Canadian Paediatric Society 86th Annual Conference • 86e congrès annuel de la Société canadienne de pédiatrie
Identifying Treatable
Lysosomal Storage Disorders:
The Importance of Early
Diagnosis
Dr Sylvia Stockler
Clinical Professor of Paediatrics
University of British Columbia
Head, Biochemical Diseases Division
BC Children's Hospital
Vancouver, British Columbia
Dr Bruno Maranda MD, MSc, FRCPC, FCCMG
Médecin Généticien
Professeur de clinique
Service de Génétique Médicale
Département de Pédiatrie
Département de Biologie Médicale
Centre hospitalier universitaire de Québec (CHUQ)
L
ysosomes are cellular compartments in
which processing and recycling of waste
and foreign bodies takes place. These functions are effected by a wide variety of acid
hydrolases with specific roles. The sheer
number of lysosomal enzymes gives rise to
numerous possible genetic defects, any of
which can lead to tissue storage of undigested cellular waste. To date, some 50 lysosomal storage disorders (LSDs ) have been
identified. Although LSDs are individually
rare, their joint incidence is approximately
1 in 10,000 individuals (similar to that of
phenylketonuria). Among the best known
are Mucopolysaccharidosis, Gaucher disease and Pompe disease; three to four cases
of each occur annually in Canada.
Paediatricians should be familiar with the
key presenting features of LSDs to ensure
that diagnosis is made as early as possible
in the disease course, as in many instances
early initiation of treatment can have a
significant impact on phenotype, survival
and quality of life. “The paediatrician is the
gatekeeper – the one who has to make that
specific differential diagnosis,” remarked
Dr Sylvia Stockler, Clinical Professor of
Paediatrics, University of British Columbia
and Head, Biochemical Diseases Division,
BC Children’s Hospital, Vancouver.
Varying Presentation
The individual LSDs produce completely different clinical pictures, Dr Stockler observed.
Table 1 lists several common disorders and
the principal tissues affected. Table 2 sum-
marizes diagnostic measures and Table 3 the
treatment modalities available.
Disorders Amenable To Enzyme
Replacement
Gaucher disease. There are several subtypes of Gaucher disease: type 1, which is
the most common (92% of cases), involves
only visceral organs; type 2 (1%) includes
infantile neurodegeneration and a severely
reduced life expectancy; and type 3 (7%)
manifests with variable involvement of
both systems. A severe neonatal onset subtype leads to hydrops fetalis and collodion
baby syndrome. Patients will also exhibit
hepatosplenomegaly, osteoporosis and
other bone disease (Erlenmeyer deformity,
marrow infiltration, bone pain or crisis)
and growth deficiency.
Examination of the bone marrow
typically shows diseased macrophages and
suppression of all blood precursor cells.
The chronic activation of monocyte-macrophage lineage leads in turn to chronic
activation of cytokines, which explains the
pronounced bone involvement. Cytokine
stimulation of B-lymphocytes also produces
late complications including multiple myeloma and other malignant lymphomas.
According to a worldwide Gaucher disease registry of more than 5000 patients,
80% had at least one skeletal abnormality
at diagnosis. The prevalence of bone disease
increases with age: 72% of patients aged less
than six years and 92% of those aged 12 to
18 exhibited bone involvement (1). “It’s
important to know about the bone disease
because [while] it’s not difficult to diagnose
hepatosplenomegaly, bone disease can start
with very subtle symptoms but sometimes
may be a hint to the correct diagnosis... [It] is
important to detect bone involvement and
start treatment prior to irreversible damage.
Avascular necrosis cannot be corrected by
any causal treatment,” Dr Stockler stressed.
Gaucher disease was the first LSD for which
enzyme replacement therapy (ERT) was
available; all such therapies developed since
employ a similar mechanism. The recombinant enzyme enters a cell by attaching to the
mannose receptor on the cell membrane. In
Gaucher disease, the ERT successfully reduces liver and spleen size and corrects bone disease. The patient’s pretreatment condition
has an influence on treatment success – for
example, those with severe thrombocytopenia are unlikely to achieve normal serum
thrombocyte levels even after several years
of therapy. However, Dr Stockler observed,
“the treatment also improves thrombocyte
function so that these children, even if they
never have normal thrombocyte levels, will
not suffer from any bleeding diatheses...The
same is true for anaemia and all other parameters we monitor.”
