Lipid metabolism & peroxisomal disorders

Question 1

3 pathways to import fatty acids

Answer 1

SC/MC via diffusion, LC ≥C10 require carnitine shuttle, VLC ≥20 in peroxisome

Question 2

Severe metabolic acidosis, profound hypoglycemia and hyperammonemia, recurrent metabolic decompensation resembling Reye syndrome, hypertrophic cardiomyopathy, dysmorphic facial features, large cystic kidneys, hypospadias and chordee, and neuronal migration defects (heterotopias) on brain MRI.

Answer 2

Multiple CoA deficiency (ETF and ETFDH)

Question 3

General symptoms of FAOD

Answer 3

Fasting intolerance w/hypoglycemia up to age 4-6, cardiomyopathy, sudden death +/- liver disease, skeletal myopathy/rhabdomyolysis in adolescents

Question 4

Treatment of FAOD

Answer 4

Avoid fasting, over-exercise.
D10 @ 1.5x maintenance or PO.
Diet: high protein, 25-35% kcal from MCT, LCFA <20%
Triheptanoin (C7 - feeds acetylCoA and C3 backbone)

Question 5

Hypoketotic hypoglycemia, vomiting -> lethargy, seizure, coma; hepatomegaly and liver dysfunction acutely

Answer 5

MCAD deficiency (ACADM)

Question 6

NBS with elevated C4 species (ethylmalonic acid), but most asymptomatic

Answer 6

SCAD deficiency (ACADS)

Question 7

Hypoketotic hypoglycemia, hepatomegaly, hypertrophic/dilated cardiomyopathy, hypotonia —> neonatal multiorgan failure

Answer 7

Early-onset cardiac VLCAD deficiency (ACADVL)

Question 8

Child with exercise intolerance, rhabdomyolysis

Answer 8

Late-onset myopathic VLCAD deficiency (ACADVL)

Question 9

Child with hypoketotic hypoglycemia and hepatomegaly

Answer 9

Late-onset hepatic VLCAD deficiency (ACADVL)

Question 10

Infant with severe metabolic acidosis, profound hypoglycemia, hyperammonemia, hepatomegaly; if survive –> Reye syndrome-like, hypertrophic cardiomyopathy, exercise intolerance

Answer 10

Multiple acyl-CoA dehydrogenase deficiency (MADD) or GA type 2 (ETFDH, ETFA, ETFB flavoproteins)

Question 11

“Ragdoll” floppiness or DD, facies (flat face, high forehead, scooped nasal bridge), neonatal seizures, liver dysfunction, coagulopathy, renal cysts.

Answer 11

Zellweger spectrum, severe (any of 13 PEX genes)

Question 12

Child with DD, retinal dystrophy, hearing loss, hypotonia, liver dysfunction, leukodystrophy

Answer 12

Zellweger spectrum, intermediate aka neonatal adrenoleukodystrophy, infantile Refsum, Heimler syndrome (any of 13 PEX genes)

Question 13

Substances tracked w/peroxisomal disorders

Answer 13

VLCFA - up in XALD and ZSD. ZSD tracks phytanic acid; also high pristanic acid, urine pipe colic acid, bile acids; low plasmalogens.

Question 14

Child with ADHD/behavioral changes, seizures, adrenal insufficiency

Answer 14

Childhood cerebral adrenoleukodystrophy (X-ALD cCALD, ABCD1 gene)

Question 15

Adult with progressive leg weakness/spasticity, bladder/bowel dysfunction, loss of sensation, sexual dysfunction, adrenal insufficiency

Answer 15

Adrenomyeloneuropathy (X-ALD AMN, ABCD1 gene, transport into peroxisome)

Question 16

NBS with elevated C26:0-lysophosphatidylcholine

Answer 16

X-ALD

Question 17

NBS with elevated C14:1

Answer 17

VLCAD

Question 18

NBS with elevated C4

Answer 18

SCAD vs ethylmalonic encephalopathy vs isobutyryl-CoA dehydrogenase deficiency; if C5 also elevated could be GA2/MADD

