Biochemical Genetics Flashcards
biochemical genetic disorders
caused by enzyme deficiency
- “inborn errors of metabolism”
- problems are due to accumulation of substrates or lack of/deficiency product
- often effectively targeted on NBS and treatable
biochemical genetics inheritance
most commonly autosomal recessive
PKU treatment
-restriction of protein in diet
+remove Phe, add tyrosine with formula
-BH4 supplementation (Kuvan) for some individuals with cofactor defect or with residual activity mutation
alkaptonuria
disorder of catabolism of tyrosine due to build up of substrates
alternative products
can be produced due to accumulation of substrates and failed conversion to normal product
PKU pathogenesis
-deficiency of PAH
-tyrosine fails to be produced
+catecholemines and neurotransmitters affected by loss of precursor
-get atypical production and urine secretion of phenylketones (phenylpyruvate, phenylacetate) due to accumulation of substrate
-elevated blood Phe levels buildup causes mental impairment
CAH
group of enzyme defects related to cortisol production from cholesterol
21-hydroxylase
most commonly mutated enzyme in CAH
- normally converts 17-hydroxyprogesterone into 11-hydroxycortisol
- excess 17-hydroxy converted to androgens
NBS detection of 21-hydroxylase deficiency
high levels of 17-hydroxyprogesterone and low levels of cortisol in the blood
-high false positive seen in babies born prematurely
low cortisol level effects
- inability to retain sodium in kidney
- problems with fasting intolerance
effects of androgen build-up
virilization in females
reasoning behind recessive inheritance of IEMs
-most enzymes operate below full capacity & most physiological substrate concentration is below enzyme saturation
+only need about 10% enzyme function to avoid symptoms
+balance allows homeostasis to be maintained and gives enzymes chance to respond dynamically to substrate concentration changes
arginase deficiency/arginemia
- failed step of urea cycle causes buildup of arginine and reduced ornithine and urea
- affected individuals tend to develop lower limb spasticity
harmful double substrate
if the doubled concentration is problematic, the enzyme is inherited in a dominant fashion
*most heterozygotes unaffected
amino acid studies
- quantitative
- usually performed on blood, but can be done on urine
- includes acids that are not part of the basic 20
- slight elevations common so best performed after fasting-abnormal is 10x normal levels
organic acid studies
- generally derivatives of AA, but others are part of carb metabolism or Krebs cycle
- mostly performed on urine via GCMS
- can be quantitative or qualitative
- slight elevations can make results difficult to interpret
when to pursue AA and OA studies
usually performed by pediatricians, but can be done as confirmatory or follow-up studies to NBS or monitoring of therapy for affected child
- unexplained DD
- unexplained acute illnesses
- FTT
acylcarnitine profile
-designed to be done on urine but now done on blood via tandem mass spec
-reflects the intracellular concentrations of acyl-CoA
+accumulating derivatives aren’t measurable in blood or urine
+report shows molecular weight or carbon number with the number of double bonds
enzyme assays
-can be performed on blood or biopsied samples
-measuring Vmax of activity in the tissue, not physiological activity
+makes some kinetic variants easy to miss because maximal activity can be normal, but at physiologic levels may not be
-stability of samples can make accuracy difficult
enzyme assay sources
\+WBC \+serum-non cell samples \+NBS dried blood spot \+skin fibroblasts \+sometimes more invasive liver or muscle biopsies are necessary
CRM assay
- checks for presence or absence of protein
- antibody levels are raised to measure immunologically-looking for reaction
- typically studied by western blot
treatment of CRM negative patients
can be more difficult because individuals have never been exposed to protein
gene sequencing for biochemical disorders
-preferable in some cases because most IEMs have causative loci & reduces issues that occur with enzymatic assay
+gene panels can also be helpful due to locus heterogeneity
+polymorphisms, VUSs and benign variants can also complicate interpretation
point mutations in IEMs
- more likely to be crm+
- likely to allow for some enzymatic activity
deletions, nonsense or intronic variants
- more likely to be crm-
- tend to eliminate enzymatic activity and may be more severe in some cases
reasons to use enzymatic tests
- less expensive
- not dependent upon particular mutations
reasons not to use enzyme assays
- activity may not be stable
- may not be active/present in easily accessible tissues
reasons to use gene sequencing
- not tissue dependent and can detect mutations that only effect certain tissues
- continuing decrease in costs for larger testing panels
reasons not to use gene sequencing
- certain gene panels may not test all mutations
- interpretation challenges
locus/non-allelic heterogeneity
mutations in different genes can cause similar or the same phenotype
mucopolysaccharidoses
group of disorders with some phenotype similarities including:
- skeletal dysplasia with joint stiffness
- organomegaly (hepato, spleno)
- often times intellectual deterioration
- course facial features that become thickened
- secretion of urine GAGs
- 6 clinical phenotypes
MPS V/Schie
no longer used as its own phenotype, as it is caused by mutation of a shared enzyme, so it is categorized as part of a spectrum of the other type
MPS III/San Fillipo
-4 clinically indistinguishable subtypes, BUT 4 different enzyme/loci deficiencies (AR; 1 in 50000-1 in 280000)
-may have most severe neurological symptoms (ASD, aggression, restlessness)
+DD, behavioral problems cause presentation in early childhood (1.5-2y), plateau by 3 and death in teenage years
+other manifestations less severe
methylmalonic acidurias
-all affected newborns secrete methylmalonic acids in the urine
+ammonia also high
-acyl carnitine profile shows elevated C3 acyl carnitine
-gene sequencing may have to further differentiate the defective enzyme or cofactor type
methylmalonyl-CoA mutase deficiency genetics
-most common methylmalonic acidemia
+failure of methylmalonyl-CoA to be metabolized to succinyl CoA in Krebs cycle
-vitamin B12 derivative defects can also cause a similar phenotype
methylmalonyl-CoA mutase deficiency phenotype
- acute acidosis in the neonatal period
- vitamin B12 derivative
Cobalamin defects
-compound is a B12 derivative that acts as a cofactor
+seven subtypes (A-G)
+not a vitamin deficiency, just failure to create cofactor
-dysfunction causes methylmalonic academia related to loss of cofactor
-each type caused by mutation of a different enzyme
+conical shape of teeth
pernicious anemia
B12 deficiency that leads to excretion of methylmalonic acid in urine
homocystinuria
-compound formed by removal of methyl from methionine
+typically free levels are low
-symptoms similar to marfan with ID and proneness to thromboembolism
-often picked up by NBS
homocystinuria co-factors
folic acid and B12
MTHFR mutation
causes possible increased risk for thrombotic events and babies with ONTDs
