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
McArdle Disease - type of disease, gene, enzyme
GSD V
gene: PYGM
Myophosphorylase
McArdle Disease - Major features
Myoglobinuria
Myopathy
Skeletal muscle weakness, exercise intolerance, Rhabdomyolysis
McArdle Disease - Treatment
Vitamin B6 supplementation
Sucrose supplementation before exercise
High dietary protein and fat
Batten Disease - type of disease, gene, enzyme, cause
Lysosomal storage disease
Many genes - PT1, TPP1, CLN3, CLN5, CLN6, CLN8, MFSD8, CTSD, CTSF, DNAJC5, ATP13A2, GRN, KCTD7
Palmitoyl protein thioesterase 1, tripeptidyl peptidase 1, cathepsin D
**Buildup of Lipofuscins
Batten Disease - Features
Onset in childhood Neurodegeneration (leads to death by teens) Vision problems Seizures Personality and behavioural changes Echolalia, breath-holding, bruxism (grinding teeth) Clumsiness Poor growth Poor circulation to lower extremities Decreased body mass
Danon Disease - type of disease, gene, enzyme, cause
Lysosomal AND Glycogen Storage disease (GSDIIb)
X LINKED : LAMP2 gene
lysosomal associated membrane protein 2
Exact pathophysiology unknown, may be accumulation of autophagic vacuoles in lysosomes
Danon Disease - Features
Myopathy (most men, half of women)
Hypertrophic, then dilated cardiomyopathy, Wolff-Parkinson-White conduction abnormality
ID (mostly in males, if females have ID it is mild)
Visual/retinal disturbances
Both males and females are severely affected:
Males more severely affected, onset in childhood/teens, live to age 19 on average.
Females less severely affected, onset in early adulthood, live to age 34 on average.
Fabry Disease - type of disease, gene, enzyme, cause, prevalence
Lysosomal storage disease
X LINKED: GLA gene
Alpha-galactosidase
Buildup of Globotriaosylceramide in blood vessel and skin epithelium, kidneys, heart, and nervous system
1/40,000 - 1/60,000 males, female incidence unknown, indicence of milder forms likely higher
Fabry Disease - Features
Both males and females can be affected!
Acroparathesias (pain and tingling in hands and feet) Pain crises Angiokeratomas Anhidrosis/Hypohidrosis Corneal opacity GI problems Left-ventricular hypertrophy Renal insufficiency, proteinuria Tinnitus, hearing loss Depression 2/2 chronic pain
Fabry Disease - Treatment
Fabrazyme ERT
Psychosocial - chronic pain, depression - often overlooked in females because males more severely affected
Gaucher Disease - type of disease, gene, enzyme, cause
Lysosomal Storage Disease
GBA gene
Glucocerebrosidase
Accumulation of glucocerebrosides
Gaucher Disease - Population frequency
1/50,000 - 1/100,000 general population
1/500 - 1/1000 AJ people are affected by type 1 Gaucher (most common disease in AJ population)
Gaucher Disease - Features
Type I Least severe form - NO CNS INVOLVEMENT Symptoms range from mild-severe Variable onset Hepatosplenomegaly Pulmonary hypertension Anemia, thrombocytopenia Bone pain, fractures, arthritis - Erlenmeyer Flask deformity***
Type II Most severe ID Bulbar and pyramidal signs convulsions Apnea, pulmonary hypertension Hypertonia Hepatosplenomegaly Thrombocytopenia, anemia Dermatologic abnormalities NO bone disease LIFESPAN 2-4 YEARS
Type III Intermediate phenotype Progressive myoclonic epilepsy Oculomotor apraxia Hepatosplenomegaly Thrombocytopenia Pulmonary hypertension Bone pain, fractures, arthritis - Erlenmeyer Flask deformity*** Survival into teens/adulthood
Perinatal Lethal Form Hydrops fetalis Icthyosis Hepatosplenomegaly Distinctive facial features Die in utero or within a few days after birth
Cardiovascular form
Heart valve calcification
May also have ocular signs, bone disease, mild splenomegaly
Note: genotype:phenotype correlations for this condition exist, but are imperfect. Some parents of affected children are found to be homozygotes.
