Metabolic Disorders Flashcards
Fructosuria
1:130,000
Autosomal recessive
Deficiency fructokinase
Incomplete metabolism of fructose in liver
Accumulation fructose-1-P
Elevated uric acid, growth abnormalities, coma
Galactosemia
prevalence: 1:60,000
genetics: AR
defect: deficiency galactose-1-P uridyltransferase (GALT)
clinical: onset few days after life with breastmilk/formula
- jaundice, vomiting, hepatomegally, hepatic failure
- FTT, lethargy, diarrhoea
- renal dysfunction, cataracts (galacticol)
- primary ovarian failure secondary to fibrosis (low E, high FSH/LF)
- neonates at risk of Ecoli sepsis
diagnosis: NBST, urine galactitol
treatment: remove galactose and lactose
galactokinase deficiency: cataracts
Smith lemli opitz syndrome
mutation 7-dehydrocholesterol reductase
DHCR7 gene
inability to synthesise cholesteral
associated microcephally, cognitive delay, physical defects
mistaken for autism
Citrullinemia
urea cycle disorder
1:57,000
autosomal recessive chromosome 9
deficit arginosuccinate synthetase
type 1 in neonate
↑ ammonia/pH, acid, urea, GABA
low protein diet
MCADD
Medium chain acyl coA dehydrogenase deficiency
- beta oxidation defect
Most common FA oxidation defect
1: 10,000 autosomal recessive ACADM gene
outcome: prevents breakdown medium chain fatty acids to acetyl-CoA
clinical: onset 3m-5yrs, acute illness with prolonged fasting cuases hypoketotic hypoglycaemia, lethargy, encephalopathy, hepatomegally, liver dysfunction
investigations: no acidosis, ↑ ammonia, hypoglycaemia, no ketones
treatment: frequent feeds with carbohydrates, carnitine
may mimic reye’s syndrome
Glycogen storage diseases
symptoms result from increased glycogen in liver, kidney and intestines
clinical: fasting hypoglycaemia, hepatomegally, hypotonia, poor growth, diarrhoea, bleeding disorders, gout, neutropenia, cherub facies
investigations: elevated lactate, uric acid, cholesterol, triglycerides, abnormal LFTs
type 1: von Gierkes
- glucose-6-P
- liver
- growth failure
- avoid fasting/administration cornstarch
type 2: Pompe
- lysosomal alpha glucosidase
- heart
- heart failure/muscle weakness
- die first 2 months
type 3: Cori
- abnormal debranching enzyme
- milder presents during childhood
type 4: Anderson disease
- abnormal glycogen branching enzyme
- present in infancy with rapidly progressive liver failure
- muscle
- increase CK
type 5: McArdle
- myophosphorylase deficiency
- rhabdomyolysis with short bursts/sustained exercise
- increase glucose/protein
- avoid intense exercise
Phenylketonuria (PKU)
1:10,000
AR
phenylalanine is an essential AA and must be consumed
cause: decreased phenylalanine hydroxylase causing phenylalanine accummulation
- BH4 is a cofactor and defects in BH4 account 2% PKU
investigations: excess phenylalanine/phenylacetate/phenylpyruvate, MRI white matter changes
diagnosis: NST
management: treat within 10 days with phenylalanine restricted diet, replace tyrosine
monitor: phenylalanine and tyrosine levels
prognosis: untreated severe mental retardation/seizures, osteopaenia, light eyes/hair, visual impairment
- phenylalanine thought to interfere with myelination, brain growth, NT synthesis
pregnancyL uncontrolled causes CHD, IUGR, microcephaly, GDD
Tyrosinemias
Type 1:
1:100,000
autosomal recessive
deficit fumarylacetoacetate hydrolase
hypoglycaemia, liver disease, hypoalbuminaemia, renal dysfunction, retardation
treat nitisinone, low protein diet, liver transplant
Type 2/3: hyperkeratosis, keratitis
Homocysteinuria
autosomal recessive
deficit cystathionine beta synthetase
Symptoms CNS, connective tissues, cardiac: dislocated ocular lens (down, outwards), myopia, musculoskeletal changes (tall, long limbs, arched feet, pectus excavatum), malar flushing, livedo reticularis, retardation, atheroma/thromboses, ID, seizures
50% pyridoxine (B6) responsive, otherwise low sulfur/AA diet and trimethylglycine
Maple Syrup Urine Disease
(branched chain ketoaciduria)
