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Section 18 Metabolic Disorders
Chapter
135
Inborn Errors of Metabolism:
Disorder of Adults?
Kothiwale VA, Varun Kumar B
INTRODUCTION
Group 1
Inborn errors of metabolism (IEMs) are individually rare, but
collectively numerous. The term was coined by Archibald Garrod,
who in 1927 presented the Huxley lecture at Charing Cross Hospital.1
Until recently, IEMs were considered a specialty of pediatricians.
Indeed, the term “inborn” has meant for a long time, a disease which
starts in the newborn period or at least in childhood. Although
most IEMs can have mild forms starting in adolescence or late in
adulthood, this concept of “adult onset IEMs” has not reached the
medical community until recently.
They refer to single gene disorders wherein loss of function of a
single enzyme results in abnormalities in synthesis or catabolism
of proteins, carbohydrates or fats, which results in a disruption in a
metabolic pathway. This results in toxic accumulations of substrates
before the disruption, intermediates from alternative pathways,
and/or defects in energy production and utilization. Nearly every
metabolic disease has several forms that vary in age of onset, clinical
severity and mode of inheritance.
The mode of inheritance determines the male to female ratio of
affected and many IEMs have multiple forms that differ in their mode
of inheritance.
It involves cellular organelles and includes lysosomal, peroxisomal,
glycosylation and cholesterol synthesis defects.
• Mucopolysaccharidosis (Hurler, Hunter, Sanfilippo, Morquio,
Maroteaux, Sly, etc.)
• Sphingolipidosis (gangliodosis, Tay-Sachs, Sandhoff )
• Lactosylceramidosis (Gaucher, Farber, Niemann-Pick, Krabbe,
sulfatase deficiency)
• Glycoproteinases (fucosidosis, manosidosis, sialidosis, aspartylglucosaminuria)
• Defects in membrane transport (cystinosis, succinic semialdehyde
dehydrogenase, Salla disease)
• Peroxisomal biogenesis defects (Zellweger syndrome, adrenoleukodystrophy, Refsum’s disease, hyperoxaluria Type I)
• Fabry’s disease, Shindler, Canavan disease, Pompe disease, acid
lipase deficiency, acid maltase deficiency, cerebrotendinous
xanthomatosis, Juvenile Batten’s disease, Kuf’s disease, etc.
CLASSIFICATION
A simple method classifies IEMs into disorders involving protein
metabolism, carbohydrate metabolism, lysosomal storage, fatty acid
oxidation defects, mitochondrial disorders, peroxisomal disorders.
A detailed and widely used classification which categorizes IEMs
from a pathophysiological perspective is as follows (Flow chart 1):2
Group 2
It includes IEMs that give rise to an acute or chronic intoxication.
• Disorders of amino acids: Cystinuria, phenylketonuria (PKU),
tyrosinemia, homocystinuria, alcaptonuria, maple syrup urine
disease, Hartnup’s disease, hyperornithinemia with gyrate
atrophy
• Organic acidurias: Beta-ketothiolase deficiency, methyl­
glutaconic academia, isovaleric academia, glutaric academia
Type I, propionic academia, multiple car­boxylase deficiency,
methyl malonic academia
Flow chart 1: Classification of IEMs
Metabolic Disorders
• Urea cycle defects: Citrullinemia, argininemia, argino­succinic
aciduria, carbomyl phosphate synthase deficiency, ornithine
transcarbamylase deficiency
• Sugar intolerance: Galactosemia, epimerase deficiency, hereditary fructose intolerance, galactokinase deficiency
• Others: Porphyrias, Wilson’s disease, aceruloplasminemia,
Lesch-Nyhan syndrome, Sjogren-Larsson syndrome.
Group 3
It includes IEMs that affect the cytoplasmic and mitochondrial
energetic processes. Mitochondrial defects are the most severe and
are generally untreatable (except ketone body defects and coenzyme
q10 defects). Cytoplasmic energy defects are generally less severe.