-can sometimes be missed on NBS
propionic acidemia phenotype
acute ketoacidosis (after 24h) and collapse in newborn
-high ammonia levels, high reaction metabolite levels
-apparent metabolic acidosis, hypoglycemia, hyperketonuria, hyperglycinemia
+vomiting, lethargy, altered mental status
propionic academias genetics
-defect of propionyl-CoA carboxylase (PCC)
+defect of either subunit gene can cause the phenotype
+ also requires working cofactor for phenotype avoidance
-inability to metabolize valine, odd chain fatty acids, methionine, isoleucine, threonine
biotin
-PCC cofactor, vitamin
+defects result in PCC dysfunction
biotin dysfunction on acyl carnitine
elevated C3 acyl carnitine levels
allelic heterogeneity
different mutations at same locus cause differences in phenotype
compound heterozygotes
two different mutations at same loci cause a homozygote phenotype
typical IEM symptom presentation
- respiratory distress-deep breathing
- vomiting
- lethargy, seizures, coma
- listlessness
- hypotonia
- severe blood acidosis
- hypoglycemia
- sometimes hepatomegaly
- no dysmorphology
transient hyperammonemia
response to neonatal asphyxia that causes low APGARs, not genetic
-children pant with rapid, shallow breaths
prodrome
initially well, but develop symptoms over a period of days
IEM timing onset
-unremarkable term pregnancies
-no acute symptoms immediately after birth (24-48h buildup)
+good APGARs
+ fed well initially
typical IEM testing findings
-PE: clear lungs, no heart murmurs, (mostly) soft palpable abdomen with no organomegaly
-no signs of infection (no fever, clear chest X-ray)
-lab tests
+anion gap greater than 5 or bicarb very low
+low blood glucose
+sometimes lactic acidosis
+very high ammonia levels
+high ketonuria
diseases with vomiting, lethargy and coma
- urea cycle defects
- galactosemia
- MSUD
- organic acidemias (propionic, methylmalonic, isovaleric)
diseases with severe acidosis
- organic acidemias (propionic, methylmalonic, isovaleric)
- primary lactic acidoses (ETC/mito disorders, pyruvate dehydrogenase deficiency)
- elevated lactic acid not as specific to IEMs
severe acidosis blood levels
-pH less than 7.1
+note: below 7 is life threatening
-bicarb less than 10
normal blood levels
- pH ~7.4
- bicarb ~25
diseases with respiratory distress
- urea cycle defects
- organic acidemias
- MSUD
- nonketotic hyperglycinemia (hiccuping & apnea)
hyperpnea
rapid breathing
-can be seen in urea cycle defects due to increased ammonia increasing respiratory drive
Kussmaul
deep breathing
-can be seen with organic academias due to overcompensation for acidosis
respiratory depression
very slowed difficulty maintaining breathing
-seen in MSUD due to loss of full neurological function
diseases with hypoglycemia
- can also lead to seizures
- not all that uncommon in newborns
- CAH
- FAODs
- galactosemia
- propionic acidemia
- gluconeogenic defects
diseases with hepatomegaly
- galactosemia
- tyrosinemia (later implication)
- FAODs
- LSDs (later implication)
- liver glycogen storage diseases
diseases that cause seizures
- due to brain intoxication by harmful buildup
- nonketotic hyperglycinemia
- urea cycle defects
- organic acidemias
- gluconeogenic defects
- LSDs (later implication)
tend to present within the first week of life
- amino acidopathies
- disorders of carbohydrate metabolism
- FAODs
- CAH
urea cycle defects
-cause acute, severe hyperammonemia
+symptoms usually initiate at levels >200, but may not be brought to care until levels are at ~1000
+high levels are toxic, causing TCA disruption and glial swelling/cerebral edema
-initial signs: tachypnea, vomiting, lethargy, seizures, bleeding
+NOT acidotic-nL blood pH
-treatable, but longer without treament=worse long term prognosis-coma and death come on quickly
-signs begin after the first 24h
normal ammonia levels
30
urea cycle defect treatments
-hemodialysis to remove ammonia
-medications
-organ transplant-namely liver
+alternative pathway excretion has helped with the need for this (benzoate + phenyl acetate-ammonia scavengers-because glycine and glutamine come from ammonia)
-limitation of protein in diet to reduce nitrogen levels and urea that would need to be synthesized
-arginine or citrulline supplementation
-treatment of secondary effects, such as intracranial pressure, coagulation problems, etc
urea cycle defect diagnostic testing
-high ammonia levels
-serum amino acids
+citrulline and ornithine are meant to be transported across membrane-elevations of these or their substrates/products (arginine, argininosuccinate) indicate which enzyme is defective
urea cycle defect enzymes
-mitochondrial \+carbamyl phosphotase synthase I \+ornithine transcarbamylase (OTC) -cytosolic \+arginosuccinate synthase \+arginosuccinate lyase \+arginase
urea cycle defect NBS
only detects argininosuccinate lyase and synthase deficiencies based on elevated citrulline levels
OTC genetics
-X-linked inheritance
+males mostly affected
+females may be protein intolerant or have more problems during pregnancy and delivery
-deficiency of enzyme causes extreme ammonia elevation, both affected and carriers may have psychiatric issues
organic acidemia presentation
- acute, severe ketoacidosis (pH <7.1) around a few days of life
- vomiting, hyperpnea, lethargy
organic acidemia treatment
-special diets and vitamin treatments
+want to reduce accumulation of toxic substrate
-dialysis
organic acidemia diagnosis
- urine organic acid study
- acylcarnitine profile
propionic acidemia diagnosis
- urine organic acid studies show elevated methyl citrate, propinyl glycine and other substrates of reaction (VOMIT-CTU)
- acylcarnitine shows elevated C3
methylmalonic acidemia presentation
-severe acute ketoacidosis, hyperketonuria after 24-48h
+metabolic acidosis, hyperammonemia
-hypoglycemia, hyperglycinemia
+vomiting, lethargy, altered mental status
isovaleric acidemia genetics
-defect of isovaleryl-CoA dehydrogenase
+comes from degradation of leucine
-follows enzyme that fails in MSUD
-requires riboflavin (B2) as a cofactor
acute isovaleric acidemia presentation
- sweaty feet, dry vomit odor
- severe ketoacidosis in newborn period, hyperammonemia, ketonuria
- vomiting, lethargy
- pancytopenia
- note a chronic intermittent form brought on by a stressor and an asymptomatic variant also exist
isovaleric acidemia testing
- elevated isovaleric acid in urine OAs
- elevated C5 acylcarnitine (studied by NBS too)
MSUD presentation
-initial signs are lethargy and hypotonia, respiratory distress/depression, seizures
-progression to acidotic state, vomiting, and coma
+if untreated get severe neurological damage due to cerebral edema
-urine and sweat smell sweet, like syrup
-older children can develop ataxia, slurred speech, altered mental status
MSUD genetics
-defect of branched chain ketoacid dehydrogenase
+failed second step of breakdown of leucine, isoleucine and valine
+3 subunit protein
-thiamine dependent
-1/185000 incidence
+higher in AJ (1/51000) & highest in mennonite (1/176)
MSUD testing
- positive urine dipstick for ketones
- blood testing will show ketoacidosis, high branched chain acids on OA panel (elevated leucine picked up on NBS)
