Metabolic Disorders

Part 1
PICU KFHH

 First lecture will be just an ..."appetizer"

We will review how two cases of a metabolic disorder
presented
The initial clinical manifestations can be non-specific or
specific, they can start early after birth or present after
many months, sometimes even years.
We will look into "complicated" and "congested"
metabolic pathways and will see how to extract useful
information from them
The "real" introduction will be the next lecture, this
"appetizer" is needed so that all can appreciate the
usefulness of some basic biochemistry knowledge when
we deal with metabolic disorders.

Case 1
PC:
Hyperactive child 18 months old with autistic behavior
(purposeless hand movements, rhythmic rocking).

PMH:
Normal BW, term newborn, free perinatal history,
except birth at home, didn't have neonatal screening
Episodes of vomiting

Clinical exam:
Cognitive delay
Parents have a dark complexion, he has lighter hair
and skin color.

Classic phenylketonuria/
Hyperphenylalaninemia
phenylalanine
essential amino acid
utilized for protein synthesis
degraded through the tyrosine pathway

disease occurs from deficiency of

phenylalanine hydroxylase (Phe to Tyr) or
tetrahydrobiopterin (BH4) (its cofactor)

CNS damage done by high phenylalanine levels

and dopamine & serotonin deficiency in BH4 deficiency

two variants
classic phenylketonuria (plasma Phe > 20mg/dl): excess Phe =>
phenylketones => excreted in urine (not toxic for CNS)
mild hyperphenylalaninemia (plasma Phe 2-10mg/dl)

(1) Phenylalanine hydroxylase, (2) pterin-carbinolamine

dehydratase, (3) dihydrobiopterin reductase, (4) guanosine
triphosphate (GTP) cyclohydrolase, (5) 6-pyruvoyltetrahydropterin synthase, (6) sepiapterin reductase, (7) carbonyl reductase, (8) aldolase reductase, (9) dihydrofolate reductase, (10)
tyrosine aminotransferase, (11) 4-hydroxyphenylpyruvate dioxygenase, (12) homogentisic acid dioxygenase, (13) maleylacetoacetate
isomerase, (14) fumarylacetoacetate hydrolase, (NE) nonenzymatic

Classic phenylketonuria
clinical manifestations
normal at birth
cognitive delay developing after a few months
90% IQ below 65
60% IQ below 35

2-5% of untreated patients: normal IQ!

other symptoms

vomiting
hyperactivity, autistic behavior
light skin complexion
temporary seborrheic or eczematoid rash
musty/mousey smell of phenylacetic acid
seizures (25%), spasticity, hyperreflexia, tremors
microcephaly, prominent maxilla, teeth anomalies, growth
retardation

Classic phenylketonuria
diagnosis
neonatal mass screening (Guthrie filter paper)
should be obtained 24-48 hr after feeding protein

confirmation by measuring plasma Phe

don't measure urine phenylketones!

Hyperphenylalaninemia from
cofactor deficiency
clinical manifestations
present in the first few months, they are progressive,
have diurnal fluctuation
extrapyramidal signs (choreoathetotic or dystonic limb
movements, axial hypotonia, hypokinesia)
feeding difficulties, hypersalivation, swallowing
difficulties
autonomic abnormalities
intellectual disability, seizures

Hyperphenylalaninemia from
cofactor deficiency
diagnosis
urine neopterin and biopterin
decreased CSF dopamine, serotonin and their
metabolites
BH4 loading test
enzyme assay (not always possible in blood)
genetic test

Classic PKU treatment

phenylalanine-restricted diet for life in patients with
classic PKU and those with MHP and Phe>6mg/dl
small amounts of Phe should be added (otherwise
lethargy, FTT, anorexia, anemia, rashes, diarrhea,
death)
Phe should be 2-6mg/dl in children 0-12yr and 2-15mg/dl
in older individuals
diet is difficult to maintain
other treatment
administration of large neutral amino acids (under study)
oral administration of BH4 (Kuvan) (effective in 40%)
recombinant Phe ammonia lyase (under study)

Classic PKU prognosis

generally good if diet maintained
osteopenia
if not under diet during pregnancy
newborn presents intellectual disability,
microcephaly, growth retardation,
congenital malformations and congenital
heart disease (Phe should be 2-6mg/dl
throughout pregnancy)

Mild hyperphenylalaninemia
treatment

Kuvan 5-20mg/kg/day
L-dopa + carbidopa
5-hydroxytryptophan
folinic acid (if dihydropteridine reductase
deficiency)
avoid TMP-SMX, MTX (inhibit
dihydropteridine reductase activity)

Mild hyperphenylalaninemia
prognosis
BH4 does not cross easily BBB (that is
why L-dopa and 5-HT are administered)
neurologic symptoms are not fully resolved
intellectual disability, tone abnormalities, eye
movements, poor balance and coordination,
seizures

hyperprolactinemia
result of hypothalamic dopamine deficiency
(method to monitor neurotransmitter
replacement)

Case 2
PC:
3 month old infant with fever, irritability, vomiting and
melena

PMH:
normal at birth

Clinical exam:
hepatomegaly
jaundice

Tyrosine
derived from ingested proteins
synthesized from Phe
precursor of

dopamine
norepinephrine, epinephrine
melanin
thyroxine

hypertyrosinemia
hereditary: fumarylacetoacetate hydrolase (I), tyrosine
aminotransferase (II), 4-hydroxyphenylpyruvate (III)
dioxygenase deficiencies
acquired: liver failure, scurvy, hyperthyroidism
nonpathologic: soon after eating, premature infants

Tyrosinemia type I
AKA: tyrosinosis, hepatorenal tyrosinemia
clinical manifestations
presents at 2-6 mo of age; the earlier the worse the prognosis
liver
acute hepatic crisis (fever, vomiting, hemorrhage, hepatomegaly,
jaundice, incr transaminases, hypoglycemia)
between crises: FTT, hepatomegaly
long term: cirrhosis and hepatocellular carcinoma

episodes of peripheral neuropathy

in 40% of patients; triggered by minor infections
leg pain, neck and trunk extensor hypertonia, vomiting and paralytic
ileus, accidental tongue biting
sometimes severe paralysis => respiratory failure
crisis of 1-7 days => recovery over weeks to months

kidney
Fanconi-like syndrome, nephromegaly, nephrocalcinosis

Tyrosinemia type I
laboratory findings
increased succinylacetone in urine or blood
(diagnostic)
incr a-FP, decr coagulation factors, incr serum
transaminases
hyperphosphaturia, hypophosphatemia,
generalised aminoaciduria

differential diagnosis
galactosemia, hereditary fructose intolerance,
citrullinemia type II

Tyrosinemia type I
treatment - management
diet low in Phy and Tyr
nitisinone (inhibits 4-HPPD)
follow-up for cirrhosis/hepatocellular
carcinoma