• Fatty acid oxidation defects: carnitine palmitoyl trans­ferase I,
II deficiency, short-chain acyl-CoA dehydrogenase deficiency,
medium-chain acyl-CoA dehydrogenase defi­ciency, very
long chain acyl CoA dehydrogenase deficiency, long-chain
3-hydroxyacyl-CoA dehydrogenase deficiency, glutaric academia
Type II, carnitine uptake deficiency, hy­droxymethylglutaryl CoA
lyase
• Mitochondrial disorders: pyruvate dehydrogenase com­plex
deficiency, pyruvate carboxylase deficiency, myoclonic epilepsy
with ragged red fibers, mitochondrial encephalopathy with
lactic acidosis and stroke, phospho­enolpyruvate carboxykinase
deficiency, Leber’s hereditary optic atrophy, neuropathy ataxia
and retinitis pigmentosa (NARP)
• Glycogen storage disorders: von Gierke’s disease (Type I),
Pompe’s disease (Type II), Cori’s or Forbes’ disease (Type III),
Anderson’s disease (Type IV), McArdle’s disease (Type V), Her’s
disease (Type VI), Tarui’s disease (Type VII), Type IX, Fanconi
Bickel syndrome (Type XI), red cell aldolase deficiency (Type
XII), Type XIII, Type 0.
CLINICAL MANIFESTATIONS
Inborn errors of metabolism (IEMs) can affect any organ system and
manifestations vary from those of acute life-threatening disease to
subacute progressive degenerative disorder. Progression may be
unrelenting with rapid life-threatening deterioration over hours,
episodic with intermittent decompensations and asymptomatic
intervals, or insidious with slow degeneration over decades. All
three groups of IEMs can manifest in adults, more so with Group I
disorders.
In neonates and children, manifestations are nonspecific and
very similar to that of septicemia, a major reason why IEMs go
undetected. There may be dysmorphic features present at birth
(generally when fetal energy is affected), or develop during the first
year of life (lysosomal disorders).
In adults, the symptoms may include mild-to-profound mental
retardation, autism, learning disorders, behavioral disturbances,
muscle weakness, progressive paraparesis, hemiparesis, dystonia,
chorea, ataxia, ophthalmoplegia, visual deficit, epileptic crisis,
hepatosplenomegaly and hypoglycemia.
Some manifestations may be intermittent, precipitated by the
stress of illness, or progressive, with worsening over time. Disorders
manifested by subtle neurologic or psychiatric features often go
undiagnosed until adulthood.
Group I
614
Onset in adulthood (upto > 70 years). Among the organs impacted,
the nervous system is by far most common. Thus, late onset forms
of IEMs often display psychiatric or neurological presentations.
These include atypical psychosis or depression, unexplained coma,
peripheral neuropathy, cerebellar ataxia, spastic paraparesis,
dementia, movement disorders, epilepsy, etc.
Section 18
Group II
They do not interfere with the embryofetal development and
they present with a symptom-free interval and clinical signs of
“intoxication”, which may be acute (vomiting, coma, liver failure,
thromboembolic complications etc.) or chronic (failure to thrive,
developmental delay, ectopia lentis, cardiomyopathy etc.). Circum­
stances that can provoke acute metabolic attacks include fever,
intercurrent illness and food intake. Clinical expression is often both
late in onset and intermittent.
Group III
Common symptoms in this group include hypoglycemia, hyper­
lactatemia, hepatomegaly, hypotonia, myopathy, car­diomyopathy,
cardiac failure, circulatory collapse, and brain involvement. Some
of the mitochondrial disorders and pentose phosphate pathway
defects can interfere with the embryofetal development and give rise
to dysmorphism, dysplasia and malformations.
In general, clinicians should consider the possibility of an IEM in
any patient with an unexplained neurological disorder. Some brain
regions like basal ganglia are highly vulnerable to energy metabolism
defects and metals. In an adult patient with an unexplained
encephalopathy or an unexplained coma, certain features are highly
suggestive of an IEM: (1) when the encephalopathy is triggered by an
extrinsic factor—surgery, fasting, exercise, treatments, high-protein
intake, new medication (Table 1), etc.; and (2) when specific brain
lesions are present on brain magnetic resonance imaging (MRI).