Fabry disease. “The peak of the iceberg”
in this disorder, said Dr Stockler, is renal
insufficiency; but patients are also prone to
stroke, cardiomyopathy, heat intolerance
and hypohydrosis, acroparesthesias (burning sensations in the hands and feet) and
angiokeratoma. Paediatricians are unlikely
to see a patient with renal or cardiac involvement, as these develop later in the
disease course. They may, however, see a
child with acroparesthesia and heat intolerance or other early features. It is important
to note that neurological testing of these
patients usually produces normal findings.
“I am afraid some are labelled with psychogenic pain,” Dr Stockler remarked.
ERT for Fabry disease clears cellular waste
in the skin, heart and kidneys and improves
the patient’s pain. It stabilizes the glomerular filtration rate in patients with mild
Table 1. Tissues Affected by lysosomal storage disorders
Tissue
Disease
Reticuloendothelial system (liver, spleen, bone marrow)
Gaucher
Niemann-Pick type 3
Fabry
Mucopolysaccharidosis
Pompe
Metachromatic leukodystrophy
Krabbe
Gangliosidosis
Neuronal ceroid lipofuscinosis
Vascular (kidney)
Connective tissue (bone, cartilage)
Muscle (skeletal, heart)
Astroglia (brain white matter)
Neurons (brain grey matter)
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Canadian Paediatric Society 86th Annual Conference • 86e congrès annuel de la Société canadienne de pédiatrie
Table 2. Diagnosis of lysosomal storage disorders
Disorder
Possible Clinical Findings
Laboratory and Other
Findings
Fabry disease
Acroparesthesia
Pain (small fibre neuropathy)
Heat intolerance
Hypohydrosis
Angiokeratoma
Vascular, CNS disease (later)
Renal insufficiency (develops later)
Deficiency of alpha
galactosidase
Gaucher
disease
Hepatosplenomegaly
Growth deficiency
CNS symptoms
Bone marrow disease
Osteoporosis
Bone deformity, pain, crisis
Deficiency of
glucocerebrosidase
Krabbe
disease
Hyperacusis, irritability
Developmental regression
Loss of vision
Progressive spasticity
Peripheral neuropathy
Seizures
Deficiency of
galactocerebrosidase
Mucopolysaccharidosis
type 1
Otitis media/sensory hearing loss
Umbilical or inguinal hernia
Hepatosplenomegaly
Dysostosis
Joint contractures
Obstructive sleep apnea
Corneal clouding
Coarse facies
Hydrocephalus
Neurodegenerative symptoms (carpal tunnel syndrome,
progressive muscle weakness, incontinence)
Thickened cardiac valves
Deficiency of
iduronidase
Niemann-Pick
disease
type C
Infantile stage
Neonatal cholestasis with or without liver failure
Hepatosplenomegaly
Later stage
Dementia
Ataxia, dysarthria, dysphagia
Supranuclear gaze palsy
Cataplexy, seizures
Cholesterol
accumulation on
skin biopsy/fibroblast
culture
Mutation of NPC 1 or 2
on molecular testing
Pompe
disease
Hypotonia
Weakness
Feeding difficulties
Gastroesophageal reflux
Respiratory problems
Sleep apnea
Cardiomegaly, heart failure
Tall QRS, shortened PR on ECG
Pseudomyotonic discharge on EMG
Deficiency of alpha
glucosidase acid
(dried blood spot)
Table 3. Treatment for Lysosomal Storage Disorders
Treatment
Disorder
Enzyme replacement (intravenous infusion)
Gaucher disease
Fabry disease
MPS 1, MPS 2, MPS 6
Pompe disease
Allogeneic hematopoietic stem cell transplantation
MPS 1 and Krabbe
Substrate reduction therapy (oral)
Niemann-Pick disease type C
Gaucher disease
7
to moderate renal failure, although in those
who have already passed the threshold of
60 mL/min/m2 it cannot entirely prevent further progression of kidney failure. “Therefore,
early recognition is very important for prophylactic treatment. [Unfortunately,] we
do not yet have biomarkers to predict early
renal involvement and that’s one of the areas
where lots of research must still be done,”
Dr Stockler commented.