Gaucher Disease - Treatment
ERT (cerezyme, VPRIV, Elelyso) for individuals with type I (cannot cross the BBB), improves some symptoms for individuals with type III.
Substrate reduction therapy (Miglustat, eliglustat) - only if ERT impossible due to allergic reaction/sensitivity/poor venous access.
Krabbe Disease - type of disease, gene, enzyme, cause
Lysosomal storage disease
GALC gene
Galactosylceramidase
Accumulation of Psychosine
Krabbe Disease - Features
Normal appearance at birth - onset at 3-6 months Irritability Fevers Limb stiffening Seizures Feeding difficulties, vomiting Mental and motor delay Muscle weakness, spasticity Deafness Optic atrophy and blindness Paralysis Death by age 2
Hurler Syndrome - type of disease, gene, cause
MPSI (Hurler, Hurler-Scheie, Scheie Syndromes - from most to least severe. Now just called “severe” or “attenuated”)
gene: IDUA gene
severe: 1/100,000 newborns
attenuated: 1/500,000 newborns (rarer!)
cause: accumulation of glycosaminoglycans in lysosomes
Hurler Syndrome - Features
No symptoms, or umbilical or inguinal hernia only at birth
Signs begin in first year of life for severe form, or in childhood for attenuated form.
Macrocephaly / hydrocephalus
DD, ID, Regression in severe form only
Hepatosplenomegaly
Skeletal anomalies, short stature, joint contractures
Narrow airway - frequent resp infections, sleep apnea
Carpal tunnel syndrome, spinal stenosis, neuropathy
Cardiac anomalies
Corneal clouding
Recurrent ear infections, hearing loss
Coarse facial features
Deep, hoarse voice
Severely affected usually die in childhood, Attenuated form lives into adulthood
Hunter syndrome - type of disease, gene, incidence, cause
MPSII
X LINKED: IDS gene
1/100,000 - 1/170,000 MALES
cause: accumulation of glycosaminoglycans in lysosomes
Hunter syndrome - features
Affects males only
Onset at ages 2-4 years
Face: full lips, large cheeks, broad nose, large tongue
Deep, hoarse voice due to vocal cord enlargement
Narrow airway - frequent resp infections, sleep apnea
Macrocephaly
DD, ID, regression IF SEVERELY AFFECTED
Hepatosplenomegaly
Umbilical/inguinal hernia
Hearing loss, recurrent ear infections
Retinopathy, vision loss; but corneas are clear!
Heart valve problems, other cardiac anomalies
Carpal tunnel syndrome, spinal stenosis, neuropathy
Short stature, skeletal anomalies
Lifespan: 10-20 years if severely affected, adulthood if less severely affected (normal intelligence)
Sanfilippo Syndrome - type of disease, incidence, gene, cause
MPS III
Most common MPS: 1/70,000
Genes: GNS, HGSNAT, NAGLU, SGSH
Cause: buildup of heparan sulfate, mostly in CNS
Sanfilippo Syndrome - Features
Onset in early childhood
Milder skeletal phenotype, mildly coarse facial features
Progressive sleep, speech, and behavioural problems
Progressive ID and regression
Seizures and movement disorders
Live into adolescence/early adulthood
Morquio Syndrome - type of disease, incidence, gene, cause
MPS IV
genes: GALNS and GLB1
incidence: 1/200,000 - 1/300,000
cause: accumulation of glycosaminoglycans in lysosomes
Morquio Syndrome - Features
Mainly affects the skeletal system
Onset in early childhood
Short stature, chest, spine, ribs, hips, wrists abn.
