Discovery of PKU- an important milestone in the
history of medicine
Discovered by Asbjørn Følling, one of the first
Norwegian physicians to apply chemical methods to
the study of medicine.
In 1934, the parents,Borgny and Harry Egeland of
two intellectually impaired children approached
Følling to ascertain whether the strange musty
odour of her children’s urine might be related to
their intellectual impairment.
He analysed their urine specimen and found
phenylpyruvic acid in their urine.
Later Følling subsequently requested urine samples
from 430 intellectually impaired patients from a
number of local institutions.
These eight individuals all presented with a mild
complexion (often with eczema), stooping figure
with broad shoulders, a spastic gait, and severe
Family studies of the affected individuals led to the
suggestion of an inherited recessive autosomal
Dr Følling published his findings and suggested the
name ‘imbecillitas phenylpyruvica’ relating the
intellectual impairment to the excreted
substance,thereafter renamed ‘phenylketonuria
HYPERPHENYLALANINEMIA CAUSED BY
DEFICIENCY OF THE COFACTOR
In affected infants with plasma concentrations >20
mg/dL, excess phenylalanine is metabolized to
phenylketones (phenylpyruvate and phenylacetate)
that are excreted in the urine, giving rise to the term
The term hyperphenylalaninemia implies lower
plasma levels (<20 mg/dL) of phenylalanine.
The brain is the main organ affected by
hyperphenylalaninemia. The CNS damage in
affected patients is caused by the elevated
concentration of phenylalanine in brain tissue. The
high blood levels of phenylalanine in PKU saturate
the transport system across the blood–brain barrier
causing inhibition of the cerebral uptake of other
large neutral amino acids such as tyrosine and
The exact mechanism of damage caused by
elevated levels of intracerebral phenylalanine
There have been a few adults with classic PKU and
normal intelligence who have never been treated
with a phenylalanine-restricted diet. Phenylalanine
content of the brain in these individuals was found
to be close to that of normal subjects when studied
by magnetic resonance spectroscopy (MRS).
Severe hyperphenylalaninemia (plasma phenylalanine
levels >20 mg/dL), if untreated, invariably results in the
development of signs and symptoms of classic PKU.
The affected infant is normal at birth. Profound
intellectual disability develops gradually if the infant
remains untreated. Cognitive delay may not be evident
for the first few months.
In untreated patients, 50-70% will have an IQ below 35,
and 88-90% will have an IQ below 65. Only 2-5% of
untreated patients will have normal intelligence.
Many patients require institutional care if the condition
remains untreated. Vomiting, sometimes severe enough
to be misdiagnosed as pyloric stenosis, may be an early
Older untreated children become hyperactive with
autistic behaviors, including purposeless hand
movements, rhythmic rocking, and athetosis.
Neurologic signs include seizures (approximately
25%), spasticity, hyperreflexia, and tremors.
Diagnosis is through new born screening in
In developing countries identification of
phenylketones in the urine by ferric chloride may
offer a simple test for diagnosis of infants with
developmental and neurologic abnormalities.
NEONATAL DIAGNOSIS OF PKU
Early diagnosis of PKU is important because the
disease is treatable by dietary means.
Newborn with PKU frequently has normal blood
levels of phenylalanine (PA) at birth
As the mother clears increased blood PA in her
fetus through placenta. So, test performed at birth
may show false –ve results.
PA begins to be elevated when newborn takes milk
(containing proteins) for at least 24 hours
Accordingly, feeding with milk for 48 hours is
sufficient to raise the newborn blood PA to levels
that can be used for diagnosis.
NEONATAL SCREENING OF PKU
Must be made within one month of birth, if mental
retardation is to be prevented.
Screening program for neonate (6 –14 days of
life) using Guthrie test is performed:
- A disk of a filter paper containing blood from a
heel prick is placed on plates impregnated with a
microorganism, Bacillus subtilis, which requires
phenylalanine for growth, the only source being the
- The growth of the organism is a positive test.
Test has to be confirmed by measuring blood
TREATMENT OF CLASSIC PKU
Principles of treatment of PKU
Treatment must begin during first 7-10 days of life to
prevent mental retardation.
Treatment aims at maintaining blood phenylalanine
levels close to normal range.
