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133 Cards in this Set

  • Front
  • Back
Tyrosenemias I, II, III
I - most severe
II - “oculocutaneous” tyrosinemia because of corneal findings, photophobia, and keratoderma
III - variable from MR and ataxia to asymptomatic
Cherry red spot is ass'd with which diseases?
Sialidase deficiency
Niemann Pick A
GM1 gangliosidosis gangliosidosis
MPS I (Hurler vs. Scheie) vs. MPS II (Hunter)
Hurler dx <18mo, Scheie dx >5yo
Hunter/MPS II similar to Hurler/MPS I but XR (vs. AR)
Hunter - milder phenotype variable CNS disease
Hunter - no corneal clouding (vs. Hurler) - hunter needs to see clearly to use gun
Hurler and Scheie are alellic, Scheie mtn have residual activity
Scheie - normal lifespan and IQ (vs. Hurler death by 10yo)
Hunter - BMT less successful than Hurler
AA disorders
toxic buildup of substrate - intoxication phenotype
don't necessarily present after illness or fasting (vs. OA, FAO)
metabolic acidosis, mild ketotic hypoglycemia (vs. FAO - hypoketotic)
generally less severe than OAD, generally chronic and not acute
conditions: alkaptonuria, homocystinuria, nonketotic hyperglycinemia/glycine encephalopathy, PKU, tyrosinemia
OA disorders
excretion of excess organic acids in urine (OA is AA minus NH4)
intoxication phenotype when catabolic and therefore degrading AA
newborn presentation: lethargy, poor feed, vomit'g, abnl muscle tone, encephalopathy, seizures, coma, death, metabolic acidosis (primary, due to build up of OA), respiratory alkalosis (secondary, to get pH up), hyperammonemia (secondary, b/c OA interfere with UC), ketotic hypoglycemia (vs. FAO), neutropenia, elevated glycine (OA block glycine oxidation) - ketotic hyperglycinemia, liver fxn usually normal
conditions: IVA, MMA, PA, MMA with homocystinuria, GA, biotinidase deficiency, others
carbohydrate disorders
energy deficient phenotype (not intoxication phenotyp)
lethargy, hypoglycemia, dysfxn due to low energy - brain, liver, muscle (myopathy), heart (CM)
disorders: galactosemia, GSD
defect in beta oxidation of FA of different lengths
presents when energy demands are high and body is trying to use fats
lethargy, irritibality, encephalopathy
myopathy (muscle weakness, rhabdomyolysis) - esp. older onset and longer chains
hypoketotic hypoglycemia (vs. others) (except SCAD)
UOA - dicarboxylic acid
+/- ammonia b/c FA block UC
+/- low carnitine
abnl blood acylcarnitine, abnl urine acylglycines, abnl UOA
conditions: SCAD, MCAD (most common), VLCAD (most severe), LCHAD & TFP (like VLCAD)
LCHAD in fetus causes HELLP and acute fatty liver in pregnant mother
UC in liver, produces arginine, ammonia -> urea for excretion
glycine and benzoate can be used to form hippurate with ammonia for alternate excretion
newborn presentation - intoxication phenotype
severe - hours to days after birth
mild - even adult onset, protein avoidance
lethargy, vomiting, poor feeding, FTT
cerebral edema (b/c ammonia builds up)
stupor, tremor, seizures
coma, death
(v.) hyperammonemia
low plasma urea
respiratory alkalosis (primary, due to tachypnea due to ammonia - vs. secondary in OA, AA)
conditions: OTC, carbamyl phosphate synthetase deficiency, arginase deficiency, N-acetylglutamate synthetase deficiency
tx: protein restriction, meet arginine requirements, augment alternate pathways for NH4 excretion
plasma >150mmol/L, normal anion gap, normal serum glucose, use plasma AA to identify which conditoin
storage of substrate in lysosome
distention of cell, disruption of cellular functions finally storage in tissues
coarse* facies
developmental regression**, MR
conditions: fabry, gaucher, MPS I, II, Pompe
