Metabolics Flashcards

Question

Medium chain acyl co-A dehydrogenase deficiency What is it? Inheritance? Clinical features Ix findings Tx

Answer 1

FA oxidation defect (most common) AR Picked up on NST High mortality rate (20-25%) Clinical ft - onset 3mo-5yo - hypoglycaemic (with LOW ketones) during periods of fasting or illness - NO acidosis - lethargy, encephalopathy, liver dysfunction, hepatomegaly - Ix: incr medium chain fatty acid - -\> secondary carnitine deficency Treatment - avoid fasting - high carb, low fat diet - may require tx w carnitine, IV hydration, dextrose

Answer 2

urea cycle defects ft high ammonia -\> drives hyperventilation -\> decr CO2 -\> alkalosis

Answer 3

Is an aminoacidopathy caused by deficiency or absence of phenylalanine hydroxylase -\> accumulation of dietary phenylalanine accumulates; the brain is the main organ affected, possibly because of disturbance of myelination. Spectrum depending on degree of enzyme deficiency/absence AR inheritance Normal at birth Light skin, hair, eyes Eczema-like rash Unpleasant, musty body odor Intellectual disability and cognitive delay if untreated Seizures Microcephaly Diagnosis - NST - Phenylalanine levels - Tyrosine normal or borderline low Tx - lifelong dietary protein restriction

Answer 4

Pompe disease = Lysosomal Glycogen storage disease type II (AR) Caused by acid alpha glucosidase deficiency -\> glycogen buildup within lysosomes GIANT HEART (Hypertrophic cardiomyopathy) -\> eventual heart failure HYPOTONIA - Floppy weak Enlarged tongue and liver Bulbar/swallowing difficulties Prognosis: if unrecognised, leads to - \> Respiratory failure - \> Cardioresp failure - \> death by 2yo Ix: GAA enzyme activity in serum Tx: enzyme replacement and supportive tx

Answer 5

Subacute necrotising encphalomyopathy Mitochondrial disorder with progressive neurodegeneration and then death Affects basal ganglia/corpus callous Multiple diff mutations and inheritance Sx - onset before 2 yo - _Episodic developmental regression_ during times of metabolic stress (infection, surgery etc) - feeding, swallowing problems - vomiting - FTT - seizures - eye stuff - _intermittent hyperventilation ('sighing' resps)_ - hepatic and renal filaure - HOCM Ix * Elevated serum and CSF lactate * MRI B - hyperintensity (White) of basal ganglia on t2 (symmetrical basal ganglia and brainstem lesions) * Muscle bx for enzyme analysis (resp chain enzymes) Prognosis * often death early childhood * most common cause of death is resp failure

Answer 6

Metachromic leukodystrophy (lysosomal storage disorder) periventricular dominant white matter abnormality (looks like a X on MRIB) Is a lysosomal storage disorder Late infantile, childhood or adult onset forms Causes central and peripheral demyelination -\> peripheral neuropathy, Decr reflexes, hypotonia, ataxia, trouble speaking and eating/swallowing, seizures

Answer 7

X-linked Adrenoleukodystrophy Posterior (occipital) white matter changes * Mutation in ABCD1 gene. * Peroxisomal disorder, increased serum VLCFA * Boys present early with ADHD like sx (behavioural difficulties) then developmental regression, loss of vision and hearing and motor and sensory function. End result vegetative state and death within 2-3 years of sx onset. * Can have assoc Addison’s disease (adrenal insufficiency) Tx HSCT

Answer 8

Joubert syndrome (Jou - lolly, eating lolly w your molars)

Answer 9

should be 0 - if there is nay insulin, this is ABNORMAL . sign of hyperinsulinaemia.