MSUD treatment
-respond well to special diet and vitamin supplementation
+Thiamine addition for some
+protein removal to reduce BCAAs
-dialysis to remove leucine
+sometimes a need for liver transplantation
galactosemia genetics
- defect of galactosemia-I-phosphate uridyltransferase (GALT), carb metabolism failure that causes buildup of galactose in liver
- frequency of 1/50000-1/80000 (AR, pan ethnic)
galactosemia presentation
-initial signs are non-specific: jaundice, hepatomegaly, feeding intolerance and vomiting
- leads to liver failure, hepatomegaly
+sometimes blood clotting abnormalities
+sepsis due to E. coli infections
-hypoglycemia seen shortly after eating
-even treated can still have neurological sequelae like speech difficulty, LD, ataxia or POI with hypergonadotrophic hypogonadism and primary or secondary anemia
-development of cataracts
galactosemia treatment
- symptoms diminish in absence of feeding (IV fluids with glucose are fine in newborns)
- responds well to diet-removal of milk from diet, sometimes certain foods must be added
galactosemia testing
-galactose in urine
-abnormal enzyme levels in blood (enzyme operates in RBC-what is measured on NBS)
+reflex testing to rule out certain variants
+heat-sensitivity can cause false positives in summer
+misses non-traditional enzyme mutations
-can measure blood galactose, but this is finicky due to level fluctuation related to intake
FAODs presentation
-sometimes seen a bit later on when children are sleeping through night (prodrome)
-develop fasting hypoglycemia
+hypoglycemia requires fasting for at least 6-12h
+note this is hypoketotic, which is different than typical cases of hypoglycemia
-long chain defects can cause liver and muscle disease including CM; can be transient in liver
-lettering indicates chain length and enzyme function
-lethargy and vomiting
+byproducts-especially in MCAD are poisonous
-associated with infant death due to failure to treat
FAODs treatment
- often just avoidance of fasting
- can supplement with carnitine if low or with MCAs for LC defects
FAODs testing
- urine OAs show levels of things that should not be present (MC dicoarboxylic acids)
- acyl carnitine profile will show long chain results (C8, C14) and possible carnitine deficiency
- absence of ketoacids in urine
- carnitine profile where total might be low with increased esterified fraction
CAH genetics
defects in cortisol synthesis
- 21-hydroxylase deficiency most common
- incidence of 1/15000 infants
CAH presentation
-fasting intolerance & hypoglycemia due to inability to respond to gluconeogenic blunting
-lethargy
-poor response to metabolic stress
-salt wasting that causes circulatory collapse
+rapid heart rate and low BP
-prenatal virilization in females
CAH testing
- cortisol deficiency
- loss of salt in urine if aldosterone deficiency
- low sodium and high potassium levels in blood due to aldosterone deficiency
- elevated 17-hydroxyprogesterone at birth (NBS)
- ACTH stimulation testing is diagnostic (normally completed by endocrinology)
CAH treatment
- HRT, cortisol replacement
- florinef and HCl replacement also sometimes needed if mineralocorticoids low
- possible surgical intervention
eval for hepatomegaly
- age at onset/recognition
- developmental status-IEMs can lead to neuron impairment (DD, seizures, etc)
- acute illness or any additional symptoms that might make you more suspicious of an infection
- difficulty of waking the affected child in the morning
- signs of hypoglycemia such as cold sweats, rapid heart rate, chills after fasting
PE with hepatomegaly
- look for coarse facial features, skeletal anomalies
- check to see whether spleen is enlarged
- presence of joint stiffness or muscle weakness, pain on exercise
labs for GSDs
-looking at electrolytes for increased anion gap
+lactic acid might be especially elevated
-looking for low blood glucose/hypoglycemia, especially in fasting samples (glucagon injection studies)
-CBC-LSDs may cause anemia or low platelet count due to splenomegaly
-possible increased urine GAGs in MPSs
-skeletal survey-looking for dysostosis multiplex
-biopsies-especially bone marrow or liver with Gaucher disease
-gene panel
LSDs
-group of disorders that result in inability to degrade cellular structural components
+get accumulation in scavenger cells of the liver, spleen, neurons, etc
-mutant enzymes are specific to deficient organelle-they are degradative, produced by the golgi apparatus and imported
+mannose-phosphate tag targets their import
glycolipids
lipid-like molecules (sphingosine) with attached carbohydrates
Farber disease
failure of ceramide to be cleaved from sphingolipid
Gaucher disease genetics
-AR GBA mutations
-cause accumulation of glucocerebroside in lysosomes due to dysfunction of glucocerebrosidase
-panethnic (1/60000-1/100000)
+can see higher incidence of type I in AJ (N370S), type II & III in Asians
*close linkage of disease gene to highly mutagenic pseudogene
Krabbe disease genetics
- accumulation of galactocerebroside in lysosomes due to galactocerebrosidase (GALC) deficiency
- incidence of 1 in 100000
Tay-Sachs genetics
-GM2 ganglioside accumulation
-failed sphingolipid cleavage by HEXA
-later onset forms due to reduced enzymatic activity
-present in all populations, but AJ, Fr Ca, Cajun, Penn Dutch founder muts
+1 in 30 AJ carrier freq (1 in 3600)
+1 in 250-300 other
mucopolysaccharidoses genetics
-defects in GAG degradation
+dermatan, keratan, heparin and chondroitin sulfates
+important in cell membranes and cartilage, making the precursors helpful for treating joint pain
-6 clinically distinct types
MPS phenotype
- skeletal problems and joint stiffness
- hepatosplenomegaly
- neurologic problems (can be progressive)
- pulmonary complications causing breathing difficulty and lung stiffness
- eye problems (retinal issues, corneal clouding)
- cardiac valve dysfunction
- hearing loss
MPS testing
- skeletal survey
- urine GAGs-generalized elevation
- enzyme analysis usually completed on leukocytes, but can use fibroblasts***gold standard
- genetic testing-full gene+del/dup especially if considering type II
GSDs
-group of disorders characterized by glycogen accumulation
+liver, heart and skeletal muscles often affected
-hepatic versions can have fasting hypoglycemia (<6h fasting)
-liver versions have liver enlargement, but no spleen involvement
-muscle weakness or pain with exercise common
*excessive glycogen in liver does not always mean one of these genetic conditions
Gaucher disease presentation
-splenomegaly-often get anemia and thrombocytopenia
+can see bruising and blood clotting
+rarer b-cell malignancies and avascular necrotic pain crises
-interstitial lung disease-can cause hypoxemia and breathing problems
-skeletal issues
+pathological fractures-no trauma
+erlenmeyer flask deformity
-5% individuals can have Parkinsons/Lewy body dementia
erlenmeyer flask x-ray deformity
suspicious for Gaucher disease if splenomegaly is seen
Gaucher Type I
-most common type, more common in AJ pop (N370S)
-no neurologic involvement-rare LBD/PD
-tends to have adult onset, but can present with hepatospleno in childhood
