Metabolic Disorders Flashcards

1
Q

What is the incidence of Alkaptonuria

A

1/250,000 - 1/1,000,000

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2
Q

Alkaptonuria pathway, enzyme, and gene

A

Pathway: Tyrosine metabolism
Enzyme: Homogentisate 1,2-dioxygenase
Gene: HGD

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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.

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4
Q

Alkaptonuria Treatment

A

Restrict dietary Phe and Tyr

Nitisone to inhibit pathway

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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)

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6
Q

Homocysteinuria pathway, enzyme, and gene

A

Pathway: Methionine synthesis
Enzyme: Cystathionine Beta-Synthase
Gene: CBS, MTHFR, MTR, MTRR, MMADHC

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7
Q

Homocysteinuria features

A

*Similar to Marfan Syndrome

Distinguish by: intellectual disability, seizures, strokes, joint contractures, hypopigmentation, psychiatric problems.

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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

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9
Q

Incidence of MSUD

A

1/185,000 worldwide

1/380 in Old Order Mennonite

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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

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11
Q

MSUD Features

A
Urine smells like maple syrup
Developmental delay
Poor feeding, Lethargy
Opisthotonic posturing
Respiratory failure
Encephalopathy (when in crisis)
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12
Q

MSUD Treatment

A

Restrict dietary Leucine

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13
Q

PKU incidence

A

1/10,000 - 1/15,000

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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

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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)
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16
Q

PKU treatment

A

Dietary Phe restriction

Biopterin supplementation

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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
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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

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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
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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

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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

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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
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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

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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

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25
Q

Incidence of SCAD, MCAD, LVHAD, 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

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26
Q

XL Adrenoleukodystrophy gene

A

ABCD1

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27
Q

XL Adrenoleukodystrophy symptoms

A
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
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28
Q

Treatment of XL Adrenoleukodystrophy

A

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.

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29
Q

General features of galactosemias

A
Symptoms onset after first feeding, worsen after feedings
Liver dysfunction 
Renal dysfunction 
Cataracts
Hypoglycemia
Lactic acidosis
Hyperuricemia
Dairy intolerance (not lactose intolerance)
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30
Q

GALT / Gal-1-P deficiency gene and common allele

A

Gene: GALT

Duarte allele: p.N314D - common, mild allele

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31
Q

GALT features

A
NO AVERSION TO GALACTOSE CONTAINING FOODS
neonatal onset: FTT, lethargy
Liver dysfunction
Hyperbilirubinemia
Renal tubular acidosis 
ID
Cataracts
Sepsis / bacterial infections
POI in females
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32
Q

GALT treatment

A

Dietary lactose restriction
Calorie supplements
Non-dairy, NON-LEGUME protein supplements

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33
Q

GALK1 Deficiency features and treatment

A

Only symptom is cataracts

Treat by restricting dietary lactose

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34
Q

GALE Deficiency features and treatment

A
Features:
Severe onset
Psychomotor delay, ID, DD
Hyperbilirubinemia 
Liver dysfunction 
Renal tubular acidosis 
Cataracts
Bacterial infections / Sepsis

Treat by restricting dietary lactose and galactose

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35
Q

Von Gierke Disease - type of disease, gene, enzyme

A

GSDI

G6PC

Glucose-6-phosphatase

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36
Q

Von Gierke Disease - major features

A
Hypoglycemia
Hyperlipidemia
Hyperuricemia
Lactic acidosis
Liver dysfunction, hepatomegaly
Renal problems, kidney stones
GI problems
DD
Seizures
Slow growth
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37
Q

Von Gierke Disease - Treatment

A

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

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38
Q

Pompe Disease - type of disease, gene, enzyme

A

GSDII, also a Lysosomal storage disease

gene: GAA

Alpha-glucosidase

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39
Q

Pompe Disease - Features

A
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
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40
Q

Pompe Disease - Treatment

A

Myozyme ERT for infantile onset

Lumizyme ERT for late onset

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41
Q

McArdle Disease - type of disease, gene, enzyme

A

GSD V

gene: PYGM

Myophosphorylase

42
Q

McArdle Disease - Major features

A

Myoglobinuria
Myopathy
Skeletal muscle weakness, exercise intolerance, Rhabdomyolysis

43
Q

McArdle Disease - Treatment

A

Vitamin B6 supplementation
Sucrose supplementation before exercise
High dietary protein and fat

44
Q

Batten Disease - type of disease, gene, enzyme, cause

A

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
Q

Batten Disease - Features

A
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
Q

Danon Disease - type of disease, gene, enzyme, cause

A

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
Q

Danon Disease - Features

A

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
Q

Fabry Disease - type of disease, gene, enzyme, cause, prevalence

A

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
Q

Fabry Disease - Features

A

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
Q

Fabry Disease - Treatment

A

Fabrazyme ERT

Psychosocial - chronic pain, depression - often overlooked in females because males more severely affected

51
Q

Gaucher Disease - type of disease, gene, enzyme, cause

A

Lysosomal Storage Disease

GBA gene

Glucocerebrosidase

Accumulation of glucocerebrosides

52
Q

Gaucher Disease - Population frequency

A

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
Q

Gaucher Disease - Features

A
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
Q

Gaucher Disease - Treatment

A

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
Q

Krabbe Disease - type of disease, gene, enzyme, cause

A

Lysosomal storage disease

GALC gene

Galactosylceramidase

Accumulation of Psychosine

56
Q

Krabbe Disease - Features

A
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
Q

Hurler Syndrome - type of disease, gene, cause

A

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
Q

Hurler Syndrome - Features

A

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
Q

Hunter syndrome - type of disease, gene, incidence, cause

A

MPSII

X LINKED: IDS gene

1/100,000 - 1/170,000 MALES

cause: accumulation of glycosaminoglycans in lysosomes

60
Q

Hunter syndrome - features

A

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
Q

Sanfilippo Syndrome - type of disease, incidence, gene, cause

A

MPS III

Most common MPS: 1/70,000

Genes: GNS, HGSNAT, NAGLU, SGSH

Cause: buildup of heparan sulfate, mostly in CNS

62
Q

Sanfilippo Syndrome - Features

A

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
Q

Morquio Syndrome - type of disease, incidence, gene, cause

A

MPS IV

genes: GALNS and GLB1
incidence: 1/200,000 - 1/300,000
cause: accumulation of glycosaminoglycans in lysosomes