Treatment should be continued for many years (at
least till age of 8) as high blood levels of
phenylalanine between 4 – 8 years leads to mental
However, life-long treatment by diet restriction of
phenylalanine is preferred
Avoiding low levels of phenylalanine in blood as it is
an essential amino acid and therefore is essential for
physical & mental growth.
Tyrosine is must be supplied in diet as it cannot be
synthesized from phenylalanine in cases of PKU
Protocol of treatment:
By feeding synthetic amino acid preparations low in
Supplemented with some natural foods such as
vegetables, fruits & certain cereals selected for their low
phenylalanine content & rich in tyrosine.
MRI brain of a 27-year-old man who was screened at birth and
was found to have a borderline phenylalanine level.
HYPERPHENYLALANINEMIA CAUSED BY
DEFICIENCY OF THE COFACTOR
In 1-3% of infants with hyperphenylalaninemia, the
defect resides in 1 of the enzymes necessary for
production or recycling of the cofactor BH4.
If these infants are misdiagnosed as having PKU,
they may deteriorate neurologically despite
adequate control of plasma phenylalanine.
More than half of the reported patients have had a
deficiency of 6-pyruvoyltetrahydropterin synthase.
Patients with hyperphenylalaninemia as a result of
BH4 deficiency also manifest neurologic findings
related to deficiencies of the neurotransmitters
dopamine and serotonin.
The clinical manifestations differ greatly from PKU.
Neurologic symptoms often manifest in the first few
months of life and include extrapyramidal signs
(choreoathetotic or dystonic limb movements, axial
and truncal hypotonia, hypokinesia), feeding
difficulties, and autonomic abnormalities.
Intellectual disability, seizures, hypersalivation, and
swallowing difficulties are also seen.
The symptoms are usually progressive and often
have a marked diurnal fluctuation.
Diagnosd by Measurement of neopterin (oxidative
product of dihydroneopterin triphosphate) and
biopterin (oxidative product of dihydrobiopterin and
BH4) in body fluids, especially urine and BH4
The control of hyperphenylalaninemia is important
in patients with cofactor deficiency, because high
levels of phenylalanine cause intellectual disability
and also interfere with the transport of
neurotransmitter precursors (tyrosine, tryptophan)
into the brain. Plasma phenylalanine should be
maintained as close to normal as possible (<6
mg/dL). This can be achieved by oral
supplementation of BH4 (5-20 mg/kg/day).
Lifelong supplementation with neurotransmitter
precursors such as l-dopa and 5-
hydroxytryptophan, along with carbidopa to inhibit
degradation of l-dopa before it enters the CNS, is
necessary in most of these patients even when
treatment with BH4 normalizes plasma levels of
TYROSINEMIA TYPE I (TYROSINOSIS,
Caused by a deficiency of the enzyme
Organ damage is believed to result from accumulation
of metabolites of tyrosine degradation, especially
fumarylacetoacetate and succinylacetone.
An acute hepatic crisis commonly heralds the onset of
the disease and is usually precipitated by an intercurrent
illness that produces a catabolic state.
Renal involvement is manifested as a Fanconi-like
syndrome with hyperphosphaturia, hypophosphatemia,
normal anion gap metabolic acidosis, and vitamin D–
resistant rickets. Nephromegaly and nephrocalcinosis
may be present on ultrasound examination. Glomerular
failure may occur in adolescents and older patients.
Episodes of acute peripheral neuropathy
resembling acute porphyria occur in approximately
40% of affected children.
These crises, often triggered by a minor infection,
are characterized by severe pain, often in the legs,
associated with extensor hypertonia of the neck
and trunk, vomiting, paralytic ileus, and,
occasionally, self-induced injuries of the tongue or
Marked weakness and paralysis occur in about
30% of episodes, which may lead to respiratory
failure requiring mechanical ventilation.
Crises typically last 1-7 days but recuperation from
paralytic crises can require weeks to months
Diagnosis is usually established by demonstration
of elevated levels of succinylacetone in urine or
A diet low in phenylalanine and tyrosine can slow
but does not halt the progression of the condition.
The treatment of choice is nitisinone, which
inhibits tyrosine degradation at 4-HPPD .This
treatment prevents acute hepatic and neurologic
HOMOCYSTINURIA CAUSED BY CYSTATHIONINE
Β-SYNTHASE DEFICIENCY (CLASSIC
most common inborn error of methionine metabolism.
