LYSOSOMAL

STORAGE DISORDERS
Clinical Presentation & Diagnosis
Gaucher Disease
Fabry
Disease
MPS I
Pompe
Disease
Mucopolysaccharidosis I
CONTENTS
INTRODUCTION TO
LYSOSOMAL STORAGE DISORDERS
GAUCHER DISEASE
INTRODUCTION
CLINICAL MANIFESTATIONS
SIGNS AND SYMPTOMS
DIAGNOSIS
FABRY DISEASE
INTRODUCTION
CLINICAL MANIFESTATIONS
DISEASE PROGRESSION
SIGNS AND SYMPTOMS
DIAGNOSIS
MUCOPOLYSACCHARIDOSIS TYPE I
INTRODUCTION
CLINICAL MANIFESTATIONS
SIGNS AND SYMPTOMS
DIAGNOSIS
POMPE DISEASE
INTRODUCTION
CLINICAL MANIFESTATIONS
SIGNS AND SYMPTOMS
DIAGNOSIS
THERAPEUTIC MANAGEMENT
REFERENCES
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5
Currently, more than 45 lysosomal storage
disorders (LSDs) are known. As a group,
LSDs occur in approximately 1 in 5,000
live births
1
making this a disease category
that a physician is likely to come across in
medical practice.
All LSDs share a common pathogenesis: a genetic
defect in one or more specic lysosomal enzymes,
activator protein or membrane protein, resulting in
decient enzymatic activity.
2
Lysosomes contain
numerous acid hydrolases that are part of a complex
pathway that reduces macromolecules into smaller
components. These components will be reused
by the cell or eventually eliminated from the body.
If a specic lysosomal enzyme is decient, the
substrate it targets accumulates in a progressive
manner, interfering with normal cellular activity and
possibly resulting in cellular death.
3

The lysosome itself was discovered in 1955
4

and by the 1960s its role in cellular digestion was
well understood. Pompe disease became the rst
disease formally recognised as a lysosomal storage
disorder.
5
By the 1970s the scientic community
had recognised many more LSDs as such and had
begun identifying and classifying the specic enzymatic
problems. The group of diseases was broken down
into sub-categories based on the type of enzymatic
defect and/or stored substrate product.
2

Symptom complexes occurring in LSD patients
were rst identied as early as the 1880s and by
the early 1900s many LSDs had been clinically
described. Although the diseases share a common
basic pathogenesis, it is not possible to generalise
LSD symptoms. The different types of substrate
stored, the different cell types affected by storage, as
well as the resultant differences in organ involvement
may lead to tremendous clinical variability, even
within a single disease.
6
Clinical manifestations
tend to affect nearly every bodily system and to be
progressive, as more waste substrate accumulates
over time and more secondary pathology evolves.
Early recognition of presenting symptoms and
timely diagnosis are essential and require good
co-operation between medical specialists.
2
If
diagnosed late and/or left untreated, patients are
at risk of developing signicant, irreversible damage
and loss of body functions, and life-threatening
complications.
Certain symptoms, especially when occurring
in clusters suggesting a multi-systemic nature,
should alert physicians to the possibility of an
LSD as underlying cause. However, many of these
symptoms initially may seem innocuous and appear
with other more common diseases, leading to
delays caused by incomplete or faulty diagnosis.
Specics in relation to the clinical presentation and
diagnosis in relation to Gaucher, Fabry, MPS I and
Pompe disease are presented hereafter. Together
with MPS VI, these four diseases represent the
sub-group of LSDs for which enzyme replacement
therapy is currently available. A general discussion
on therapeutic management is also provided.
1. INTRODUCTION
TO LYSOSOMAL STORAGE DISORDERS
2.1. Introduction
Gaucher disease is the most common disorder among the
group of lysosomal storage diseases. The deciency of
glucocerebrosidase (acid -glucosidase), a lysosomal hydrolase,
leads to accumulation of large quantities of glucocerebroside
in the lysosomes of cells of the macrophage lineage.
7

Lipid-engorged cells, known as Gaucher cells (Figure 1),
displace healthy normal cells, particularly in bone marrow
and visceral organs, and induce secondary pathology
through largely still unknown pathways. The most frequent
symptoms include progressive skeletal manifestations
and haematological symptoms. If left untreated, irreversible
disability and early mortality are the rule.
Gaucher disease is a pan-ethnic disorder inherited in an
autosomal, recessive way. The estimated prevalence of
symptomatic disease is 1 in 100,000.
7
However, in the
Ashkenazi Jewish population prevalence may be as high
as 1:450.
8
In most countries, 5-10% of
the Gaucher patients exhibit a neuronopathic phenotype.
9
2.2. Clinical Manifestations
The Gaucher phenotypes represent a continuum ranging
from a phenotype with few signs to the most severe
congenital form. Particularly in non-neuronopathic (type 1)
disease, the clinical expression is remarkably variable.
Patients with mild, slowly progressive disease may not come
to medical attention at all, whereas other type 1 patients
may develop severe crippling skeletal deformities.
If the disease is diagnosed early in life, the clinical course
will, in general, be more severe.
10
Disease progression
is unpredictable and can occur at any age (Figures 2A
and 2B). For many years, the main focus in the clinical
management was on the visceral and haematological
manifestations. It is only in recent years that the extent,
progression and clinical consequences of skeletal
involvement, usually the most debilitating aspect, have
become adequately appreciated.
2. GAUCHER DISEASE
Figure 2A. Young type 1 Gaucher patient with signicant early symptoms.
Figure 2B. Adult type 1 Gaucher patient with minimal symptoms.
Figure 1. Microscopic appearance of a Gaucher cell: brillary, crumpled
silk appearance of the cytoplasm and an eccentrically placed nucleus
(Periodic Acid Schiff). (From Prof J.A. Barranger)
7
GAUCHER DISEASE
Organ System Sign/Symptom
General Reduced quality of life due to constellation of symptoms, in particular the skeletal manifestations
Skeletal Chronic bone pain and/or acute bone crises (with high fever, chills, leukocytosis, increased ESR)
Bone marrow infltration
Osteopenia
Bone remodelling failure (Erlenmeyer fask deformity)
Osteonecrosis
Osteolysis, osteosclerosis
Bone fracture (spontaneous)
Skeletal growth retardation
Visceral organs Abdominal pain, early satiety, feeling of fullness, frequent diarrhoea
Splenomegaly
Hepatomegaly (may progress to cirrhosis, portal hypertension, ascites, oesophageal varices)
Cholelithiasis
Haematological Anaemia: pallor, fatigue, exertional dyspnoea, palpitations, need for regular blood transfusions
Thrombocytopenia, platelet function abnormalities: spontaneous bleeding or haemostatic problems
after trauma or surgery, post-partum bleeding, heavy menstrual blood loss
Leukopenia: increased risk of infection
Gammopathy
Lungs Dyspnoea (exertional), tachypnoea, cough, recurrent respiratory infections
Interstitial/restrictive lung disease with pulmonary function test abnormalities
Pulmonary hypertension with dyspnoea on exertion or at rest, syncope cyanosis, fnger clubbing
Hepatopulmonary syndrome
CNS By defnition, no CNS symptoms in non-neuronopathic (type 1) Gaucher disease. For symptoms in
types 2 and 3, please refer to text
Skin Yellow/brownish discolouration
Bruises, petechiae
Heart Symptoms resulting from restrictive cardiomyopathy and defective valves
Eyes Pingueculae
Opacities
Saccade initiation failure (ocular motor apraxia) in type 3 disease
Lymphatic Enlarged lymph nodes
System Affected thymus, Peyers patches, adenoids, tonsils
Metabolic Diffculty gaining weight, pubertal delay
Malignancies Increased risk of neoplastic disease
Table 1. Possible signs and symptoms of Gaucher disease
8
2.2.1. Skeletal
Bone pain
Various types of chronically present bone pain may occur.
Episodes of severe, debilitating, acute bone pain (bone
crises) are often accompanied by high fever, chills,
high white blood cell count and increased erythrocyte
sedimentation rate.
11

