Metabolic Medicine

Part two
Hevi Pediatric Teaching
Hospital
5-5-2013
 Disorders of Amino Acid Metabolism (tyrosinemia,
homocystinuria, NKH, MSUD, and PKU)
Urea Cycle Defects
Disorders of Organic Acid Metabolism ( propionic
acidemia, isovaleric acidemia, methylmalonic aciduria,
and glutaric aciduria)
Disorders of Fatty Acid Metabolism (MCAD)
Disorders of Carbohydrate Metabolism (hereditary
fructose intolerance, galactosemia, and GSDs)
PEROXISOMAL DISORDERS (Zellweger syndrome,
X-linked adrenoleukodystrophy)
MUCOPOLYSACCHARIDOSES (MPS) (Hurler
syndrome)
SPHINGOLIPIDOSES (Gaucher disease, Niemann-
Pick disease)
 Disorders of Amino Acid
Metabolism
Disorders of amino acid metabolism
include
tyrosinemia,
homocystinuria,
NKH,
MSUD, and
PKU.
 Phenylketonuria
PKU is inherited in an autosomal
recessive
Classic PKU results from a deficiency of
the PAH enzyme, which is responsible for
converting phenylalanine into tyrosine.
Other forms of PKU can be caused by
deficiencies in the synthesis of biopterin,
which is cofactor for the PAH enzyme.
 Clinical Manifestations of
Untreated PKU
Eczema.
Hypopigmentation.
Seizures.
Limb spasticity.
Mousy odor.
Severe mental retardation.
 Women of childbearing age with PKU
must maintain strict adherence to
their diet because of the teratogenic
effects of elevated phenylalanine.
Infants born to mothers with
uncontrolled PKU can have
microcephaly, growth retardation,
developmental delay, and congenital
heart disease.
 Treatment
Phenylalanine-restricted diet in
infancy, ideally continued throughout
lifetime.
More recently, a synthetic form of
biopterin has become clinically
available and allows further
liberalization of diet in some
patients.
 Tyrosinemia
There are five known inherited
disorders of tyrosine metabolism.
We will address tyrosinemia types I .
 Tyrosinaemia (type 1)
Tyrosinaemia type 1 results from a block in the
catabolism of tyrosine, producing byproducts
which damage the liver and kidney.
Clinical features of tyrosinaemia
Early onset (severe) liver disease with
coagulopathy, proximal renal tubulopathy
Late onset: Faltering growth and rickets
(secondary to renal Fanconi)
Development of hepatocellular carcinoma in
late childhood/adolescence
 Diagnosis
Tyrosine is raised in the plasma and
the presence of succinylacetone in
urine is pathognomonic.
Confirm by liver enzymology
(fumarylacetoacetase).
 Treatment
Dietary restriction of tyrosine and
phenylalanine with or without liver
transplantation;
however, the drug Nitisinone
(NTBC)is now used in some patients
to create a block upstream of the
pathway of tyrosine metabolism,
leading to accumulation of less toxic
metabolites.
 Maple Syrup Urine Disease
(MSUD)
MSUD results from deficient activity of the BCKD
(branched-chain keto acid dehydrogenase)
occurs in approximately 1 in 200,000 births.
It derives its name from the sweet smelling
urine of affected patients.
Deficiency of this enzyme leads to accumulation
of the BCAAs including leucine, isoleucine, and
valine.
Much of the toxicity is related to the elevated
level of leucine, which is neurotoxic.
 Clinical Manifestations
(Vary According to Level of Functional Enzyme Present)

Severe forms present in infancy with

lethargy, vomiting, hypotonia,
seizures, and/or death.
 Patients with intermediate levels of
enzyme can present during childhood
or adulthood with episodic neurologic
decompensation, often during an
intercurrent illness.
Chronic progressive forms of MSUD
exist and can present with gradual
neurologic problems including
seizures and developmental delay.
 Diagnosis:
Elevated branch-chain amino acids plus
alloisoleucine
Elevated branch-chain oxo-acids on urinary
organic acids
Enzymology on fibroblasts
Ammonia, lactate, and bicarbonate are often
normal.