+can also have some more severe phenotype overlap
+despite same level of enzyme deficiency can still see variability in manifestations within same family
-splenomegaly with anemia and thrombocytopenia always + osteopenia + pulmonary disease seen to some degree
+can also see B-cell malignancy
*major clinical heterogeneity
Gaucher Type II
- often called infantile form
- rapid deterioration due to neurologic involvement
Gaucher Type III
- neuronopathic
- chronic; slowly progressive neurologic deterioration
- common L444P mutation, Swedish founder mutation
- upward gaze disturbance
NPD A & B genetics
allelic and due to sphingomyelinase deficiency
NPD C genetics
-cholesterol trafficking defect that leads to lipid build-up
-AR NPC1, NPC2 defects
+four subtypes related to age of onset
NPD general phenotype
-always have hepatosplenomegaly
+children can look malnourished due to enlarged belly and otherwise poor growth
-neurologic involvement
+hypotonia in childhood, difficulty with exercise or gait disturbance in adulthood
+deterioration-especially in Type C-gradual gait disturbance and ocular anomalies
NPD A phenotype
-“infantile”, most severe form
+higher incidence in AJ
-often die by 3y due to neurologic deterioration
NPD B phenotype
- milder, despite being allelic with Type A
- often present later and have less or no neurological involvement
NPD C phenotype
- sometimes can see ascites prenatally, then have FTT, jaundice and growth deficiency
- always have hepatosplenomegaly
- usually presents in childhood with gait disturbance and ataxia, cataplexy/loss of control and muscle tone also happens
- palsy of upward gaze occurs
- SNHL sometimes
- often see gradual buildup to ID, DD, psychiatric conditions, seizures
- respiratory failure also a major issue
skeletal implications of MPSs
-coarsening facial features
-joint stiffness
+claw hand deformity
+kink of spine (gibbus)
+difficulty raising arms above shoulders
+bent over posture and hip stiffness
-dysostosis multiplex on X-ray
dysostosis multiplex
*seen on X-ray in individuals with MPSs, but not only specific to
-refers to involvement of many bones
+spindling of bones in hand (not tapered in middle)
+hooking of spinal vertebrae (rounded rather than square)
+broad ribs
MPS I/Hurler-Scheie genetics
-two phenotypes with some patients falling in between
-due to L-alpha-iduronidase deficiency (IDUA)
+1 in 100000 incidence
+genotype-phenotype correlations
MPS II/Hunter
-X-linked condition-few heterozygous females
-deficiency of IDS
+incidence of 1 in 100000
+gen-phen correlations exist, but many private mutations
-similar phenotype to Hurler without corneal clouding
MPS IV/Morquio
-2 subtypes caused by two different enzymes (incidence of 1 in 75000; AR)
-no neurological involvement, but more severe skeletal abnormalities which can require many surgeries
+lax wrists** and hyper mobile joints
-severe corneal clouding
MPS VI/Maroteaux-Lamy
-arylsulfatase B deficiency (AR)
-phenotype similar to Hurler, but distinguished by skeletal features, corneal clouding, and lack of neurological effects
+claw hand deformity & carpal tunnel
+limited mobility and significant pain requiring assistive mobility devices and surgeries
-large tonsils and adenoids
MPSVII/Sly
- most rare form (AR; <1 in 250000)
- organomegaly and skeletal dysplasia more prominent
- can also have respiratory disease, and progressive ID, DD
- high mortality with few individuals living into 20s
- hydrops can be seen in severe cases
Hepatic GSDs
- GSD I/von Gierke
- GSD III/Forbes, Cori disease
- GSD VI and higher/Hers disease
- GSD IV/Andersen
- GSD 0
GSD I genetics
-disorder of the release of glucose from the liver causes glucose buildup and excessive synthesis
-two subtypes: a-glucose-6-phosphotase deficiency, b-transporter enzyme defect
-AR incidence of 1 in 100000
+R83C common EEJ mutation carrier freq 1.4%, prevalence 1 in 20000
GSD Ia/von Gierke phenotype
*most severe GSD & most common, but no myopathy
-massive hepatomegaly even when sugar is well controlled
+mostly due to fat storage
-severe hypoglycemia after short fast
-hyperlipidemia, hyperuricemia
+can cause kidney problems and gout-like symptoms
-can have severe lactic acidemia due to inability of glucose release-not due to muscle defect
-doll-like facies
GSD III/Forbes, Cori disease phenotype
-moderate hepatic involvement, but possible more prominent muscle involvement
+muscle weakness, progressive CM (HCM earlier in life)
+hepatomegaly able to be reduced because gluconeogenesis is functional
-can have severe hypoglycemia (not type I level)
-lactic acidemia
-sometimes hyperlipidemia or hyperuricemia
GSD III genetics
glycogen debrancher enzyme deficiency
GSD VI+ genetics
-deficiency of hepatic phosphorylase and those that activate phosphorylase
+Type IX for example is an X-linked kinase deficiency with mild hypoglycemia
GSD IV/Andersen phenotype
- liver damage, cirrhosis, hepatospleno and progressive failure
- FTT
- myopathy and cardiomyopathy-tends to become most severe symptom
GSD IV genetics
disorder of glycogen synthesis due to deficiency of the glycogen brancher enzyme
+synthesize straight chain that liver can’t handle
+build-up of amylopectin
GSD 0 genetics
- glycogen synthase deficiency
- no glycogen present in liver or muscles
GSD 0 phenotype
-very rare
evaluation for neuromuscular IEMs
-age of presentation and staticness
+if later onset or regression more indicative
-ethnicity
-hyperaccusis presence
-lethargy or lack of attentiveness with potential seizures
hyperaccusis
startle reflex with loud noises
PE for neuromuscular IEMS
-eye functions
+abnormal movements-loss of acuity and roaming
+abnormal findings-ex: cherry red spot
-organomegaly
-muscle weakness, stiffness, exercise intolerance
neuromuscular IEMs labs
-most routine lab work normal
-lactate levels-elevated lactic acids in mito
-CK levels elevated related to muscle damage
-MRI
+changes in white matter identify CNS involvement
-muscle biopsy
-enzyme and gene assays for formally pinpointing diagnosis
neuromuscular IEM etiology
muscle weakness primarily due to brain involvement and CNS dysfunction, muscles are normal
- no hepatosplenomegaly
- often see eye involvement because its neuronal tissue
cherry red spot
eye anomaly due to neuronal tissue damage, causing retinal paleness
muscular IEMs etiology
defects of muscle metabolism without brain involvement
- see DD due to muscle weakness
- weakness and pain, stiffness with exercise
myoglobinuria
serious condition that can lead to kidney failure and is a sign of muscle breakdown
-causes pink urine
Tay-Sachs phenotype
-typical infantile presentation
+regression, seizures, myoclonic jerks, exaggerated startle-no organomegaly except for possible macrocephaly (cerebral gliosis) development
+retinal cherry red spot, vision deterioration to blindness
+see rapid decline of previously healthy child after 6mo
+respiratory failure, can see aspiration leading up to this
-later onset forms present with muscle weakness and gait anomalies (think SMA or ALS)
+can also see psychiatric symptoms (40%), cerebellar atrophy and abnormal eye movements
Tay-Sachs testing
-carrier screening began in 1970s
