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, Refsums disease, hyperoxaluria Type I)
Fabrys disease, Shindler, Canavan disease, Pompe disease, acid
lipase deficiency, acid maltase deficiency, cerebrotendinous
xanthomatosis, Juvenile Battens disease, Kufs 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, Hartnups 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, Wilsons 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, Lebers hereditary optic atrophy, neuropathy ataxia
and retinitis pigmentosa (NARP)
Glycogen storage disorders: von Gierkes disease (Type I),
Pompes disease (Type II), Coris or Forbes disease (Type III),
Andersons disease (Type IV), McArdles disease (Type V), Hers
disease (Type VI), Taruis 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 factorsurgery, 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 1Drugs which aggravate inborn errors of metabolism
Disease

Drugs

Mechanism

Urea cycle disorders Valproate

Blockage of urea cycle

Porphyrias

Imipramine,
meprobamate

Porphyrogenic

Wilsons 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 mothers 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 2Urine 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 IEMs 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 Pompes disease.7 Laronidase is developed as
a treatment strategy for mucopolysaccharidoses I,8 recombinant
alpha-Gal A for Fabrys 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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Metabolic Disorders

Section 18

TABLE 3Inborn 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 -glucosidase

(b) Type III (Coris disease)

History of early hypoglycemia and hepatomegaly

Leukocyte glycogen debrancher enzyme assay

(c) Type V (McArdles 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-Sachs and Sandhoffs disease

Slow progressive disorder, pyramidal signs,

cerebellar degeneration

Leukocyte total hexosaminidase and hexosaminidase

A

Chorea and/or dystonia

Glutamic aciduria type 1

Reyes 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

Wilsons 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
Krabbes leukodystrophy

Pes cavus, hemiparesis, spastic tetraparesis

Leukocyte -galactocerebrosidase

X-linked adrenoleukodystrophy

In males, gait disturbance, spastic paraparesis,

rarely dementia, Addisons 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

Febrys 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...

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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 Battens 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)

Gauchers 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)

Gauchers disease type III

Horizontal supranuclear gaze defect,

developmental delay, hydrocephalus, skeletal
abnormalities, psychosis

Leukocyte b-glucosidase

Juvenile Battens disease

Seizures, visual loss, retinitis pigmentossa,

dementia

Skin or rectal biopsy for histological analysis, blood

for DNA analysis for the common mutation

Lebers 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

Refsums 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

Wilsons 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 4Vitamins 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/Leighs disease

Thiamine

Respiratory chain disorders

Riboflavin

618

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