Biochemical Genetics - Final

What are some referral indications that should make you think 'metabolic condition'? (7)

Abnormal newborn screen
Acute crisis (hyperammonemia, lactic acidosis)
Hypoglycemia
Unexplained altered mental status or developmental regression
Organomegaly (hepatomegaly, splenomegaly)
SIDS/FH of SIDS
Stroke-like episodes

If the urine smells like sweaty feet, what condition should you think of?

Isovaleric acidemia

If the urine smells like maple syrup, what condition should you think of?

Maple syrup urine disease

If the urine smells like boiled cabbage, what condition should you think of?

Hypermethioninemia

If the urine smells like tomcat urine, what condition should you think of?

Multiple carboxylase deficiency

If the urine smells musty, what condition should you think of?

PKU

If the urine smells fishy, what condition should you think of?

Trimethylaminuria

An individual has elevated uric acid and has severe deficiency of hypoxanthine-guanine phosphoribosyltransferase. What condition does this suggest?

Lesch-Nyhan Syndrome (HPRT1)

What condition is associated with the HPRT1 gene?

Lesch-Nyhan Syndrome

What is biotinidase?

An enzyme that helps to recycle biotin to be used by the body. It breaks down complex biotin that comes from food into free biotin.

How is biotinidase deficiency treated?

Treated by providing patient with a vitamin that has biotin in its free form.
Patient needs to be on it for life. It can reverse symptoms a lot, but if they spent a long time being undiagnosed there may be damage that cannot be undone.

What does ERT stand for?

Enzyme replacement therapy

What are some limitations of NBS? (5)

False negatives
False positives
Many metabolic disorders are not screened
Questionable clinical utility for some screened disorders
Financial constraints

Why is copper balance essential?

Copper acts as a cofactor for several enzymes involved in growth, cardiovascular integrity, lung elasticity, neovascularization, neuroendocrine function, and iron metabolism
Too much copper \= toxicity (CU2+ reacts with H2O2 to form free radicals \= tissue damage)
Too little copper \= disrupt pathways where copper is needed as a cofactor

Which foods are sources of copper?

Shellfish
Seeds
Nuts
Organ meats
Wheat-bran cereals
Whole-grain products
Chocolate
Tap watter

What is the suggested copper intake per day?

0.75mg

What condition is associated with ATP7B?

Wilson Disease

What is Apocerulloplsmin?

Copper carrying protein (referred to as apocerulloplasmin when it is carrying copper, and cerulloplasmin when no copper is attached)

What inheritance pattern is associated with Wilson Disease?

AR

What gene is associated with Wilson Disease?

ATP7B

What is a red-flag for Wilson Disease?

Kayser Fleischer Rings (KF rings)

A patient has KF rings, what condition should you think of?

Wilson Disease

A patient has a blue/grey ring around their iris, what is this and what condition should you think of?

This is a KF Ring
Think Wilson Disease

What features are associated with Wilson Disease? (10)

Recurrent Jaundice
Acute self-limited hepatitis-like illness
Autoimmune-type hepatitis
Fulminant hepatic failure
Chronic liver disease
Movement disorders/rigid dystonia
Depression
Neurotic behaviors
Disorganized personality, cognitive decline
Kayser fleischer rings (KF rings)

Of the individuals with Wilson disease, KF rings are less likely to appear in individuals with WHAT other feature?

Liver disease

Proband has a combination of hepatic, neurologic and psychiatric findings - what condition do you think of?

Wilson disease

What is the preferred method of testing for wilson disease

Detection of biallelic pathogenic variants in ATP7B

Patient has low ceruloplasmin, what condition do you think of?

Wilson Disease

Low ceruloplasmin + elevated urine copper \= what condition?

Wilson disease

Why might genetic testing for the ATP7B gene be preferred to biochemical testing for individuals suspected of having Wilsons disease?

Because low ceruloplasmine or elevated urine copper can be caused by other conditions

Why would ceruloplasmin be low in individuals with Wilson Disease?

People with Wilsons disease have excess copper, and as soon as copper binds to ceruloplasmin it becomes apoceruloplasmin. So the reason ceruloplasmin is low is because copper has bound to most of it.

Is there any genotype/phenotype correlation associated with Wilson Disease?