-enzyme activity assay on blood serum or leukocytes
+serum not accurate for women on OCPs or pregnant
+beware pseudo deficiency (35% non-AJ & 2% AJ not true carriers)
-gene testing
+targeted panels with varying sensitivity
+full gene sequencing 99% sensitive
Krabbe phenotype
infantile onset of muscle stiffness, less weakness
- opisthotonic posturing with leg scissoring common
- irritability and crying without cause
- startle reaction/hypersensitivity
- absence of organomegaly or eye problems
- can develop vomiting and seizures, until plateau transitions to burn out when nerves are too damaged, then kids have blindness, decerebration and absence of voluntary movement
- typically see death within 18mo
opisthotonic posturing
common in Krabbe where children throw head back with an arched back or arched shoulders due to stiffness
Krabbe disease treatment and screening
-enzyme testing on some NBS tests (0-5% GALC activity diagnostic)
-GT should be sequencing and del/dup
+30kb del accounts for 45% of mutant alleles in infantile form
+c.857G>A seen in late onset
-BMT only possible treatment, but see poor results after symptoms begin
GSD II/Pompe genetics
LSD causes muscle lysosome accumulation of glycogen due to deficiency of alpha-glucosidase/maltase
- incidence of infantile 1 in 138000, incidence of LO 1 in 57000
- pseudodeficiency allele common in some populations
GSD II/Pompe phenotype
Infantile-typically death within 1y -hypotonia shortly after birth -cardiomegaly, ECG anomalies \+short PR interval -muscle breakdown \+high blood CK -progressively fatal heart (CARDIOMEGALY) and respiratory failure -no hypoglycemia or hepatomegaly -can see some later onset forms with progressive weakness, respiratory failure and later onset myopathy
GSD II diagnosis and treatment
-sometimes people may need heart transplants
-ERT available using M-6-P tag
+most success seen if provided prior to ventilation-but doesn’t mean certain survival
+crm- patients can create antibodies that cause recurrence
-sequencing more diagnostic? due to pseudodeficiency
GSD V/McArdle genetics
muscle (myo)phosphorylase deficiency
GSD V/McArdle phenotype
-mostly normal but signs of muscle breakdown (rhabdomyolysis)
+exercise intolerance with pain and cramping, myoglobinuria and high CK
+no hepatomegaly, but kidney disease due to myoglobin levels
-recommend reduced exercise and sometimes high carb diet
VLCAD phenotype
- present with muscle weakness and cardiomegaly/cardiomyopathy
- can sometimes begin in newborn period
- may also have fasting intolerance
- develop secondary renal disease
VLCAD labs
-lipid myopathy seen on muscle biopsy
-acylcarnitine and blood carnitine levels abnormal
+purpose of carnitine is to transport these, so levels can be high due to deficiency
VLCAD treatment
can sometimes see improvement with medium chain triglyceride supplementation
genetic hypoglycemia
- GSDs-inability to release produced glucose
- FAODs-dont have supplies to create energy
- disorders of gluconeogenesis-units of energy cannot be made or transported
- CAH-cortisol deficiency causes decreased ability to put resources towards glucose transport
evaluation for fasting intolerance
- prodrome
- time length of fast that caused symptoms
- presence of lethargy or vomiting
- PE for hepatomegaly or muscle weakness
fasting intolerance IEMs signs
- onset after newborn period
- lethargy and possible vomiting due to fasting and byproduct buildup
- can see hepatomegaly due to products buildup, namely fats
- lactic acidemia (esp GSDs and gluconeogenesis disorders)
- hypoketosis (FAOD defects reduce blood and urine ketones)
fasting intolerance IEMs labs
-anion gap measurement \+lactic acidosis can increase difference -lactic acid level measurement -additional blood chemistries \+can see high uric acid and triglycerides -blood and urine ketones \+low if FAOD -urine OAs -acylcarnitine and carnitine profiles
FAODs genetics
-acetyl-CoA produced by this cycle which is an energy source needed to produce glucose during periods of fasting
gluconeogenesis disorder genetics
- failure of glucose to be produced from amino acid skeletons due to deficiency of F-6-BPase or 1,6BPase and pyruvate carboxylase
- rarely diagnosed
gluconeogenesis disorder presentation
- association with severe lactic academia because acid can’t be recycled
- severe hypoglycemia post-fast
- sometimes hepatomegaly due to fat buildup
- no OA abnormalities
GSD I management
-frequent feedings with cornstarch supplementation q6h
+can need overnight N-G or G-tube feedings
-behavior problems due to challenges with eating schedule
-late onset problems such as liver adenomas or hepatomas that can become cancerous, glomerulosclerosis, IBS due to neutropenia in type B
GSD VI+ presentation
- hepatomegaly
- fasting hypoglycemia
- mild lactic academia and/or hyperlipidemia
MCAD presentation
-most common FAOD, often picked up by NBS
+previously thought to be associated with SIDS (18% death is first symptom)
-normal except when fasting-have hypoketotic hypoglycemia
+can require hospitalization during illness, as coma can occur
-hyperammonemia that leads to liver disease
-lethargy, coma and hypotonia due to neurologic problems
VLCAD presentation
-long chain fatty acid disorder
-may have muscle and cardiac involvement due to loss of fuel source
+CM
-can have exercise intolerance and skeletal muscle involvement
-hypoketotic hypoglycemia
LCHAD presentation
- “trifunctional enzyme deficiency”
- hypoketotic hypoglycemia-but can develop without fasting
- cardiomyopathy or cardiac malfunction
- retinal findings or retinopathy
- female heterozygotes (carrying affected pregnancy) can develop HELLP and have fatty liver during pregnancy
NBS rationale
test all infants for treatable conditions and provide treatments to the symptoms before they become harmful and irreversible
NBS goal
improving outcomes of treatment and prevention
NBS principles
-reliable
-inexpensive
-reasonable confirmatory testing
-tests for treatable disorder
-early treatment improves outcome beyond waiting for symptom development
-reasonable disease frequency
+higher PPV of test
hypothyroidism
-incidence of 1 in 3000
-most common condition picked up by NBS, but not an IEM
+see elevated TSH that requires follow-up by endo to determine specific issue
-mostly due to hypo- or aplasia of thyroid, though can be due to pituitary insufficiency
-symptoms can cause lethargy, poor feeding and growth, DD, hoarse cry
-treat with growth hormone
PKU NBS
-originally Guthrie bacterial assay measured serum phenylalanine levels-now replaced by chemical methods
-measures Phe levels (>4mg% called positive)
+only 5% of positives are true positives
classical PKU genetics
-incidence of 1/32000, 1/12000 Caucasians
+milder variants half as common-still need treatment
-levels of Phe >10mg% need treatment, classic type is >20mg%
-PAH deficiency
+greater than 200 known mutations
-tetrahydrobiopterin (BH4) cofactor
problems with assay NBS
-measures substrate or protein in blood, which may be age or diet dependent
+ex: Hb ratios, amount of Phe
-not all conditions have enzyme or substrates measurable by this technique
-not a diagnostic test