The diagnosis is usually made after 3 yr of age, when
subluxation of the ocular lens (ectopia lentis) occurs.
Progressive intellectual disability is common.
Psychiatric and behavioral disorders have been
observed in more than 50% of affected patients.
Convulsions occur in approximately 20% of patients.
Thromboembolic episodes involving both large and
small vessels, especially those of the brain, are common
and may occur at any age.
Elevations of both methionine and homocystine (or
homocysteine) in body fluids are the diagnostic
Freshly voided urine should be tested for
homocystine because this compound is unstable
and may disappear as the urine is stored.
Treatment with high doses of vitamin B6 (200-
1,000 mg/24 hr) causes dramatic improvement in
most patients who are responsive to this therapy.
Restriction of methionine intake in conjunction with
cysteine supplementation is recommended for
patients who are unresponsive to vitamin B6.
HOMOCYSTINURIA CAUSED BY DEFECTS
IN METHYLCOBALAMIN FORMATION
Methylcobalamin is the cofactor for the enzyme
methionine synthase, which catalyzes
remethylation of homocysteine to methionine.
The clinical manifestations are similar in patients
with all of these defects. Vomiting, poor feeding,
failure to thrive, lethargy, hypotonia, seizures, and
developmental delay may occur in the first few
months of life.
Laboratory findings include megaloblastic
anemia, homocystinuria, and hypomethioninemia.
The presence of megaloblastic anemia
differentiates these defects from homocystinuria
due to methylenetetrahydrofolate reductase
Treatment with vitamin B12 in the form of
hydroxycobalamin (1-2 mg/24 hr) is used to correct
the clinical and biochemical findings.
Results vary among both diseases and sibships
HOMOCYSTINURIA CAUSED BY DEFICIENCY OF
This enzyme reduces 5,10-
methylenetetrahydrofolate to form 5-
methyltetrahydrofolate, which provides the methyl
group needed for remethylation of homocysteine to
Clinical findings vary from apnea, seizure,
microcephaly, coma, and death to developmental
delay, ataxia, and motor abnormalities or even
Premature vascular disease or peripheral
neuropathy has been reported as the only
manifestation of this enzyme deficiency in some
Laboratory findings include moderate
homocystinemia and homocystinuria.
The methionine concentration is low or low normal.
This finding differentiates this condition from classic
homocystinuria caused by cystathionine β-synthase
Absence of megaloblastic anemia distinguishes this
condition from homocystinuria caused by
Treatment of severe MTHFR deficiency with a
combination of folic acid, vitamin B6, vitamin B12,
methionine supplementation, and betaine has been
tried. Of these, early treatment with betaine seems
to have the most beneficial effect
Occurs due to sulfite oxidase
deficiency(Molybdenum Cofactor Deficiency).
The enzyme and or the cofactor deficiencies
produce identical clinical manifestations.
Refusal to feed, vomiting, severe intractable
seizures (tonic, clonic, myoclonic), cortical atrophy
with subcortical multicystic lesions, and severe
developmental delay may develop within a few
weeks after birth.
The accumulation of sulfites in body fluids in this
condition causes the inhibition of antiquitin enzyme
which is necessary for conversion of α-aminoadipic
semialdehyde to α-aminoadipic acid; the resultant
accumulation of α-aminoadipic semialdehyde and
its cyclic form P6C causes the inactivation of
pyridoxal-5-phosphate (active form of vitamin B6)
and, hence, the vitamin B6–dependent epilepsy.
These children excrete large amounts of sulfite,
thiosulfate, S-sulfocysteine, xanthine, and
hypoxanthine in their urine.
No effective treatment is available; large doses of
vitamin B6 (5-100 mg/kg) result in dramatic
alleviation of seizures but do not seem to alter the
devastating neurologic outcome. Most children die
in the 1st 2 yr of life.
In this autosomal recessive disorder, named after
the first affected family, there is a defect in the
transport of monoamino-monocarboxylic amino
acids (neutral amino acids), including tryptophan,
by the intestinal mucosa and renal tubules.
Most children with Hartnup defect remain
asymptomatic. The major clinical manifestation in
the rare symptomatic patient is cutaneous
Some patients may have intermittent ataxia
manifested as an unsteady, widebased gait. The
ataxia may last a few days and usually recovers
Mental development is usually normal
Two individuals in the original kindred were
cognitively impaired. Episodic psychiatric
manifestations such as irritability, emotional
instability, depression, and suicidal tendencies,
have been observed; these changes are usually
associated with bouts of ataxia.
