Complex Molecule Disorders Flashcards by Erin Alexander

What are the 2 most common peroxisomal disorders?

Zellweger spectrum and X-ALD

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Mutations in what genes cause Zellweger spectrum disorder?

PEX1*, PEX6, PEX12, PEX26

*most common

No common variants

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What is the reason/mechanism behind the development of Zellweger?

Individuals cannot make the peroxisome

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What is the age of presentation of Zellweger?

Severe: Neonatal
Mild: Childhood

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What body systems are the most affected by Zellweger?

Neurologic, liver, skeletal

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What is a key radiographic feature of Zellweger?

Stippling of bone (knee cap example)

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What biochemical testing is done for Zellweger? Treatment?

Very long chain fatty acids

No treatment, just symptomatic support

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True or false: X-ALD is on NBS

True

on RUSP

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What is the reason/mechanism behind the development of X-ALD?

No transporter into the peroxisome for VLCFA

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Mutations in what gene cause X-ALD? What is the mode of inheritance?

ABCD1; X-Linked

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What percentage of X-ALD cases are de novo?

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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

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What are the demographics/features of childhood cerebral onset of X-ALD?

Adrenoleukodystrophy
4-8 years old
Neurological regression
Males

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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’”

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What is the workup and treatment for X-ALD?

Very Long Chain Fatty Acids

Stem cell transplant (mostly reserved for severe/childhood cerebral cases)

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What are sphingolipidoses disorders?

Conditions where your body cannot break down sphingolipids

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What 3 sphingolipidoses do NOT have neurological involvement?

Gaucher, Fabry, and Pompe

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Mutations in what gene cause Gaucher Type 1?

GBA

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Where can buildup occur in Gaucher Type 1? What are the symptoms?

Bone, liver, spleen

Bone pain, bone marrow infiltration, anemia, thrombocytopenia, hepatosplenomegaly

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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

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What is the carrier frequency of Gaucher T1 in AJ population?

1 in 15

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What is the biochemical testing workup for Gaucher T1? Treatment?

Workup: Lyso-Gb1, enzyme
Treatment: ERT, Substrate reduction (pills)

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Mutations in which gene cause Fabry disease? What is the mode of inheritance?

GLA; X-Linked (females are affected)

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What is the typical age of presentation for Fabry?

Boys: childhood
Females: adulthood

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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