Treatment
Restriction of intake of the BCAAs.
The enzyme cofactor thiamine is given in the
hope of improving residual enzyme activity.
 Homocystinuria
Homocystinuria is an autosomal
recessive condition.
classically caused by cystathionine
beta-synthase deficiency. This enzyme
is responsible for metabolizing
homocysteine to cystathionine.
Pyridoxine is a cofactor for this
enzyme.
 Clinical Manifestations
Mental retardation.
Eye lens dislocation(classically downward)
Marfanoid body habits(span greater than
height)high arched palate, arachnodactyly
Restricted joints movement.
Osteoporosis.
Acute vascular thrombosis.
 Treatment
50% of patients will respond to
pyridoxine supplementation.
Folate should also be supplemented
as depletion affects response.
Other treatment modalities include
methionine-restricted, cystine-
supplemented diet.
Betaine is effective at lowering
homocysteine .
 Nonketotic Hyperglycinemia

NKH results from defects in the

glycine cleavage system.
Glycine is a neurotransmitter;
excitatory centrally and inhibitory
peripherally.
 Clinical features
Increased fetal movements (inutero seizures)
Hiccups and hypotonia.
Progressive apnea/encephalopathy.
Seizures.
Developmental delay.
EEG shows a burst suppression pattern;
 Diagnosis:
elevated glycine on urinary or plasma
amino acids.
CSF glycine to plasma glycine ratio
greater than 0.08 is diagnostic of NKH.
Ketosis and acidosis are not seen.
Enzymology ;is traditionally assessed
in the liver, but a new assay using
lymphocytes is now available.
 Treatment
Sodium benzoate and
dextromethorphan may help to
reduce seizure activity and increase
arousal in some patients.
Sodium-Valproic Acid (Depakene)
should be avoided since it can raise
CSF glycine levels.
 Urea Cycle Defects
(Disorders of Protein/Nitrogen Metabolism)

In normal individuals, excess nitrogen is

converted into urea, which is excreted in the
urine by a process known as the urea cycle.
A defect in this cycle will lead to abnormal
nitrogen metabolism, and an elevation in
ammonia, which at high levels is neurotoxic.
Excess nitrogen is also stored as glutamine and
glycine, which are also elevated in these
disorders.
All disorders of the urea cycle are inherited in an
autosomal recessive manner, except OTC
deficiency, which is inherited in an X-linked
manner.
 Clinical features of Urea cycle
defects:
Vomiting (may be a cause of cylical
vomiting)
Encephalopathy. (intoxication following
symptom free period in neonate) .
Tachypnoea (ammonia stimulate respiratory
center)
Progressive spastic diplegia and developmental
delay (arginase deficiency)
Milder forms can present during childhood with
episodic encephalopathy triggered by
intercurrent metabolic stress.
 Diagnosis
The specific deficient enzyme in a
patient with a suspected urea cycle
defect can be identified by
examining the patterns of urine
organic acids and plasma amino
acids.
Final confirmation of the diagnosis
requires enzymology.
Characteristics of urea cycle defects
 Treatment
Acute treatment during crisis periods
is centered around reducing the
levels of ammonia by
dialysis and IV medications
designed to provide alternative
mechanisms of nitrogen excretion,
such as sodium benzoate and
phenylbutyrate.
 Disorders of Organic Acid
Metabolism
Defects in the catabolism of amino
acids result in the accumulation of
organic acids which are detected in
urine.
Disorders of organic acid metabolism
include
propionic acidemia, isovaleric
acidemia, methylmalonic aciduria, and
glutaric aciduria.
 Propionic acidaemia (PA) and
methylmalonic aciduria (MMA) result
from blocks in branched-chain amino
acid degradation,
isovaleric acidaemia (IVA) is the
result of a block in leucine
catabolism.
glutaric aciduria type 1 (GA-1)
results from a block in lysine and
tryptophan metabolism.
 Clinical features of organic
acidaemias
Acute neonatal encephalopathy (intoxication), or
chronic intermittent forms
Dehydration
Marked acidosis (anion gap), ketosis .