Two main groups of IEMs are responsible for encephalopathies
in adults: intoxications (mainly, urea cycle disorders, homocysteine
remethylation defects and acute porphyrias) and energy metabolism
defects (respiratory chain disorders, pyruvate dehydrogenase
deficiency and biotine responsive basal ganglia disease).
In the first group, MRI is usually normal or can show poorly
specific features whereas in the second group, MRI is almost always
abnormal, showing bilateral lesions of basal ganglia (Leigh syndrome)
or pseudo-strokes (mainly in the case of respiratory chain defects).
DIAGNOSIS AND MANAGEMENT
Inborn errors of metabolism may present in adolescence or adulthood
as a psychiatric disorder. In some instances, an IEM is suspected
because of informative family history or because psychiatric
symptoms form part of a more diffuse clinical picture with systemic,
cognitive or motor neurological signs.
There are 3 important steps in the diagnosis and management of
an IEM.
1. Suspicion
The symptoms and signs for an IEM are very common and nonspecific;
therefore, one should think of IEM as an etiology in unexplained/
peculiar cases and try to rule out the possibility.
TABLE 1 │ Drugs which aggravate inborn errors of metabolism
Disease
Drugs
Mechanism
Urea cycle disorders Valproate
Blockage of urea cycle
Porphyrias
Imipramine,
meprobamate
Porphyrogenic
Wilson’s disease
Neuroleptics
Blockage of D2 dopamine
receptors
GM2 gangliosidosis
Tricyclic
antidepressants,
phenothiazines
?Increased lipid storage
Respiratory chain
disorders
Valproate
Blocks the respiratory
chain
Chapter 135 Inborn Errors of Metabolism: Disorder of Adults?
Section 18
2. Evaluation
Once the possibility of an IEM is suspected, how should it be
evaluated? There are four parts to the evaluation of an IEM:
A. History, family history: One of the most important clue is a history
of deterioration after an initial period of apparent good health
ranging from hours to weeks. Developmental delay, particularly
missing milestones may be present. Another key feature is change
in the diet and unusual dietary preferences particularly protein or
carbohydrate aversion. The family history is very important. Most
IEM are autosomal recessive, so there may have been siblings
with similar illnesses or deaths from “sepsis” or “sudden infant
death syndrome (SIDS)”. The parents may be consanguineous
or come from a genetic isolate. There are also X-linked, and
mitochondrial inherited IEM, so a family history must include
information about the mother’s siblings, their children, etc.
B. Physical examination: The physical examination of patients with
IEM is usually normal except for nonspecific findings. Physical
findings that are important include: facial dysmorphism, cataracts,
hepatosplenomegaly and myopathy.
C Initial screening tests: The initial evaluation of an IEM should
begin with simple urine and blood analysis. The first step is
checking for unusual odors in urine (Table 2), some of which are
not specific, but a positive result can direct toward one or more
specific tests.
The blood tests encompass complete blood count, blood gases and
blood electrolytes. The panel of tests should also include lactate,
liver function test, cholesterol, pyruvate, urea, creatinine and uric
acid. A low neutrophil count may be indicative of organic acidemias.
The lactate/pyruvate ratio of less than 25 cancels the possibility of
lactic acidosis, organic acidurias, urea cycle defects and fatty acid
metabolism. High levels of lactate and pyruvate are symbolic of
mitochondrial defects.3 An elevated ammonia level in blood points
to urea cycle abnormalities and some organic acidemias. Serum and
urine amino acid analyses reveal hyperalaninemia. A value above
16 for the anion gap is suggestive of organic acidurias. Glucose level
is checked to rule out hypoglycemia, which is a common feature of
many IEMs.
D. Advanced screening tests: There are numerous biomarkers used
in many laboratories that specialize in biochemical genetics.