Answer 10

Fatty acid oxidation defects (inability to break down stored fats into ketones for energy during periods of fasting/illness/stress etc) - \> require SIGNIFICANT catabolic stress for presentation, thus often presents later in childhood or adulthood c/w glycogen storage disorders - \> ex: MCAD (most common), VLCAD, LCHAD, CPT1 Diagnosis via: Serum acylcarnitine profile

Answer 11

Urea cycle defect -\> OTC deficiency \*\*Ammonia is acutely poisonous to the brain\*\*\*

Answer 12

Mother! Not father IE inheritance for mitochondrial DNA disease is inherited down maternal lineage

Answer 13

X-linked adrenoleukodystrophy

Answer 14

Lysosonal storage diseases ddx - Mucopolysaccharoidosis (type 1 is Hurler disease - coarse facial features, skeletal features, seizures, dev dealy etc) - Fabry's disease (foamy urine, angiokeratomas, burning pain to extremities, renal failure)

Answer 15

1. Galactosaemia 2. Some types of glycogen storage disorder (GSD1 Van Gierke and 2 Pompe and 3 Cori/Forbes = massive; GSD6, GSD 9 mild-mod) 3. Tyrosinaemia (aminoacidopathy)

Answer 16

Lysosomal storage disease (ex: Gaucher disease)

Answer 17

Glycogen storage disorders

Answer 18

X-linked adrenoleukodystrophy - occipitocortico distribution involving corpus collosum

Answer 19

Glycogen storage disorder type 1 (Van Gierke disease) - \> large amounts of glycogen stored in liver but are unable to catabolise it/break it down into glucose to be used as fuel - \> during periods of stress/starvation/illness they become hypoglycaemic (instead release fat stores -\> incr ketones and FFA)

Answer 20

Glutaric aciduria type 2 (could also be type 1) Expect ammonia to be high tx: low lysine diet, carnitine, emergency diet

Answer 21

Measures the breakdown products of fat Carnitine transports fatty acyl CoA into mitochondria -\> beta oxidation makes acetyl CoA which enters krebs cycle to form ketones Measures fats bound to carnitine Diagnosis of fatty oxidation defects