+risk for false positives
DNA-based NBS
-allows for detection of a wider range of conditions
+does not require specific enzyme or substrate analysis from sample
-diagnostic for tested mutations
+but this is expensive
+misses mutations not targeted
-now often a reflex to abnormal results-stepwise
+ex: look for elevated trypsinogen related to CF, then test for common mutations
DNA-based CF NBS
-5 mutation test identifies 85% of mutant genes
+varies by ethnic group
+of affected 72% patients homozygotes, 26% heterozygotes, 2% completely missed by this method
-have either a large number of false positives or false negatives
-should be followed up by diagnostic sweat chloride
recommended core NBS panel
-34 conditions \+9 organic acidemias \+5 FAODs \+6 AAopathies \+2 endocrine conditions \+3 Hb-opathies \+9 others-hearing SCID, CF
classic PKU phenotype
-asymptomatic until a few months of life
-strange odor, can also see fair pigmentation
-non-reversible (sometimes mitigated) ID, DD, seizures, aggressive behavior if untreated
+treatment should begin in first week of life
tetrahydrobiopterin deficiencies
- much rarer than PKU, but cause similar defects
- require supplementation, rather than just special diet
- identified by low levels in urine
maternal PKU effects
high phenylalanine can be vertically transmitted and is teratogenic
- microcephaly, ID
- CHDs
- skeletal anomalies
- levels should be well controlled prior to conception and during pregnancy due to level and outcome correlation
Duarte galactosemia variant
-mutation of GALT/GalPut locus that causes low enzymatic activity
+N314D allele
-5% population frequency
+picked up by NBS, but does not require diet
MCAD genetics
- incidence of 1/6500-1/17000
- defective medium chain acyl-CoA dehydrogenase
- A985G (K304E) variant accounts for >90% cases of affected Caucasian individuals
MCAD testing
-acylcarnitine profile shows elevated C8 acylcarnitine regardless of diet or fasting status
-urine OAs
+suberic and sebacic MC dicarboxylic acids and hexanoglycine are elevated
-can sometimes get positive NBS for low activity variants, so need to due further investigation
modes of IEM therapy
- provide deficient product
- block toxic effects
- activate enzymatic activity with cofactor supplementation
- dietary substrate restriction
- alternative pathway therapy
- transplantation
- enzyme and gene RT
tyrosinemia type 1 treatment
-orfadin to block metabolism of this product, accumulation of toxic substance
+if this not used would require liver transplant
-limit protein in diet
+reduce phenylalanine and tyrosine
tyrosinemia type 1 genetics
-deficiency in breakdown of tyrosine
-fumerylacetoacetate hyrdrolase (FAH) fails to cleave product into 2 and causes buildup of maleylacetoacetate
+succinylaccetone buildup causes toxicity
tyrosinemia type 1 phenotype
- liver failure
- hepatocellular carcinoma
- renal Fanconi’s-failed reabsorption
- porphyria-like neurological crises
- can have rotten-egg smell
vitamin and cofactor therapy
-can activate residual activity
+sometimes poor cofactor binding occurs
-may overcome activation defects
methylmalonic acidemia treatment
-B12 supplementation
+especially useful with cobalamin defects
-liver and kidney transplant
alternative pathway treatment
-uses existing pathways to augment excretion of toxic metabolites as non-toxic compounds
+may use endogenous compounds or exogenous drugs
hyperphe
- residual PAH activity results in AA level above normal
- can have a variable phenotype with variable levels and can require anywhere from new treatment, to slight diet restriction to full blown formula supplementation
homocystinuria treatment
- dietary restriction of methionine
- addition of B6 and B12 to diet
- prescribe betaine/cystadane to force excretion of product as methionine
hyperhomocysteinemia
- mild elevation of homocysteine with unclear cause
- predisposition to CAD
- recommended monitoring and treatment with folate, B6, B12
tyrosinemia type 2 genetics
deficiency of tyrosine aminotransferase deficiency
tyrosinemia type 2 phenotype
corneal, palmar, solar lesions/crystallizations
chronic intermittent MMA and PA
may present later with acute encephalopathy, episodic ketoacidosis, DD, recurrent vomiting and FTT
long term untreated PA
- severe ID
- hypotonia
- recurrent life-threatening metabolic decompensation
- end organ failure (especially fatal if cardiomyopathy occurs)
long term untreated MMA
- normal intellect to mild ID
- recurrent metabolic decompensation
- end organ failure
PA and MMA treatment
- low protein diet with substrate restriction
- antibiotics to reduce gut bacterial PA production
- biotin or hydroxy B12 cofactor supplementation
- elimination of toxic buildup via carnitine
- provide bicitra for acid-base stabilization
Cbl C disease
- methylmalonic acidemia+homocystinuria
- causes ID, seizures, nystagmus, cardiac abnormalities, abnormal dentition
isovaleric acidemia treatment
- low protein diet restricting leucine intake
- excretion of harmful substrates via carnitine and glycine pathways
- provide bicitra for acid-base stabilization
3-MCC
-most common OA, but mostly asymptomatic
+possible deterioration from illnesses
-part of leucine catabolism pathway
-symptomatic individuals may have ketoacidosis, vomiting, hypoglycemia
-treatment includes protein restriction, biotin supplementation and excretion via carnitine
hyperammonemic encephalopathy
usually occurs in urea cycle defects despite therapy
-intercurrent infection, fasting, protein loads and surgery can all be triggers
arginosuccinate lyase deficiency
affected individuals tend to have coarse hair and cirrhotic changes
heparan sulfate
GAG present in all cells
-if degradation affected in MPS can see cognitive effects
keratan sulfate
GAG in corneal and collagenous tissues
dermatan sulfate
GAG in skin and blood vessels
MPS treatment
-some have available ERTs-can help with hepatosplenomegaly
-BMT-risky and must be completed in early infancy
+only way to treat cognitive symptoms
-surgeries, PT, OT to treat manifestations
-continued research as well
Hurler phenotype
-normal at birth, then rapid progression within first 2y life
+coarsening of facial features including thick, coarse hair growth, lip thickening, enlargement of tongue and adenoids and nasal bridge flattening
-hepatosplenomegaly, cardiac disease
-skeletal anomalies-kyphosis, hip dysplasia, thickened ribs
-hydrocelphalus, corneal clouding
-DD by 18mo, then plateau and decline occur
-death by age 8-10y
Hurler-Scheie
-normal at birth with symptom onset between 3-10y
+symptom progression variable and can sometimes shorten lifespan-less coarse features, varying hepatospleno, mostly normal intellect
-corneal clouding, cardiac involvement, hearing loss common
-can also often see hernias and severe skeletal anomalies
MPS IX/Natowicz
- AR, 1 known case in world, hyaluronidase deficiency
- short stature
- soft tissue masses that swell with fever
- mildly dysmorphic features
2 null HEXA alleles
gives infantile Tay Sachs (ex: c.1274_1277dupTATC, c.1421+1G>C, c.1073+1G>A)
1 null + 1 late onset HEXA allele
causes late onset Tay Sachs
2 late onset HEXA alleles