Neutropenia +/- thrombocytopenia (acute marrow
suppression)
Progressive extra pyramidal syndrome (MMA, PA) basal
ganglia necrosis
Renal insufficiency (MMA)
Pancreatitis .
Cardiomyopathy (PA, MMA)
Patients with isovaleric acidemia are often described
as having a peculiar body odor (sweaty feet)
 Diagnosis
Both the acylcarnitine profile and
urine organic acid profile are
essential in making a diagnosis.
 Treatment
Protein restriction.
Carnitine supplementation (provides
alternate methods of propionic acid and
methylmalonic acid secretion).
There are B12 responsive forms of
methylmalonic aciduria.
Propionate is partly produced by gut organisms,
therefore decompensation in PA and MMA may
be precipitated by constipation.
Metronidazole is used in MMA and PA to alter
the gut flora to reduce propionate production
and help avoid constipation.
 Glutaric Aciduria Type 1
Glutaric aciduria type 1 is due to a deficiency in glutaryl-
CoA .
Clinical Manifestations:
Macrocephaly
Normal development before catastrophic decompensation
(usually <1 year)
Choreoathetosis and dystonia (basal ganglia involvement)
Magnetic resonance imaging features:
bifrontotemporal atrophy, subdural haematomas, basal
ganglia decreased signal
 Diagnosis
Elevated levels of glutaric acid in the
urine or CSF.
Abnormal acylcarnitine profile.
Patients do not generally have
hypoglycemia, acidosis, or
hyperammonemia.
Treatment
Lysine and tryptophan restricted diet.
Carnitine supplementation.
Support during intercurrent illnesses.
Disorders of Fatty Acid Metabolism

The fat oxidation defects commonly present

with hepatic, cardiac or muscle symptoms.
Fatty acids are a major fuel source in the
fasted state
Fatty acids are oxidized by most tissues except
the brain, which is reliant on hepatic fatty acid
for ketone production.
Fatty acids are the preferred substrate for
cardiac muscle.
during prolonged exercise they are a vital
energy source for skeletal muscle.
 Long-chain free fatty acids are
esterified in the cell cytosol and then enter
the mitochondria as fatty acylcarnitines.
Medium- and short-chain fatty acids
are able to enter the mitochondria
directly.
They then undergo beta oxidation until
they become acetyl-CoA, which is then
used to make ketone bodies.
These disorders are all inherited in an
autosomal recessive manner.
 Medium-chain acyl-CoA.
dehydrogenase (MCAD) deficiency
MCAD deficiency is the commonest fat oxidation
disorder.
Clinical features of MCAD deficiency
Hypoketotic hypoglycaemia(During prolonged fasting)
Encephalopathy
Reye-like syndrome: hepatomegaly, deranged liver
function
Mean age at presentation 15 months, commonest
precipitant is diarrhoea
Sudden infant death (consider in older infant> 6
months)
 Diagnosis
Detection requires a strong clinical
suspicion .
The presence or absence of ketosis should
be sought in all cases of hypoglycaemia.
Plasma-free fatty acids are raised, while
ketone formation is impaired.
Urinary organic acids reveal a
characteristic dicarboxylic aciduria in
the acute state.
Acylcarnitines are elevated .
 Management
Prevention is better than cure.
Once the diagnosis is known, further
decompensations can be avoided by
employing an emergency regimen of
glucose polymer drinks during
intercurrent illnesses or admission for
a 10% dextrose infusion if the
drinks are not tolerated.
 Disorders of Carbohydrate
Metabolism
Disorders of carbohydrate
metabolism include:
hereditary fructose intolerance,
galactosemia,
and the GSDs (Glycogen storage
disease)
 Galactosemia
Galactosemia is a result of deficient (galactose-1-
phosphate uridyl transferase)
Most patients present in the first or second week of
life with hepatomegaly, jaundice, vomiting,
hypoglycemia, hypotonia, and cataracts (oil droplet
cataract)
Neonates also present with Escherichia coli sepsis.
 Diagnosis
Diagnosis is based on the clinical
picture, the presence of reducing
substances in the urine
Enzymology : by measuring the level
of galactose 1 phosphate
uridyltransferase (Gal 1-Put) in red
cells.