Answer 22

``` GAMT deficiency (guanidinoacetate methyltransferase deficiency) -\> leads to cerebral creatinine deficiency ``` Treatable! Oral creatinine and ornithine supplements

Answer 23

GAG:Cr ratio for diagnosis of mucopolysaccharidoses (the only lysosomal storage disorder you can diagnose this way)

Answer 24

Phenylketonuria - form of aminoacidopathy where deficiency in phenylalanine hydroxylase prevents metabolism of phenylalanine to tyrosine Ix: high levels serum phenylalanine (picked up on NST usually) Tx - limit phenylalanine (low protein diet), supplement tyrosine

Answer 25

Amino acidopathy High serum levels of isoleucine, leucine and valine Due to decr activity of alpha ketoacid dehydrogenase Presentation: acute onset encephalopathy either soon after birth or intermittently during periods of stress or illness. sweet/fenugrek smelling urine during periods of metabolic crisis.

Answer 26

Mitochondrial disorder (ex: Leigh syndrome)

Answer 27

**Glutaric aciduria type 1** (type of organic acidaemia) * Metabolic ketoacidosis, hyperammonaemia, hypoglycaemia, and encephalopathy - decompensation following infection/illness * Microencephalic macrocephaly is typical and if present at birth, can be the earliest sign. * Tx - Low protein diet, L-carnitine, B12 + biotin, avoid catabolism **Also Menkes disease** (disorder of copper metabolism -\> LOW levels) * Also ft prolonged jaundice, hypothermia, hypotonia, and feeding difficulties, normal hair at first replaced by sparse brittle hair, development of seizures and developmental regression ~2-3months; loose skin, lax joints. * Diagnosis - Low levels of serum caeruloplasmin and copper + light microscopy of hair follicle +/- genetic testing for ATP7A gene * Tx - copper injfections

Answer 28

Leigh syndrome Mitochondrial disorder

Answer 29

OTC deficiency - is x-linked

Answer 30

Medium chain acyl-CoA dehydrogenase deficiency is a rare genetic metabolic disorder characterised by a deficiency of the enzyme 'medium chain acyl-CoA dehydrogenase' (MCAD). - \> This enzyme is found to be most active in the liver, leukocytes, and fibroblasts, and is necessary for the oxidation of medium chain fatty acids. - \> Failure to break down these fats can lead to the abnormal accumulation of fatty acids in the LIVER and the BRAIN. - \> Causes decreased ATP production and ketogenesis. - \> The rate of gluconeogenesis is similarly reduced, and the endogenous glucose supply is rapidly exhausted, resulting in HYPOGLYCAEMIA. - \> Patients get _HYPOKETOTIC hypoglycemia triggered by fasting or illness, with vomiting, lethargy, hepatomegaly, seizures_ - \> Cause of sudden death in infancy Think of it with: HYPOKETOTIC hypoglycemia, HEPATOMEGALY (fatty liver) and elevated FFA May also be assoc w cardiomegaly and arrhythmia and rhabdomyolysis (heart and skeletal muscle particularly reliant on FA) Diagnosis: urine organic acids and blood acylcardnitine profile, fibroblast FAOD enzyme studies Tx: regular oral feeds/intake of carb solution (IV/PO) uring periods of catabolic stress

Answer 31

Lysosomal storage disorder. - Features include neuropathic pain, hypohydrosis, poor exercise tolerance and corneal opacities. - Angiokeratomas and telangiectasia are usually evident in the second decade of life and are seen in the groin and peri umbilical area. - Symptoms are usually present by 10 years of age but the diagnosis is often delayed. - Cardiovascular and renal complications are common in adulthood and can results in a fatal cerebrovascular event or ESRF.

Answer 32

Galactosaemia - Deficiency in GALT enzyme (galactose 1 phosphate urtidyl transferase) - Therefore unable to metabolise galactose or lactose (glucose+galactose) Diagnosis: Red blood cell enzyme assay (low GALT) Children present after commencing feeds (usually second half of first week of life) with jaundice, hepatomegaly and vomiting. - Cataracts are not present initially. - Galactosaemia is included in newborn screening but children may present before screening results are available. - Red blood cell galactose-1-phosphate activity will be reduced but is not accurate if the child has received a blood transfusion in the preceding three months. - May also present with E COLI SEPTICAEMIA, renal tubulopathy - Urine: positive reducing substances but negative for glucosuria Tx: Lactose/galactose free diet (soy- or casein hydrosylate based formula)

Answer 33

Tay Sachs - lysosomal storage disorder - beta herosamidase A deficiency

Answer 34

Hurler's disease mucopolysaccharidosis type I Diagnosis: elevated urine GAGs, white cell enzymes (deficiency in alpha-L iduronidase) Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year.

Answer 35

Vitamin B12 deficiency

Answer 36

Urea cycle defect ammonia level This scenario describes a child with a urea cycle defect. They present at 24-48 hours of life. The clues in this scenario are the tachypnoea (suggesting hyperventilation) and his mother is a vegetarian (The child is likely to have OTC deficiency, the only X linked urea cycle defect. Affected female carriers often become vegetarian because they cannot tolerate the high protein load in meat.) The most helpful investigation is ammonia - children with urea cycle defects will have extremely high levels of ammonia

Answer 37

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) typically presents in children aged 18 months to three years during a period of stress (usually a viral infection). Children younger than this usually feed so frequently that it masks the disorder. The treatment is to avoid prolonged periods of fasting. Diagnosis: Acylcarnitine profile

Answer 38

An autosomal recessive disease in which gene expression of glucose-6-phosphatase (which normally catalyze reactions that ultimately convert glycogen compounds to glucose) is absent, resulting in hypoglycemia due to lack of glucose production. Accumulation of glycogen in liver and kidney leads to organomegaly, particularly massive hepatomegaly. Increased concentrations of lactic acid and hyperlipidemia appear in the plasma. Clinical gout often appears in early childhood Metabolic acidosis High free fatty acids and beta-hydroxybutyrate (ketones) Very low insulin levels, and high levels of glucagon, cortisol, and growth hormone (adaptation to chronically low BSLs) Elevated lactate Diagnosis is conirmed by laboratory and genetic techniques such as liver biopsy with electron microscopy, assay of glucose-6-phosphatase activity in the tissue or specific gene testing.

Answer 39

Used in perisistent hyperinsuliaemic hypoglycaemia of infancy Binds to the SUR1 subunit of K-ATP channel, causing opening of the K-ATP channels and inhibition of insulin secretion

Answer 40

High levels insulin and c-peptide IRRESPECTIVE OF PLASMA GLUCOSE LEVEL Low plasma free fatty acids, beta-hydroxybutyrate (ketones), and insulin growth factor binding protein 1 (IGF-BP1) (due to IGF-BP1 gene transcription suppression by insulin). Increase in plasma glucose in response to glucagon administration during hypoglycaemia (will not get this with glycogen storage disorders) A glucose infusion rate above 6–8 mg/kg/min to maintain normoglycemia is typical of this condition.

Answer 41

- This condition can be caused by various defects in metabolism of galactose. - Galactose is formed (along with glucose) from lactose breakdown during energy utilization. - The most common defect is galactose-1-phosphate uridyl transferase (GALT) deficiency - These infants may present with hyperketotic hypoglycemia, which may be post-prandial (post breast or lactose formula feed) due to accumulation of galactose-1-phosphate. - Other common manifestations include hepatosplenomegaly, transaminitis, jaundice, e coli sepsis, seizures, developmental delay, DIC, cataracts, urinary excretion of glucose and aa (proximal renal tubular defect) - They also may have growth delays and ovarian failure - The newborn screening test measures RBC GALT enzyme activity, and differ according to location in which it is performed. - Treatment includes avoidance of lactose and galactose (soy or casein hydrosylate based formulas).

Answer 42

- AR, deficiency of fructose-1-phosphate aldolase isoenzyme b, which inhibits gluconeogenesis through accumulation of fructose-1-phosphate. = unable to metabolise fructose or sucrose (glucose and fructose) - Present with hypoglycemia (abdo pain, vomiting, diarrhoea) when fructose or sucrose is introduced into the diet (solid diet of fruit and veg). - Additionally, they may have hepatomegaly (Fruc-1-Ph accumulates in hepatocytes) , failure to thrive, hyperuricemia, and lactic acidosis. - Diagnosis via liver biopsy: enzyme analysis and genetics - Tx: avoidance of fructose ingestion - Untreated fructose intolerance may lead to progressive renal and liver failure +/- growth retardation, seizures, deadness

Answer 43

1. Tyrosinaemia (deficiency in FAH enzyme -\> incr serum tyrosine and succinylacetonuria) 2. Hyperglycinaemia (elevated CSF: plasma glycine ratio. tx sodium benzoate lowers glycine levels) 3. PKU (elevated phenylalanine, low tyrosine. deficient phenylalanine hydroxylase) 4. Also Tyrosinaemia 5. Tyrosinaemia 6. MSUD (elevated serum isoleucine, leucine, valine due to dysfunctional alphaketoacid dehydrogenase) 7. Homocystinuria. Elevated serum homocysteine and methionine due to deficient cystathione synthase..

Answer 44