biochemical/metabolic disorders that can be associated with congenital malformations and/or dysmorphic features due to prenatal onset?
-disorders of glycosylation (esp. type 1)
-mtDNA (severe forms - brain malforamtions, ex. absence of corpus callosum
-FAOD - CPTII deficiency ass'd with dysmorphic features, malformations
-peroxismal disorders - zellweger has dysmorphic features and organ malformations
Ammonia levels in:
OAD - high (secondary to inhibition of UC by OA)
UCD - v. high, highest of all metabolic disorders
mitochondrial - can be high b/c first part of UC is in mitoch. and abnromal enviroment can interfere
FAO - high because FA block UC
LSD - normal!!
Trichorrhexis nodosa (or “kinky hair”) is assocaited with what two diseases?
Argininosuccinic aciduria
what is the toxic compound in MSUD?
XL metabolic disorders?
G6PD deficiency
PDHC E1 alpha (mitochondrial)
Barth syndrme
3-MCC - defect in leucine met'm
AD metabolic disorders?
familial mediteranean fever
forms of Kearns-Sayre syndrome caused by nuclear mutations that lead to mtDNA deletions
Which UCD is not ass'd with high ammonia?
arginase deficiency.
Which urea cycle defect can be associated with progressive liver disease?
Argininosuccinic acid lyase deficiency
Which FAOD is most often linked with fatty liver of pregnancy?
general inheritance of each of these mitochondrial DNA mutations:
point - usually inherited
deletion - usually sporadic
duplication - usually inherited
beware the del/dup combo
protein synthesis for all mtDNA-encoded polypeptides is defective in which conditions?
A8344G, MERRF mutation in tRNAlys
7kb deletion in the greater arc
markers for possible mitochondrial disease?
-dicarboxylic acids (ethylmalonate and glutarate)
-generalized organic aciduria (not one specific)
-elevated 3-methylglutaconate
-plasma carnitines - need for carnitine supplementation?
-lactat in CSF in children with prominent neurological disease
-tissue biopsy - findings are suggestive, but can be non-specific; fiber size variation, mitochondrial proliferaiton, bizarre mitoch shape, ragged red fibers are rarely foudn in children, enzyme testing on tissue can sometimes identify the deficiency,
is prenatal testing available for mitochondrial disease?
no, not for the majority of cases
what are the most common presentations of mtDNA depletion syndrome?
liver failure
(infantile onset and encephalopathy are common)
cardinal features of Leigh disease?
respiratory dysfunction
cranial nerve abnormalities
hyperintense signals on MRI
mitochondrial dietary management?
preventing fasting-related symptoms
shunting more electrons via complex I or II
small, frequent, low-fat meals for GI motility issus
features of mitochondrial disease
-energy deficient state
-neuromuscular or multi-system disease
-lactic acidosis
-abnormal findings on UOA and muscle biopsy
most subunits of the electron transport train are both nuclear-encoded and mtDNA-encoded, which one isn't?
all subunits of complex 2 are nuclear-encoded (only, no mtDNA).
what is the inheritance pattern for conditions that lead to multiple mtDNA deletions (and are a rare cause of KSS)?
AR or AD
pyruvate dehydrogenase complex
-PDHC E1 alpha is most common
-birth defects
-congenital 'overhwehelming' lactic acidosis
-carbohydrate induced episodic ataxia
-cystic brain lesions
pyruvate carboxylase
mitochondrial disorder
similar to PDHC deficiency
-severe lactic acidosis
-high ammonia
-high citrulline
-high lysine
which tissues use FAO at all times?
muscle (skeletal and cariac) and liver
what shuttles long chain fatty acids across the mitochondrial inner membrane?
carnitine. disorders of any of the 4 proteins in the carnitine cycle mimic long chain FAOD (i.e. skeletal myopathy, CM and/or fasting intolerance)

