Metabolic Disorders Flashcards
What is the incidence of Alkaptonuria
1/250,000 - 1/1,000,000
Alkaptonuria pathway, enzyme, and gene
Pathway: Tyrosine metabolism
Enzyme: Homogentisate 1,2-dioxygenase
Gene: HGD
Alkaptonuria pathogenesis and symptoms
Homogentisic acid builds up, gets stored in connective tissues and excreted in urine.
Leads to: black urine, ochronosis (build up of blue-black pigment in skin&bones), arthritis in spine & joints, height loss, bone/cartilage necrosis, kidney/prostate stones, heart valve calcification.
Alkaptonuria Treatment
Restrict dietary Phe and Tyr
Nitisone to inhibit pathway
Homocysteinuria incidence
1/200,000 - 1/335,000 worldwide
More common in Ireland (1/65,000); Germany (1/17,800); Norway (1/6400); Qatar (1/1800)
Homocysteinuria pathway, enzyme, and gene
Pathway: Methionine synthesis
Enzyme: Cystathionine Beta-Synthase
Gene: CBS, MTHFR, MTR, MTRR, MMADHC
Homocysteinuria features
*Similar to Marfan Syndrome
Distinguish by: intellectual disability, seizures, strokes, joint contractures, hypopigmentation, psychiatric problems.
Homocysteinuria treatment
Protein restricted diet
Vitamin B6 effective for 50% of patients
Betaine provides alternate homocysteine breakdown pathway
If residual enzyme activity - folate and B12
Incidence of MSUD
1/185,000 worldwide
1/380 in Old Order Mennonite
MSUD pathway, enzyme, and genes
Pathway: Branched chain amino acids (Ile, Leu, Val)
-mnemonic: “I Love Vermont Maple Syrup”
Enzyme: Branched chain alpha ketoacid dehydrogenase complex
Genes: BCKDHA, BCKDHB, DBT
MSUD Features
Urine smells like maple syrup Developmental delay Poor feeding, Lethargy Opisthotonic posturing Respiratory failure Encephalopathy (when in crisis)
MSUD Treatment
Restrict dietary Leucine
PKU incidence
1/10,000 - 1/15,000
PKU Pathway, Enzyme, and Gene
Pathway: phenylalanine breakdown to tyrosine
Enzyme: phenylalanine hydroxylase
Gene: PAH
*could also be due to biopterin deficiency
PKU features
Untreated: Severe ID Microcephaly Musty odour Seizures Behavioural problems Exaggerated reflexes Characteristic hypopigmentation (due to no tyrosine)
Treated: Psychiatric and developmental problems depending on how well treatment is maintained Characteristic hypopigmentation (due to no tyrosine)
PKU treatment
Dietary Phe restriction
Biopterin supplementation
Tyrosinemia pathway, enzyme, and gene
Pathway: Tyrosine metabolism Enzymes and associated genes: 4-fumarylacetoacetase (FAH) - Type I Tyrosine transaminase (TAT) - Type II P-hydroxyphenyl pyruvate dioxygenase (HPD) - Type III
Tyrosinemia incidence
Type I: 1/100,000 worldwide 1/60,000 - 1/74,000 in Norway 1/16,000 in Quebec 1/1846 in SLSJ region of Quebec
Type II:
1/250,000 worldwide
Type III:
Very rare
Tyrosinemia Type I, II, III features
All types: Cabbage smell
Type I: Most severe Crises - altered mental state, abd. Pain, resp failure, peripheral neuropathy Acute liver failure, jaundice, increased risk HCC Renal failure Rickets - soft bones FTT Chronic weakness Death by age 10 if untreated
Type II: Keratosis palmoplantaris (painful hyperkeratosis of hands and feet) ID in 50% Ocular and cutaneous findings Poor growth
Type III: Normal liver function Mild ID Seizures Intermittent ataxia
Tyrosinemia type I, II, III treatment
Type I: orfadin to block 2nd step in pathway (prevent metabolite accumulation)
Type II: dietary restriction of Phe and Tyr
Type III: dietary restriction of Phe, Tyr, Met
Signs of FAO disorders
FTT in infancy; SIDS
Fasting intolerance - vomiting, seizures, respiratory problems, lethargy, brain damage, coma, death (because cannot use fat for energy)
**most common genetic cause of hypoketotic hypoglycemia (except SCAD) (may be abn only during crises)
Low plasma carnitine
Myopathy and cardiomyopathy for LCHAD and VLCAD
Treatment of disorders of fatty acid oxidation