Hypermobile joints and contractures
Charcteristic feature - odontoid hypoplasia (can lead to spinal cord damage)
Cloudy cornea
Recurrent ear infections and hearing loss
Narrow airway - frequent resp infections, sleep apnea
Umbilical and inguinal hernia
mildly coarse facial features
heart valve abnormalities
NO ID
Life expectancy varies from late childhood to adulthood depending on severity. Death due to spinal cord compression or airway obstruction.
Maroteaux-Lamy Syndrome - type of disease, incidence, gene, cause
MPS VI
incidence: 1/250,000 - 1/600,000 newborns
gene: ARSB (arylsulfatase B)
cause: accumulation of glycosaminoglycans in lysosomes
Maroteaux-Lamy Syndrome - Features
Macrocephaly Hydrocephalus Coarse Facial Features Macroglossia Hepatosplenomegaly Umbilical/Inguinal hernia Narrow airway - frequent resp infections, sleep apnea Skeletal anomalies Carpal tunnel syndrome, spinal stenosis, neuropathy short stature cardiac anomalies corneal clouding recurrent ear infections, hearing loss NORMAL INTELLECT
Usually live into adulthood with treatment
Sly Syndrome - type of disease, incidence, gene, cause
MPS VII
Incidence - 1/250,000 newborns
Gene: GUSB (Beta Glucuronidase)
cause: accumulation of glycosaminoglycans in lysosomes
Sly Syndrome - Features
Most severe cases - hydrops fetalis
Otherwise, symptoms start in early childhood
Macrocephaly
Hydrocephalus
Coarse facies
Macroglossia
Hepatosplenomegaly
Umbilical/Inguinal hernia
Narrow airway - frequent resp infections, sleep apnea
Corneal clouding
Recurrent ear infections, hearing loss
May have DD/ID (progressive)
Skeletal anomalies that become more pronounced with age
Cardiac problems
Carpal tunnel syndrome, spinal stenosis, neuropathy
Treatment for MPS disorders?
ERT to treat visceral symptoms, cannot treat cognitive symptoms (types I, II, III, VII) because cannot cross BBB
Which MPS disorders do not affect intelligence?
Types IV and VI (Morquio and Maroteaux Lamy)
can remember this by the numbers with the V’s in them and the names that start with M! (both M and V are Roman numerals)
What hallmark findings are common among MPS disorders?
Dysostoses multiplex
Macrocephaly
Coarse Facial Features, deep voice
Carpal tunnel syndrome, spinal stenosis, neuropathy
Hepatosplenomegaly
Umbilical/Inguinal hernia
Narrow airway - frequent resp infections, sleep apnea
Corneal clouding EXCEPT IN SANFILLIPO AND HUNTER (Type II and III)
Cardiac anomalies EXCEPT IN SANFILLIPO (type III)
Progressive ID, Regression EXCEPT IN TYPES IV and VI
Niemann-Pick Disease - type of disease, incidence, gene, cause
Lysosomal storage disorder
Incidence: Types A and B: 1/250,000 Type A 1/40,000 in AJ population Type C: 1/150,000 Type C1 - French Acadian Nova Scotian founder effect
Gene: SMPD1 - sphingomyelinase (Types A and B);
NPC1 or NPC2 - (Type C)
Cause:
Types A and B: accumulation of sphingomyelin (not broken down) - impairs brain, lungs, liver, spleen
Type C: prevents cholesterol and other lipid transport to proper locations.