Osteonecrosis
Osteonecrosis frequently occurs at a site of previous
bone crisis and may progress to fracture or joint collapse
and subsequent osteoarthrosis.
12

Bone marrow inltration
Inltration of the bone marrow with Gaucher cells appears
to start in the lumbar spine and then affect the femoral
meta- and diaphyses, and epiphyses. The reduced fat
content is best visualised using magnetic resonance
imaging (MRI; T1+T2-weighted) in which the T1-weighted
signal is decreased in affected areas (Figure 3).
13
Osteopenia
In almost all patients, osteopenia (causing increased
risk of fractures in severe cases
14
) can be demonstrated
using dual-energy X-ray absorptiometry (DEXA) or X-ray
(Figures 4A and 4B).
Lytic lesions, Sclerosis
These lesions may be late consequences of prior necrosis
or local marrow inltration.
15
Bone remodelling failure
Erlenmeyer ask deformity detectable on X-ray at the end
of the long bones (Figure 5) occurs regardless of disease
severity.
13,14
Growth retardation, Pubertal delay
Skeletal growth retardation is very common among children
and they may reach and close-off puberty at a later age
than normal.
16
Figure 3. Patterns of bone marrow inltration with Gaucher cells (distal femur). The left picture shows normal bone marrow without inltration,
the middle two pictures a homogeneous pattern of inltration, and the picture on the right shows a heterogeneous pattern of inltration with prominent
osseous deformities. (From Dr L.W. Poll)
Figures 4A (left) and 4B (right). X-rays of the humerus showing varying degrees of osteopenia:
mottled, permeative appearance. (From Dr L.W. Poll)
Figure 5. X-ray of the distal femur showing classic
Erlenmeyer ask deformity. (From Dr L.W. Poll)
9
GAUCHER DISEASE
2.2.2. Visceral
Splenomegaly
An enlarged spleen may be one of the signs leading to
suspect Gaucher disease (Figures 6A and 6B) and can
be quantied very precisely by sonography, volumetric MRI
or computerised tomography.
7
Patients may experience
a stinging pain in the side upon exercise. With disease
progression, irreversible splenic changes may develop due
to infarction, necrosis and brosis. Clinically, episodes of
splenic infarction may translate into localised mild abdominal
pain with point tenderness or even acute abdomen with fever.
Hepatomegaly
Liver enlargement may add to abdominal distension,
discomfort and early satiety. Enlargement generally occurs
later than splenomegaly and is less marked. Although
hepatocellular function is usually preserved, slight elevations
of liver function tests may be present.
17
Liver infarction
may cause episodes of pain. Pathology may progress to
cirrhosis, portal hypertension, ascites and oesophageal
varices. The occurrence of hepatocellular carcinoma
has been reported.
18
Gastrointestinal tract
Frequent diarrhoea is not uncommon.
7
2.2.3. Haematological
Anaemia, thrombocytopenia, neutropenia, pancytopenia,
and coagulopathy are among the key manifestations
19
and
are primarily caused by displacement of haematopoietic
elements. Sequestration of blood products in the enlarged
spleen may result in further reductions of blood cells and
coagulation factors.
20
Patients may require regular blood
transfusions. Signicant haemostatic problems usually
only become apparent after trauma or surgery. Post-partum
bleeding and heavy menstrual blood loss can occur. Patients
are believed to be more susceptible to infections.
21, 22
2.2.4. Pulmonary
Restrictive lung disease caused by pulmonary brosis can
lead to dyspnoea, tachypnoea and cough. Limitation of
diaphragmatic excursions due to visceromegaly contributes
to pulmonary symptoms.
23
Pulmonary hypertension, from
a variety of causes, both pulmonary and extra-pulmonary,
may occur.
24

2.2.5. Neuronopathic
In the classical acute neuronopathic (type 2) form,
neuronopathic symptoms are characterised by an onset
within the rst 6 months and rapid progression. Typically, all
these patients die within the rst 3 years of life. In addition
to the systemic manifestations, prominent brainstem
findings are present, including spasticity, persistent
retroexion of the head, strabismus, oculomotor apraxia,
trismus, dysphagia, laryngeal stridor and exaggerated
deep tendon reflexes.
25
Figure 6A. and 6B. Macroscopic aspects of Gaucher spleens.
Figure 6A. This picture shows a cross sectional aspect, among
others showing brotic scarring (white-yellow streaks) and a zone
with recent infarction.
Figure 6B. This picture shows a highly nodular aspect of the surface
of the spleen of another patient. (From Prof J.A. Barranger)
10
Chronic neuronopathic (type 3) disease comprises
a variety of disease variants. Patients may have an
onset during childhood with hepatomegaly and skeletal
lesions,
26
and in addition, early development of a slowing
of conjugate horizontal saccadic eye movements.
27
Later
on, treatment-resistant generalised tonic-clonic and
myoclonic seizures, dementia, progressive spasticity and
ataxia may develop and intellectual function may be lost.
Neurological degeneration results in death in the second
or third decade of life.
Another type 3 variant may include fatal complications
of portal or pulmonary hypertension.
28
Among the many
atypical neurological features, the most important are
extrapyramidal involvement leading to rigidity in childhood
and to a Parkinson-like presentation in older patients.
29

A third variant is associated with cardiac valve calcications,
corneal clouding, oculomotor ataxia and mental retardation
and is linked with homozygosity for the D409H mutation.
30
2.2.6. Gammopathies and malignancies
Gammopathies and malignancies (e.g. multiple myeloma,
lymphomas, chronic lymphatic leukaemia) are not uncommon
and may be caused by chronic stimulation of the immune
system by accumulated glucocerebroside, or by hypersecretion
of cytokines by Gaucher cells.
31, 32
2.2.7. Hypermetabolism
A hypermetabolic state is believed to be caused by the
large mass of metabolically overactive Gaucher cells
and can have signicant indirect effects on weight gain,
growth and caloric requirements.
7