Galactosaemia should be considered
in all cases of severe early-onset
jaundice.
 Treatment includes a lactose-free
diet throughout life.
Long-term complications, in spite of
good control, thought to be due to
endogenous production of
galactose from glucose.
Includes: developmental delay,
particularly involving speech, feeding
problems and infertility in girls.
Hereditary Fructose Intolerance
It is result from a defect of fructose 1,6-
bisphosphate aldolase.
When patients are exposed to fructose, they can
have gastrointestinal symptoms with nausea and
vomiting, seizures, and coma.
Liver failure and proximal renal tubule defects can
be seen.
Exacerbations may occur following exposure to
fructose contained in medicines
A chronic form can also develop leading to
growth failure and chronic renal and liver damage.
Treatment :Lifelong avoidance of fructose.
Glycogen Storage Disorders
Glucose is stored in the liver and muscles as
glycogen.
The glycogen storages disorders are a large
class of disorders that cause defects in glycogen
production or utilization.
They primarily present with either muscle or liver
abnormalities or both.
Hepatic forms present with hepatomegaly and
hypoglycaemia,
the muscle forms present with weakness and
fatigue.
 GSD Ia (von Gierke
disease)
Enzyme :Glucose-6-phosphatase
Major Organ Involvement: Liver,
kidney
 Clinical Features :
Hypoglycemia ; Fasting tolerance is limited,
usually 1 -4 h.
Massive hepatomegaly in the absence of
splenomegaly is strongly suggestive of a hepatic
GSD because glycogen is not stored in the spleen.
Nephromegaly is common.
Abnormal fat distribution results in 'doll-like' faces
and thin limbs.
Long-term complications include renal
insufficiency, liver adenomas with potential
for malignant change, gout, osteopenia and
polycystic ovaries.
 Investigations: show raised plasma lactate
levels, hyperuricaemia and hyperlipidaemia.
Treatment consists of frequent feeds during
the day with continuous feed overnight.
From age 2, uncooked corn starch is
introduced as a slow-release form of glucose,
prolonging the gap between feeds.
Allopurinol controls the uric acid level in the
blood.
Liver transplantation is reserved for
patients with malignant change in an adenoma
or failure to respond to dietary treatment.
 GSD II (Pompe disease)
Enzyme :Lysosomal alpha-glucosidase , acid maltase
deficiency
Major Organ Involvement: Muscle,
Clinical Features : generalized Myopathy, cardiomyopathy,
hypotonia, weakness, hyporeflexia and large tongue.
ECG reveals giant QRS complexes.
Vacuolated lymphocytes are seen on the blood film.
Confirmatory enzymology is performed on fibroblasts.
ERT (enzyme replacement therapy )recently available, which
extends life expectancy.
 GSD III Debrancher (Cori
disease): affects liver and
muscle.
GSDIV Brancher (Andersen
disease), GSD VI (Hers disease)
and GSD IX: affects liver.
GSD V (McArdle disease) and
GSD VII(Tarui disease): affects
Muscles.
 PEROXISOMAL
DISORDERS
Peroxisomes harbour many vital
cellular functions, including
the synthesis of plasmalogens,
(essential constituents of cell walls),
cholesterol and bile acids, and
the oxidation of very long- chain fatty
acids and breakdown of phytanic
acid (vitamin A) and glyoxylate.
 Disorders are biochemically
characterized by the number of
functions impaired.
Multiple enzymes affected
(peroxisomal biogenesis defects) -
Zellweger syndrome (ZS)
Several enzymes involved-
rhizomelic chondrodysplasia punctata
(RCDP)
Single enzyme block- X-linked
adrenoleukodystrophy (XALD), Refsum
disease, hyperoxaluria
 Inheritance is autosomal recessive
with the exception of the XALD.
The first-line investigation is
very-long-chain fatty acids which are
elevated in ZS and XALD.
Further investigation requires
fibroblast studies.
 Zellweger syndrome
ZS is the classic peroxisomal
biogenesis disorder with distinctive
dysmorphic features.
prominent forehead, hypertelorism,
large fontanelle.