conditions: carnitne uptake deficinecy (defect of plasma membrane carnitine transporter), CPT I, CPT II
role of molecular analysis in mitochondrial disease?
mutation remains unknown in most cases (also means that prenatal testing isn't an option).

cases with known mutations are generally mtDNA mutations (b/c genome is smaller), while nuclear-encoded diseases tend to not have identified mutations.
prenatal testing for electron transport genes?
molecular - if nuclear-encoded mtn is known (ex. SURF1)

mtDNA - often not available prenatally, also genotype doesn't predict phenotype well b/c of heteroplasmy, so low utility.

enzyme and/or metabolic testing is available for some disorders
what is involved in mitochondrial disorder treatment?
individualized, may include:
-avoidance of catabolism
-dietary manipulations - frequent feeding, low fat, high fat...
-carnitine supplementation
-v. high doses of vitamins - riboflavin (-> flavin, which is a component of ETC compelxes), coenzyme Q10 (shuttles electrons within ETC)
-creatine - increase strength and bulk (high-energy store in muscle)
-supportive therapy
mtDNA mutation rate compared to nuclear DNA?
mtDNA has a 10-fold higher mtn rate
b/c of exposures to high concentratin of oxygen free radicals from ox phos, lack of protective histones, ineffective DNA repair
no introns so random mutaitons usually affect dcoding sequences
b/c of mtn rate, mitochondrial efficiency declines through adulthood - contributes to aging and to age-dependent penetrance/severity of mitochondrial disease
what odor is associated with untreated PKU?
"mousy" odor (ACMG), musty, sweet (esp. ear wax)
what odor is associated with IVA?
sweaty feet
what odor is associated with untreated MSUD?
maple syrup in the urine! clearly.
peroxisomes are...
bound by a single (not double) membrane
many peroxismal proteins show minimal posttranslational processing
ubiquitous in mammalian cells except RBC
several hundred/cell
some steps of bile acid metabolism occur here
(ACMG q'n)
what is the typical presentation of type 1a glycogen storage disease (aka glucose-6-phosphatase deficiency, von Gierke)
a 6 month old with hepatomegaly, renomegaly, hypoglycemia and lactic acidosis

also - doll like facies, thin extremities, short stature
what is the enzyme defect in Gaucher?
alpha - glucosidase
what common mutation for Gaucher is ass'd with the nonneuropnopathic phenotype?
N370S (1226G)
what are the ranges for phe levels?
normal: 30-90umol/L (i.e. uM);
benign hyper: 120-600:
hyper: 600-100;
abnormal >1000-1200 (>20mg%)

therapeutic target range
-<12yo 2-6mg%
->12yo 2-10mg%
-preconcept/pregnant: <6mg%
what are some causes of false positives for PKU on NBS?
blood spot too thick
sample improperly prepared
liver immaturity
protein overload (newborns fed cow's milk)
heterozygosity for PAH deficiency in premature babies
a combo of any of these

also, testing shouldn't be done until >24hr old b/c it takes that long for phe concentrations to manifest
NBS for galactosemia
*what is tested?
*results for G/G, G/N, D?
*sensitivity ~100%
*tested: GALT (galactose-1-phosphate uridyltransferase) enzyme activity and total RBC galactose-1 phosphate conc and galactose
*2nd tier: molecular GALT testing
*enzyme activity:
-classic: G/G <5%
-het G/N 50%
-G/D - may have positive NBS
*galactose-1-phosphate conc (substrate of GALT, so builds up)
-classic: 2-5mg/dL despite therapy
which metabolic disorders are well treated by BMT?
x-linked adrenoleukodystrophy
adenosine deaminase deficiency
Gaucher type 3

NOT - sanfilippo, hunter
key issues in Tay-Sachs carrier testing?
-serum hexA enzyme analsysi is not accurate during pregnancy (must do WBC hexA)
-molecular testing is not helpful in non-AJ as most mutations won't be detected
What conditions involve defects in cholesterol biosynthesis?
mevalonic aciduria (mevalonate kinase, early step in chol biosynth)
hyper IgD syndrome (mevalonate kinase, early step in chol biosynth)
CHILD syndrome
what disorders are assocaited with an elevated plasma tyrosine?
liver disease
inborn errors of tyrosine catabolism
-tyrosinemia type I (hepatorenal)
-tyrosinemia type II (oculocutaneous)
-4HPPD deficiency
-NTBC tx
are cataracts typically seen in mitochondrial disease?
Which metabolic diseases have ERT clinically available?
MPS-1 (Hurler, Scheie)
MPS-2 (Hunter)
Pycnodysostosis, a skeletal dysplasia, is caused by mutations in
Cathepsin K, a lysosomal enzyme

