Complex Molecule Disorders Flashcards
What are the 2 most common peroxisomal disorders?
Zellweger spectrum and X-ALD
Mutations in what genes cause Zellweger spectrum disorder?
PEX1*, PEX6, PEX12, PEX26
*most common
- No common variants
What is the reason/mechanism behind the development of Zellweger?
Individuals cannot make the peroxisome
What is the age of presentation of Zellweger?
Severe: Neonatal
Mild: Childhood
What body systems are the most affected by Zellweger?
Neurologic, liver, skeletal
What is a key radiographic feature of Zellweger?
Stippling of bone (knee cap example)
What biochemical testing is done for Zellweger? Treatment?
Very long chain fatty acids
No treatment, just symptomatic support
True or false: X-ALD is on NBS
True
on RUSP
What is the reason/mechanism behind the development of X-ALD?
No transporter into the peroxisome for VLCFA
Mutations in what gene cause X-ALD? What is the mode of inheritance?
ABCD1; X-Linked
What percentage of X-ALD cases are de novo?
4%
What are the 2 types of presentation for X-ALD? Is there any genotype-phenotype correlation for which one someone will develop?
- Childhood cerebral onset
- Adult-onset adrenomyeloneuropathy (AMN)
No; we’re never able to know which one will develop
What are the demographics/features of childhood cerebral onset of X-ALD?
Adrenoleukodystrophy
4-8 years old
Neurological regression
Males
What are the demographics/features of adrenomyeloneuropathy onset of X-ALD?
Adrenoleukodystrophy
20-40 years old
Progressive leg stiffness
Bowel/bladder dysfunction
Males & some females
“Issues with everything ‘South of the Border’”
What is the workup and treatment for X-ALD?
Very Long Chain Fatty Acids
Stem cell transplant (mostly reserved for severe/childhood cerebral cases)
What are sphingolipidoses disorders?
Conditions where your body cannot break down sphingolipids
What 3 sphingolipidoses do NOT have neurological involvement?
Gaucher, Fabry, and Pompe
Mutations in what gene cause Gaucher Type 1?
GBA
Where can buildup occur in Gaucher Type 1? What are the symptoms?
Bone, liver, spleen
Bone pain, bone marrow infiltration, anemia, thrombocytopenia, hepatosplenomegaly
What is the typical age of presentation of Gaucher T1?
Late childhood - young adulthood
Age of diagnosis/onset depends on how quickly buildup is happening
What is the carrier frequency of Gaucher T1 in AJ population?
1 in 15
What is the biochemical testing workup for Gaucher T1? Treatment?
Workup: Lyso-Gb1, enzyme
Treatment: ERT, Substrate reduction (pills)
Mutations in which gene cause Fabry disease? What is the mode of inheritance?
GLA; X-Linked (females are affected)
What is the typical age of presentation for Fabry?
Boys: childhood
Females: adulthood
What are most common symptoms of Fabry?
Neuropathic pain:
- hands and feet
- tingling and prickling
- burning
Decreased sweating
GI:
- cramps
- constipation
- diarrhea
Angiokeratomas:
- lower abdomen
- bathing trunk
W/O treatment:
- kidney disease
- abnormal heart rhythms
- heart enlargement
- increased stroke risk
What is the biochemical workup and treatment for Fabry?
Workup: GL3, enzyme, (females: genetic testing only)
Treatment: ERT, substrate reduction (pills)
Mutations in what gene cause Pompe Disease? What is the mechanism?
GAA
Repeat disorder
How much enzyme is present in infantile-form Pompe disease? Late-onset (juvenile or adult-onset)?
Infantile: little or no enzyme
Late-onset: reduced enzyme
When is typical onset for infantile and late onset Pompe disease?
Infantile: first few months of life
Late-onset: any age
What are signs of infantile-form Pompe disease?
Hypertrophic cardiomyopathy (HCM) (enlarged heart), skeletal muscle weakness (diaphragm & other breathing muscles)
What are signs of late-onset Pompe disease?
Proximal limb weakness (shoulders & hips), progressive diaphragm weakness (breathing difficulties)
heart not involved
What is the late-onset Pompe disease compound heterozygote state variant?
GAA c.336-13T>G
What is the biochemical workup and treatment for Pompe Disease?
Workup: Urine Hex4, enzyme
Treatment: ERT
True or false: Individuals with Pompe Disease do NOT have normal cognition
False
Mutations in what genes cause Niemann Pick C?
NPC1
NPC2
What symptoms do almost all individuals affected by Niemann Pick C have?
Progressive neurologic
What signs are seen in early infantile onset Niemann Pick C?
Delay in developmental milestones, developmental regression
What signs are seen in infantile & childhood onset Niemann Pick C? (around 6 years old)
Slurred speech, learning difficulties, unsteady gait, clumsiness, seizures or cataplexy (a sudden and brief episode of muscle weakness that typically occurs in response to strong emotions, such as laughter, excitement, surprise, or anger)
What signs are seen in teenage & adult onset Niemann Pick C?
Psychiatric symptoms
Progressive cognitive impairment
What is the biochemical workup and treatment for Niemann Pick C?
Workup: Oxysterols
Treatment: Miglustat
What is average age of onset for Krabbe and Tay-Sachs/Sandhoff/GM2?
5-6 months of age
What is the average age of onset of neuronal ceroid lipofuscinosis?