2.2.8. Quality of life
Quality of life can be severely impaired in patients
33,34

and their family members. The symptoms may diminish
patients feelings of well-being and functional health and
prevent them from working or pursuing family or leisure
activities. Particularly the skeletal involvement may be a
prominent cause of decreased ability to perform normal
activities of daily living. In children, learning difculties,
low self-esteem, psychosexual problems and behavioural
abnormalities can occur.
11
2.3. Diagnosis
Individuals will be presenting uniquely in terms of age
of presentation, clinical symptoms and rate of disease
progression. Due to this phenotypic diversity, it may be a
challenge to clinically suspect the diagnosis. As patients may
encounter several types of practitioners and specialists,
multidisciplinary consultation is imperative. The most
common initial misdiagnoses are presented in Table 2.
2.3.1. Biochemical assessments
The most efcient and reliable method of diagnosis is the
assay of glucocerebrosidase activity in peripheral blood
leukocytes or cultured broblasts.
35
In general, Gaucher
patients have an enzyme activity that is 30% of normal
activity. In some patients, the correct diagnosis may rst
be suspected after a bone marrow aspiration for the
evaluation of chronic anaemia, thrombocytopenia, and/or
splenomegaly shows Gaucher cells. Bone marrow
morphology has been abandoned as nal conrmatory
diagnostic test because of the invasiveness of the procedure
and the risk of misdiagnosis of Gaucher disease in patients
with haematological malignancies.
36

2.3.2. Mutation analysis
To date, more than 300 mutant alleles have been identied.
37

Attempts to establish correlations between genotypes
and clinical outcomes have led to some, more or less,
accurate conclusions, i.e., presence of at least one N370S
allele is associated with type 1 disease and excludes
neuronopathic involvement, and homozygosity for L444P
generally predicts type 3 disease. An important role for
genotyping relates to screening and genetic counselling
of the index patients family.
2.3.3. Biochemical markers
Some disease biomarkers have been identied in patients
with Gaucher disease which include chitotriosidase
38
and
CCL18/PARC.
39
Lipid-laden macrophages are thought
to hypersecrete chitotriosidase, a chitinase, and plasma
levels are dramatically elevated in symptomatic patients.
House hold labels such as growing pains or
accidental fracture
Recurrent nose bleeding due to non-specifed
bleeding disorders
Leukaemia
Lymphoma
Osteomyelitis
Legg-Calv-Perthes disease
Table 2. Potential misdiagnoses of Gaucher disease
11
GAUCHER DISEASE
3.1. Introduction
Fabry disease is an inherited, X-chromosome linked,
lysosomal storage disorder caused by a defect in the
gene encoding for the lysosomal enzyme -galactosidase
A.
40
Partial or complete deciency of this enzyme leads
to an inability to catabolise glycosphingolipids with
terminal -galactosyl residues. Progressive accumulation
of glycosphingolipids (particularly globotriaosylceramide,
GL-3) occurs in vascular endothelial cells (Figure 7), neural
cells, cardiomyocytes and various types of renal cells.
Cellular dysfunction and/or death leads to secondary
tissue responses such as hypertrophy, inammation,
brosis and sclerosis. The insidious cascades of disease
processes initially result in early symptoms in childhood
or adolescence, and later on, in severe renal, cardiac, or
cerebrovascular complications. If hemizygotes (males)
remain untreated, lifespan is markedly shortened with
death occurring in the fourth or fth decade of life.
40