actually a LSD

what metabolic disorders have a risk for malignancy?
GSD type 1 (liver ca)
tyrosinemia (liver ca)
immunodeficiency disorders
DNA repair disorders
neonatal hypotonia, seizures, apnea, and hiccups are features of?
nonketotic hyperglycinemia
features of disorders of creatine synthesis or transport include?
reduced creatinine excretion
severely delayed language dev't
abnl brain MR spectroscopy - decreased creatine
genetics - 2 AR, 1 XR (CRT transporter)
treatment - creatine supplementation
B53. A lysosomal storage disease that does not involve the central nervous system is:
A. Hunter syndrome
B. Type I Gaucher disease
C. Niemann-Pick A
D. Tay-Sachs disease
E. Krabbe disease
type 1 gaucher disease
B54. A lysosomal storage disease in which hepatosplenomegaly is not prominent is:
A. Hurler disease
B. Pompe disease
C. Mannosidosis
D. Wolman disease
E. Tay-Sachs disease
Tay-Sachs (vs. other storage disorders)
clinical features of congenital defect in glycosylation?
very broad clinical spectrum: CNS, eye, skeletal, clotting, immune system, more
inverted nipples
progressive liver disease
abnormal deposition of subcutaneous fat
bleeding diathesis
MR; ataxia; RP
testing: transferrin isoelectric focusing
most commonly recognized CDG: CDG-1a - phosphomannomutase 2 deficiency
Where do very long branch-chain fatty acids undergo beta-oxidation?
in peroxisomes
what is the differential dx for a newborn with poor feeding, vomiting and lethargy?
cardiac defect
CNS catastrophe
GI obstruction
metabolic defect
what features of acute metabolic distress in infancy increase suspicion it's a metabolic defect?
fhx neonatal deaths
initially normal
poor feeding -> vomiting -> lethargy -> coma
peculiar odor
disturbed acid/base status - metabolic acidosis, respiratory alkalosis
differential diagnosis - hyerpammonemic newborn
lethargic, NH4 >50uM
preterm? --> THAN (transient hyperammonemia of the newborn)

full term? --> inborn error -->
-pyruvate dehydrogenase deficiency
-electron transport defects
differential diagnosis - hyerpammonemic newborn
lethargic, NH4 >50uM
with acidosis (+/- ketonuria) --> OAD

without acidosis (+/- ketonuria) --> UCD
-which UCD? - check plasma citrulline
---high (>1000uM) - ASD
---100-300 uM - ALD
---low (<10uM)
-------low urine orotic acid - CPSD
-------high urine orotic acid - OTCD
what is the preferred substrate for cardiac and skeletal muscle?
long chain fats - hence myopathy and cardiomyopathy in LCHAD and VLCAD but not shorter FAOD.
what does liver oxidize FA to?
ketone bodies
-provide energy for gluconeogenesis, ureagenesis
-used as fuel in CNS
differential diagnosis - hyerpammonemic newborn
lethargic, NH4 >50uM
preterm? --> THAN (transient hyperammonemia of the newborn)

full term? --> inborn error -->
-pyruvate dehydrogenase deficiency
-electron transport defects
differential diagnosis - hyerpammonemic newborn
lethargic, NH4 >50uM
with acidosis (+/- ketonuria) --> OAD

without acidosis (+/- ketonuria) --> UCD
-which UCD? - check plasma citrulline
---high (>1000uM) - ASD
---100-300 uM - ALD
---low (<10uM)
-------low urine orotic acid - CPSD
-------high urine orotic acid - OTCD
what is the preferred substrate for cardiac and skeletal muscle?
long chain fats - hence myopathy and cardiomyopathy in LCHAD and VLCAD but not shorter FAOD.
what does liver oxidize FA to?
ketone bodies
-provide energy for gluconeogenesis, ureagenesis
-used as fuel in CNS
MSUD (maple syrup urine disease)
AR deficiency of BCKD
symptoms - poor feeding, vomiting, lethargy, coma, seizures
characteristic odor
second step in breakdown of branched chain amino acids
Dx - Paa - increased lue, ile, val, alloisoleucine; decreased ala
Uoa - increased branch chain keto acids
tx - acute: restrict branch chain aa, may require hemofiltration
-chronic: dietary restriction of branch chain aa, avoid deficiency of ile of val
valine, odd chain FA, methionine, isoleucine, threonine