The main laboratory finding is aminoaciduria,
which is restricted to neutral amino acids (alanine,
serine, threonine, valine, leucine, isoleucine,
phenylalanine, tyrosine, tryptophan, histidine).
Urinary excretion of proline, hydroxyproline, and
arginine remains normal. This finding differentiates
Hartnup disorder from other causes of generalized
aminoaciduria, such as Fanconi syndrome
Diagnosis is established by the striking intermittent
nature of symptoms and the previously described
Treatment with nicotinic acid or nicotinamide (50-
300 mg/24 hr) and a high-protein diet results in a
favorable response in symptomatic patients
The term "organic acidemia" or "organic aciduria" (OA)
applies to a group of disorders characterized by the
excretion of nonamino organic acids in urine.
Most organic acidemias result from dysfunction of a
specific step in amino acid catabolism, usually the result
of deficient enzyme activity.
The pathophysiology results from accumulation of
precursors and deficiency of products of the affected
The majority of the classic organic acid disorders are
caused by abnormal amino acid catabolism of branched
chain amino acids or lysine.
OA also includes disorders causing accumulation of
other organic acids include those derived from those
associated with lactic acid and dicarboxylic acidemias
associated with defective fatty acid degradation
CLINICAL MANIFESTATIONS OF OA
The organic acidemias share many clinical similarities.
A neonate affected with an organic acidemia (OA) is
usually well at birth and for the first few days of life.
The usual clinical presentation is that of toxic
encephalopathy and includes vomiting, poor feeding,
neurologic symptoms such as seizures and abnormal
tone, and lethargy progressing to coma.
Several rare OAs present with neurologic signs without
concomitant biochemical findings such as
hyperammonemia and acidosis, e.g. D2hydroxyglutaric
aciduria, 3methylglutaconic aciduria caused by
3methylglutaconic acid dehydratase deficiency, and
Methylmalonic aciduria, cblC variant, may present with
developmental delay, minor dysmorphology, and
hypotonia without acidosis.
Lateonset 3methylcrotonyl carboxylase deficiency may
present as developmental delay without Reyelike
syndrome, in contrast to the earlyonset form.
In the older child or adolescent, variant forms of the OAs
can present as loss of intellectual function, ataxia or
other focal neurologic signs, Reye syndrome, recurrent
ketoacidosis, or psychiatric symptoms.
A variety of MRI abnormalities have been described in
the OAs, including distinctive basal ganglia lesions in
glutaricacidemia type I (GA I), white matter changes in
maple syrup urine disease (MSUD), and abnormalities
of the globus pallidus in methylmalonic acidemia.
Macrocephaly is common in GA I.
Individuals with organic acidemias have a greater
risk of infection and a higher incidence of
pancreatitis, which can be fatal.
Methylmalonic acidemia is associated with an
increased frequency of renal failure and the cblC
variant of methylmalonic acidemia is associated
with pigmentary retinopathy and poor
developmental outcome in the earlyonset form.
Acidosis: Serum bicarbonate lower than:
22 mmol/L in individuals younger than age one
17 mmol/L in neonates
In most organic acidemias, the acidosis is severe,
with an anion gap higher than 20. Early in the
course, however, the acidosis may be less severe
and the anion gap smaller.
Ketosis: A positive (not trace) urine dipstick for
ketones OR A urine organic acid profile containing
excess βhydroxybutyrate and acetoacetic acid as
defined by the norms of the laboratory performing
Neonates do not normally produce much
acetoacetate, ketosis detected in neonates by
dipstick should prompt serious consideration of an
Hyperammonemia: Plasma ammonium
concentration exceeding the reference range for the
laboratory performing the test and the age of the
affected individual, usually greater than:
150 μg/dL in neonates
70 μg/dL in infants to age one month
35-50 μg/dL in older children and adults
Abnormal liver function tests:
Hypoglycemia: Serum glucose lower than:
40 mg/dL in term and preterm infants
60 mg/dL in children
76 mg/dL over age 16 years
Neutropenia: Absolute neutrophil count (ANC) less
than 1500/mm . Total white cell counts vary with
age and local laboratory reference ranges may
need to be taken into account.