1-2 years old
What is the average age of onset of metachromatic leukodystrophy?
2+ years old
Mutations in what gene cause Krabbe?
GALC
Mutations in which genes cause Tay-Sachs/Sandhoff/GMS Gangliosides?
HexA, HexB
Mutations in which genes cause neuronal ceroid lipofuscinosis?
CLN1, CLN2, CLN3, CLN4, CLN5…
Mutations in which gene cause metachromatic leukodystrophy?
ARSA
What symptoms are seen in infantile and childhood onset forms of neurological sphingolipidoses?
Neurological deterioration
Loss of all skills
Blindness
What symptoms are seen in adult/late onset forms of neurological sphingolipidoses?
Motor difficulties
Psychiatric symptoms
What is a key symptoms of Tay-Sachs compared to the other sphingolipdoses?
“Cherry red spot” in the eye
What is the biochemical workup in Krabbe?
Psychosine
What is the biochemical workup in GM2?
Urine oligosaccharides
What is the biochemical workup in NCL?
None - DNA testing
What is the biochemical workup in MLD?
Urine sulfatides
What is the biochemical workup for all sphingolipidoses except for NCL?
Enzyme levels
What is treatment for Krabbe and MLD?
Stem cell transplant
What does disease progression typically look like in complex molecule disorders?
Normal at birth, progressive disease
When is the typical diagnosis age of MPS?
Young childhood
What are the skeletal findings of MPS?
Dysostosis multiplex (abnormalities on x-ray)
Joint contractures
What are the nervous system findings in MPS?
Progressive neurological deterioration in MPSI severe, MPSII, MPSIII
Carpal tunnel
What are the eyes/ears findings in MPS?
Optic atrophy
Retinal detachment
Hearing loss
What are the face & neck findings in MPS?
Coarsening of facial features
Airway narrowing (high risk for anesthesia)
What are the other organ findings in MPS?
Heart (valves and muscle)
Liver and spleen enlargement
What is the gene for MPSI (Severe and attenuated)? What is the genotype-phenotype correlation for each?
IDUA
Severe: p.Gln70Ter or p.Trp402Ter
Mild: Missense variants
What feature is special to MPSI Severe (Hurler) and Attenuated (Scheie)?
Corneal clouding
What feature is special to MPSI Scheie?
Normal cognition
What is the gene for MPSII (Hunter)? Mode of inheritance?
IDS; X-Linked
What feature is special to MPSII (Hunter)?
Significant behavioral concerns (late)
What are the genes for MPSIII (Sanfilippo)?
SGSH, NAGLU, HGSNAT, GNS
What feature is special to MPSIII (Sanfilippo)?
Significant behavioral concerns early)
What are the genes for MPS IV (Morquio)?
GALNS, GLB1
What feature is special to MPSIV (Morquio)?
Significant skeletal concerns, normal cognition
What is the biochemical workup for MPS? Treatments?
Workup: Urine glycosaminoglycans (AKA urine mucopolysaccharides), enzyme levels
Treatments: ERT (none for MPSIII)
MPSI: stem cell transplant
What is the most common Congenital Disorder of Glycosylation (CDG)?
PMM2-CDG
What genes are related to other less common CDGs?
MPI, ALG6, ALG3, ALG12, DPM1, MPDU1
What are the neurological implications of PMM2-CDG?
Cognitive disability
Epilepsies
Stroke
What are the organ formation implications of PMM2-CDG?
Distinctive facial features
Abnormal fat distribution, inverted nipples
Renal cysts
Brain malformations
What are the organ function implications of PMM2-CDG?
Immune dysfunction
Coagulopathy (bleeding/clotting)
Hormones (i.e hypothyroid)
Liver dysfunction
What is the biochemical workup and treatment for PMM2-CDG?
Workup: N-Glycan profile, O-Glycan profile “carbohydrate deficient transferrin”
Treatment: symptomatic
Rarely: specific sugars
What condition is a cholesterol synthesis disorder?
Smith-Lemli-Opitz
What conditions are cholesterol breakdown disorders?
FH, Lysosomal acid lipase, cerebrotendinous xanthomastosis
What are features of Smith-Lemli-Opitz? Age of presentation?
Growth restriction
Cognitive disability
Distinctive features
2-3 toe syndactyly
Cardiac defects
Underdeveloped male genitalia
Infants
What is the gene for Smith-Lemli-Opitz?
DHCR7
What is the biochemical workup and treatment for Smith-Lemli-Opitz?
Workup: 7-Dehydrocholestrol
Treatment: Symptomatic, ?cholesterol
What are features of FH? Age of presentation?
Xanthelasma
Tendon xanthomas
Corneal arcus
Severely elevated LDL (>190 mg/dL) leading to MI
Adults
What genes are associated with FH?
LDLR, APOB, PSCK9
What is the biochemical workup and treatment for FH?
Workup: Lipid panel (HDL, LDL, triglycerides)
Treatment: statins/cholesterol-lowering medications
What gene is associated with Lysosomal acid lipase (LAL)?
LIPA
What features do we see in LAL?
Atherosclerosis, heart attack, stroke, liver damage/cirrhosis
What is the biochemical workup and treatment for LAL?
Workup: lipid panel, enzyme levels
Treatment: ERT
What gene is associated with cerebrotendinous xanthomastosis?
CYP27A1