restrict in PA, MMA
complications of MMA and PA?
basal ganglia infarcts ('metabolic strokes')
bone marrow suppression
progressive renal disease
biotinidase deficiency
deficiency of biotinidase
affects functioning of multiple enzymes
symptoms - gradual, remitting onset; hypotonia; seizures; rash and alopecia; MR and hearing loss in late diagnosed pt
dx - reduced biotin in plasma and urine
-uoa: 3-oh-isovaleric acid
tx: oral biotin (10-100mg/day)
-symptoms: PFVLCSz, tachypnea
-genetics: all AR, except OTC is XR
-dx/tests: high ammonia, high glutamine, alanine and specific AA, cpds
-treatment: protein restriction, meet arginine requirement, alternate pathways of waste nitrogen excretion (benzoate, phenylacetate
which UCD is ass'd with hepatomegaly?
AS lyase deficiency
which UCD is ass'd with spastic diplegia?
arginase deficiency
HHH syndrome
ornithine transporter, associated with urea cycle
tests: high ornithine, high ammonia
tx: restrict protein, supplement citrulline
nonketotic hyperglycinemia (NKH)
4 components to system
defect in Gly -> NH4, CO2, etc.
PFLCSz, hypotonia, apnea, hiccups, burst suppression EEG
dx - respiratory acidosis; paa - high gly; csf - v. high gly
tx - benzoate, NMDA channel blockers
how is diagnosis of classical PKU made?
Plasma phe >1200uM (or 20mg%) on unrestricted diet
normal blood biopterin or urine pterin metabolites
When do you treat with a reduced phe diet?
for phe levels >500uM
also do sapropterin (kuvan) trial (BH4 like?)
at what level of maternal Phe does the embryonopathy occur?

what are the features?

what maternal Phe should aim for?
maternal phe>1200, more than 90% of infants have:
-microcephaly and SGA
-dysmorphic facies
-increased incidence of other malformations (CHD etc.)

aim for maternal phe <300uM with diet restriction
supplement with tyr
biopterin (BH4) defects
symptoms - DD, microcephaly, dystonia, seizures
BH4 is cofactor for several enzymes - PAH, TyrH, TrpH, NO synthase
dx - paa: high phe corrected by BH4 administration
-abnl blood and urine biopterin metabolites
tx - control phe levels with diet or BH4; amine replacement for synthetic defects
hepatorenal tyrosinemia
AR deficiency of fumarylacetoacetate hydrolase
liver failure with bleeding diathesis (increased PT) and increased AFP
renal fanconi syndrome with rickets
neurologic crises - secondary to porphrin disturbances
increased risk hepatic ca (40% by 5yo)
dx-paa - high tyr, high met, bld spot succinylacetone
uoa - high succinylacetone
tx - NTBC, restrict phe and tyr in diet, liver transplant
type 1 glutaric aciduria
AR deficiency of glutaryl-CoA dehydrogenase
symptoms - macrocephaly, acute encephalopathic crisis followed by choreoathetosis (involuntary movements), dystonia
dx - metabolic acidosis, high ammonia during episode
-uoa- glutaric acid
-MRI - atrophy of frontal lobe with basal ganglia changes
tx - fluids, glucose, carinitie in episode; riboflavin, trial lys-restricted diet
canavan disease
aspartoacylase deficiency
increased incidence in AJ
symptoms - loss of skills starting 2-4mo
hypotonia, poor head control, seizures
dx - uoa: n-acetylaspartate (NAA)
-MRI: diffuse white matter abnl
-MRS: increased NAA
-molecular: E285A
tx - supportive
how is galactosemia diagnosed?
NBS - high galactose, low GALT
high RBC Gal-1-P (GALT substrate)
high urine RS
molecular - Q188R common mtn
hereditary fructose intolerance
AR deficiency of aldolase B
symptoms - asymptomatic in absence of dietary fructose
-nausea, vomiting, hypoglycemia, metabolic acidosis after fructose intake (sucrose, fruits, honey)
dx - controlled fructose load; molecular (A149P ~70% of alleles)
tx - fructose avoidance
GSD type 1
G6Pase (90%, type 1a)
G6P translocase (10%, type 1b)
symptoms - irritable infant with chubby cheeks, hepatomegaly
dx - hypoglycemia 3-4hr post feed; dose not respond to glucagon; metabolic acidosis with high lactate; high uric acid; high chol and TG
tx - freq't feeding; cornstarch
type 1b - antibiotics, GCSF
inborn errors with malformations.
excess substrate or insufficient product interferes with morphogenesis, causing malformations
sterol synthetic defects
peroxisomal disorders
glutaric acidemia type II
pdh deficiency
some ETC disorders
what proportion of defects in OxPhos are nuclear-encoded?
all complexes of ETC have subunits encoded in nuclear genome
AR inheritance