Pompe disease is a neuromuscular disorder
characterized by intralysosomal glycogen accumulation and disruption of muscle architecture. Patients with the infantile form usually present at three to four months of age,
noted Dr Bruno Maranda, Clinical Professor,
Université Laval and Medical Geneticist at
the Centre hospitalier universitaire de Québec. Key symptoms are hypotonia and cardiomegaly. These may lead to respiratory and
feeding difficulties, gastrointestinal reflux,
sleep apnea and heart failure, among other
issues. An electrocardiogram may show tall
QRS complexes and a shortened PR interval. Pompe disease progresses rapidly; most
patients require ventilation within a few
months and survival past 12 months is rare.
In the past, the diagnosis of Pompe disease required muscle biopsy, which involved
a three-month wait for results. Fortunately,
it can now be done through a simple dried
blood spot assay available at most laboratories; results take about one week, Dr Maranda
indicated. Supportive laboratory findings
include abnormal values for creatine kinase,
aspartate and alanine aminotransferases and
lactate dehydrogenase. Electromyography
may show pseudomyotonic discharge, which
is highly specific for Pompe disease.
Although it is not curative, ERT may
modify the disease course. “You need to have
a clear discussion with the parents. Nobody
can assure them of cure or remove all of the
disease symptoms. The treatment might fail;
however, if we do nothing, it’s certainly a
rapidly fatal disorder... The severity of symptoms at diagnosis has a negative impact on
treatment response and prognosis, so early
identification is the key... We know that if
the patient is already too symptomatic, the
muscle architecture is modified in such as way
that it is unable to internalize the protein.
So there is a time window during which you
can give the drug,” Dr Maranda emphasized.
Studies of ERT in Pompe disease show a significant difference between treated patients
and the putative disease course in terms of
survival, requirement for ventilation, and
cardiomyopathy, Dr Maranda stated (2). In
one recent report, patients receiving ERT
had a 71% survival at 104 weeks versus 26%
Canadian Paediatric Society 86th Annual Conference • 86e congrès annuel de la Société canadienne de pédiatrie
for an untreated reference cohort. Neonatal
treatment also appears to be effective (3).
Diseases Addressed by Stem Cell
Transplantation
All seven subtypes of mucopolysaccharidosis (MPS) primarily affect connective
tissue; however, this LSD has a wide spectrum of severity and serious cases may also
exhibit neurological manifestations.
MPS 1 typically presents in the first year
of life. A common feature is frequent otitis
media and eventual hearing loss. Additional
early signs are umbilical or inguinal hernia
and hepatosplenomegaly. Children with
MPS 1 also develop dysostosis multiplex, as
well as joint contractures, corneal clouding,
thickened cardiac valves and obstructive
sleep apnea. Neurological features include
hydrocephalus, carpal tunnel syndrome
accompanied loss of hand skills, and/or progressive muscle weakness and incontinence
secondary to spinal cord compression.
Most patients with MPS 1 also have coarse
facies, although exceptions exist. “There
are attenuated cases with only mild connective tissue involvement. It is important to
diagnose them because they can have severe
complications and are the ones who respond
best to treatment,” Dr Stockler indicated.
The standard treatment for severe MPS 1
is hematopoietic stem cell transplantation
(HSCT) from allogeneic bone marrow or
umbilical cord blood. “The transplantation
of stem cells... results in the engraftment of
monocytes, not only in the periphery but
also in the brain, in the form of microglial
cells. These donor-derived cells will provide
synthesis of normal enzyme in the central
nervous system and this will hopefully correct the waste storage and prevent primary
pathophysiological sequelae,” Dr Stockler
explained. When HSCT takes place before
age two, she observed, “We know that we
will find a shift in the phenotype from a
severe to a milder form, so these patients
certainly will not be cured but will have a
milder form of disease and a better quality
of life. And, importantly, we can prevent
neurological damage.” Patients who are
candidates for HSCT may be treated with
ERT until a suitable donor is located. ERTmediated improvements include enhanced
mobility and range of motion, as well as reduction of visceromegaly and sleep apnea.
However, ERT has no effect on cerebral
manifestations as the enzyme does not pass
the blood-brain barrier.
Krabbe disease affects only the central
nervous system. This LSD may first manifest in infants as irritability and hyperacusis. Additional symptoms include vision
loss, spasticity, peripheral neuropathy and
seizures. The disease is rapidly progressive,
typically leading to death within the first
year. Allogeneic HSCT from a healthy
adult donor or umbilical cord blood from
unrelated babies can dramatically improve
the disease course for patients with infantile
Krabbe disease. A study published in 2004
showed that 11 infants who underwent
transplantation of umbilical cord blood in
the neonatal period had 100% survival at
age four and improvement in central myelination and developmental skills. Some
had normal cognitive function but mild to
moderate delays in gross motor function and
expressive language skills (4). Despite the
apparent improvement in disease course,
“transplantation is just an interim step in
the treatment of these diseases. Hopefully,
in a few years, we will have even better
treatments for these children.”