Niemann-Pick Disease - Features
Type A
hepatosplenomegaly by 3 months of age
FTT
normal development until age 1yr - then regression
interstitial lung damage - recurrent infection, resp failure
*cherry red spot
typically do not live past early childhood
Type B presents in mid-childhood similar to type A, but less severe hepatosplenomegaly, recurrent lung infections, thrombocytopenia Short stature and delayed bone age 1/3 have cherry red spot Usually survive into adulthood
Type C presents in childhood ataxia vertical supranuclear gaze palsy (can't look up/down) dystonia severe liver disease interstitial lung disease progressive problems with speech and swallowing progressive ID 1/3 have seizures may survive into adulthood
Tay-Sachs Disease - type of disease, carrier rate, gene, cause
Lysosomal storage disease
Carrier rate: 1/30 AJ, 1/300 general population
Gene: HEXA
Cause: buildup of GM2 ganglioside
Tay-Sachs Disease Features
Severe form (most common): Normal development up until 6 months of age, then progressive neurodegeneration Motor and developmental regression Loss of responsiveness Visual deterioration Seizures Progressive macrocephaly Recurrent infection Cherry red spot on opththalmologic exam Average life span is 2 years
Adult-onset form:
No cherry red spot
slowly progressive neurodegeneration, muscle wasting
Dementia, psychiatric problems, psychosis
Can be clinically indistinguishable from ALS or adolescent-onset SMA
Isovaleric Acidemia - type of disease, incidence, gene, pathway, cause
type of disease: organic acidemia, also amino acid disorder
incidence: 1/250,000 in the US
gene: IVD (isovaleric acid coA dehydrogenase)
Pathway: Leucine metabolism
Accumulation of isovaleric acid causes symptoms
Isovaleric acidemia - Features
**Smelly feet odour** Protein aversion Metabolic acidosis Thrombocytopenia Vomiting, poor feeding, lethargy, coma Seizures Developmental delay 50% severe neonatal onset wiht rapid death 50% chronic with asymptomatic intervals
Biotin deficiency can be a phenocopy
Isovaleric acidemia - Treatment
Dietary Leucine restriction
Glycine supplementation during acute episodes
Lesch-Nyhan Syndrome - type of disease, incidence, gene, pathway, cause
Disease type: X-LINKED Organic acidemia
Incidence: 1/380,000 individuals (1/190,000 males then?)
Gene: HPRT1 (hypoxanthine phosphoribosyltransferase 1)
Pathway: Purine recycling
Cause: Buildup of uric acid, low dopamine (cause for low dopamine is unknown)
Lesch-Nyhan Syndrome Features
Females - typically only hyperuricemia Males - highly variable, severe casees can result in death in first or second decade 2/2 renal failure ID/DD Poor growth Opisthotonic posturing Dysphagia **Self-injury Hyperuricemia Renal failure
General Features of Urea Cycle Disorders:
Inheritance?
AR, except OTC, which is XL and also the most common!
General Features of Urea Cycle Disorders: Symptoms
Protein intolerance
Poor feeding
Acute metabolic crises: respiratory alkalosis, hyperammonemia, vomiting, lethargy, seizures, coma
DD and ID if untreated
General Features of Urea Cycle Disorders: Treatment
Dietary protein restriction
Ammonul to provide alternate ammonia removal
Glutamine to “buffer” nitrogen
Ravicti - nitrogen scavenger therapy for NAGS, OTC, CPS1 (the proximal urea cycle disorders)
Arginine supplementation - only for ASS and ASL
Essential amino acid supplementation
Liver transplant in severe cases
How to distinguish between proximal and distal urea cycle disorders?
Plasma citrulline is LOW in proximal disorders, HIGH in distal disorders.
Proximal urea cycle disorders are those that function in the mitochondria, whereas distal function in the cytosol.