causes late onset Tay Sachs (ex: p.G269S, p. G250D)
NPD A and B genetics
-due to acid sphingomyelinase deficiency (SMPD1) \+A: neuronopathic \+B: non-neuronopathic -incidence: 1 in 250000 \+AJ and NA founder mutations
NPD A phenotype
- hepatosplenomegaly by 3mo
- developmental plateau 9-12mo age before regression and progressive hypotonia
- interstitial lung disease
- cherry red spot
- death by age 3y
NPD B phenotype
similar features to A without neurological decline
NPD C
- due to improper transport of cholesterol into lysosome
- can range in severity and cause white matter disease, which can lead to death in teens
NPD A and B testing
-enzymatic analysis
+ <10% ASM enzymatic activity by blood serum or leukocytes diagnostic
-GT
+90% sensitivity for founder panel (90% A cases are from 3 AJ muts, 90% B cases from Mahgreb NA-in these populations)
metachromatic leukodystrophy genetics
- incidence of 1 in 40000-160000
- AR caused by mutation of ARSA
- common alleles responsible for majority of mutations where some gene-phen corr exists with age of onset
late infantile MLD phenotype
- onset between 1-2y
- early development is normal, though children are “clumsy”
- nerves atrophy and cognitive decline begins
- speech difficulties develop and hypotonia transforms into increased muscle tone
- seizures, vision & hearing loss can also occur
- death usually by age 4-most kids surviving better with care
infantile MLD testing
-enzyme analysis
+<10% ARSA activity (note: pseudo deficiency can artificially lower activity so requires multi-step workup)
-urine analysis shows high levels of sulfatides
-genetic testing via targeted panels & gene sequencing
long term GSD Ia complications
- liver adenocarcinoma progress from adenomas
- renal disease
- osteopenia/bone thinning
- delayed puberty
- short stature
GSD Ib phenotype
-similar to type A with doll like facies and high levels of cholesterol, lactic acid, uric acid and associated complications
-more prone to infections and inflammation
+IBD, low WBC/neutropenia with bacterial infections
hereditary fructosuria
- frucaldolase B deficiency
- causes severe hypoglycemia and vomiting with fructose intake
- removing fructose from diet reverses liver disease and liver failure that can cause death
F-1,6-BPase deficiency
- causes severe lactic acidosis with hypoglycemia and ketosis
- can be rapidly lethal
- defect of gluconeogenesis
carb deficient glycoproteinoses genetics
-incorrect synthesis of oligosaccharides in glycoproteins and glycolipids
-100 types classified
+N (more common) and O types defined by attachment
carb deficient glycoproteinoses phenotype
- present in infancy with some types being lethal
- neurological abnormalities (hyporeflexia, nystagmus, seizures) and DD
- multiorgan dysfunction-heart disease, liver and/or kidney problems, protein losing enteropathy of GI
- hypoglycemia
- skin abnormalities (peau d’orange)
- with 1a get dysmorphism
SCAD genetics and phenotype
- common NBS referral due to asymptomatic variant but common AJ (319C>T) and non (625G>A) exists
- muscular symptoms-myopathy, CM
- DD
carnitine disorders
- 4 types that cause failure of LCFAs to be transported across mitochondrial membrane
- present with hypoglycemia and muscle weakness with rhabdomyolysis that lead to CM and exercise intolerance
- treated with levocarnitine, and avoidance of fasting with a low fat diet
Zellweger syndrome phenotype
- severe infantile presentation that causes death within the first year-sz and ID if survive past this
- severe neonatal hypotonia and GR
- dysmorphic features: tall boxy forehead due to skull abnormalities with large anterior fontanelle, profile hypoplasia
- shallow orbits, down slanting and narrow PFs
- brain development defects-“dumpy” neurons
- congenital cataracts
- hepatomegaly and cirrhosis with cystic kidneys
- contractures and epiphyseal stippling on X-ray
Zellweger genetics and diagnosis
-causes absence of peroxisomes leading to impaired plasmologen synthesis
+mutations of PEX genes
-elevated VLCFAs in fasting plasma is main indicator
-incidence of 1 in 25000-1 in 100000
X-linked ALD genetics and diagnosis
*most common peroxisomal disorder
-due to defects in ABCD1, peroxisomal ALDP transporter membrane protein
-elevated VLCFAs in all tissues (C26, C24)
+low cortisol, high ACTH with AIS
-7 subtypes
-part of NBS by biochemical measurements
+4.1-19% de novo rate skewed by NBS
-ABCD1 gene sequencing
+if VUS or negative, send plasmologen
XLALD phenotype
-variation occurs even within one family creating counseling and prognostic prediction challenges
-mean onset age at 7y with behavioral difficulties, emotional lability and school difficulties, can also see dementia, cerebellar ataxia, deafness, paralysis in cerebral type (4-8y) and spastic paresis, sensory ataxia, impotence, sphincter dysfunction and hair loss in myeloneuropathic type (20s, middle age)
-can see white matter changes on MRI that move from back to front and inflammation of lymphocytes
+progression becomes fatal within 2y of this manifestation
-development of PAD can cause fatigue, extreme weight loss, abdominal pain and hyper pigmentation (bronzing)
-80% carriers with neurologic symptoms by 60y and not <20y, can see mild myeloneuropathic features and very rare adrenal insufficiency
XLALD treatment and monitoring
-BMT by autologous retroviral method
-gene therapy trials-cosyntropin
-neurology screening to look for white matter changes and suggest timing of BMT (Loes score >3)
-serum ACTH & cortisol level measurements-challenging in infants due to irregular circadian rhythm
+hydrocortisone injections if AI
-monitoring growth, especially if being prescribed hydrocortisone & for iatrogenic Cushing (DM, HTN)
Refsum disease
-AR deficiency of phytanoyl-coenzyme A hydroxylase deficiency
-typical onset in early adulthood
-features: RP, peripheral neuropathy with demyelination, cerebellar ataxia, deafness, skin changes, shortened 4th toe
+infantile presents like Zellweger
-treatment: low phytanic acid/phytol diet (limit dairy, lamb, veal, beef) and plasmapheresis
rhizomelic chondrodysplasia punctata
- failed import of some peroxisomal proteins
- causes abnormal facies, skin lesions and severe proximal limb shortening
neonatal ALD
- presents like Zellweger
- adrenal disease without renal disease
- AR
Gaucher diagnosis and treatment
- measure leukocyte GBA (beta-glucosidase) activity (up to 15% activity)
- be aware of pseudogene detection (0% activity) this way
- genetic testing to help clarify if real diagnosis and geno-pheno correlation
- responds well to ERT, can also give Miglustat (SRT)
- monitoring of blood counts, coagulation, iron and lipids, growth, spinal and bone density, MRI of liver, spleen, bones, biomarker analysis
Fabry genetics
-X-linked alpha-gal-A (A-GAL) mutations
+private mutations common
-accumulation of GL-3 (ceramide trihexidase) leads to organ dysfunction
-18% females with a severe manifestation/adverse event
Fabry phenotype
-acroparasthesia (severe distal pain in hands and feet)
-abdominal pain, diarrhea after eating that can lead to nausea vomiting and weight loss or malnutrition