ex. Leigh syndrome - nuclear and mt mutations; 50% SURF1
mitochondrial depletion syndromes
genetically heterogeneous including deficiency of: mt thymidine kinase; mt deoxyguanosine kinase; twinkle - mtDNA helicase; mt polymerase gamma; adenine nucleotide translocator;
reduced ration of mt to nuclear DNA content
-BBS types 1-14
-orofaciodigital syndrome (OFD1)
-meckel-gruber syndrome (MGS)
-joubert syndrome (types 1-7)
-senior-loken syndrome (SLS)
-nephronophthisis (types 1-9)
-almstrom syndrome
nuclear membrane disorders - laminopathies
lamins - multifunctional filamentous proteins of nucler lamina, just under inner nuclear membrane
LMNA mtn: progeria; emery-dreifuss MD; mandibuloacral dysplasia; generalized lipodystrophy; restrictive dermopathy
disorders of ER
rough ER: translocation; glycosylation; folding; sorting

smooth and rough ER: phospholipid synthesis; ion transport
general characteristics of lysosomal storage disorders
-progressive clinical course
-variability in clinical course
-abnl cellular storage
-heterogeneity in stored material
-secondary enzyme alterations
-variability of organ and cellular manifestations
-theoretical basis for therapy
general phenotypic features of LSDs
-onset: in utero to several years
-loss of milestones
-coarse facies
-eye: corneal clouding, cherry red spots, pigmentary retinopathy
-early and recurrent hernia
-skeletal abnormalities
-non-immune hydrops
diagnostic approach to LSDs
-blood smear
-radiologic exam
-ophthalmologic exam, fundoscopic and slit lamp
-uring mucopolysaccharides and glycoproteins
-serum lysosomal enzymes
-consider bone marrow
-biochemical studies of fibroblast +/o luekocytes
-other - depending on specific disorder
LSD - types/groups of disorders
hydrolase deficiencies (>40)
-MPS (hurler, hunter)
-sphingolipidoses (niemann-pick)
-GSD type II (pompe)