Gas chromatography/mass spectrometry
Firstline diagnosis in the organic acidemias is urine
organic acid analysis by GC/MS, utilizing a capillary
Organic acids can be measured in any physiologic
fluid. However, it is most effective to use urine to
identify the organic acids that signal these
disorders, as semiquantitative methods may not
identify the important compounds in plasma
The organic acids found in the urine provide a high
degree of suspicion for the specific pathway
The urinary organic acid profile is nearly always
abnormal in the face of acute illness with
However, in some disorders the diagnostic analytes
may be present only in small or barely detectable
amounts when the affected individual is not acutely
Thus, it is critical to obtain a urine sample during
the acute phase of the illness, even if the sample
needs to be frozen and saved until the testing can
Metabolic Findings in Organic
Acidemias Caused by Abnormal
Amino Acid Catabolism
Many of the organic acidemias respond to
treatment, and in the neonate especially, early
diagnosis and prompt management are essential to
a good outcome.
The aim of therapy is to restore biochemical and
The treatments, while similar in principle, depend
on the specific biochemical lesion and are based on
the position of the metabolic block and the effects
of the toxic compounds
Treatment strategies are:
Dietary restriction of the precursor amino acids
Use of adjunctive compounds to:
Dispose of toxic metabolites
Increase activity of deficient enzymes
o Longterm care: Frequent monitoring of growth,
development, and biochemical parameters is
essential. Longterm outcome can be excellent in
the organic acidemias. However, appropriate
management does not guarantee a good outcome,
as individuals affected with an OA are medically
MANAGEMENT OF ACUTE DECOMPENSATION
Frequent episodes of decompensation can be
devastating to the central nervous system.
Any source of catabolic stress,such as vomiting,
diarrhea, febrile illness, and decreased oral intake can
lead to decompensation, which requires prompt and
During acute decompensation, treatment strategies are
directed toward elimination of the toxic amino acid
precursors by restriction of their intake and the use of
adjunctive measures such as hemodialysis.
During acute decompensation, critical care support is
often required, acidosis may need to be corrected, and
careful and frequent biochemical monitoring is crucial.
CLASSIC MAPLE SYRUP URINE DISEASE
Decarboxylation of leucine, isoleucine, and valine is
accomplished by a complex enzyme system
(branched-chain α-ketoacid dehydrogenase
[BCKDH]) using thiamine (vitamin B1)
pyrophosphate as a coenzyme.
This mitochondrial enzyme consists of 4 subunits:
E1α, E1β, E2, and E3. The E3 subunit is shared
with 2 other dehydrogenases in the body, namely
pyruvate dehydrogenase and α-ketoglutarate
Deficiency of any of these subunits causes maple
syrup urine disease (MSUD)named after the sweet
odor of maple syrup found in body fluids, especially
This form has the most severe clinical
Affected infants who are normal at birth develop
poor feeding and vomiting in the 1st wk of life;
lethargy and coma may ensue within a few days.
Physical examination reveals hypertonicity and
muscular rigidity with severe opisthotonos. Periods
of hypertonicity may alternate with bouts of
flaccidity manifested as repetitive movements of the
extremities (boxing and bicycling).
Neurologic findings are often mistakenly thought to
be caused by generalized sepsis and meningitis.
Cerebral edema may be present; convulsions occur
in most infants, and hypoglycemia is common.
In contrast to most hypoglycemic states, correction
of the blood glucose concentration does not
improve the clinical condition.
Aside from the serum glucose, routine laboratory
findings are usually unremarkable, except for
varying degrees of metabolic acidosis.
Death usually occurs in untreated patients in the
first few weeks or months of life.
Diagnosis is often suspected because of the
peculiar odor of maple syrup found in urine, sweat,
It is usually confirmed by amino acid analysis
showing marked elevations in plasma levels of
leucine, isoleucine, valine, and alloisoleucine (a
stereoisomer of isoleucine not normally found in
blood) and depression of alanine.
Leucine levels are usually higher than those of the
other 3 amino acids.
Urine contains high levels of leucine, isoleucine,
and valine and their respective ketoacids.
These ketoacids may be detected qualitatively by
adding a few drops of 2,4-dinitrophenylhydrazine
reagent (0.1% in 0.1N HCl) to the urine; a yellow
precipitate of 2,4-dinitrophenylhydrazone, is formed
in a positive test.
