Hevi Pediatric Teaching Hospital
• 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-
• MUCOPOLYSACCHARIDOSES (MPS) (Hurler syndrome)
• SPHINGOLIPIDOSES (Gaucher disease, Niemann-Pick
Disorders of Amino Acid Metabolism
• Disorders of amino acid metabolism include
• MSUD, and
• 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.
• Women of childbearing age with PKU must
maintain strict adherence to their diet
because of the teratogenic effects of elevated
• Infants born to mothers with uncontrolled
PKU can have microcephaly, growth
retardation, developmental delay, and
congenital heart disease.
• 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.
• There are five known inherited disorders of
• 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
• Tyrosine is raised in the plasma and the
presence of succinylacetone in urine is
• Confirm by liver enzymology
• Dietary restriction of tyrosine and
phenylalanine with or without liver
• 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
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
• Much of the toxicity is related to the elevated
level of leucine, which is neurotoxic.
(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.
• Elevated branch-chain amino acids plus
• Elevated branch-chain oxo-acids on urinary
• Enzymology on fibroblasts
• Ammonia, lactate, and bicarbonate are often
• Restriction of intake of the BCAAs.
• The enzyme cofactor thiamine is given in the
hope of improving residual enzyme activity.
• Homocystinuria is an autosomal recessive
• classically caused by cystathionine beta-
synthase deficiency. This enzyme is
responsible for metabolizing homocysteine to
• Pyridoxine is a cofactor for this enzyme.
• 50% of patients will respond to pyridoxine
• Folate should also be supplemented as
depletion affects response.
• Other treatment modalities include
• Betaine is effective at lowering homocysteine .
• NKH results from defects in the glycine
• Glycine is a neurotransmitter; excitatory
centrally and inhibitory peripherally.
• Clinical features
• Increased fetal movements (inutero seizures)
• Hiccups and hypotonia.
• Progressive apnea/encephalopathy.
• Developmental delay.
• EEG shows a burst suppression pattern;
• elevated glycine on urinary or plasma amino
• 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
• 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
• All disorders of the urea cycle are inherited in an
autosomal recessive manner, except OTC
deficiency, which is inherited in an X-linked
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
• Progressive spastic diplegia and developmental
delay (arginase deficiency)
• Milder forms can present during childhood with
episodic encephalopathy triggered by
intercurrent metabolic stress.
• 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
• Acute treatment during crisis periods is
centered around reducing the levels of
• dialysis and IV medications designed to
provide alternative mechanisms of nitrogen
excretion, such as sodium benzoate and
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
• Progressive extra pyramidal syndrome (MMA, PA) basal
• Renal insufficiency (MMA)
• Pancreatitis .
• Cardiomyopathy (PA, MMA)
• Patients with isovaleric acidemia are often described as
having a peculiar body odor (sweaty feet)
• Both the acylcarnitine profile and urine
organic acid profile are essential in making a
• Protein restriction.
• Carnitine supplementation (provides alternate
methods of propionic acid and methylmalonic
• There are B12 responsive forms of methylmalonic
• 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-
• Clinical Manifestations:
• 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
• Elevated levels of glutaric acid in the urine or
• Abnormal acylcarnitine profile.
• Patients do not generally have hypoglycemia,
acidosis, or hyperammonemia.
• 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
• Fatty acids are oxidized by most tissues except
the brain, which is reliant on hepatic fatty acid for
• Fatty acids are the preferred substrate for cardiac
• 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.
dehydrogenase (MCAD) deficiency
• MCAD deficiency is the commonest fat oxidation
• Clinical features of MCAD deficiency
• Hypoketotic hypoglycaemia(During prolonged fasting)
• Reye-like syndrome: hepatomegaly, deranged liver
• Mean age at presentation 15 months, commonest
precipitant is diarrhoea
• Sudden infant death (consider in older infant> 6
• 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 .
• 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
• Disorders of carbohydrate metabolism
• hereditary fructose intolerance,
• and the GSDs (Glycogen storage disease)
• 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 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
• 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
• 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
• 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
• 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
• the muscle forms present with weakness and
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
• 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
• 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.
• Peroxisomes harbour many vital cellular
• the synthesis of plasmalogens, (essential
constituents of cell walls), cholesterol and bile
• the oxidation of very long- chain fatty acids
and breakdown of phytanic acid (vitamin A)
• 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
• 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
• ZS is the classic peroxisomal biogenesis
disorder with distinctive dysmorphic features.
• prominent forehead, hypertelorism, large
• 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.
• Loss of all peroxisomal functions - raised very-
long-chain fatty acids, phytanate and bile acid
intermediates and decreased plasmalogens.
• Confirmatory enzymology on fibroblasts.
• Management is supportive.
• Docosahexaenoic acid supplementation has
• The paediatric cerebral form presents with severe
neurological degeneration, usually between 5 and 10
• Brothers in the same family may present at different
• Clinical features of XAID
• School failure, behaviour problems
• Visual impairment
• 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.
• 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.
• 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.
• Mucopolysaccharides (glycosaminoglycans) are
structural molecules integral to connective
tissues such as cartilage.
• Degradation occurs within lysosomes, requiring
• Patients with MPS appear normal at birth and
usually present with developmental delay in the
• The features of storage become more obvious
Type Disorder Inheritanc
AR + +++ +++ +++
XL - +++ +++ +++
AR + + + +++
AR + +++ + -
AR + +++ +++ -
AR + +++ +++ +++
• Hurler syndrome is the classical MPS with storage
affecting the body and CNS.
• Sanfillipo syndrome predominantly affects the
• 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 typifies the MPS group and
their associated clinical problems.
• The enzyme deficiency is a-iduronidase, a
• 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
• The ends of the radius and ulna angulate toward each
• 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
• 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.
• Urinary screen for glycosaminoglycans (raised
dermatan and heparan sulphate).
• Enzymology confirmed on white cells.
• Treatment depends on early recognition to
allow early bone marrow transplantation,
which significantly modifies the phenotype.
• Enzyme replacement clinical trials are
• Supportive care is the mainstay of
untransplanted patients, with particular
regard to the chest and airway requiring 3-
monthly sleep studies.
• 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.
• The presence of vacuolated lymphocytes on
the blood film is a further clue.
• Hexosaminidase A deficiency is confirmed on
white cell enzymology.
• Currently, management is supportive.
However, research into substrate-deprivation
therapy, thereby avoiding accumulation in the
first place, is under investigation.
• 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),
• Convergent squinting and horizontal gaze palsy
• Type 3
• Sub-acute neuronopathic
• Convergent squint and horizontal gaze palsy
• Splenomegaly > hepatomegaly
• Slow neurological deterioration
• Elevated angiotensin-converting enzyme (ACE)
and acid phosphatase are markers for the
• 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.
• 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
• There is no effective treatment for type 2.
• 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
• Pulmonary infiltrates .
• Bone marrow aspirate for Niemann-Pick cells.
• White cell enzymes.
• Genotyping may help distinguish between the
two types before the onset of neurological