Pathogenic variants that abolish ATP7B function lead to increased severity/earlier onset

How is Wilsons Disease treated?

Lower copper accumulation ASAP!
Use:
Copper chelating agents (increase urinary excretion of copper)
High dose oral zinc (interferes wtih absorption of copper from intestines, copper excreted in feces)
Diet (eliminate high copper foods)
Liver transplant

What is another name for Kinky Hair Disease?

Menkes Disease

What is another name for Menkes Disease?

Kinky Hair Disease

What clinical features are associated with Menkes disease?

Loss of early developmental milestones
Failure to thrive
Intractable seizures
Hypotonia
Short, sparse, light colored kinky hair
Light skin
Prolonged jaundice (neonatal)
Transient hypoglycemia (neonatal)
Temperature instability (neonatal)
Vascular tortuosity

What is the typical lifespan of an individual with Menkes disease?

7 months-3.5 years

What gene is associated with Menkes disease?

ATP7A

What gene is associated with Occipital Horn Syndrome (OHS)?

ATP7A

What features are associated with OHS?

Occipital horn
Lax skin and joints
Dysautonomia (chronic diarrhea, orthostatic hypotension)
Vascular tortuosity
Typical-mild cognitive delay

What is the typical lifespan of an individual with OHS?

normal

What gene is associated with distal motor neuropathy (DMN)?

ATP7A

What features are associated with distal motor neuropathy?

Progressive DMN without sensory symptoms
Distal muscle weakness and atrophy in feet and hands
No cognitive impairment

What is the typical lifespan of an individual with distal motor neuropathy?

Normal

What are the 3 ATP7A-related disorders in order of most severe to least severe?

Menkes disease (severe copper deficiency)
Occipital horn syndrome (mid copper deficiency)
ATP7A-related distal motor neuropathy (mild copper deficiency)

What inheritance pattern do ATP7A-related disorders follow?

X-linked

What is the best molecular testing to order for an individual suspected of having an ATP7A-related disorder?

ATP7A sequencing with CNV or del/dup analysis

What is a genotype/phenotype correlation associated with ATP7A-related disorders?

The amount of residual ATPase enzyme activity correlates with phenotype (severe variant such as a deletion \= severe disease)

How could an ATP7A-related disorder be treated?

Subcutaneous injections of copper histidinate before 28 days of life enhances survival and improves neurologic outcomes

What are amino acidopathies?

A group of inborn errors of metabolism that result from a deficiency of an enzyme leading to abnormal metabolism of amino acids

What neonatal features (5) should make you think of an amino acidopathy?

Lethargy
Feeding difficulties
Vomiting
Coma
Seizures

What is a red flag for an amino acidopathy?

Protein aversion/vegan/vegetarian

If phenylalanine is elevated, which condition should you think of?

PKU

Defects in which enzyme could cause PKU?

Phenylalanine hydroxylase (PAH)

What inheritance pattern does PKU follow?

AR

What is hyperphenylalanemia?

Having elevated phenylalanine without symptoms

What is the role of PAH?

Breaks down phenylalanine into tyrosine

What determines the severity of PKU?

Amount of enzyme activity

What would an individual with PKU's tyrosine levels look like?

Decreased

What features would an individual with untreated PKU have?

ID
mousy /musty urine odor
Eczema
Reduced hair, skin, and iris pigment
Microcephaly
epilepsy/tremor/spasticity
Growth delay
Behavioural concerns

For a pregnant individual with PKU, what is the 'goal' phe levels they should have?

1-3mg/dL

Children, who do not have PKU, of gestational carriers with PKU have which (5) features?

ID
Behavior problems
Microcephaly
CHD
IUGR

What does a PKU Diet look like?

Low protein/specifically avoid phenylalanine
Supplemental tyrosine
Vitamins and minerals

Which two medications are available for treatment of PKU in addition to diet?

Kuvan - manufactured co-factor (BH4) to stimulate PAH enzyme activity - requires some residual enzyme activity
Pegvaliase - breaks down phe to normal levels (high risk of allergic reaction)

What does MSUD stand for?

Maple syrup urine disease

What caused MSUD?

Branched-chain a-ketoacid dehydrogenase deficiency (absence or inactivity of BCKD)

MSUD is a disorder in the metabolism of which amino acids?