Neuroimaging during the acute state may show
cerebral edema, which is most prominent in the
cerebellum, dorsal brainstem, cerebral peduncle,
and internal capsule.
After recovery from the acute state and with
advancing age, hypomyelination and cerebral
atrophy may be seen in neuroimaging of the brain.
The enzyme activity can be measured in leukocytes
and cultured fibroblasts.
T2-weighted MRI demonstrates elevated signal intensity of white matter
in the thalamus, globus pallidus, and posterior limb of the internal
capsule (A); midbrain (B); and pons and cerebellar white matter (C)
Treatment of the acute state is aimed at hydration
and rapid removal of the branched-chain amino
acids and their metabolites from the tissues and
body fluids by hemodialysis or peritoneal dialysis.
Cerebral oedema should be treated with mannitol,
diuretics or hypertonic saline.
Treatment after recovery from the acute state
requires a diet low in branched-chain amino acids.
These amino acids cannot be synthesized
endogenously, small amounts of them should be
added to the diet; the amount should be titrated
carefully by performing frequent analyses of the
plasma amino acids.
Liver transplantation has been performed in a
number of patients with classic MSUD with
promising results. These children have been able to
tolerate a normal diet.
The long-term prognosis of affected children
Severe ketoacidosis, cerebral edema, and death
may occur during any stressful situation such as
infection or surgery, especially in midchildhood.
Cognitive and other neurologic deficits are common
This condition is caused by the deficiency of the enzyme
isovaleryl CoA dehydrogenase.
Lethargy, convulsions, and coma may ensue in acute
The characteristic odor of “sweaty feet” may be present
(in body sweat and cerumen, but not in the urine).
Diagnosis is established by demonstrating marked
elevations of isovaleric acid and its metabolites
(isovalerylglycine, 3-hydroxyisovaleric acid) in body
fluids, especially urine. The main compound in plasma is
isovalerylcarnitine, which can be measured even in a
few drops of dried blood on a filter paper.
Along with other supportive measures,as
isovalerylglycine has a high urinary clearance,
administration of glycine (250 mg/kg/24 hr) is
recommended to enhance formation of
isovalerylglycine. l-Carnitine (100 mg/kg/24 hr
orally) also increases removal of isovaleric acid by
forming isovalerylcarnitine, which is excreted in the
After recovery from the acute attack, the patient
should receive a low-protein diet (1.0-1.5 g/kg/24
hr) and should be given glycine and carnitine
supplements. Pancreatitis (acute or recurrent
forms) has been reported in survivors.
Normal development can be achieved with early
and proper treatment.
HOLOCARBOXYLASE SYNTHETASE DEFICIENCY
(MULTIPLE CARBOXYLASE DEFICIENCY NEONATAL
OR EARLY FORM)
Infants with this rare autosomal recessive disorder
become symptomatic in the first few weeks of life.
Symptoms may appear as early as a few hours
after birth to 21 mo of age.
Clinically, the affected infants who seem normal at
birth develop breathing difficulties (tachypnea and
apnea) shortly after birth.
Feeding problems, vomiting, and hypotonia are also
If the condition remains untreated, generalized
erythematous rash with exfoliation and alopecia (partial
or total), failure to thrive, irritability, seizures, lethargy,
and even coma may occur.
Developmental delay is common.
Immune deficiency manifests with susceptibility to
The urine may have a peculiar odor, which has been
described as similar to tomcat urine.
Laboratory findings include metabolic acidosis,
ketosis, hyperammonemia, and the presence of a
variety of organic acids (lactic acid, propionic acid, 3-
methylcrotonic acid, 3-methylcrotonylglycine,
tiglylglycine, methylcitrate, and 3-hydroxyisovaleric acid)
in body fluids.
Diagnosis is confirmed by the enzyme assay in
lymphocytes or cultured fibroblasts or by identification of
the mutant gene
Treatment with biotin (10 mg/day orally) usually
results in an improvement in clinical manifestations
and may normalize the biochemical abnormalities.
Early diagnosis and treatment are critical to prevent
irreversible neurologic damage.
In some patients, however, complete resolution
may not be achieved even with large doses (up to
80 mg/day) of biotin.