Despite the X-linked nature, a major fraction of female
heterozygotes also suffer from signicant morbidity
and premature mortality.
The estimated incidence of Fabry disease is 1 in 40,000
males and the disease is found among all ethnicities.
40
3.2. Clinical Manifestations
Virtually all males with the defective gene develop the
disease, mainly in the form of classical Fabry disease
(associated with less than 1% residual enzyme activity).
Females may be affected as severely as men; however,
they may also remain asymptomatic in the presence of
histological evidence of organ system involvement.
40
A
cardiac variant (isolated or predominant cardiac involvement)
is seen in some males with residual enzymatic activities
between 5 to 10%.
41,42
Given the variety of organ systems
involved, Fabry disease requires a multidisciplinary approach
towards diagnosis and clinical management.
3.2.1. Disease progression
The age of presentation of Fabry disease is variable, as are the
presenting symptoms and the clinical course. Symptom onset
generally occurs earlier in males than in females.
43
Classical
disease usually presents in childhood (acroparesthesias,
pain crises, hypohidrosis) due to disease progression in the
peripheral and autonomous nervous systems. Other early
signs or symptoms include angiokeratomas, ocular opacities,
fatigue and exercise intolerance.
Further deposition of substrates and resultant organ-specic
cascades of disease progression ultimately lead to life-
threatening complications in adulthood, particularly involving
the kidneys, heart and central nervous system. Renal
dysfunction resulting from progressive glomerulosclerosis,
tubular atrophy and interstitial brosis becomes apparent
generally in the third or fourth decade of life
44,45
(in females
at later age) and patients likely progress to end-stage renal
disease. Cardiovascular complications include arrhythmias,
left ventricular hypertrophy, heart failure, myocardial ischemia
or infarctions.
46,47
Early stroke and transient ischemic attacks
are other important causes of late morbidity, as well as
premature mortality in Fabry disease patients.
48,49
3. FABRY DISEASE
Figure 7. Vascular endothelium in Fabry disease.
Electron micrograph showing the vascular endothelium of a small vessel from a patient with Fabry disease.
Note that the endothelium is lled with electron-dense vesicles (lysosomes) containing undegraded glycosphingolipid. (From R.J. Desnick, PhD, MD)
12
FABRY DISEASE
Organ System Sign/Symptom
General Reduced quality of life due to constellation of symptoms and prognosis
Nervous system Acroparesthesias, pain crises
Stroke
Transient ischemic attacks
Thrombosis
Skin Angiokeratomas
Hypohidrosis/anhidrosis
Gastrointestinal Nausea, vomiting
Diarrhoea
Postprandial bloating and pain
Early satiety
Diffculty gaining weight
Kidneys Microalbuminuria
Impaired concentration ability
Increased urinary GL-3 excretion
GFR reduction, end-stage renal disease
Heart Arrhythmias
Left ventricular hypertrophy
Vascular insuffciency
Myocardial infarction
ECG abnormalities
Valvular disease (mitral insuffciency)
Ear-Nose-Throat Hearing loss, sudden deafness
Tinnitus
Vertigo
Lungs Coughing
Dyspnoea, wheezing
Exercise intolerance
Skeletal Osteopenia, osteoporosis
Table 3. Possible signs and symptoms of Fabry disease
3.2.2. Pain
Episodic acroparesthesias described as chronic, nagging,
tingling, burning pain in hands and feet occur in many
patients. Illness, exercise, fatigue, stress or weather changes
may trigger acute, agonizing pain in the extremities, lasting
for minutes to weeks.
50
Crises are usually accompanied by
fever and elevated erythrocyte sedimentation rates. The
pain is caused by loss of small peripheral sensory neurons in
the dorsal root ganglia
51
and small ber dysfunction.
52
13
3.2.3. Angiokeratomas
Cutaneous vascular lesions, known as angiokeratomas, are
the most obvious rst clinical features.
53
These clusters
of reddish purple, non-blanching lesions (Figure 8A) are
primarily distributed on the buttocks, groin, umbilicus
(Figure 8B) and upper thighs. They range in size from
pinpoint to several millimetres and can be at or slightly
raised. With age, they become larger and more numerous.
3.2.4. Hypohidrosis/Anhidrosis
An impaired ability to perspire leads to heat, cold, and
exercise intolerance. Production of tears and saliva may
be reduced.
54
Selective peripheral nerve damage
40,54
and
lipid deposits in the small blood vessels surrounding
sweat glands
55
have been reported as causal factors.
3.2.5. Ophthalmological
Corneal opacities, beginning as diffuse haziness and progressing
to pale grey to brownish/yellowish spiral streaks in the
corneal epithelium (cornea verticillata, Figure 9),
are often seen.
56
This nding is only visible by slit-lamp
microscopy. Vasculopathy in the form of narrowing of
arterioles, dilation of veins and exaggerated tortuosity of
retinal and conjunctival vessels is common (Figure 10).
Cream-coloured anterior capsular deposits in the lens are
less common than the whitish, granular spoke-like deposits
in the posterior lens.
56,57
The posterior Fabry cataracts are
best observed by retroillumination. Ocular lesions rarely
affect vision.
58
However, central retinal artery occlusion
causing sudden visual loss has been described.
59
3.2.6. Gastrointestinal
Gastrointestinal symptoms include nausea, vomiting, episodic
diarrhoea, postprandial bloating and pain, early satiety
and difculty gaining weight,
60
and are thought to be
due to GL-3 deposition in mesenteric blood vessels and
autonomic ganglia.
61
Acute abdominal pain may mimic
appendicitis or renal colic.
40
Abnormal gastric emptying
has been documented in symptomatic patients.
62
3.2.7. Renal
Microalbuminuria, impaired concentration ability and urinary
excretion of GL-3 as signs of involvement of renal cells have
been reported in adolescents.
63
Most patients with classical
Fabry disease develop proteinuria in late adolescence.
Polarization microscopy of free urine or urinary sediment
reveals birefringent lipid globules with characteristic Maltese
crosses.
40
Diffuse lipid accumulation in all glomerular,
vascular, and interstitial cells and tubular involvement
may be observed in a kidney biopsy specimen (Figure 11).
With age, GFR reduces progressively due to secondary
damage in the form of glomerulosclerosis, tubular atrophy
and interstitial brosis. In classically affected males, end-stage
renal disease is inevitable. The late renal complications are
the most frequent cause of death among Fabry males.
Figures 8A and 8B. Angiokeratomas in Fabry disease.
Clusters of these characteristic dark red to blue-black
angiectases are typically found between the umbilicus
and thigh (bathing trunk distribution). (From R.J.
Desnick, PhD, MD)
Figure 10. Typical conjunctival involvement in Fabry disease. Note the
sausage-like and markedly dilated vessels. (From R.J. Desnick, PhD, MD)
Figure 9. Distinctive corneal opacity in Fabry disease. This corneal opacity
characteristic of Fabry disease is visible only by slit lamp microscopy. Note
the whorl-like corneal rays emanating from a single vertex like the spokes
of a wheel. It is a useful diagnostic indicator. (From R.J. Desnick, PhD, MD)
14
FABRY DISEASE
3.2.8. Cardiac
Arrhythmias, left ventricular hypertrophy, heart failure,
ischemia and myocardial infarctions are common potentially
life-threatening cardiac manifestations at later age.
46,47
3.2.9. Cerebrovascular
A variety of late cerebrovascular complications have been
0reported including brain imaging abnormalities, early stroke,
transient ischemic attacks and thromboses.
48,49
Fabry patients
appear to be vulnerable to early ischemic stroke due to thrombosis
of small arteries thickened by the vascular accumulation of lipid.
64
3.2.10. Ear-nose-throat
Progressive hearing loss, sudden deafness, tinnitus and
vertigo with dizziness and nausea are frequently reported.
65,66
3.2.11. Pulmonary
Coughing, dyspnoea, wheezing and exercise intolerance
are not uncommon.
67
Spirometry results may indicate
obstructive ventilatory impairment.
68
3.2.12. Skeletal
Bone mineral density abnormalities (osteopenia, osteoporosis)
have been reported in Fabry males.
69
3.2.13. Quality of life
The physical and functional well-being of patients and their
family members can be signicantly reduced. Symptoms
such as pain, tinnitus, chronic fatigue and reduced exercise
intolerance may inuence school performance or the patients
professional career and limit patients to engage in social
activities and sports. Patients may develop chronic
depression given the burden of disease and reduced life span.
70
3.3. Diagnosis
Although Fabry disease usually presents in childhood or
adolescence, it often goes unrecognised until adulthood
when organ system damage has occurred and patients may
have struggled for years with debilitating symptoms for
which there seemed to be no explanation.
71
Early diagnosis
is of particular concern. Common misdiagnoses are
presented in Table 4.
3.3.1. Biochemical assessments
Diagnosis of Fabry disease in males is conrmed by low or
absent -galactosidase activity in leukocytes or cultured
skin broblasts.
72
This assay does not necessarily identify
affected heterozygote carriers (who may have clinical
symptoms or sub-clinical disease) as their enzyme
activity may fall within the (low) normal range in one third
of the patients.
3.3.2. Mutation analysis
Although the disease is X-linked, females may also be
affected due to non-random X-chromosomal inactivation
during embryonic development. Over 240 mutations
in the -galactosidase gene (locus Xq22.1) have been
identied.
73
Phenotype-genotype correlations are difcult to
establish as striking differences in disease manifestations
have been reported between hemizygotes from the same
family.
74
As most Fabry families have private mutations,
75