trafficking disorders
-mucolipidoses II and III

lysosomal transport disorders
-sialic acid storage
MPSs - general phenotype
usually nl at birht
gradual slowing of dev't
coarse facies
with (hurler) and without (hunter) corneal clouding
skeletal inv't (decreased ROM, claw hand); dysostosis multiplex
otitis and hearing loss
recurrent herniae
cardiac involvement
MPS 1- Hurler
prototypical MPS
AR -
onset 6-12mo, rarely live to age 10
dx - corneal involv't (vs. hunter), MPS spot
iduronidase deficiency in WBC or fibrobalsts
tx - symptomatic, early BMT, ERT
MPS II - Hunter
XLR (vs. hurler!)
variable pheno, similar to hurler on the severe end
no corneal involvement
dx - +MPS spot
iduronate sulfatase deficiency
MPS III - Sanfilipo
AR - 4 loci, 2 more common
more CNS involvement - hyperactive, aggresive, insomnia
dx - MPS spot +/-; enzyme assay
tx - symptomatic
Niemann-Pick A & B
AR, increased frequency in AJ
A- poor feeding, respiratory problems before 6mo, hepatosplenomegaly, cherry red spot (50%)
dx - foam cells in marrow, sphingomyelinase deficiency, molecular studies
tx - supportive
B - later onset, hepatosplenomegaly, diffuse pulmonary involvement
Niemann-Pick C
NPC1 (95%), NPC2 (5)
similar pheno to A & B
childhood onset forms with ataxia, dysarthria, progressive
dx - foam cells in marrow, sphingomyelinase normal, abnl accumulation of unesterified cholesterol in lysosomes
tx - supportive
AR deficiency of glucocerebrosidase
sphingolipidosis, LSD
N370S - protective for CNS
type I - non-neuronopathic; (1/400-1/1000 AJ); splenomegaly, hypersplenism, bone pain (pseudo-osteomyelitis)/lytic lesions; abn pigmentation
type II - acute neuronopathic; rapidly progressive w onset in first year; opisthotonus; no AJ predilection
type III - adolescent neuronopathic
dx - gaucher cell infiltrate marrow and other tissues, 'crumpled paper' cytoplasm
tx - ERT for type I
Tay-Sachs disease
AR - hexosaminidase A deficiency
sphingolipidosis, LSD
onset: 6-12mo with slowing development; hyperacusis, apathy, cherry red macular, progressing to seizures, blindness, spasticity and death by 2-5y
**no hepatosplenomegaly
tx - none
carrier screening in high risk pop'n (AJ, French canadian) - molecular testing only useful for AJ/common mtn
hexosaminidase A enzyme composed of alpha and beta subunits. HEXA = Tay-Sachs, HEXB = Sandhoff w pheno similar to Tay-Sachs
with which disorders do you see a cherry red spot?
Sialidase deficiency
Niemann-Pick A
GM1 gangliosidosis
XL - nearly all females affected
Sphingolipidosis, LSD
males - neuropathy, acroparesthesias, provoked by exercise and temperature changes, angiokeratomas, corneal opacities, renal & cardiac disease
dx - gb3 levels, alpha-galactosidase activity, molecular
tx - ERT, for certain alleles - galactose
peroxisome functions?
-beta-oxidation of VL and L chain FA, straight and branched chain
-peroxidase-based respiration
-plasmalogen and bile acid synthesis
-glyoxylate transamination
disorders of peroxisomes
multiple deficiencies - peroxisome biogenesis disorders:
-zellweger syndrome spectrum
-rhizomelic chondrodysplasia punctata (RCDP)

single function deficiencies:
-x-linked adrenoleukodystropyhy (ALD)
-refsum disease
zellweger syndrome spectrum
12 PEX genes
PEX1 most common (68%)
signif locus heterogenetiy - 12 compl'n groups
disorders of peroxisome biogenesis
-Zellweger (most severe, die by 1yo)
-neonatal adreno-leukodystrophy,
-infantile Refsum disease (least severe)
dev'l & met'c
FTT, DD, dysmorphic features
hypotonia, cerebral atrophy, seizures
liver cysts, hepatic dysfxn
bony stippling (chondrodysplasia punctata of patella, long bones)
childhood cataracts, RP
hearing loss
hemorrhage, intracranial bleeding
hepatic involvement, renal cysts
tests: high VLCFA, low RBC plasmalogens, high plasma pipicolic acid
molecular screening - "PEX gene screen"
tx: symptomatic, avoid phytanic acid (cow's milk)
x-linked adrenoleukodystrophy
progressive neurodgenerative disorder ass'd with adrenal involvmenet
highly variable clinical phenotype:
-childhood cerebral: childhood onset, rapid progression
-adrenomyeloneuropathy (AMN): onset 20-30s with spastic paraparesis
-adrenal only
no geno-pheno corr'n
defective met'm of VLCFA
dx- high VLCFA, genetic tests
tx - BMT in boys w mRI abnormalities
- lorenzo's oil (?)
refsum disease
AR deficiency of phytanoyl-CoA hydroxylase
crebellar ataxia
polyneuropathy, RP, elevated CSF
dx - high phytanic acid, molecular testing
tx - phytanic acid-restricted diet
NBS criteria
-serious & reasonable frequency
-difficult to dx clinically & requires test
-irreversible damage w/o treatment
-test is rapid, sensitive & specific
-feasible intervention improves outcome
-NBS program is cost effective
What happens when there's a truly abnormal result on NBS?
truly abnl = single or multiple analytes >> cut off
-lab notifies MD ASAP, gives contact for metabolic specialists
-ACT sheet specific to disorder
-FACT sheet for families
disorders on MS/MS:
by acylcarnitines
-9 OA (IVA, GA-1, HMG, MCD, MUT, Cbl A,B, 3MCC, PROP, BKT)

by AA
- 6 AA disorders (PKU, MSUD, HCY, TYR I , ASA, CIT)