Avoid prolonged fasting - frequent feedings to maintain blood glucose Avoid high fat diets Avoid illness (vaccinate!) For people with LCHAD/VLCAD: Can give MCT oil to supplement calories, and trihepatonoin to reverse/prevent cardiomyopathy
Enzymes and genes for SCAD, MCAD, LCHAD, VLCAD
SCAD: short chain acyl-coA dehydrogenase; ACADS
MCAD: medium chain acyl-coA dehydrogenase; ACADM
LCHAD: long chain 3-hydroxyacyl-coA dehydrogenase; HADHA
VLCAD: very-long chain acyl-coA dehydrogenase; ACADVL
Incidence of SCAD, MCAD, LCHAD, VLCAD
SCAD: 1/35,000 - 1/50,000
MCAD: 1/17,000 (most common dFAO)
LCHAD: 1/62,000 in Finland, likely lower worldwide
VLCAD: 1/40,000 - 1/120,000
Incidence of SCAD, MCAD, LVHAD, VLCAD
SCAD: 1/35,000 - 1/50,000
MCAD: 1/17,000 (most common dFAO)
LCHAD: 1/62,000 in Finland, likely lower worldwide
VLCAD: 1/40,000 - 1/120,000
XL Adrenoleukodystrophy gene
ABCD1
XL Adrenoleukodystrophy symptoms
Childhood Cerebral Form: Onset age 4-8 years Progressive neurodegeneration Behavioural and learning defecits Seizures Adrenocortical dysfunction Total disability and death within 0.5-2 years
Adrenomyeloneuropathy:
Onset in 20s
Lower body: Progressive stiffness/weakness, loss of sphincter control, sexual dysfunction
Adrenocortical dysfunction
Neuropathy
40-50% show leukodystrophy on MRI; 10-20% of these will have severe cognitive decline and early death
Isolated Addison’s disease
Adrenal insufficiency, skin hyperpigmentation from excess ACTH. No other symptoms.
In females (if symptomatic): Mild myelopathy/sensory changes in lower extremities Small portion show cognitive decline Usually no adrenocortical dysfunction
Treatment of XL Adrenoleukodystrophy
Corticosteroid replacement therapy is necessary
Hematopoietic stem cell transplant is risky, but may rescue brain involvement, so can be offered to those with brain involvement.
General features of galactosemias
Symptoms onset after first feeding, worsen after feedings Liver dysfunction Renal dysfunction Cataracts Hypoglycemia Lactic acidosis Hyperuricemia Dairy intolerance (not lactose intolerance)
GALT / Gal-1-P deficiency gene and common allele
Gene: GALT
Duarte allele: p.N314D - common, mild allele
GALT features
NO AVERSION TO GALACTOSE CONTAINING FOODS neonatal onset: FTT, lethargy Liver dysfunction Hyperbilirubinemia Renal tubular acidosis ID Cataracts Sepsis / bacterial infections POI in females
GALT treatment
Dietary lactose restriction
Calorie supplements
Non-dairy, NON-LEGUME protein supplements
GALK1 Deficiency features and treatment
Only symptom is cataracts
Treat by restricting dietary lactose
GALE Deficiency features and treatment
Features: Severe onset Psychomotor delay, ID, DD Hyperbilirubinemia Liver dysfunction Renal tubular acidosis Cataracts Bacterial infections / Sepsis
Treat by restricting dietary lactose and galactose
Von Gierke Disease - type of disease, gene, enzyme
GSDI
G6PC
Glucose-6-phosphatase
Von Gierke Disease - major features
Hypoglycemia Hyperlipidemia Hyperuricemia Lactic acidosis Liver dysfunction, hepatomegaly Renal problems, kidney stones GI problems DD Seizures Slow growth
Von Gierke Disease - Treatment
Avoid hypoglycemia and hyperglycemia - body cannot use glycogen, so when it is made, it builds up in liver and kidneys
Cornstarch between meals, nighttime glc infusions, eat complex carbs and high fat/protein diet.
Severe cases - liver transplant
Pompe Disease - type of disease, gene, enzyme
GSDII, also a Lysosomal storage disease
gene: GAA
Alpha-glucosidase
Pompe Disease - Features
Infantile Onset: Cardiomegaly, cardiomyopathy Enlarged tongue Respiratory distress Hypotonia Death within 1yr if untreated
Late Onset: Slowly progressive proximal muscle weakness - looks like Limb-Girdle MD Hypotonia Impaired cough, dysphagia Delayed motor milestones Cardiomyopathy
Pompe Disease - Treatment
Myozyme ERT for infantile onset
Lumizyme ERT for late onset
