, spares U fibers. ^ VLCFAs

Question 7

Kearns-Sayer Syndrome

Cause, symptoms

Answer 7

• mito disease
• Triad: 1. Progressive external ophthalmoplegia 2. onset <20 years, and 3. at least one of: short stature, pigmentary retinopathy, cerebellar ataxia. heart block, and increased CSF protein

Question 8

Congenital Disorders of Glycosylation

General cause? Most common manifestions?

Answer 8

Type I CDGs - abnormal synthesis of Glycans
Type 2 CDGs - abnormal processing and modification

Dev delay, liver involvement, often lipodystrophy with prominent fat pads, inverted nipples….hypogonadism, stroke-like episodes, peripheral neuropathy, ataxic, dysmorphic

Question 9

Incontinentia pigmenti vs hypomelanosis of Ito

Causes, symptoms

Answer 9

IP:
AD X linked mutation in NEMO gene
- hyperpigmented Blashko lines that changes over time, +/- cognitive issues, pyramidal tract findings, and ocular abnormalities

HoI:
- chromosomal malformations
- same skin findings, + ID, macro/microcephaly, cerebral/cerebellar hypoplasia, eye issues, skeletal hemihypertrophy, congenital heart disease

Question 10

Miller-Dieker Syndrome

Cause, symptoms

Answer 10

Mutation in LIS1 -> abnormal neuronal migration

• Classic (4 layer) lisencephaly + seizures, abnormal face, dev delay

Question 11

NF1

Causes, symptoms

Answer 11

AD mutation of NF1 gene on 17q11.2

Two or more of:
1. 6+ Cafe au lait spots (>5mm prepuberty, >15mm postpuberty)
2. inguinal or axillary freckling
3. two + cutaneous neurofibroma
4. One + plexiform neurofibroma
5. two+ Lisch nodules (iris hamartomas)
6. optic pathway glioma
7. Bony lesions (sphenoid wing dysplasia, thin long bone cortex)
8. NF1 in a first-degree relative

Question 12

Gaucher

Cause, symptoms

Answer 12

Lysosomal storage disease
GBA mutation causes v glucocerebrosidase = ^ glucocerebrosides

hepatosplenomegaly, skeleton, pulm infiltrates, + spasticity, ataxia, choreoathetosis, Parkinsonism in surviving patients, tissue paper macrophages on histology

Question 13

Tay Sachs and Sandhoff’s

Causes, symptoms

Answer 13

GM2 Gangliosideoses
Deficiency in hexosaminidase A (TS, HEXA) or Hexosaminidase A & B (Sandhoff, HEXB)

Tay Sachs = infant w/ increased startle, seizures, blindness, motor regression + cherry red spot

Sandhoff = Tay Sachs + hepatosplenomegaly

Question 14

Canavan’s Disease
Cause, symptoms

Answer 14

AR mutation in ASPA causing deficiency of aspartoacylase -> ^ N-acetylaspartic acid

• irritability, motor regression, eye problems, megalencephaly with diffuse white matter disease and U fiber involvement

Question 15

Krabbe’s Disease

Cause? Symptoms?

Answer 15

AR loss of galactocerebrosidase causing increased galactocerebroside in macrophages which become globoid cells

• irritability, hypertonic with opisthotonos, low grade fevers, blindness, polyneuropathy with areflexia, motor regression

Question 16

NF2

Cause, diagnostics?

Answer 16

AD mutation in MERLIN on 22

One of the following:
1. Bilateral CN VIII Schwannomas
2. Unilateral vestibular schwannoma and family HX of 1st degree relative w/ NF2
3. A positive FH OR Unilateral vestibular schwannoma AND 2 of: neurofibroma, schwannoma, meningioma, glioma, posterior subcapsular lenticular opacities
4. multiple meningiomas and unilateral vestibular schwannoma or two of above

Question 17

GM1 Gangliosidosis

Cause, Symptoms?

Answer 17

AR mutation of GLB1 causing beta-galactosidase deficiency and increased gangliosides

• ataxia, weakness, spasticity, seizures, cherry red spot, dysmorphic features, hepatosplenomegaly

Question 18

Alexander’s Disease

Cause, symptoms, MRI?

Answer 18

Glial fibrillary acid protein (GFAP) mutation

• Infant form with macrocephaly, dev delay, seizures, spasticity and quadriparesis. Bulbar signs in older patients
• MRI w/ frontal white matter changes including U fibers with diffuse Rosenthal fibers

Question 19

Hurler’s Syndrome
Hunter’s Syndrome
Sanfilippo Syndrome

Causes, symptoms?

Answer 19

Mucopolysaccharidoses (MPS)

Hurler’s Syndroem (MPS 1) - v alpha-L-iduronidase = ^ dermatan and heparan sulfate = coarse facial features, skeletal dysplasia, dwarfism., hearing loss and corneal clouding, macroglossia, hernias, visceromegaly, heart disease

Hunter’s Syndrome (MPS 2) - v iduronate sulfatase = ^ dermatan sulfate and heparan sulfate = Hurler pheotype but w/ ivory skin lesiosn and no corneal clouding

Sanfilipo (MPS3) = ^ heparan sulfate only = ID

Question 20

Menke’s Disease

Cause, Symptoms

Answer 20

• Copper deficiency (cant absorb)
• infant w/ kinky hair, elastic skin, seizures, cortical atrophy, severe dev delay, abnormal intra and extracranial blood vessels, subdural hematomas and hygromas, as well as GI, GU, and bony abnormalities