Metabolics Flashcards
1wk baby lethargy/poor feeding & vomiting, improves with IVF but worsens with feeds- can present in coma
High ammonia, low pH and bicarb, hypoglycemia +/- low neutrophils
Elevated FFAs
Methylmalonic acidemia
- MMA intermediate in pathway of branched AAs (L,I,V)/cholesterol > TCA cycle
- B-12 is cofactor in this pathway
- Can result from enzyme/B12 defect
Rx: B12 & biotin (proprionic acid), supplementation, supress gut bacteria- metronidazole
6mo baby- neurological regression, splenomegaly & neck retraction
Infantile Gaucher Disease
Sphingolipidoses
AR deficiency in glucocerebrosidase- toxic accumulation in liver, spleen, BM
Type 2
<2yrs, NO BONY dx
- Cog imp, seizures, retroflexion of neck, supranuclear gaze palsy/strabismus
- Rapidly progressive
Type 3
>2yrs, BONY & NEURO dx
- + visceral involvement
- Slowly progressive
3y/o unresponsive with hypoglycemia after illness (gastro)
Hypoglycemia is with LOW ketones
+/- high ammonia/metabolic acidosis
FAO defect
Unable to produce ketones when fasting/mobilise sugar
- Rhabdo, CM (dilated/hypertrophic), rec. hypoglycemia
Most common = MCADD
Others VLCADD, SCAD, Carnitine def
Progressive cardiomyopathy & skeletal muscle weakness in 3y/o
Carnitine deficiency
FAO defect
1-4 yrs
Defect in carnitine uptake
Only fasting hypoketosis if reduced dietary carnitine
10y/o boy with personality change, decreased academic performence, loss of purposeful hand movements with writhing/athetoid
Adrenoleukodystrophy
Peroxisomal disorder
X-linked, mutation in ATP-binding casette protein
Catalyses change CoA to VLCFA
- Accumulation of VLCFA (↑ C26:C22)
- Periventricular WM changes- parieto-occipital
Onset ~5-10yrs
Sx: regression in learning/behavior change, gait disturbance/ataxia, seizures, then adrenal insufficiency (85% adrenal happens after neuro sx)
Rx: dietary restriction of VLCF, immunomodulation, erucic acid- Lorenzo’s oil
Death within 10yrs
3mo baby with high forehead/flat facies, hypotonia & hepatomegaly
Bloods show ↑ VLCFA
Zellweger syndrome
AR mutation in PEX gene- unable to transport proteins into peroxisome
Ix: raised VLCFA, MRI- polymicrogyria
Wide clinical spectrum- dysmorphic + FTT
CNS: Hypotonia/seizures/SNHL/WM abnormalities & dysgenesis
Eye: cataracts, glaucoma, corneal clouding, brushfield spots
Death in infancy
Infantile rufism = also similar, elevated phytanic acid (PEX 1,6,7 mutation)
8mo boy- vomiting, lethargy, hypoglycemia & low ketones
- AR mutation in ACADM gene- used to oxidise MCT to acetyl CoA
- 3mo -5yrs onset
- Hypoglycemia with low ketones when fasted, no metabolic acidosis
- Rx: avoid fasting, regular glucose meals, carnitine supplementation
Infant with microcephaly/ptosis, cleft , 2-3 syndactyly/polydactyly, ambiguous genitalia (or underdeveloped), ECD/HLHS, renal anomalies & GI anomalies
Bloods show low serum cholesterol
Smith-Lemli-Opitz
AR deficiency in 7-DHC, abnormality in cholesterol metabolism (unable to make cell membranes/myelin/sex steroids)
Ix: ↑ 7-DDHC
↓ Serum cholesterol
DHCR7 gene mutation – sequence analysis
Rx: cholesterol supplementation, HMG-CoA reductase inhibition
15y/o Ashkenazi Jew with chronic fatigue, splenomegaly
Gaucher disease
Sphingolipidoses
AR deficiency in glucocerebrosidase- toxic accumulation in liver, spleen, BM
Type 1 99% Ashkenazi Jews
- Osteopenia, lytic bony lesions
- HSM
- Anemia and thrombocytopenia
WITHOUT neurological disease
Ix: Bone marrow: Gaucher cells with crumpled tissue cytoplasm
3mo girl with irritability/dev regression, opisthotonus & absent DTRs
Infantile Krabbe Disease (sphingolipidoses)
AR mutation in GALC gene- Deficiency of galactocerbrosidase beta galactosidase leading to demyelination, forms globoid cells.
Infantile = rapidly progressive
Juvenile = weakness, visual loss & regression
Adult = loss of dexterity, parasthesia/pain
Ix: ↓ galactocerebrosidase, MRI symmetrical grey & WM atrophy
Rx: enzyme replacement if infantile- usually death 2-5yrs
3mo with rapidly progressive neurologic deterioration (ataxia, spasticity, oculomotor apraxia), hepatosplenomegaly & cherry red spot on macula
Raised lipids on bloods
Niemann Pick
AR mutation in sphingomyelinase gene
- accumulation of sphingomyelin
This scenario = type A
Type B= later onset/milder symptoms, +/- low plts, ILD
Type C = prolonged jaundice, abnormal cholesterol transport
Ix: low ASM enzyme, raised lipids, SMPD1 mutation
Rx: supportive, liver/BM transplant
15y/o boy with recurrent episodes of burning pain in feet.
Corneal opacities/cherry red spots on eye exam and angiokeratomas on lower legs
Proteinuria on dipstick
Fabry disease
X-linked recessive- absent lysosomal enzyme, α-galactosidase A
Usually males, females if lyonisation
Onset teens
Fabry crisis- pain/burning LL, renal impairment, CM, skin lesions & corneal opacities
Death in 50s
18mo boy with FTT, spasticity, choreoathetosis & self mutilation
Lesch-Nyhan
X linked- HPRT1 mutation
Onset 3-6mo
- Motor dysfunc (EPSE) + cognitive disturbance/self harm + uric acid overproduction
High urate, low HPRT enzyme activity
Rx: supportive, control of high urate
2y/o boy, delayed motor development, sighing resps/apnoea & pale optic discs
Leigh disease
nDNA/mtDNA mutation for genes in respiratory chain
Poor swallowing, vomitting, FTT, delayed milestones, HOCM, eye changes
Ix: lactic acidosis, MRI brain lesions = bilaterally symmetric areas of low attenuation in the BG and brainstem
Rx: metabolic cocktail (riboflavin, thiamine, CoQ; biotin, creatinine, succinate, idebenon, high fat diet)
2y/o girl- N development until 1yrs -> language regression, decreased purposeful movements and hand wringing
Retts
MECP2 gene mutation (less common CDKL5, FOXG1)
Missense, framshift and non-sense
Sporadic in >99% of cases
Almost all in females
Normal dev then regression 1-2yrs
Deceleration of head growth, autistic features, seizures, apnoeas
Loss of language
Stereotyped hand movements
Supportive Rx only
Slow decline into death ~45yrs