genetic counselling of the patients family (family pedigree)
is the denitive way to identify affected relatives, both
males and females.
Rheumatoid or juvenile arthritis
Rheumatic fever
Fibromyalgia/chronic fatigue syndrome
Neurosis/malingering
Raynauds syndrome
Multiple sclerosis
Lupus angiokeratomas
Growing pains
Petechiae
Table 4. Potential misdiagnoses of Fabry disease
Figure 11. Glycosphingolipid-enlarged renal cells. Light microscopy of
renal capillary endothelium. Arrows indicate areas of GL-3 accumulation.
15
MPS I
4.1. Introduction
Mucopolysaccharidosis I (MPS I) is the most common
disorder of the group of seven mucopolysaccharide
storage disorders. MPS I is caused by a decient activity
of -L-iduronidase, a lysosomal enzyme involved in the
degradation of the glycosaminoglycans (GAG) heparan
sulfate and dermatan sulfate.
76
These compounds are
important component of the extracellular matrix surrounding
cells and are integral part of the cell membranes. They
play a major role in the structure of the connective tissue
and cartilage and in joint uids. At the cellular level, GAG
are involved in the cell regulation and in the cell-cell
communication. In MPS I, progressive accumulation of
undegraded GAG occurs in virtually all bodily tissues. As
a result, widespread cellular, tissue and organ dysfunction
occur which, if progressed to an advanced stage, may be
irreversible. There is a remarkable variability in severity of
the multisystemic and progressive disease manifestations,
with life-threatening complications occurring across the
disease spectrum.
MPS I affects all races and is inherited in an autosomal
recessive manner. The estimated world-wide incidence
of MPS I is approximately 1:100,000 newborns.
76
4.2. Clinical manifestations
MPS I encompasses diverse clinical phenotypes and
remarkable differences are noted in age of onset, presenting
features, rate of disease progression and co-morbidities.
It is appropriate to consider MPS I as a continuum of
clinical involvement ranging from the most severe to the most
attenuated phenotype.
2
Although the most severe phenotype
(Hurler) is well described and can be accurately delineated,
there is no clear distinction between the other historical
sub-classications, i.e. Hurler-Scheie (intermediate form)
and Scheie syndrome (attenuated form).
77
There are no
diagnostic tests available that, a priori, can differentiate
between these forms. In all its clinical variants, the level of
neurological involvement differs. Severe patients have an
aggressive disease course and patients suffer progressive
mental retardation. Generally, they do not live beyond
5-8 years with death most often the result of progressive
neurological disease and cardiorespiratory failure.
78
In
patients with slower disease progression, life expectancy is
generally 20 years or less, whereas attenuated patients, who
have no intellectual impairment, are at risk of experiencing
potentially fatal cardiovascular or surgical complications. Thus,
whatever the phenotype and rate of disease progression,
MPS I is associated with signicant morbidity.
Given the multi-systemic nature of the disease, all relevant
organ systems need to be assessed for disease involvement.
79

Signs and symptoms of MPS I have been reviewed earlier.
76,79
4.2.1. Central nervous system
In the most severe patients, cognitive and motor development
slow down after the age of 6 months, then plateaus and
eventually declines from around age 5 onwards, resulting
in severe learning disability and minimal language skills.
Progressive GAG accumulation in both neurons and
astrocytes is believed to be the primary cause of rapid
neurodegeneration.
80
Communicating hydrocephalus is a
common nding in severely affected patients and manifests
as head enlargement, bulging fontanels and separation of
sutures. Papilloedema and vomiting may be noted in an
advanced stage. Progressive cervical myelopathy due to
thickening of the meninges and ligaments is common in
MPS I and may require spinal cord decompression. Acute
spinal cord compression may occur across the MPS I
disease spectrum.
81
4. MUCOPOLYSACCHARIDOSIS I
(HURLER, HURLER-SCHEIE, SCHEIE SYNDROME)
17
Table 5. Possible signs and symptoms of Mucopolysaccharidosis I
Organ System Sign/Symptom
General Quality of life impairment throughout disease spectrum
Central nervous Cognitive and motor development impairment
system Progressive and profound mental retardation
Learning disability, poor language skills
Communicating hydrocephalus: head enlargement, bulging fontanels, separation of sutures,
headache, papilloedema, vomiting
Spinal cord compression (cervical myelopathy)
Acute quadriplegia due to vertebral deformity, atlanto-occipital instability or spondylolisthesis
Peripheral Poor hand function (fexion contractures, carpal tunnel syndrome)
nervous system Triggering
Tarsal tunnel syndrome, spinal root entrapment
Musculoskeletal Dysostosis multiplex
Gibbus deformity
Hip dysplasia, knock knees
Kyphosis, scoliosis, lumbar lordosis
Back pain
Progressive arthropathy with joint pain, stiffness and contractures
Claw hand deformity
Walking capacity decreased, toe walking
Short stature
Thoracic cage abnormalities
Myopathy
Head/Facial/Skin Coarse facial features: fat nose, thickened nostrils, lips, ear lobules, enlarged tongue
Large head, prominent forehead, short neck
Thickened skin
Hypertrichosis; coarse, straight, thatch-like hair
Retarded tooth eruption; abnormally shaped, pointed teeth
Predisposition to caries
Eyes Visual acuity impairment, blindness
Corneal clouding with photosensitivity and reduced central visual acuity
Glaucoma
Optic atrophy
Retinal pigmentary degeneration with decreased peripheral vision and night blindness
Ear-Nose-Throat Upper airway obstruction, noisy breathing, runny nose
Recurrent otitis media
Hearing loss
Lungs Hypoventilation syndrome with shortness of breath, leading to atelectasis, vulnerability
to pulmonary infections and impaired gas exchange
Obstructive sleep apnoea-hypopnoea syndrome leading to fatigue, daytime somnolence,
pulmonary hypertension and cor pulmonale
Reactive airways disease, wheezing
Heart Valvular dysplasia, aortic and mitral stenosis/insuffciency
Arterial intimal plaques, coronary artery obstruction
Left ventricular hypertrophy
Cardiomyopathy, congestive heart failure
Arrhythmia
Heart failure
Endocardial fbroelastosis (sudden infant death)
Visceral/ Hepatosplenomegaly, abdominal enlargement
Gastrointestinal Umbilical/ inguinal hernia (recurrent)
Abdominal pain, discomfort, early satiety, vomiting
Loose stools, diarrhoea, constipation
18
MPS I
4.2.2. Peripheral nervous system
Poor hand function results from exion contractures
of the joints and/or carpal tunnel syndrome, although
most patients lack the typical carpal tunnel syndrome
symptoms.
82
Other entrapment syndromes include tarsal
tunnel syndrome and spinal root entrapment. Triggering
may be caused by thickening of the exor tendons.
4.2.3. Musculoskeletal
Structural remodelling defects of the growing bone leads
to dysostosis multiplex and are seen in all forms of MPS I.
Skeletal defects may include deformities of the long
bones, point-shaped metacarpal bones (Figure 12),
dysplastic femoral heads and anterior beaking of vertebral
bodies. Gibbus deformity or dorsolumbar kyphosis may be
present at birth. Acute complications include spinal injury
due to spondylolisthesis and atlanto-occipital instability
due to odontoid dysplasia. Patients are at risk to develop
hip dislocation. Adult patients usually have short stature
with abnormal curvature of the spinal column. Severe
back pain is not uncommon. Progressive arthropathy
presenting as an inability to stretch digits may be notable
as early as age 2. The joints are affected symmetrically,
initially without pain or inammation. Fine motor skills of
the hand are impaired and a claw hand deformity may
develop (Figure 13). Additionally, stiffness, pain and exion
contractures may develop in virtually all joints. Walking
capacity decreases and toe walking can be observed.
Eventually, patients may become wheelchair bound.
4.2.4. Head/Facial
Facial coarsening results from GAG storage in connective
tissues and defective remodelling of skeletal structures in
the orofacial region (Figure 14). These changes pose high
anaesthesia risks in the form of difculties with in- and
extubation.
83
In attenuated disease, these features manifest
slower or may be absent. Severely affected children
generally have large heads and short necks. Tongue
enlargement and thickening of nostrils, lips and ear
lobules become evident, particularly in the most severe
form. Hypertrichosis, abnormal hair texture, retarded
tooth eruption and pointed teeth with dental diastema
are further possible symptoms.
Figure 12. Signs of skeletal dysplasia on an X-ray of the hand
of a severe MPS I patient: point-shaped metacarpal bones.
(From J.E. Wraith, MD)
Figure 13. Claw hand deformity in a patient with attenuated MPS I.
(From J.E. Wraith, MD)
19
Figure 14. Boy with severe MPS I: typical coarse facial
features. (Printed with permission of patients parents)
4.2.5. Ophthalmological
Ocular ndings may include visual acuity impairment
(or blindness), corneal clouding, glaucoma and retinal
degeneration. Diffuse corneal clouding, associated with
photosensitivity, is a feature of all MPS I forms (Figure 15).
Peripheral clouding with good visual acuity has been
reported in attenuated cases.
84
Glaucoma may occur
although intraocular pressure may be difcult to measure
accurately due to the thickened cornea. In severely affected
children, optic atrophy may develop after long-standing
optic nerve head oedema.
85
4.2.6. Ear-Nose-Throat
Patients frequently have a runny nose, noisy breathing and
recurrent otitis media. Hearing loss is common
86
and may be
due to oropharyngeal GAG storage, dysostosis of auditory
bones, nerve damage and damage due to recurrent ear infections.
4.2.7. Lower respiratory tract
Patients may be short of breath due to reduced diaphragmatic
excursions and be vulnerable to obstructive sleep apnoea-
hypopnoea syndrome and pulmonary infections.
87
Other
features include wheezing, fatigue, daytime somnolence,
pulmonary hypertension and cor pulmonale.
4.2.8. Cardiovascular
Life-threatening cardiac pathology occurs across the
entire disease spectrum.
88
Progressive valvular stenosis
and insufciency may evolve into dilated cardiomyopathy
with congestive heart failure. Particularly in the severe
phenotype, thickening and narrowing of arteries leads
to obstructive coronary artery disease. With disease
progression, attenuated patients may also be at risk
to develop these cardiac complications, including
arrhythmia.
4.2.9. Gastrointestinal
Hepatosplenomegaly is common across MPS I patients
although spleen size may be normal in the attenuated
form. Hepatic function is usually preserved. Recurrent
umbilical and inguinal hernias result from increased
intra-abdominal pressure in combination with weakened
connective tissue. Abnormal gastrointestinal passage
can cause pain, discomfort, early satiety, diarrhoea
and vomiting.
4.2.10. Quality of life
Quality of life of severely affected children progressively
reduces due to unrelenting neurodegeneration, progressive
functional disability and poor social functioning. Sleep
apnoea syndrome and sleep disturbances are among the
most debilitating symptoms as they cause restless nights
for patients and their parents. For the other patients in the
disease spectrum, progressive limitations in joint mobility
and endurance are recognized as major causes of disability
and discomfort limiting activities of daily living. A range
of other symptoms (hearing difculty, chronic diarrhoea,
etc.) may further limit their ability to enjoy life.
Figure 15. Diffuse corneal clouding in a MPS I patient.
20
MPS I
4.3. Diagnosis
In particular individuals with a non-Hurler phenotype
(Figure 16) will be presenting uniquely and it may be a
challenge to clinically suspect the diagnosis. As patients
may encounter several types of practitioners and specialists,
multidisciplinary consultation is imperative for early
diagnosis and therapeutic intervention. Common initial
misdiagnoses are presented in Table 6.
4.3.1. Biochemical assessments
In case of clinical suspicion of mucopolysaccharidosis,
a useful preliminary diagnostic test is quantitative (and
qualitative) determination of GAG in the urine. However,
this test is only indicative and does not discriminate
between mucopolysaccharide storage disorders. Denitive
diagnosis of MPS I can only be obtained via enzyme
deciency testing, i.e., by demonstrating low or absent
-L-iduronidase activity in leukocytes, plasma or cultured
skin broblasts.
89
4.3.2. Mutation analysis
To date, more than 100 mutations in the gene encoding
-L-iduronidase have been identied.
90
Two null mutations
(W402X, Q70X) and the P533R mutation account for over half
of the mutant MPS I alleles in the Caucasian population.
76