CPS1 - inheritance, type of disorder, enzyme
AR Proximal Urea Cycle Disorder
carbamoyl phosphate synthetase 1
NAGS - inheritance, type of disorder, enzyme
AR Proximal Urea Cycle Disorder
N-acetylglutamate Synthetase
OTC - inheritance, type of disorder, enzyme
XL Proximal Urea Cycle Disorder
Ornithine Transcarbamoylase
**Most common urea cycle disorder
OTC Features
Elevated ornithine, uracil, orotic acid
Females can be affected
May present neonatally or in childhood after illness or high protein intake
ASS - inheritance, type of disorder, enzyme, distinguishing feature
AR Distal Urea Cycle Disorder
Arginosuccinic acid synthetase
ELEVATED CITRULLINE
ASL - inheritance, type of disorder, enzyme, distinguishing feature
AR Distal Urea Cycle Disorder
Arginosuccinic acid lyase
ELEVATED CITRULLINE AND ARGINIOSUCCINIC ACID
ARG - inheritance, type of disorder, enzyme, distinguishing feature
AR Distal Urea Cycle Disorder Arginase ELEVATED ARGININE NO HYPERAMMONEMIA (usually) Different presentation - slow onset with muscle weakness
Alpha-1-antitrypsin deficiency inheritance and gene
AR
Gene: SERPINA1
Alleles are referred to as PIZ (pathogenic) and PIM (most common normal allele)
Alpha-1-antitrypsin deficiency features
Decreased A1AT in lungs, increased abnormal A1AT in liver
COPD
Liver disease
C-ANCA positive vasculitis (C-ANCA is A1AT substrate)
Necrotizing panniculitis (inflammation of the fatty brbrous tissue beneath the skin)
Canavan Disease gene, enzyme, carrier frequency, cause
Gene: ASPA
Enzyme: Aminoacetylase 2
Carrier frequency: 1/40 - 1/82 in AJ population
Cause: Accumulation of N-acetylaspartic acid
Canavan Disease Features
Classic triad: hypotonia, head lag, macrocephaly Leukodystrophy Symptoms onset in infancy and progress rapidly ID, Regression Paralysis Blindness Seizures Death in teens typically
Milder form with only dev delay exists
G6PD gene, enzyme, incidence, cause
Gene: G6PD (X-LINKED)
Enzyme: Glucose-6-Phosphate Dehydrogenase
Incidence:
MOST COMMON HUMAN ENZYMATIC DISORDER.
Most common in Africa, Middle East, Asia, Mediterranean.
Affects 1/10 African American males.
Cause:
G6PD: processing of carbohydrates, and protects red blood cells from reactive oxygen species. Mutations cause hemolytic anemia.
G6PD may play a protective role against malaria.
G6PD Features
Presentation is usually mild
Prolonged neonatal jaundice - can lead to kernicterus if untreated (bilirubin induced brain dysfunction)
Hemolytic crisis in response to illness, antimalarial drugs, sulfonamides, analgesics, fava beans**
Diabetic ketoacidosis
Severe crisis can lead to kidney failure
Hemochromatosis - gene, cause, symptoms, and treatments
Mutations in HFE lead to iron accumulation
Symptoms: Asymptomatic in most, especially females Hepatomegaly, cirrhosis, HCC Diabetes Cardiomyopathy, Arrhythmia Arthritis Skin pigmentation
Treatment:
Low iron diet
Phlebotomy
May require liver transplant
Smith Lemli Opitz Syndrome - Gene, Enzyme, Cause
Gene: DHCR7
Enzyme: 7-dehydrocholesterol reductase
Cause: Accumulation of 7-dehydrocholesterol
SLOS - Features
Moderate to severe ID
Microcephaly
Behaviour: Aggression, ASD, Self-injury
Strabismus, Cataracts, Functional eye abnormalities, Ptosis
Congenital heart defects
GI issues, pyloric stenosis, feeding difficulties
Renal anomalies
Dysmorphic features: 2,3 toe syndactyly; postaxial polydactyly; ambiguous genitalia; hypospadias; bitemporal narrowing; short, upturned nose; Micrognathia, Epicanthus, capillary hemangioma of the nose
Wilson Disease - Gene, Enzyme, Cause
Gene: ATP7B
Enzyme: Ceruloplasmin
Cause: Copper accumulation
Wilson Disease - Features
Liver disease: Recurrent jaundice, hepatitis, fatty liver, hemolytic anemia
Neurologic disease: Tremors, poor coordination, loss of fine motor control, chorea, spastic dystonia
Psychiatric: depression, anxiety, phobias, antisocial behaviour, poor memory, shortened attention span
**Kayser-Fleischer rings in eyes
Other: renal problems, arthritis, pancreatitis, cardiomyopathy, sunflower cataracts
