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
10y/o girl with progressive dementia, repetitive myoclonic jerking movement of head & trunk
Subacute sclerosing panencephalopathy
12y/o girl with ataxia, scoliosis, absent DTRs
Freidrich’s ataxia- most common inherited CNS ataxia
9d/o lethargy, fever, conjugated hyperbili, hepatomegaly & ↓ BSL
Galactosemia
Deficiency I galactose 1 uridyl transferase 🡪 cannot break down lactose/ galactose
not part of NST
<2wks- jaundice, FTT, hepatomegaly, liver failure
High urine reducing substances
Rx: soy formula
6mo started on solids- hepatomegaly, lethargy, jaundice, dehydration- reducing sugars +ve stool/urine
Hereditary fructose intolerance
4mo hypotonia, poor feeding, macroglossia, cardiomegaly/short PR
Pompe disease
Glycogen storage disease
AR defect in alpha glucosidase
>2mo - progressive resp failure, hypotonia, CM, delayed milestones
Rx enzyme replacement
2mo with fever, irritability, vomiting, jaundice & decreased GCS, ↓BSL
Tyrosinemia
AR- FAH gene mutation, tyrosine= recursor of dopamine, noradrenalin, adrenalin, melanin and thyroxine
not part of NST
Onset 2-6mo (older - better prog)
- Hepatic crisis precipitated by illness- ↑ALT/AST, bilirubin
- ↓BSL
- Boiled cabbage odour
- Pain/weakness/hypertension
Rx: low phe/tyr diet
Nitisinone - slows effects of ↑tyrosine
At risk of HCC
1mo with poor feeding, vomiting, lethargy, opisthotonus/seizures, ↓BSL, ↑ isoleucine/leucine/valine, sweet smelling
Maple syrup urine disease
AR- defect in branched chain AA enzyme BCKDC
Classic = E1 alpha/beta, E2- newborn with apnoea/dystonia/odour by week 1, can have worsening with illness prompting catabolism
Intermediate- E1 alpha - neurological Sx/dev delay
Intermittent - ketoacidosis/neurological Sx during illnesses
Normal BSL, ammonia & pH- raised urinary ketone
DNPH test – add reagent to urine and precipitates
Rx- avoid branched AAs, dialysis/liver Tx
5d old with tachypnoea, poor feeding, coma/↓ GCS
Metabolic alkalosis/raised HCO3, ↑ ammonia
OTC deficiency
Xlinked deficiency in OTC enzyme- involved in urea synthesis
↑ ammonia >1000, low citrulline, ↑ orotic acid
No ketones, metabolic acidosis
2nd resp alkalosis if ammonia = ↑ RR
Deranged LFTs
Coagulopathy
Often lethal in neonatal period
Rx: low protein diet, replace arg/citrulline, Na benzoate to remove toxins/dialysis, liver Tx
7yo male, myoclonic jerks, GTCs, ataxia, dementia & macular degeneration
Batten disease
Infant with vomiting, pale skin/hair, eczema like rash
Older child with hyperactive/autistic behaviour, profound ID, purposeless movements, seizures, enamel hypoplasia & short stature
PKU
Deficiency of the enzyme phenylalanine hydroxylase (PAH) or cofactor tetrahydrobiopterin (BH4) = accumulation of phenylalanine
Ix: raised serum phe/biopterin def (2% of cases)
Rx: low phe diet, LNAAs (compete with phe), BH4 admin
4y/o with ectopia lentis/glaucoma, BLUE eyes/pale skin, long limbs & high arched palate, recurrent VTE + ID
Homocystenuria
Error of methionine metabolism (homocysteine intermediate met -> cys)
B6 repsonsive – milder form 🡪 60%
B6 non-responsive 🡪 40%
↑ plasma total homocystine and methionine
↑ urine homocystine
Rx: high dose B6/folic acid, restrict cys/met intake if unresponsive
Treatment of hyperammonemia
- Sodium benzoate (conjugates with glycine to reduce in blood)
- Low protein feeds
- High lipid formula
- Adequete hydration