Genotyping is of limited help to establish the prognosis
since there is no reliable genotype/phenotype correlation,
unless both alleles are null mutations in which case the
patient will have a severe phenotype.
(Juvenile) Rheumatoid arthritis
Arthrogryposis
Degenerative rheumatic disorder
Cartilage disease
Connective tissue disease (e.g. scleroderma)
Autoimmune disease
Table 6. Potential misdiagnoses of
Mucopolysaccharidosis I (selection)
Figure 16. Nine year old patient with an attenuated phenotype:
abdominal distension, umbilical hernia, exion contractures in
joints and lumbar lordosis. (From Prof.Dr. F.A. Wijburg)
21
5.1. Introduction
Pompe disease is a lysosomal storage disorder caused
by insufcient activity of acid -glucosidase.
91
This
lysosomal enzyme is responsible for the degradation of
intralysosomal glycogen, which represents only a small
percentage (1-3%) of total cellular glycogen. Enzymatic
deciency results in lysosomal glycogen accumulation
within multiple cell types and tissues. Eventually this leads
to cellular dysfunction or damage, particularly in cardiac,
respiratory, and skeletal muscle tissue (Figure 17).
91,92
The
clinical presentation of Pompe disease is highly variable.
At the most severe end of the disease spectrum death
occurs within the rst year of life due to cardiorespiratory
failure in 80% of infants (who typically have cardiac as
well as skeletal muscle involvement). In late-onset
patients, relentlessly progressive skeletal and respiratory
muscle weakness may progress to wheelchair and/or
ventilator-dependency and ultimately death between early
childhood or late adulthood.
Pompe disease has also been referred to as glycogen
storage disease type II, glycogenosis type II and acid
maltase deciency and is the most severe form of the
12 glycogen storage diseases.
Pompe disease is an autosomal-recessive disorder with
variable penetrance. Current estimates put the overall
disease incidence at 1 in 40,000 live births.
93,94
It can
be extrapolated that the worldwide prevalence may be
somewhere between 5,000 and 10,000.
5.2. Clinical Manifestations
Historically, patients have been classied into several
different subtypes: classical infantile onset, non-classical
infantile onset, childhood and juvenile onset, and adult
onset Pompe disease.
91,95
This classication has been
based on the age at onset of symptoms, extent of organ
involvement and rate of progression to death but is arbitrary
as the disease spectrum actually represents a continuum
with overlap between the subtypes.
91
Therefore, the
disease may be better characterised based on the age
of onset of rst symptoms (before or after the age of 12
months) and the presence or absence of cardiomyopathy.
This results in two major classications of the disease, i.e.
infantile-onset and late-onset, respectively. It is estimated
that approximately one third of those with Pompe disease
have the rapidly fatal infantile-onset form,
93
while the
majority of patients present with the slowly progressive
late-onset form.
5. POMPE DISEASE
Figure 17. Electronmicrograph of muscle cell from a Pompe disease patient.
22
POMPE DISEASE
Organ System Sign/Symptom
Musculoskeletal Progressive muscle weakness
Profound hypotonia
Floppiness (foppy baby)
Head lag
Failure to meet developmental motor milestones
Macroglossia
Arefexia
Lungs Progressive respiratory weakening, respiratory insuffciency
Frequent respiratory infections
Death due to cardiorespiratory failure
Heart Cardiomegaly (massive)
Left ventricular hypertrophy, outfow track obstruction
Visceral/ Diffculty swallowing, sucking and/or feeding
Gastrointestinal Failure to thrive
Hepatomegaly
Table 7. Possible signs and symptoms of infantile-onset
Pompe disease
Organ System Sign/Symptom
Musculoskeletal Progressive proximal muscle weakness, especially in the trunk and lower limbs
Unsteady gait, toe walking
Lower back pain
Reduced deep tendon refexes
Diffculty climbing stairs
Scapular winging
Gower sign (dystrophy as a result of extreme muscle weakness)
Delayed motor milestones (children)
Lordosis, scoliosis
Lungs Respiratory insuffciency/failure
Orthopnoea
Sleep apnoea
Exertional dyspnoea, exercise intolerance
Respiratory infections
Visceral/ Feeding diffculties
Gastrointestinal Diffculty chewing and swallowing
Hepatomegaly
Miscellaneous Morning headaches
Daytime somnolence
Table 8. Possible signs and symptoms of late-onset
Pompe disease
23
24
5.2.1. Infantile-onset form of Pompe disease
Although patients may not exhibit obvious symptoms at
birth, the course of infantile-onset Pompe disease typically
progresses rapidly within the rst few months of life (Table 7).
Onset at a mean age of approximately 6 weeks has been
reported.
96
Massive deposition of glycogen in the heart and
skeletal muscle results in progressive cardiomyopathy,
generalised muscle weakness and hypotonia (oppy
baby appearance, Figure 18).
91,92
Spontaneous movements
decline as muscle deterioration advances at early stages,
and weakening of the diaphragm and other respiratory
muscles, compounded by pooling secretions, begins to
impair respiratory function. Feeding difculties and poor
weight gain may manifest early. Motor development is
often completely arrested, or if motor milestones are
achieved, they are subsequently lost. Clinical investigation
usually reveals moderate hepatomegaly and sometimes
macroglossia. However, the hallmark sign is marked
cardiomegaly (Figure 19) with left ventricular thickening
which may result in outow tract obstruction.
91
Mental
development is generally not affected. Death from
cardiorespiratory failure usually occurs by age one.
91,95
5.2.2. Late-onset form of Pompe disease
The late-onset form can present anytime during early
childhood up until adulthood with a diffuse array of
manifestations (Table 8). This form is more clinically
heterogeneous, with greater variation in clinical presentation
and disease progression.
97
It is distinguished from the
infantile-onset form by the absence of severe cardiac
involvement. In children, the disease may present with
delayed motor milestones or loss of muscle function, but
intelligence is generally normal. In many cases, the rst
observations may be difculty walking or climbing stairs,
reecting the gradual progression of proximal muscle
weakness. Typically muscle weakness is more severe in the
legs than in the arms. Subsequently, signs of involvement
of the muscles of the trunk (scoliosis, back pain) and the
main respiratory muscle, the diaphragm (shortness of
breath), may appear.
91
In other cases, respiratory symptoms
may surface prior to any recognition of muscle weakness.
As in the infantile-onset form, there is generally hypotonia
and eventual respiratory distress. Some patients display an
unsteady gait and, occasionally, toe walking. Macroglossia
and hepatomegaly may be present in some cases.
91