-Hb SS
-Hb S/beta thal
-Hb S/C

hemoglobin disorders
FS (Hb SS) -> CBC and/or DNA -> refer to specialist
FSC (Hb SC) -> refer to specialist
FSA (Hb Sbeta thal) -> refer to specialist
FAS (Hb AS) -> no further testing
NBS - AA disorders and their metabolities
-PKU - high phe
-HCY - high met
-MSUD - high leucine
-argininemia - high arginine
-arginosuccinic aciduria (ASA); -citrullinemia I (CIT) & II - citrulline
-TYR I, II & III - tyrosine
NBS - FAOD analytes
-carnitine uptake deficiency - C0
-CPT 1 deficiency - C0; C0/C16+C18
-CPT2/CACT - C16 &/or C18:1
-glutaric acid 2/ethylmalonic encephalopathy - C4;C5
-LCHAD, TFP - C16-OH +/- C18:1-OH
-MCAD - C8; C6, C10
-SCAD/ethyl malonic enceph/isobutyryl CoA Dehydro D - C4
-VLCAD - C14:1 +/-
NBS - OAD and analytes
-biotinidase, HMC - C5-OH
-glutaric acidemia 1 - C5-DC
-IVA, short/branched chain acylCoA dehy d - C5
-MMA, PA - C3
NBS by other methods (not NBS) - how done?
biotinidase deficiency - enzyme assay
CF - immnoreactive trypsinogen and/or DNA (sensitivity increased with DNA testing)
hearing - auditory brainstem response (ABR)/evoked otoacoustic emissions (OAE)
galactosemia NBS outcomes
classical GALT - high galactose, low GALT
galactokinase (GALK) - high galactose, low GALK
epimerase (GALE) - high galactose, low GALE
defect in absorption of cystine & dibasic AA (lysine, arginine, ornithine) - increased excretion
cystine stone formation in childhood, recurrent if untreated
tx - preventive hydration, penicillamine or n-acetylcysteine, alkalinization of urine to increase cystine solubility
Galactosemia mutations
>160 mutations
-classic - Q188R - 70% of Caucasian alleles, 1/128 carrier rate
-duarte - N314D - common 1/27 - activity: D/N (75%), D/D (50%), D/G (25%)
-LA (N314D+L218L) - 140% activity
endocrine disorders on NBS and their abnl results
primary congenital hypothyroidism (CH)- high TSH or low T4 +/- high TSH

congenital adrenal hyperplasia (CAH, 21-hydrox.) - high 17OHP

TSH >24hr of age
confirm with T4, TSH, TRH
PHE levels
-classical PKU: >1200uM or >20mg%
-non PKU HPA: 120uM(nl)-1000uM (?treat? controversial)

-aim w tx for 120-360uM or 2-6mg%
-maternal PKU aim for 120-350uM or <6mg% for several months prior to conception
lab results in OTC
-v. high ammonia (>2000),
-high glutamine (with ammonia), -high orotic acid** (only UCD with this) (b/c CAP (OTC substrate) builds up and gets converted to orotic acid)

low - citrulline (product of OTC), arginine (2 steps after OTC);

normal UOA (vs. UOA disorders)
AS (arginosuccinate synthase) deficiency
aka citrullinemia
-AS is step after OTC, citrulline -> ASA

-Paa -- citrulline vs. high (>1000) - b/c citrulline is the substrate
-v. high ammonia (1000-3000 µmol/L)

-Paa - v. low argininosuccinic acid
-step before OTC, product is CAP


-orotic acid (vs. OTC) (b/c no CAP made to go to orotic acid)
-citruline (like OTC) (b/c no CAP --> citrullne, i.e. downstream of enzyme defect)
how to differentiate between OAD and UCD in hyperammonemia?
-present - UOAD
-absent - UCD
approach to investigation of lactic acidosis
lactate/pyruvate ratio
-increased --> mitochnodrial disease
-normal --> glycemia?
----hypoglycemic --> GSD, gluconeogenesis disorders
----normoglycemic --> PDH deficiency, PC def, type A

abnl uOA
-dicarboxylic acids --> FAOD
-characteristic organic acids --> OAD
most common symptoms in Gaucher type 1 (nonneuronopathic)?
-bone disease
-growth retardation
-brusing, bleeding
-bone pain/crisis
-abdominal pain