Question 19

NBS with elevated C16 & C18

Answer 19

CPT2 or CACT deficiency for C16, C18:1; LCHAD for C16-OH and C18:1-OH

Question 20

NBS with elevated C0 (and C0/C16+18 ratio)

Answer 20

CPT1 deficiency

Question 21

Treatment of X-ALD

Answer 21

HSCT (early), treatment of adrenal insufficiency w/steroids, ex vivo gene therapy Skysona (elivaldogene autotemcel)

Question 22

Child or adult with peripheral neuropathy, ataxia, ichthyosis, retinitis Pigmentosa, hearing loss, cardiomyopathy

Answer 22

Classic/Adult Refsum disease (PHYH, PEX7 milder)

Question 23

Rhizomelic chondrodysplasia punctata, congenital cataracts, growth impairment, profound ID, early death

Answer 23

Rhizomelic chondrodysplasia punctata (PEX7)

Question 24

Female X-ALD carrier symptoms

Answer 24

50% mild AMN-like symptoms without much WM involvement, not a/w adrenal insufficiency

Question 25

Dysmorphic facies, cerebellar ataxia, DD, cataracts, HSM, RP, lymphadenopathy, periodic fevers

Answer 25

Mevalonate kinase deficiency
Cholesterol synthesis defect.
High mevalonic acid on UOA, decreased cholesterol.

Question 26

Autoinflammatory disorder with 5-7 days of fevers every 4-6 weeks, flu-like symptoms, rash, arthralgia.

Answer 26

HyperIgD syndrome, w/residual mevalonate kinase deficiency (cholesterol synthesis defect)

Question 27

Cleft palate, microcephaly/brain malformations, 2-3 toe syndactyly, polydactyly, hypospadias, CHD, DD, ASD, growth delay, adrenal insufficiency

Answer 27

Smith-Lemli-Opitz syndrome (DHCR7)
Increased 7-dehydrocholesterol (malformations due to interruption of SHH signaling)

Question 28

Cleft palate, microcephaly, 2-3 toe syndactyly, multiple congenital anomalies + hepatic cirrhosis, normal cholesterol level.

Answer 28

Latherosterolosis (SC5DL), Cholesterol synthesis defect.

Question 29

Alopecia, congenital cataracts, erythrodermic ichthyosis, hypotonia, DD, ID, seizures

Answer 29

Lanosterol synthase deficiency (LSS)
Normal cholesterol levels, Cholesterol synthesis defect.

Question 30

Unilateral skin defects with ipsilateral limb aplasia/dysplasia, sparing face. Epiphyseal stippling.

Answer 30

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome: NSDHL - X dominant, male lethal. CK syndrome is a milder version w/hypomorphic variants. Cholesterol synthesis defect.

Question 31

Ichthyosis along Blashko lines, chondrodysplasia punctata

Answer 31

Chondrodysplasia punctata type 2: EBP, X dominant w/male lethal. Milder form = MEND syndrome. Cholesterol synthesis defect.

Question 32

Hydrops, ectopic calcification, moth-eaten skeletal dysplasia

Answer 32

HEM syndrome: laminin B (LBR), usually lethal due to hydrops in utero. Affects cholesterol biosynthesis as well as connective tissue.

Question 33

Chronic diarrhea in childhood -> cataracts & xanthomas -> premature atherosclerosis, ataxia, demyelination +/- dementia.

Answer 33

Cerebrotendinous xanthomatosis: CYP27A1, due to bile acid synthesis defect. Decreased bile acids, elevated cholestAnol

Question 34

Treatment of cerebrotendinous xanthomatosis

Answer 34

Chenodeoxycholic acid (CDCA) - can reverse CNS disease, but xanthomas remain. Improve bile function, inhibits upstream pathways.