Adults also present with progressive myopathy, primarily
in the trunk and lower limbs. Not all areas may be affected
equally and there have been reports of distal muscle
weakness and scapular winging.
98
Although not all patients
develop respiratory muscle symptoms, a key clinical feature
that may help to distinguish late-onset Pompe disease from
other neuromuscular disorders is the early involvement
of the respiratory muscles. Respiratory muscle weakness
with ventilatory restriction typically serves as the most
debilitating and lethal feature. As respiratory insufciency
advances, patients may experience morning headaches,
orthopnoea, exertional dyspnoea, REM-sleep hypopnoea
or apnoea, somnolence and/or exercise intolerance.
Progression of diaphragm weakness leads to lower vital
capacity in a lying down versus upright position (more than
10% difference), and this also contributes to hypoxia during
sleep. Vital capacity appears to correlate with respiratory
muscle function.
99
The Gower sign may be present (Figure 20).
Figure 18. Photograph of an infant with characteristic
oppy-baby appearance.
Figure 19. Chest X-ray of an infant with Pompe disease
showing cardiomegaly. (From B. Byrne, MD)
Figure 20. Gower sign: A procedure in which an individual raises him/
herself by putting the hands onto the knees to keep the legs extended,
then pushing the trunk upward by walking the hands up the thighs.
POMPE DISEASE
25
Late-onset Pompe disease
Duchenne muscular dystrophy
Glycogen storage diseases III, V, VI
Limb girdle muscular dystrophy
Polymyositis
Rigid spine syndrome
Scapuloperoneal syndromes
Infantile-onset Pompe disease
Acute Werdnig-Hoffman disease
(Spinal muscular atrophy I)
Danon disease
Endocardial fbroelastosis
Glycogen storage diseases III, IV, VI
Idiopathic hypertrophic cardiomyopathy
Mitochondrial disorders
Myocarditis
As the disease course for late-onset Pompe disease
varies widely, morbidity and life expectancy are difcult
to predict. Patients may exhibit early (childhood) or later
(childhood or adulthood) onset of symptoms, typically
followed by a progressive course in 5 to 25 years of life.
Some patients with less severe symptoms remain functional
with only minimal disability for years but generally patients
become wheelchair bound and many ultimately require
non-invasive or invasive ventilation.
91,100
Those who
present as juveniles generally live into the third decade,
while those who present later can demonstrate a greater
range of outcomes. Death usually results from respiratory
failure.
91
Of interest, the duration of onset of symptoms
was a better predictor of functional status than the age
of onset in one large study.
101
This may indicate that the
variety may lie more in time prior to symptom onset than
in the disease progression after such onset.
5.2.3. Quality of life
Pompe disease has a devastating and profound impact on
the quality of life of infantile onset patients and their care
givers, given the severe functional decits and markedly,
premature death.
91,100
Also in late-onset patients, physical
health domains of quality of life are markedly affected.
102

