Metabolic Disorders Flashcards
1
Q
What is the incidence of Alkaptonuria
A
1/250,000 - 1/1,000,000
2
Q
Alkaptonuria pathway, enzyme, and gene
A
Pathway: Tyrosine metabolism
Enzyme: Homogentisate 1,2-dioxygenase
Gene: HGD
3
Q
Alkaptonuria pathogenesis and symptoms
A
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.
4
Q
Alkaptonuria Treatment
A
Restrict dietary Phe and Tyr
Nitisone to inhibit pathway
5
Q
Homocysteinuria incidence
A
1/200,000 - 1/335,000 worldwide
More common in Ireland (1/65,000); Germany (1/17,800); Norway (1/6400); Qatar (1/1800)
6
Q
Homocysteinuria pathway, enzyme, and gene
A
Pathway: Methionine synthesis
Enzyme: Cystathionine Beta-Synthase
Gene: CBS, MTHFR, MTR, MTRR, MMADHC
7
Q
Homocysteinuria features
A
*Similar to Marfan Syndrome
Distinguish by: intellectual disability, seizures, strokes, joint contractures, hypopigmentation, psychiatric problems.
8
Q
Homocysteinuria treatment
A
Protein restricted diet
Vitamin B6 effective for 50% of patients
Betaine provides alternate homocysteine breakdown pathway
If residual enzyme activity - folate and B12
9
Q
Incidence of MSUD
A
1/185,000 worldwide
1/380 in Old Order Mennonite
10
Q
MSUD pathway, enzyme, and genes
A
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
11
Q
MSUD Features
A
Urine smells like maple syrup Developmental delay Poor feeding, Lethargy Opisthotonic posturing Respiratory failure Encephalopathy (when in crisis)
12
Q
MSUD Treatment
A
Restrict dietary Leucine
13
Q
PKU incidence
A
1/10,000 - 1/15,000
14
Q
PKU Pathway, Enzyme, and Gene
A
Pathway: phenylalanine breakdown to tyrosine
Enzyme: phenylalanine hydroxylase
Gene: PAH
*could also be due to biopterin deficiency
15
Q
PKU features
A
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)
16
Q
PKU treatment
A
Dietary Phe restriction
Biopterin supplementation
17
Q
Tyrosinemia pathway, enzyme, and gene
A
Pathway: Tyrosine metabolism Enzymes and associated genes: 4-fumarylacetoacetase (FAH) - Type I Tyrosine transaminase (TAT) - Type II P-hydroxyphenyl pyruvate dioxygenase (HPD) - Type III
18
Q
Tyrosinemia incidence
A
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
19
Q
Tyrosinemia Type I, II, III features
A
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
20
Q
Tyrosinemia type I, II, III treatment
A
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
21
Q
Signs of FAO disorders
A
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
22
Q
Treatment of disorders of fatty acid oxidation
A
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
23
Q
Enzymes and genes for SCAD, MCAD, LCHAD, VLCAD
A
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
24
Q
Incidence of SCAD, MCAD, LCHAD, VLCAD
A
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
25
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
26
XL Adrenoleukodystrophy gene
ABCD1
27
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
```
28
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.
29
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)
```
30
GALT / Gal-1-P deficiency gene and common allele
Gene: GALT
| Duarte allele: p.N314D - common, mild allele
31
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
```
32
GALT treatment
Dietary lactose restriction
Calorie supplements
Non-dairy, NON-LEGUME protein supplements
33
GALK1 Deficiency features and treatment
Only symptom is cataracts
| Treat by restricting dietary lactose
34
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
35
Von Gierke Disease - type of disease, gene, enzyme
GSDI
G6PC
Glucose-6-phosphatase
36
Von Gierke Disease - major features
```
Hypoglycemia
Hyperlipidemia
Hyperuricemia
Lactic acidosis
Liver dysfunction, hepatomegaly
Renal problems, kidney stones
GI problems
DD
Seizures
Slow growth
```
37
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
38
Pompe Disease - type of disease, gene, enzyme
GSDII, also a Lysosomal storage disease
gene: GAA
Alpha-glucosidase
39
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
```
40
Pompe Disease - Treatment
Myozyme ERT for infantile onset
| Lumizyme ERT for late onset
41
McArdle Disease - type of disease, gene, enzyme
GSD V
gene: PYGM
Myophosphorylase
42
McArdle Disease - Major features
Myoglobinuria
Myopathy
Skeletal muscle weakness, exercise intolerance, Rhabdomyolysis
43
McArdle Disease - Treatment
Vitamin B6 supplementation
Sucrose supplementation before exercise
High dietary protein and fat
44
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
45
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
```
46
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
47
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.
48
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
49
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
```
50
Fabry Disease - Treatment
Fabrazyme ERT
Psychosocial - chronic pain, depression - often overlooked in females because males more severely affected
51
Gaucher Disease - type of disease, gene, enzyme, cause
Lysosomal Storage Disease
GBA gene
Glucocerebrosidase
Accumulation of glucocerebrosides
52
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)
53
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.
54
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.
55
Krabbe Disease - type of disease, gene, enzyme, cause
Lysosomal storage disease
GALC gene
Galactosylceramidase
Accumulation of Psychosine
56
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
```
57
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
58
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
59
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
60
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)
61
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
62
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
63
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
64
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.
65
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
66
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
67
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
68
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
69
Treatment for MPS disorders?
ERT to treat visceral symptoms, cannot treat cognitive symptoms (types I, II, III, VII) because cannot cross BBB
70
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)
71
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
72
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.
73
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
```
74
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
75
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
76
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
77
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**
78
Isovaleric acidemia - Treatment
Dietary Leucine restriction
| Glycine supplementation during acute episodes
79
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)
80
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
```
81
General Features of Urea Cycle Disorders:
| Inheritance?
AR, except OTC, which is XL and also the most common!
82
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
83
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
84
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.
85
CPS1 - inheritance, type of disorder, enzyme
AR Proximal Urea Cycle Disorder
| carbamoyl phosphate synthetase 1
86
NAGS - inheritance, type of disorder, enzyme
AR Proximal Urea Cycle Disorder
| N-acetylglutamate Synthetase
87
OTC - inheritance, type of disorder, enzyme
XL Proximal Urea Cycle Disorder
Ornithine Transcarbamoylase
**Most common urea cycle disorder
88
OTC Features
Elevated ornithine, uracil, orotic acid
Females can be affected
May present neonatally or in childhood after illness or high protein intake
89
ASS - inheritance, type of disorder, enzyme, distinguishing feature
AR Distal Urea Cycle Disorder
Arginosuccinic acid synthetase
ELEVATED CITRULLINE
90
ASL - inheritance, type of disorder, enzyme, distinguishing feature
AR Distal Urea Cycle Disorder
Arginosuccinic acid lyase
ELEVATED CITRULLINE AND ARGINIOSUCCINIC ACID
91
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
```
92
Alpha-1-antitrypsin deficiency inheritance and gene
AR
Gene: SERPINA1
Alleles are referred to as PI*Z (pathogenic) and PI*M (most common normal allele)
93
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)
94
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
95
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
96
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.
97
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
98
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
99
Smith Lemli Opitz Syndrome - Gene, Enzyme, Cause
Gene: DHCR7
Enzyme: 7-dehydrocholesterol reductase
Cause: Accumulation of 7-dehydrocholesterol
100
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
101
Wilson Disease - Gene, Enzyme, Cause
Gene: ATP7B
Enzyme: Ceruloplasmin
Cause: Copper accumulation
102
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