TABLE 2 │ Urine odor in different inborn errors of metabolism
Disorder
Odor
Compound
Phenylketonuria
Musty
Phenyl acetate
Tyrosinemia
Cabbage
Rancid butter
Hydroxybutyric acid
Oxomethylbutyric acid
Maple syrup urine
disease
Maple syrup
Burnt sugar
Oxoisocaproic acid
oxomethyl valeric acid
Isovaleric acidema,
glutaric academia
type II
Sweaty feet
Isovaleric acid
Methylcrotonyl-CoA
Carboxylase deficiency
Cat urine
Hydroxyisovaleric acid
Multiple carboxylase
deficiency
Cat urine
Hydroxyisovaleric acid
Methylmalonic
academia
Acid smell
Methylmalonic acid
Cystinuria
Sulfurus
Hydrogen sulfide
Hydroxy methyl glutaric
acidurias
Cheesy
Cheesy
These include carnitine, acylcarnitines, lysosomal enzymes, etc
(Table 3).4 These tests are key to exclusion or inclusion of an IEM.
Magnetic resonance spectroscopy of brain shows high lactate
levels in individuals with mitochondrial disorders.5
3. Treatment
The basic principle for treatment of the acute inborn errors is
reduction of the substrate that accumulates due to catabolic enzyme
deficiency. The specific treatment of individual metabolic disease is
too vast to be described in detail. The treatment strategies commonly
employed are discussed. In general, Group III are considered
untreatable, and the following strategies apply on most part to
Groups I and II. The brief approaches are as follows:
Prevent catabolism: Administration of calories is used in acute
episodes to slow down the catabolism.
Limit the intake of the offending substance: Simple restriction of
certain dietary components such as galactose and fructose form
the basis of treatment in galactosemia and fructose intolerance.
Neonates with PKU should be given a protein substitute that is
phenylalanine-free. Patients with Group I are commonly considered
for this line of treatment.
Increase excretion of toxic metabolites: Rapid removal of toxic
metabolites (in IEM’s Group II) can be achieved by exchange
transfusion, dialysis, forced diuresis, using alternative pathways
for the excretion of toxic metabolites.6 For example, carnitine
is useful in elimination of organic acids in the form of carnitine
esters, sodium benzoate and phenylacetate are useful in treating
hyperammonemia, etc.
Enzyme replacement therapy: Patients with Group I IEMs have
various forms of enzyme deficiencies and are considered for enzyme
replacement. For example, human alphaglucosidase enzyme is
safe and effective in Pompe’s disease.7 Laronidase is developed as
a treatment strategy for mucopolysaccharidoses I,8 recombinant
alpha-Gal A for Fabry’s disease,9 imiglucerase in management of
Gaucher disease,10 etc.
Increase the residual enzyme activity: People with Group II IEMs
can benefit by increasing the residual enzyme activity. This is done
by administration of pharmacologic doses of the vitamin cofactor
for the defective enzyme (Table 4). If the enzyme is reasonably
functional, increasing the vitamin concentration will increase
enzyme activity via a mass action effect. A study showed that B12
decreases the urinary levels of methyl malonate by enhancing
activity of transcobalamin II.11
Reduce substrate synthesis: In glycolipid lysosomal storage disease,
glycohydrolase that catalyzes glycosphingolipid (GSL) is defective
leading to accumulation of GSL in lysosome and precipitation of
the disease. The imino sugar N-butyldeoxynojirimycin (NB-DNJ)
inhibits the first step in GSL synthesis12 and balances the rate of GSL
synthesis with the impaired rate of GSL breakdown.