The mental health appears to be preserved in most patients,
even in quite advanced stages of disease. Ventilator support
and tracheostomy may improve quality of life and extend
survival in those with severe respiratory impairment.
5.3. Diagnosis
Because of the rarity of the disease, precious time is often lost
between the onset of symptoms and consideration of a diagnosis
of infantile-onset Pompe disease.
92
Patients with more slowly
progressive disease are often difcult to diagnose, as their
symptoms initially are often more subtle and attenuated.
97
The
most common initial misdiagnoses are presented in Table 9.
Important tests to discriminate between Pompe disease and
other diseases include biochemical tests, electromyography,
chest X-ray, cardiac echo and ECG, and the ischemic forearm test.
5.3.1. Biochemical assessments
Diagnosis of Pompe disease is conrmed by low or absent acid
-glucosidase activity in cultured skin broblasts, a muscle biopsy
or puried lymphocytes.
91
Enzyme activity testing via cultured
skin broblast is currently the gold standard but requires several
weeks, which poses a challenge in infantile-onset patients. The use
of a non-invasive acarbose-based assay performed on dried
blood spot samples is currently being investigated.
The phenotypes generally correlate with the amount of residual
enzyme activity as measured in cultured skin broblasts.
92
Most
infants generally demonstrate less than 1% of normal enzyme activity,
while juveniles appear to have less than 10% and adults less than
40%. A muscle biopsy can provide histopathological information
about the level of glycogen storage, although it should be noted
that glycogen content can vary depending on the site of biopsy.
92

As an early step, creatine kinase (CK) may be tested as it is a
rather sensitive (but not specic) marker of Pompe disease.
103

The greatest elevation can be found in infantile-onset patients
(as high as 2000 IU/L),
104
while in some cases, adults may have
CK levels within the normal reference range.
Unlike other glycogen storage diseases, Pompe disease does
not cause hypoglycemia or low energy production.
Prenatal diagnosis may be requested in case of subsequent
pregnancies in families with an affected child, or when a
parent presents with the late-onset form. Prenatal diagnosis
can be made with either amniocentesis or, more commonly,
direct enzyme analysis of uncultured chorionic villi cells. DNA
analysis may be used as a supportive method.
105
5.3.2. Mutation analysis
Pompe disease is caused by mutations in the acid -glucosidase
gene traced to the long arm of chromosome 17(17q).
91
More
than 120 mutations in this gene that give rise to Pompe
disease have been identied to date.
92
The type of mutation
is often a good predictor of clinical phenotype. For example,
at least half of all Caucasian patients with late-onset disease
share the same mutation. However, there are several examples
of genotype-phenotype discordance in the literature.
91
Table 9. Potential misdiagnoses of Pompe
disease (selection)
6. THERAPEUTIC MANAGEMENT
Treatment options vary across the LSDs
and patients often undergo a variety of
therapies and care. Palliative care, for
example, dialysis, surgery or physical
therapy, can be effective in managing
symptoms. However, they do not affect
the biochemical cause of the disease
and usually do not prevent disease
progression.
106
Disease-specic therapies
may address the underlying enzyme and/or
storage problem and are available for some
of the LSDs. These therapies include
enzyme replacement therapy, substrate
inhibition and haematopoietic stem cell
transplantation (HSCT).
2
To date, the
broadest clinical experience has been
obtained with enzyme replacement therapy.
Enzyme replacement therapy involves regular
intravenous administration of the decient enzyme.
Initial research on enzyme replacement therapy
began in the mid-1960s. By the 1980s, clinical trials
with placentally-derived -glucocerebrosidase were
underway, revolutionising the treatment of Gaucher
disease. In the early 1990s, advances in recombinant
DNA manufacturing enabled production of
Pr
Cerezyme

(imiglucerase for injection)
107
in quantities large
enough to treat Gaucher disease patients world-wide.
2

Cerezyme therapy provides exogenous enzyme,
via intravenous infusion, for uptake into lysosomes
and for subsequent facilitation of the breakdown of
glucocerebroside in lysosomes. Replacement of the
missing enzyme using Cerezyme has been shown to
be very well tolerated, highly safe, and efcacious in
ameliorating symptoms and signs in most disease
domains. It is effective in preventing further disease
deterioration or development of irreversible
manifestations.
108

The rationale of cause specic therapy, replacing
the missing or malfunctioning enzyme, has also
proven to be effective for other lysosomal storage
diseases. These diseases include, among others,
Fabry disease (e.g.,
Pr
Fabrazyme

, agalsidase
beta),
109,110
Mucopolysaccharidosis I also known
as Hurler, Hurler/Scheie and Scheie syndromes
(
Pr
Aldurazyme

, laronidase)
79,111
and Pompe disease
(
Pr
Myozyme

, alglucosidase alfa).
112,113
IgG antibody formation towards the therapeutic
protein may occur and patients who are positive for
IgG antibodies may have a higher risk of developing
a hypersensitivity reaction.
107,109,111,112
For Gaucher disease, international panels of experts
have collaborated on developing therapeutic and
outcome monitoring recommendations, both for
paediatric
10,11,114
and adult Gaucher patients.
115,116
In
addition, based on the collective expertise and review
of clinical data, a disease management model for
Gaucher disease was designed.
108
It includes information
on how to individualise the treatment based on an
ongoing inventory of the status of all the potentially
involved organ compartments in each individual patient.
Enzyme enhancement therapy has been suggested
to be an attractive approach for genetic diseases
resulting from protein misfolding and/or mistrafcking.
26
Low molecular-weight pharmacological chaperones
might rescue misfolded or unstable proteins, thereby
increasing protein function and clinical benet.
117
Substrate inhibition therapy intends to slow the rate
of production of the substrate that is accumulating
as a result of the enzyme deciency. Recently,
substrate inhibition therapy has been introduced
for treatment of symptomatic patients with mild to
moderate non-neuronopathic Gaucher disease for
whom Cerezyme, the standard of care, is unsuitable.
118

In HSCT, healthy stem cells (usually from bone marrow,
sometimes from cord blood)
106
are transplanted
intravenously to the patient to produce the enzyme
as well as new healthy cells. It was rst attempted
in the 1980s
2
and since then has been used almost
exclusively to treat a selected group of severely
affected MPS I patients. Despite its challenges and
risks (difculty nding a good donor match; transplant
failure or rejection;
119
toxicity of the conditioning
regimen
106
) it has had some positive results in Hurler
patients, especially when performed early in the
course of the disease.
2
Combinations of enzyme
replacement therapy with HSCT are currently
being investigated.
Bone marrow transplantation (and splenectomy)
is discouraged in Gaucher disease patients given
the related morbidity and mortality.
120
In Pompe
disease, bone marrow transplantation has not
been successful.
121,122
Gene therapy involves replacing the patients
mutated gene with a normal copy to allow proper
enzyme production. Gene therapy is still only in
pre-clinical (animal) studies and much research is
needed, especially in identifying appropriate vectors
for gene delivery.
2
Registry programmes that create a structured
format for the long-term collection of data for the
Gaucher, Fabry, MPS I and Pompe patient populations
are in place. These programmes may provide a greater
understanding of the natural course of disease,
long-term safety and outcomes.
27
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