Leucine, isoleucine, valine

For an individual with MSUD, what would Plasma amino acids (Aa) and Urine organic acids (OA) show?

Plasma AA: elevated valine, very elevated leucine, isoleucine, alloisoleucine
Urine OA: elevated branched-chain oxo- and hydroxyacids

Which 3 genes could be responsible for MSUD?

BCKDHA
BCKDHB
DBT

Can biochemical testing distinguish between which of the 3 genes is causing a case of MSUD?

No, they are biochemically indistinguishable

What are features associated with classic, untreated MSUD?

Poor feeding
Lethargy
Irritability
Encephalopathy
Apnea
Reflexive bicycling
Maple syrup odor
With severe intoxication → cerebral edema, coma, central respiratory failure

What are some signs of a metabolic decompensation event in infants/toddlers?

Nausea
Poor appetite
Altered consciousness
Acute dystonia
Ataxia

What are some signs of a metabolic decompensation event in adults?

Cognitive impairment
Hyperactivity
Hallucinations
Focal dystonia
Choreoathetosis
Ataxia
Mood swings
Nausea
Vomiting

What does the diet management of an individual with MSUD look like?

Formula that is free of leu, ile, val that provides protein + vitamins and minerals
Low protein diet (restricting ile, leu, val)
Provide alternative metabolic pathways using carnitine

What would be considered a cure for MSUD?

Liver transplant

What causes tyrosinemia (Deficiency of what?)

Deficiency of fumarylacetoacetic hydrolase

What gene is associated with tyrosinemia?

FAH

What inheritance pattern does tyrosinemia follow?

AR

For an individual with tyrosinemia type 1, what would their urine OA labs show?

Elevated succinylacetone + elevated 4-OH-phenyl derivatives

For an individual with tyrosinemia type 1, what would their plasma AA labs show?

Elevated tyrosine, elevated methionine

For an individual with tyrosinemia type 1, asisde from plasma AA and urine OA labs, what other molecular findings might be noted?

Elevated alpha-feto protein (serum) + elevated aaminolaevulinic acid

Which highly toxic substance is elevated in individuals with tyrosinemia type 1?

Succinylacetone

If tyrosinemia type 1 goes untreated, what feature might these individuals have?

Hepatocellular carcinoma

For acute tyrosinemia type 1, what is the age of onset?

Prior to 6 months

For acute tyrosinemia type 1, what are the 2 major features?

Acute liver failure
Boiled cabbage/rotten mushroom odor

For acute tyrosinemia type 1, what is the lifespan for individuals left untreated?

2 years

For subacute tyrosinemia type 1, what is the age of onset?

6-12 months

For subacute tyrosinemia type 1, what are the 6 major features?

Liver disease
Renal tubular involvement
Failure to thrive
Hepatosplenomegaly
Rickets and hypotonia
Coagulopathy

For subacute tyrosinemia type 1, what is the typical lifespan for individuals left untreated, and what is usually the cause of death?

10 years
Cirrhotic liver

For chronic tyrosinemia type 1, what is the age of onset?

\>12 months

For chronic tyrosinemia type 1, what are the 5 major features?

Chronic liver disease
Renal disease
Rickets
Cardiomyopathy
Porphyria-like syndrome (neurologic crisis \= change in mental status, abdominal pain, peripheral neuropathy, respiratory failure)

Why is it important for individuals with tyrosinemia type 1 who take nitisinone to combine this medication with a low tyrosine diet?

They may get corneal crystals (corneal opacities)

What medication is often used to treat individuals with tyrosinemia type 1?

Nitisinone (orfadin)

What does the medication Nitisinone, which treats tyrosinemia type 1, do? What will it not help? What should be done in combination with this medication?

Blocks formation of fumarylacetoacetate and succinylacetone
Tyrosine levels will still be elevated
A low tyrosine diet should be maintained in combination with this medication

Homocystinuria is caused by a deficiency in what enzyme?

Cystathionine beta-synthase

What gene is associated with homocystinuria?

CBS

What inheritance pattern is associated with homocystinuria?

AR

What is the typical age of onset for homocystinuria?

School-age

In which population is the prevalence of homocystinuria much higher?

Qatar

Plasma AA Labs for an individual with homocystinuria would show WHAT?

Elevated methionine, VERY elevated homocysteine, low cysteine