``` McArdles disease (GSD 5) Cx: rhabdomyolysis -\> incr serum CK, urine myoglobinuria -\> AKI ```

Answer 45

Pompe disease (GSD type 2) -\> also assoc w infantile cardiomegaly and hepatomegaly, hypotonia

Answer 46

Smith–Lemli–Opitz syndrome (SLOS) - \> AR condition - \> Deficiency of 7-dehydrocholesterol reductase (DHCR7; primarily catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol). - \> In SLOS, this results in decreased cholesterol and increased 7DHC levels Presentation : - 2nd/3rd toe syndactyly is most common - FTT, Dev delay, ID, autistic features - Cardiac: ASD, VSD, PDA, HTN - Hypospadius, cryptorchidism, ambiguous genitalia in males - Renal anomalies

Answer 47

Pathopneumonic for **Wolman disease** - lysosomal storage disorder - AR , LIPA gene mutation - prognosis : death in infancy

Answer 48

**Krabbe disease** = _lysosomal storage disorder and leukodystrophy_ (myelin sheath/white matter degeneration) - AR GALC gene mutation -\> Galactosyltransferase deficiency - Build-up of unmetabolised lipids -\> myelin sheath degeneration - Presents in infancy (3-4months) with feeding difficulty, painful spasticity, stiffness, seizures, vision loss - Progressive neuroloical deterioration and death by 2 yrs of age