 Clinical features of Zelweger syndrome
Dysmorphic faces;
Severe neurological involvement including
hypotonia, seizures and psychomotor
retardation.
Sensorineural deafness.
Ocular abnormalities - retinopathy,
cataracts
Hepatomegaly and liver dysfunction
Calcific stippling (especially knees and
shoulders)
Faltering growth.
 Diagnosis
Loss of all peroxisomal functions -
raised very-long-chain fatty acids,
phytanate and bile acid
intermediates and decreased
plasmalogens.
Confirmatory enzymology on
fibroblasts.
 Treatment
Management is supportive.
Docosahexaenoic acid
supplementation has been tried.
 X-linked adrenoleukodystrophy
(XALD)
The paediatric cerebral form presents with
severe neurological degeneration, usually
between 5 and 10 years.
Brothers in the same family may present at
different ages.
Clinical features of XAID
School failure, behaviour problems
Visual impairment
Quadreplegia
Seizures (late sign)
Adrenal insufficiency
 Adrenal involvement may precede or
follow neurological symptoms by years.
Some only develop neurological
symptoms, and others just have
adrenal insufficiency.
All males developing adrenal
failure should have very-long-chain
fatty acid measurements taken to
ensure that the diagnosis is not
missed.
 Diagnosis
Elevated very-long-chain fatty acids, blunted
synacthen response or frank hypoglycaemia.
Neuroimaging shows bilateral,
predominantly posterior, white-matter
invotvement.
The differential diagnosis for
neurodegeneration in the school-age
child includes:
Subacute sclerosing panencephalitis .
Batten disease
Wilson disease
Niemann-Pick C disease.
 Management
Lorenzo's oil (oleic and erucic acid)
normalizes the very-long-chain fatty acids.
Bone marrow transplantation is the
mainstay of therapy in patients before
neurodegeneration and those diagnosed
after presentation with adrenal insufficiency.
Adrenal function should be closely
monitored, and steroid replacement therapy
should be given once it is indicated.
 MUCOPOLYSACCHARIDOSES
(MPS)
Mucopolysaccharides (glycosaminoglycans)
are structural molecules integral to connective
tissues such as cartilage.
Degradation occurs within lysosomes,
requiring specific enzymes.
Patients with MPS appear normal at birth and
usually present with developmental delay in
the first year.
The features of storage become more obvious
with time.
 Classification
Type Disorder Inheritan Corneal Skeleto Hepato- MR
ce cloudin n Splenomeg
g aly
I Hurler
AR + +++ +++ ++
+
II Hunter
XL - +++ +++ ++
+
Sanfillipo
III AR + + + ++
+
Morquio
IV AR + +++ + -
Maroteaux
VI -Lamy
AR + +++ +++ -
VII Sly
AR + +++ +++ ++
+
 Hurler syndrome is the classical MPS with
storage affecting the body and CNS.
Sanfillipo syndrome predominantly
affects the CNS.
Morquio and Maroteaux-Lamy
syndromes affect the body with Atlantoaxial
instability often necessitating prophylactic
cervical spinal fusion in the first 2-3 years.
Hunter syndrome is phenotypically similar
to Hurler syndrome, however there is no
corneal clouding and scapular nodules are
seen.
 Hurler syndrome
Hurler syndrome typifies the MPS
group and their associated clinical
problems.
The enzyme deficiency is a-
iduronidase, a deficiency .
 Clinical features of Hurler syndrome
Coarse faces, macroglossia, hirsutism,
corneal clouding
Airway/ear, nose, throat
problems,secretory otitis media.
Dysostosis multiplex
Cardiomyopathy, valvular disease
Hepatosplenomegaly
Hernias- umbilical, inguinal, femoral
Stiff joints
Developmental delay and retardation
 Radiographs show a characteristic skeletal
dysplasia known as dysostosis multiplex
The earliest radiographic signs are thick
ribs and ovoid vertebral bodies.
The lower ribs are broad and spatulate .
The skull is large, the orbits shallow and the
sella turcica shoe shaped or J-shaped .
 The bones of the upper extremities become
short and taper toward the ends, often with
enlargement of the mid-portions.