Replacement of the end product: Hypoglycemia is a frequent finding
in patients with glycogen storage diseases, and can be prevented
by frequent feeds. Raw cornstarch (2 g/kg every 6 hours) has been
shown to be effective in preventing hypoglycemia in glycogen storage
disease Type I as also decreasing hyperlipidemia, hyperuricemia and
lactic acidemia.13
Transplantation and gene therapy: Hematopoietic cell transplantation
(HCT) has been used as effective therapy for IEMs, mainly lysosomal
storage diseases and peroxisomal disorders. The main rational for
HCT in IEMs is based on the provision of correcting enzymes by
donor cells within and outside the blood compartment.14
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Section 18
TABLE 3 │ Inborn errors of metabolism according to symptom groups
Disease
Clinical symptoms
Investigation
Fatty acid oxidation defects
Cardiomyopathy, hypoglycemia, liver disease,
myoglobinuria
Urine organic acids (fasting)
Glycolytic pathway disorders
Anemia, liver disease, muscle weakness,
cardiomyopathy, endocrinological disorders, ptosis
Red cells or muscle biopsy for enzyme assays
Respiratory difficulties due to diaphragmatic
weakness
Lymphocyte acid á-glucosidase
(b) Type III (Cori’s disease)
History of early hypoglycemia and hepatomegaly
Leukocyte glycogen debrancher enzyme assay
(c) Type V (McArdle’s disease)
Myoglobinuria, exercise intolerance, cramps
Ischemic exercise test
(d) Phosphorylase b kinase deficiency
Cardiomyopathy, liver disease
Erythrocyte or liver phosphorylase b kinase assay
Muscle weakness or exercise intolerance
Glycogen storage disease
(a) Type II (acid maltase deficiency)
Motor neuron disease
Adult polyglucosan storage disease
Dementia, neurogenic bladder, sensory loss
Leukocyte glycogen brancher assay
Tay-Sach’s and Sandhoff’s disease
Slow progressive disorder, pyramidal signs,
cerebellar degeneration
Leukocyte total hexosaminidase and hexosaminidase
A
Chorea and/or dystonia
Glutamic aciduria type 1
Reye’s syndrome
Hypoglycemia, slow progressive disorder, gait,
disturbance, dysarthria
Urine organic acids
Blood spot for acyl carnitines
Lesch-Nyhan syndrome
Renal stones, gout
Plasma urate and urine, urate/creatinine ratio
Methylmalonic aciduria with
homocystinuria
Anemia
Urine organic acids and amino acids, urine, and
plasma homocystine
Niemann-Pick disease type C
Supranuclear ophthalmoplegia, ataxia, psycho-motor
retardation, dementia, splenomegaly
Bone marrow aspirate fibroblast cholesterol
incorporation and staining
Wilson’s disease
Cataracts, Kayser-Fleischer rings, liver disease,
dementia, renal failure, parkinsonian features,
dysarthria, loss of coordination of voluntary
movement
Plasma copper and ceruloplasmin, urine, copper, liver
copper
Leukodystrophy
Krabbe’s leukodystrophy
Pes cavus, hemiparesis, spastic tetraparesis
Leukocyte â-galactocerebrosidase
X-linked adrenoleukodystrophy
In males, gait disturbance, spastic paraparesis,
rarely dementia, Addison’s disease. In females,
onset >30 y, spastic paraparesis, vibration sense
loss, long tract signs, peripheral neuropathy
Plasma very long chain fatty acids
Ataxia
Abetalipoproteinemia
Muscle weakness, fat malabsorption, retinitis
pigmentosa
Plasma cholesterol and triglycerides, blood film
(acanthocytes), lipoproteins
Aceruloplasminemia
Presenile dementia, diabetes mellitus, retinal
dystrophy
Plasma and urine copper
Cerebrotendinous xanthomatosis
Spasticity, cataracts, tendon xanthomas
Urine cholesterol
Hartnup disease
Skin lesions, dementia
Plasma and urine amino acids
Pyruvate dehydrogenase deficiency
(X-linked)
Episodes in males triggered by carbohydrate
feeding
Pre and postprandial blood lactate, CSF lactate,
fibroblast pyruvate dehydrogenase
Sialidosis (mucolipidosis type I)
Type I: Visual defect with lens or corneal
opacity, ataxia, myoclonus, generalized seizures
sometimes with nystagmus, ataxia, dementia,
cherry red spot
Type II: Mycoclonus, blindness, cherry red spot,
dysmorphic features, angiokeratoma
Urine oligosaccharides fibroblast alphaneuraminidase
Febry’s disease
Angiokeratoma, renal disease, development delay
Leukocyte alfa-galactosidase A
Homocystinuria
Lens dislocation, occlusive cerebrovascular
disease, osteoporosis, skeletal deformities, mental
retardation
Urine and plasma homocystine and methionine
Strokes and stroke-like episodes
Contd...
616
Chapter 135 Inborn Errors of Metabolism: Disorder of Adults?
Section 18
Contd...