Substrate Reduction Therapy
Niemann-Pick disease type C (NPC) is a
progressive neurovisceral disorder usually
produced by a defect in the NPC1 gene.
Approximately three of four cases present
in the paediatric population. It is more
frequently observed in Nova Scotia than
in the rest of Canada due to a founder effect in Acadians. NPC involves neuronal
accumulation of glycosphingolipids and
cholesterol accumulation in the liver and
spleen. The first clinical phase is marked
by neonatal cholestasis or jaundice which
may be accompanied by liver failure or
variable/transient
hepatosplenomegaly;
liver symptoms predominate in neonatal
cases. A second phase, which may occur
years later, involves neurodegeneration
that typically includes dementia, ataxia,
dysarthria, dysphagia, vertical supranuclear
gaze palsy, and cataplexy or seizures. Given
the delay between the first and second
phases, said Dr Maranda, “it’s very important to ask about neonatal liver disease or
splenomegaly when you are thinking about
Niemann-Pick C or when you see a child
with regression or dementia.”
Diagnosis of NPC requires a skin biopsy
and fibroblast culture, a procedure performed in very few laboratories. Molecular
testing is also possible but is generally
advisable only in Nova Scotia where one
genetic mutation explains most cases.
NPC is treated via substrate reduction.
“[Miglustat], a small molecule, inhibits the
production of the metabolites that are toxic
for the cell such as glycosphingolipids... and
stimulate the synthesis of globoseries, lactoseries, and ganglioseries. Since it’s a small
molecule it passes the blood brain barrier
so it works for diseases with neurological
8
manifestations,” Dr Maranda explained.
A recent clinical trial including 29 patients older than 12 years (20 randomized
to miglustat and 9 to standard care) and
10 younger children (all given miglustat)
determined that miglustat treatment improved horizontal saccadic eye movement
(a measure of improvement of neuronal
disease) as well as secondary end points
such as swallowing. Treated patients also
exhibited minor improvements on a Mini
Mental Status examination, while patients
receiving standard care experienced a nonsignificant decline in mental function (5).
Side effects of miglustat include gastrointestinal symptoms such as diarrhea, flatulence
and abdominal pain, transient tremor and
paresthesia, Dr Maranda reported. Overall,
he added, “several case reports and clinical
trials suggest miglustat can modify the disease progression by improving or stabilizing
the neurological manifestations of NPC.”
Current European guidelines recommend
initiating the therapy upon diagnosis of
NPC, irrespective of the presence of neurological symptoms, he noted. Canadian
guidelines on the use of the agent have not
yet been issued.
Early Recognition is Vital
Enzyme replacement has been a major advance in the management of LSD, allowing
attenuation of numerous signs and symptoms and improved quality of life. “We are
not at a point where we can reverse the
manifestations; rather, we are at a point
where we shift the phenotype to the
milder end,” Dr Stockler remarked. Substrate reduction therapy has also been an
important development in NPC treatment
and may eventually be an effective option
in other LSDs that affect the CNS. Early
initiation of therapy can make a major
difference to the patient’s condition and
prognosis and depends on early identification of symptoms and diagnosis.
References
1. www.lsdregistry.net, accessed July 2009.
2. Kishnani PS, Corzo D, Nicolino M et al. Recombinant human acid [alpha]-glucosidase:
major clinical benefits in infantile-onset Pompe disease. Neurology 2007;68(2):99-109.
3. Nicolino M, Byrne B, Wraith JE et al. Clinical outcomes after long-term treatment with
alglucosidase alfa in infants and children with
advanced Pompe disease. Genetics in Medicine 2009;11(3):210-19.
4. Escolar ML, Poe MD, Provenzale JM et al.
Transplantation of umbilical-cord blood in
babies with infantile Krabbe's disease. New
Engl J Med 2004;352:2069-2081.
5. Patterson MC, Vecchio D, Prady H, Abel L,
Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled
study. Lancet Neurology 2007;6(9):765-72.