The ends of the radius and ulna angulate toward
each other.
claw hand of the patient with Hurler syndrome
is pathognomonic of dysostosis multiplex.
The metacarpals are broad at their distal ends
and taper at their proximal ends.
The phalanges are thickened and bullet-shaped.
 The clavicle is absolutely characteristic, while
the lateral portion may be hypoplastic or even
absent.
The vertebrae are hypoplastic, scalloped
posteriorly and beaked anteriorly, especially at
the thoracolumbar junction .
There is anterior vertebral wedging, with
typically a hooked-shaped vertebre.
 Diagnosis
Urinary screen for
glycosaminoglycans (raised
dermatan and heparan sulphate).
Enzymology confirmed on white
cells.
 Management
Treatment depends on early recognition
to allow early bone marrow
transplantation, which significantly
modifies the phenotype.
Enzyme replacement clinical trials are
currently underway.
Supportive care is the mainstay of
untransplanted patients, with particular
regard to the chest and airway requiring
3-monthly sleep studies.
 SPHINGOLIPIDOSES
Sphingolipids are complex membrane lipids.
They are all derived from ceramide and can be
divided into three groups:
cerebrosides, sphingomyelins and
gangliosides.
Lysosomal hydrolases break these molecules down;
deficiencies result in progressive storage and
disease.
Typical features include psychomotor retardation,
neurological degeneration including epilepsy, ataxia
and spasticity, with or without hepatosplenomegaly.
 Tay-Sachs disease
Clinical features:
Developmentar regression within first year.
Macrocephcdy
Hyperacusis
Cherry-red spot.
Spastic quadriplegia
 Diagnosis
The presence of vacuolated
lymphocytes on the blood film is a
further clue.
Hexosaminidase A deficiency is
confirmed on white cell enzymology.
Management
Currently, management is supportive.
However, research into substrate-
deprivation therapy, thereby avoiding
accumulation in the first place, is under
investigation.
 Gaucher disease
Glucocerebrosidase deficiency results in
the accumulation of cerebroside in the visceral
organs +/- the brain depending on the type.
Clinical features of Gaucher disease
Type 1
Non-neuronopathic (commonest)
Splenomegaly > hepatomegaly
Anaemia, bleeding tendency
Skeletal pain, deformities, osteopenia
Abdominal pain (splenic infarcts)
 Type 2
Acute neuronopathic
Severe CNS involvement (especially bulbar),
rapidly progressive
Convergent squinting and horizontal gaze palsy
Hepatosplenomegaly
Type 3
Sub-acute neuronopathic
Convergent squint and horizontal gaze palsy
(early sign)
Splenomegaly > hepatomegaly
Slow neurological deterioration
 Diagnosis
Elevated angiotensin-converting enzyme (ACE)
and acid phosphatase are markers for the
disease.
Bone marrow aspiration may reveal Gaucher
cells
White cell enzymes for glucocerebrosidase
give the definitive diagnosis.
The enzyme chitotriosidase is markedly
elevated and may be used to follow disease
activity.
 Management
Enzyme replacement therapy is effective in
visceral disease in types 1 and 3.
Bone marrow transplant has been used in
the past, and may have benefit for cerebral
involvement in type 3.
Splenectomy has been used to correct
thrombocytopenia and anaemia and relieve
mechanical problems but may accelerate
disease elsewhere.
There is no effective treatment for type
2.
 Niemann-Pick disease
Niemann-Pick (sphingomyelinoses)
Types A and B are biochemically and
genetically distinct from C and D.
 Type 1 (sphingomyelinase
deficiency)
Clinical features of type 1
Type A (infantile)
Feeding difficulties
Hepatomegaly > splenomegaly
Cherry-red spot
lung infiltrates
Neurological decline, deaf, blind,
spasticity
 Type B (visceral involvement)
Milder course, no neurological
involvement
Hepatosplenomegaly
Pulmonary infiltrates .
Ataxia
Hypercholesterolaemia
 Diagnosis
Bone marrow aspirate for Niemann-Pick
cells.
White cell enzymes.
Genotyping may help distinguish
between the two types before the onset
of neurological signs.
Management
Supportive.
THANKS