autosomal recessive
1: 200,000
cause: deficiency branched chain alpha keto acid dehydrogenase
- affects branched chained AAs (valine, leucine, isoleucine) in protein rich foods
- build up of AAs and toxic biproducts (ketoacid)
clinical: sweet smelling urine, metabolic crisis with hypoglycaemia, vomiting, lethargy, dehydration, hypotonia, cerebral oedema, seizures
investigations: ↑ glucose/ketones, normal ammonia/pH, increased branched chain AAs, urine DNPH testing
management: restrict branched chain AAs esp leucine
Carnitine deficiency
Cofactor for the transport of long chain FA into the inner membrane of the mitochondria
causes hypoketotic hypoglycaemia, weekness, lethargy, cardiomyopathy (heart uses fat as energy)
treat oral carnitine
Diagnosis IEM
Mitochondrial disorders
(primary lactic acidosis)
1:2500
autosomal recessive mostly
cause: insufficient substrate mitochondira causes TCA and ATP insufficiency
clinical: damage to energy dependent organs (brain, heart, liver, kidney, muscle)
eg. Alper disease (brain, liver), Leigh disease (subacute necrotising encephalomyelopathy)
investigations: metabolic + lactic acidosis, increased pyruvate, hypoglycaemia, liver dysfunction
days to weeks: lethal acidosis
Urea cycle defect
OTC deficiency
1: 60,000 X linked
- defective ornithine transcarbamylase
- most common urea cycle disorder
Clinical: protein aversion, vomiting, decreased GCS, encephalopathy, DD, autistuc features, cerebral oedema
Investigations: elevated ammonia, no acidosis, deranged LFTs, abnormal coagulation, low AAs citrulline/arginine\, low urine orotic acid
Treatment: low protein diet, AA supplement (arginine/citrulline), liver transplant
Mucopolysaccharidoses
- MPS broken down from connective tissue via specific enzymes
- AR (Hurler’s X lined)
cause: MPS lysosomes unable to breakdown GAG
clinical: DD within 1 yr with mental/physical deteriorations, skeleton, HSM, MR, eyes - Hurlers: course features, hirsutism, macroglossia, corneal clouding, ENT problems, cardiomyopathy, DD, MR
Oligosaccharidoses: like MPS but less common and presents earlier
Sphingolipidoses: abnormal sphingolipids accumulate in reticuloendo system
- DD, MR, neurological degeneration
Peroxisomal disorders
Peroxisome: major function break down VLCFA
Zellweger syndrome (leukodystrophy)
1:100,000
autosomal recessive (PEX gene)
cause: peroxisomes involved in metabolic function: metabolise VLCFA/acids, synthesise bile acids/myelin precursors
clinical: impaired neuronal migration/position and brain development
- high forehead, flat orbital ridge, wife fontanelle, hepatomegally, hypotonia
investigation: increased VLCFA/phytanic acid
prognosis: die at 1 year of age
Lysosomal storage disorders
cause: unable to degrade mucopolysaccharides, sphingolipids, glycoproteins
storage disease: stored in cells causing destruction
clinical: DD, corneal clouding, joint stiffness, hepatomegally, short stature, bone deformity, CNS defects
diagnosis: increased urinary GAGS
Mucopolysaccharidoses (MPS)
eg. Hurler’s/Scheie
- deficiency alpha-L-iduronidase needed to breakdown glycoaminoglycans
- treat with IV recombinant
Long chain acyl-CoA dehydrogenase deficiency
Autosomal recessive
cause: deficit long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase
issue: prevents breakdown fatty acids to acetyl-CoA
Organic acidemia
cause: accumulation organic acids
- produced metabolism AAs/FAs/carbs
- acidemia occurs with metabolites aren’t broken down and unable to fuel CAC
diagnosis: newborn screen
investigations: increased plasma AAs/urinary organic acids, high anion gap metbolic acidosis, carnitine deficiency, thrombocytopaenia/leucopenia
clinical: present first 1-2 weeks, poor feeding, lethargic, floppy, vomiting
management: low protein diet, avoid fasting, carnitine supplements
Methylmalonia acidemia: deficiency methylmalonic-COA mutase or cofactor B12
Proprionic acidemia: deficieny proprionyl-COA carboxylase