64
Q

Morquio Syndrome - Features

A

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
Q

Maroteaux-Lamy Syndrome - type of disease, incidence, gene, cause

A

MPS VI

incidence: 1/250,000 - 1/600,000 newborns
gene: ARSB (arylsulfatase B)
cause: accumulation of glycosaminoglycans in lysosomes

66
Q

Maroteaux-Lamy Syndrome - Features

A
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
Q

Sly Syndrome - type of disease, incidence, gene, cause

A

MPS VII

Incidence - 1/250,000 newborns

Gene: GUSB (Beta Glucuronidase)

cause: accumulation of glycosaminoglycans in lysosomes

68
Q

Sly Syndrome - Features

A

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
Q

Treatment for MPS disorders?

A

ERT to treat visceral symptoms, cannot treat cognitive symptoms (types I, II, III, VII) because cannot cross BBB

70
Q

Which MPS disorders do not affect intelligence?

A

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
Q

What hallmark findings are common among MPS disorders?

A

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
Q

Niemann-Pick Disease - type of disease, incidence, gene, cause

A

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
Q

Niemann-Pick Disease - Features

A

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
Q

Tay-Sachs Disease - type of disease, carrier rate, gene, cause

A

Lysosomal storage disease

Carrier rate: 1/30 AJ, 1/300 general population

Gene: HEXA

Cause: buildup of GM2 ganglioside

75
Q

Tay-Sachs Disease Features

A
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
Q

Isovaleric Acidemia - type of disease, incidence, gene, pathway, cause

A

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
Q

Isovaleric acidemia - Features

A
**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
Q

Isovaleric acidemia - Treatment

A

Dietary Leucine restriction

Glycine supplementation during acute episodes

79
Q

Lesch-Nyhan Syndrome - type of disease, incidence, gene, pathway, cause

A

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
Q

Lesch-Nyhan Syndrome Features

A
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
Q

General Features of Urea Cycle Disorders:

Inheritance?

A

AR, except OTC, which is XL and also the most common!

82
Q

General Features of Urea Cycle Disorders: Symptoms

A

Protein intolerance
Poor feeding
Acute metabolic crises: respiratory alkalosis, hyperammonemia, vomiting, lethargy, seizures, coma
DD and ID if untreated

83
Q

General Features of Urea Cycle Disorders: Treatment

A

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
Q

How to distinguish between proximal and distal urea cycle disorders?

A

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
Q

CPS1 - inheritance, type of disorder, enzyme

A

AR Proximal Urea Cycle Disorder

carbamoyl phosphate synthetase 1

86
Q

NAGS - inheritance, type of disorder, enzyme

A

AR Proximal Urea Cycle Disorder

N-acetylglutamate Synthetase

87
Q

OTC - inheritance, type of disorder, enzyme

A

XL Proximal Urea Cycle Disorder
Ornithine Transcarbamoylase
**Most common urea cycle disorder

88
Q

OTC Features

A

Elevated ornithine, uracil, orotic acid
Females can be affected
May present neonatally or in childhood after illness or high protein intake

89
Q

ASS - inheritance, type of disorder, enzyme, distinguishing feature

A

AR Distal Urea Cycle Disorder
Arginosuccinic acid synthetase
ELEVATED CITRULLINE

90
Q

ASL - inheritance, type of disorder, enzyme, distinguishing feature

A

AR Distal Urea Cycle Disorder
Arginosuccinic acid lyase
ELEVATED CITRULLINE AND ARGINIOSUCCINIC ACID

91
Q

ARG - inheritance, type of disorder, enzyme, distinguishing feature

A
AR Distal Urea Cycle Disorder
Arginase
ELEVATED ARGININE
NO HYPERAMMONEMIA (usually)
Different presentation - slow onset with muscle weakness
92
Q

Alpha-1-antitrypsin deficiency inheritance and gene

A

AR
Gene: SERPINA1
Alleles are referred to as PIZ (pathogenic) and PIM (most common normal allele)

93
Q

Alpha-1-antitrypsin deficiency features

A

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
Q

Canavan Disease gene, enzyme, carrier frequency, cause

A

Gene: ASPA
Enzyme: Aminoacetylase 2
Carrier frequency: 1/40 - 1/82 in AJ population
Cause: Accumulation of N-acetylaspartic acid

95
Q

Canavan Disease Features

A
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
Q

G6PD gene, enzyme, incidence, cause

A

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
Q

G6PD Features

A

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
Q

Hemochromatosis - gene, cause, symptoms, and treatments

A

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
Q

Smith Lemli Opitz Syndrome - Gene, Enzyme, Cause

A

Gene: DHCR7
Enzyme: 7-dehydrocholesterol reductase
Cause: Accumulation of 7-dehydrocholesterol

100
Q

SLOS - Features

A

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
Q

Wilson Disease - Gene, Enzyme, Cause

A

Gene: ATP7B
Enzyme: Ceruloplasmin
Cause: Copper accumulation

102
Q

Wilson Disease - Features

A

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