3-METHYLGLUTACONIC ACIDURIA TYPE III
(COSTEFF OPTIC ATROPHY SYNDROME)
Clinical manifestations in these patients include
early onset optic atrophy and later development of
choreoathetoid movements, spasticity, ataxia,
dysarthria, and mild developmental delay.
These patients excrete moderate amounts of 3-
methylglutaconic and 3-methylglutaric acids.
Activity of the enzyme 3-methylglutaconyl CoA
hydratase is normal.
The reason for the increased excretion of these
organic acids remains unclear.
No effective treatment is available.
This condition is a result of a deficiency of HMG-
CoA lyase.This enzyme catalyzes the conversion of
HMG-CoA to acetoacetate and is a rate-limiting
enzyme for ketogenesis.
Episodes of vomiting, severe hypoglycemia,
hypotonia, acidosis with mild or no ketosis, and
dehydration may rapidly lead to lethargy, ataxia,
Urinary excretion of 3-hydroxy-3-methylglutaric acid
and other proximal intermediate metabolites of
leucine catabolism (3-methylglutaconic acid and 3-
hydroxyisovaleric acid) is markedly increased
causing the urine to smell like cat urine
Mevalonic acid, an intermediate metabolite of
cholesterol synthesis, is converted to 5-
phosphomevalonic acid by the action of the enzyme
mevalonate kinase (MVK).
Clinical manifestations in severe form include
intellectual disability, failure to thrive,growth
retardation, hypotonia, ataxia, hepatosplenomegaly,
cataracts, and facial dysmorphism (dolichocephaly,
frontal bossing, low-set ears, downward slanting of
the eyes, and long eyelashes).
Along with high mevalonic acid in urine, Serum
concentration of creatine kinase is markedly
PROPIONIC ACIDEMIA (PROPIONYL
COENZYME A CARBOXYLASE
In the severe form of the condition, patients develop
symptoms in the first few days or weeks of life.
Poor feeding, vomiting, hypotonia, lethargy,
dehydration, and clinical signs of severe
ketoacidosis progress rapidly to coma and death.
Seizures occur in approximately 30% of affected
Moderate to severe intellectual disability and
neurologic manifestations reflective of
extrapyramidal (dystonia, choreoathetosis, tremor),
and pyramidal (paraplegia) dysfunction are
common sequelae in the older survivors.
Neuroimaging shows these abnormalities, which
usually occur after an episode of metabolic
decompensation, to be a result of damage to the
basal ganglia, especially to the globus pallidus.
This phenomenon has been referred to in the
literature as metabolic stroke. This is the main
cause of neurologic sequelae seen in the surviving
In acute form, besides supportive measures, gut
sterilization by neomycin or metronedazole should
be done to curtail the production of propionic acid
by intestinal flora.
Long-term treatment consists of a low-protein diet
(1.0-1.5 g/kg/24 hr) and administration of l-carnitine
(50-100 mg/kg/24 hr orally).
Mental development and IQ of patients with
methylmalonic acidemia may remain within the
normal range despite repeated acute attacks and
regardless of the nature of the enzyme deficiency.
Vitamin B12 should be added in treatment of the
patients having defects in B12 metabolism.
Metabolic strokes have been reported in a few
patients during an acute episode of metabolic
These patients have survived with major
extrapyramidal (tremor, dystonia) and pyramidal
GLUTARIC ACIDURIA TYPE 1
Glutaric aciduria type 1 (GA-1) is an autosomal
recessive disorder of lysine, hydroxylysine, and
tryptophan metabolism caused by deficiency of
It results in the accumulation of 3-hydroxyglutaric
and glutaric acid.
Glutaric acid has a cytotoxic effect and causes
cerebral atrophy and brain damage.
It is characterized by macrocephaly at birth or
shortly after, dystonia, and many times resembling
seizures at the first episode, with degeneration of
the caudate and the putamen.
MRI brain reveals frontotemporal atrophy, dilated sylvian fissures with open
opercula (arrow), diffuse hyperintense lesions in bilateral basal ganglia, and
both frontal whitematter and bilateral periventricular area.Widening of the
sylvian fissure gives the characteristic “bat-wing” appearance.
Therapy consists in carnitine supplementation to
remove glutaric acid, a diet restricted in amino
acids capable of producing glutaric acid, and
prompt treatment of intercurrent illnesses.
Early diagnosis and therapy reduce the risk of
acute dystonia in patients with GA-1