Lipid metabolism & peroxisomal disorders Flashcards
3 pathways to import fatty acids
SC/MC via diffusion, LC ≥C10 require carnitine shuttle, VLC ≥20 in peroxisome
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.
Multiple CoA deficiency (ETF and ETFDH)
General symptoms of FAOD
Fasting intolerance w/hypoglycemia up to age 4-6, cardiomyopathy, sudden death +/- liver disease, skeletal myopathy/rhabdomyolysis in adolescents
Treatment of FAOD
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)
Hypoketotic hypoglycemia, vomiting -> lethargy, seizure, coma; hepatomegaly and liver dysfunction acutely
MCAD deficiency (ACADM)
NBS with elevated C4 species (ethylmalonic acid), but most asymptomatic
SCAD deficiency (ACADS)
Hypoketotic hypoglycemia, hepatomegaly, hypertrophic/dilated cardiomyopathy, hypotonia —> neonatal multiorgan failure
Early-onset cardiac VLCAD deficiency (ACADVL)
Child with exercise intolerance, rhabdomyolysis
Late-onset myopathic VLCAD deficiency (ACADVL)
Child with hypoketotic hypoglycemia and hepatomegaly
Late-onset hepatic VLCAD deficiency (ACADVL)
Infant with severe metabolic acidosis, profound hypoglycemia, hyperammonemia, hepatomegaly; if survive –> Reye syndrome-like, hypertrophic cardiomyopathy, exercise intolerance
Multiple acyl-CoA dehydrogenase deficiency (MADD) or GA type 2 (ETFDH, ETFA, ETFB flavoproteins)
“Ragdoll” floppiness or DD, facies (flat face, high forehead, scooped nasal bridge), neonatal seizures, liver dysfunction, coagulopathy, renal cysts.
Zellweger spectrum, severe (any of 13 PEX genes)
Child with DD, retinal dystrophy, hearing loss, hypotonia, liver dysfunction, leukodystrophy
Zellweger spectrum, intermediate aka neonatal adrenoleukodystrophy, infantile Refsum, Heimler syndrome (any of 13 PEX genes)
Substances tracked w/peroxisomal disorders
VLCFA - up in XALD and ZSD. ZSD tracks phytanic acid; also high pristanic acid, urine pipe colic acid, bile acids; low plasmalogens.
Child with ADHD/behavioral changes, seizures, adrenal insufficiency
Childhood cerebral adrenoleukodystrophy (X-ALD cCALD, ABCD1 gene)
Adult with progressive leg weakness/spasticity, bladder/bowel dysfunction, loss of sensation, sexual dysfunction, adrenal insufficiency
Adrenomyeloneuropathy (X-ALD AMN, ABCD1 gene, transport into peroxisome)
NBS with elevated C26:0-lysophosphatidylcholine
X-ALD
NBS with elevated C14:1
VLCAD
NBS with elevated C4
SCAD vs ethylmalonic encephalopathy vs isobutyryl-CoA dehydrogenase deficiency; if C5 also elevated could be GA2/MADD
NBS with elevated C16 & C18
CPT2 or CACT deficiency for C16, C18:1; LCHAD for C16-OH and C18:1-OH
NBS with elevated C0 (and C0/C16+18 ratio)
CPT1 deficiency
Treatment of X-ALD
HSCT (early), treatment of adrenal insufficiency w/steroids, ex vivo gene therapy Skysona (elivaldogene autotemcel)
Child or adult with peripheral neuropathy, ataxia, ichthyosis, retinitis Pigmentosa, hearing loss, cardiomyopathy
Classic/Adult Refsum disease (PHYH, PEX7 milder)
Rhizomelic chondrodysplasia punctata, congenital cataracts, growth impairment, profound ID, early death
Rhizomelic chondrodysplasia punctata (PEX7)
Female X-ALD carrier symptoms
50% mild AMN-like symptoms without much WM involvement, not a/w adrenal insufficiency
Dysmorphic facies, cerebellar ataxia, DD, cataracts, HSM, RP, lymphadenopathy, periodic fevers
Mevalonate kinase deficiency
Cholesterol synthesis defect.
High mevalonic acid on UOA, decreased cholesterol.
Autoinflammatory disorder with 5-7 days of fevers every 4-6 weeks, flu-like symptoms, rash, arthralgia.
HyperIgD syndrome, w/residual mevalonate kinase deficiency (cholesterol synthesis defect)
Cleft palate, microcephaly/brain malformations, 2-3 toe syndactyly, polydactyly, hypospadias, CHD, DD, ASD, growth delay, adrenal insufficiency
Smith-Lemli-Opitz syndrome (DHCR7)
Increased 7-dehydrocholesterol (malformations due to interruption of SHH signaling)
Cleft palate, microcephaly, 2-3 toe syndactyly, multiple congenital anomalies + hepatic cirrhosis, normal cholesterol level.
Latherosterolosis (SC5DL), Cholesterol synthesis defect.
Alopecia, congenital cataracts, erythrodermic ichthyosis, hypotonia, DD, ID, seizures
Lanosterol synthase deficiency (LSS)
Normal cholesterol levels, Cholesterol synthesis defect.
Unilateral skin defects with ipsilateral limb aplasia/dysplasia, sparing face. Epiphyseal stippling.
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.
Ichthyosis along Blashko lines, chondrodysplasia punctata
Chondrodysplasia punctata type 2: EBP, X dominant w/male lethal. Milder form = MEND syndrome. Cholesterol synthesis defect.
Hydrops, ectopic calcification, moth-eaten skeletal dysplasia
HEM syndrome: laminin B (LBR), usually lethal due to hydrops in utero. Affects cholesterol biosynthesis as well as connective tissue.
Chronic diarrhea in childhood -> cataracts & xanthomas -> premature atherosclerosis, ataxia, demyelination +/- dementia.
Cerebrotendinous xanthomatosis: CYP27A1, due to bile acid synthesis defect. Decreased bile acids, elevated cholestAnol
Treatment of cerebrotendinous xanthomatosis
Chenodeoxycholic acid (CDCA) - can reverse CNS disease, but xanthomas remain. Improve bile function, inhibits upstream pathways.