-eye anomalies that do not impair vision: corneal whorls/rays, corneal and lenticular opacities
-heat sensitivity and hypohidrosis
-abdominal, inguinal and mucosal angiokeratomas that worsen over time
-cardiomegaly, CMs, conduction anomalies and valve anomalies with systolic dysfunction
-kidney disease
+ESRD can shorten lifespan
-risk for early stroke
Fabry diagnosis and treatment or management
- enzyme activity at least between 2-5% used to be gold standard, now mostly jump to GT
- slit-lamp exam to look for eye abnormalities
- cardiology and nephrology evaluations
- ERT, SDT in works, EET for residual activity mutations in Europe
biotinidase deficiency genetics and diagnosis
-AR biotinidase enzyme dysfunction \+serum and plasma show <10% activity \+incidence of 1 in 60000 -GT reveals balletic BTD mutations -mild to moderate urine ammonia, ketones, OAs -high blood acyl carnitines
biotinidase deficiency symptoms
- lethargy, hypotonia, seizures
- psychomotor deficits causing DD, ataxia
- alopecia, skin rashes
- vision problems
- metabolic ketoacidosis, organic aciduria, hyperammonemia
- SNHL
- increased immunological dysfunction risk
- partial deficiency (10-30%) causes symptoms only if triggered
biotinidase deficiency treatment
-exogenous biotin daily and avoidance of raw eggs
-annual hearing and vision evals plus genetics or metabolic consult
+may require DD intervention
Wilson’s disease genetics
-AR mutation of ATP7B and potential PRNP modifier cause copper buildup in body
+incidence of 1/30000
+Sardinian, Asian and European incidence as high as 1/10000 (1/90 carrier freq)
Wilson’s disease diagnosis and testing
-low serum ceruloplasmin, high serum copper because its not bound and the copper and free radicals are in blood \+sometimes need liver biopsy -high urine copper (bile copper absence) -brain MRI -slit-lamp exam -ATP7B gene sequencing
Wilson’s disease phenotype
- liver disease with acute hepatitis and cirrhosis, jaundice
- neurological manifestations cause movement disorders of basal ganglia and dementia, ID or psychiatric disorder related to neuronal toxicity in cerebral cortex
- Kayser-Flescher ring development later
- renal disease, CM and hemolytic anemia are rarer
Wilson’s disease treatment and management
- copper chelating agents and/or zinc and copper diet limitations (chocolate, mushrooms, shellfish, nuts, liver)
- biannual serum copper, ceruplasmin, liver biochemistries, INR, CBC, urinalysis, PE and neurological evals
- annual 24h urinary copper excretion
Menke’s disease genetics and diagnosis
-low serum copper and ceruloplasmin
-pili torti microscopically visualized
-XLR ATP7A gene mutations (1/100000)
+cause harmful copper to buildup in small intestine and kidney
+reduced enzymatic activity and transport to other tissues
*less severe version of condition is occipital horn syndrome
Menke’s disease phenotype
- onset between 6-8w and most with death by 3y
- FTT, hypotonia
- seizures, regression, DD
- brittle wooly-hair, sagging facial features
- low body temperature
- subdural hematomas
- bladder diverticula
- osteoporosis and fracturing
- Kayser-Fleischer rings
Menke’s disease management
- no cure
- pain and seizure meds
- feeding tubes and bladder surgeries
- PT/OT, orthotics
Antley-Bixler genetics and diagnosis
-low uE3 prenatally, high maternal urine steroids, may also see radiologic anomalies on ultrasound
-elevated 1-hydroxylase progesterone in serum
-urine steroid profile shows elevated pregnenediol, pregnanediol
-RARE AR mutation deficiency of cytochrome P450 Oxidoreductase (POR)-potentially under diagnosed
+GT can’t confirm 5.5% cases molecularly, sometimes only one mutation identified too
Antley-Bixler phenotype
-skeletal anomalies
+brachycephaly or trapezoidocephaly due to coronal and lambdoidal craniosynostosis-DD?
+radiohumeral synostosis and joint contractures, thigh bone bowing
+arachnodactly
-dysmorphic features-frontal bossing and midface hypoplasia, low-set ears
-GU anomalies
+ambiguous genitalia and external anomalies
+sometimes infertility, PCOS
-choanal atresia or stenosis cause breathing problems
-maternal visualization with affected pregnancies increases acne, hirsutism and causes nose and lip enlargement with voice deepening
Antley-Bixler treatment and management
- steroid replacement therapy for cortisol deficiencies, possible DHT or testosterone replacement for males and estrogen replacement for females
- genitalia, craniosynostosis, nasal surgeries
- PT, OT, EI
- very severe types may result in still birth
spectrum of POR deficiency
- milder phenotype can cause male and female infertility, primary amenorrhea, PCOS
- moderate causes ambiguous genitalia, infertility
- Antley-Bixler phenotype is most severe
Antley-Bixler Syndrome without steroidal deficiency
- caused by FGFR2 mutation
- only skeletal symptoms present
SLOS phenotype
- onset in newborn period but can see oligo, kidney agenesis and IUGR prenatally
- dysmorphic features: narrow forehead, epicanthal folds, ptosis, anteverted nares with short nose, low set ears, palatal clefting and short mandible
- microcephaly-ID and autism, behavioral problems, seizures
- bilateral 2-3 toe syndactyly
- poor feeding, FTT, hypotonia
- kidney, lung, GI and heart anomalies
- GU anomalies (hypospadias)
- sometimes cataracts
SLOS genetics and diagnosis
- high serum 7-DHC concentration
- low enzyme function
- AR so GT shows biallelic (often compound hets) DHRC7 mutation
- incidence of 1/20000-1/60000, higher incidence in central European populations (Czechoslovakia), rare in African and Asian pops
SLOS treatment and management
- supplementation with exogenous cholesterol
- limitation of psychotropic meds and sun exposure
- surgical repair of physical anomalies
- multidisciplinary care team (neuro, optho, cardio, nephro, gastroentro, ENT)
Lesch Nyhan phenotype
-neurological and behavioral abnormalities
+development of self-injurious behaviors
+dystonia, chorea and ballismus/limb flailing
+wheelchair bound with little head and body control
+DD, hypotonia
-uric acid accumulation
+orange urine crystals, sometimes see kidney and bladder stones later
+gouty arthritis in joints-can be seen in carriers too
-MRI anomalies
Lesch Nyhan genetics and diagnosis
-XLR mutation of HPRT1 (<1.5% enzyme activity)
+causes failed purine recycling leading to high levels of uric acid
+incidence of 1/380000
-high uric acid levels in blood and urine
-low levels of dopamine in brain
Lesch Nyhan management
-ST, PT, OT, EI
-allopurinol for uric acid levels
-urology and psychiatry referrals
+monitor for stones
+sometimes need protective equipment, restraints, or teeth removal to protect from self-injury
-neuro eval and meds to help control spasticity
Kelley-Seegmiller syndrome
production of <8% HPRT1 enzyme
AIP
- AD mutation of HBMS
- look for elevation of urine PBG and sometimes ALA; urine MUST be protected from light for accurate reading
- many affected patients show no symptoms, but more likely in women, as hormonal changes, diet changes, etc can trigger
- symptoms can include: abdominal pain, constipation, tachycardia, peripheral neuropathy, seizures and behavioral changes
- intravenous hematin helps control symptoms during attacks