Disease
Clinical symptoms
Investigation
Mitochondrial myopathy,
encephalopathy with lactic acidemia
and stroke-like episodes (MELAS)
Seizures, developmental delay, sensorineural
hearing loss, diabetes mellitus
Blood of mtDNA analysis
Urea cycle defects
Postprandial vomiting, coma, confusion
Blood ammonia, plasma, and urine amino acids
Epilepsy
Electron transport chain disorders
Any combination of symptoms
CSF and blood lactate, blood mtDNA analysis,
muscle biopsy for enzyme assay
Juvenile Batten’s disease
Visual loss, retinitis pigmentosa
Skin or rectal biopsy for histological analysis, DNA for
the common mutation
Myoclonic epilepsy with ragged red
fibers (MERRF)
Myoclonus
Blood for mtDNA analysis
Pyridoxine dependent seizures
Persistent seizures responsive to pyridoxine
Pyridoxine response trial (primary defect not known)
Gaucher’s disease type III
Horizontal supranuclear gaze defect,
developmental delay, hydrocephalus, skeletal
abnormalities, psychosis
Leukocyte b-glucosidase, bone marrow aspirate
Ornithine transcarbamylase deficiency
Episodic symptoms (often postprandial), sleep
disorders, comatose episodes
Plasma ammonia (1 h postprandial), plasma amino
acids, urine amino acids and orotic acid
Porphyrria
Limb, neck, or chest pain, muscle weakness,
abdominal pain, photosensitivity
Urine and fecal porphyrins, urine delta aminolevulinic
acid and porphobilinogen
Galactokinase deficiency
Cataracts
Postprandial urine sugar, chromatography
Hyperornithinemia with gyrate atrophy
of the retina
Optic atrophy
Plasma and urine amino acids (ornithine)
Gaucher’s disease type III
Horizontal supranuclear gaze defect,
developmental delay, hydrocephalus, skeletal
abnormalities, psychosis
Leukocyte b-glucosidase
Juvenile Batten’s disease
Seizures, visual loss, retinitis pigmentossa,
dementia
Skin or rectal biopsy for histological analysis, blood
for DNA analysis for the common mutation
Leber’s hereditary optic atrophy
Bilateral optic atrophy (may be alcohol or tobacco
triggered)
Blood for mtDNA analysis
Neuropathy ataxia and retinitis
pigmentosa
Retinitis pigmentosa, ataxia, neuropathy
Blood for mtDNA analysis
Niemann-Pick disease type C
Psychomotor retardation leading to dementia
ataxia with dystonia, vertical supranuclear
ophthalmoplegia
Bone marrow aspirate, fibroblast cholesterol uptake
and staining
Refsum’s disease
Peripheral neuropathy, retinitis pigmentosa,
cerebellar ataxia
Plasma phytanic acid
Sialidosis
Cherry red spot
Urine oligosaccharides, fibroblast alfa-neuraminidase
Tyrosinemia type II
Cataracts, skin lesions, slight development delay
Plasma and urine amino acids
Wilson’s disease
Cataract, Kayser-Fleischer rings, liver disease,
dementia, renal failure, parkinsonian features,
dysarthria, loss of coordination of voluntary
movement
Plasma copper and ceruloplasmin, urine copper, liver
copper
Behavioral and/or psychiatric disorders and/or dementia
Eye disorders
CONCLUSION
The most common mistake made in the management of IEM is
delayed diagnosis or misdiagnosis. In unexplained cases, the
possibility of an IEM should be entertained, as many disorders
are treatable and, in most cases, successful outcome is dependent
on rapid diagnosis and early instigation of therapy. Even with
untreatable disorders, it is important to establish the diagnosis in
the index case in order to allow prenatal diagnosis in subsequent
pregnancies.
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Metabolic Disorders
Section 18
TABLE 4 │ Vitamins in treatment of inborn errors of metabolism
Disorder
Vitamin used in the treatment
Maple syrup urine disease
Thiamine
Homocystinuria
Pyridoxine, folic acid and
vitamin B12
Propionic academia
Biotin
Methylmalonic academia
Hydroxycobalamin
Glutaric academia
Riboflavin
Biotinidase deficiency
Biotin
Hartnup disease
Nicotinic acid
Pyruvate dehydrogenase
deficiency/Leigh’s disease
Thiamine
Respiratory chain disorders
Riboflavin
618
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