1. Storage disorders in
children
Dr Vidyut Bhatia
Pediatric Gastroenterologist
Indraprastha Apollo Hospital, New Delhi
Editor: Celiac Focus

2. Inborn error of metabolism—Garrod’s
hypothesis
C Not enough, substrate
A B insufficiency/deficit
D
Toxic!!
Substrate
excess

3. Storage within the cell
Lysosomal: Lysosomal storage disorders
Cytoplasmic: Glycogen storage disorders

4. Glycogen
Glycogen is a glucose polymer joined in straight
chains by alpha 1,4 linkages and branched by
alpha 1,6 linkages. It forms a tree like molecule
Glycogen is the storage form of glucose and is
found in abundance in the liver, muscles and
kidneys

5. Glycogen polymer

6. Cont.
Glycogenesis:
The conversion of excess glucose to glycogen for
storage

7. Cont.
Glycogenolysis:
The degradation of glycogen to glucose.
A phosphorylase enzyme splits the alpha 1,4
linkage releasing glucose-1-phosphate, a
debranching enzyme then splits the alpha 1,6
linkage

8. Glycogen Storage Disease
(GSD)
GSD as a group reflect an inability to metabolize glycogen
to glucose in the liver.
It mainly occurs because of a number of enzymatic defects
along the pathway
There are eleven distinct types of diseases that are
commonly considered to be glycogen storage diseases and
all of them are caused as a result of enzymatic defect in the
pathway including type I and III.

9. Cont.
The system for glycogen metabolism relies on a
complex system of enzymes. These enzymes are
responsible for creating glycogen from glucose,
transporting the glycogen to and from storage
areas within cells, and extracting glucose from
the glycogen as needed. Both creating and
tearing down the glycogen macromolecule are
multistep processes requiring a different
enzyme at each step. If one of these enzymes is
defective and fails to complete its step, the
process halts.

10. Incidence and mode of inheritance
Overall frequency of all forms of GSD is
approximately one in 20,000-25,000 live births
The most common forms of GSD are Types I, II,
III, V and IX, which may account for more
than 90% of all cases

11. GSD Type I and III
GSD type I a: caused by a defect in the enzyme glucose
1,6 phosphatase which impairs gluconeogenesis
Patient is not able to metabolize glycogen stored in the
liver
GSD type III also referred to as debrancher enzyme
defect that prevents glycogen breakdown beyond branch
points

12. Symptoms of type I and
III
Poor physical growth
Hypoglycemia
Hepatomegaly
Abnormal biochemical parameters especially for
cholesterol and triglycerides

13. Diagnosis of hepatic glycogenoses
Glucagon challenge (historical): Intra-muscular
administration of glucagon results in poor
blood glucose level elevation, and elevates
levels of lactate
Liver biopsy: The biopsy sample is tested for its
glycogen content (which is increased) and
assayed for enzyme activity and presence
(which is defective or absent) Liver histology
reveals ,in addition, steatosis typically with
absence of fibrosis

14. Cont.
DNA based gene mutation analysis:
The genes for many enzymes , which their defects or
deficiencies are responsible for GSD have been
encoded and mutations have been identified.
Molecular technologies have provided a non-
invasive way of diagnosis, and pre-natal diagnosis is
being developed as well

15. Dietary Management in GSD
The therapeutic objective of dietary
management for GSD is to provide a
constant source of exogenous glucose to
maintain plasma glucose in a safe range and
to “avoid hypoglycemia”

16. Description and Precautions
Prolonged fasting of <5 to 7 hours must be avoided
Some patients cannot even tolerate fasting for >3.5
hours
Normal blood glucose concentration (70-120mg/dl)
(2 hours postprandial) must be maintained through
out the day and night to ameliorate biochemical
abnormalities.
Therapy with raw cornstarch administered at regular
intervals and a high carbohydrate, low fat diet is
advocated

17. Lysosomal Storage Disorders
Sandoff 2%
Gaucher
Gm1 Gangliosidosis 2%
14%
Mucolipidosis II/III 2%
Niemann Pick A/B 3%
Maroteaux-Lamy 3% MPS I H/S
9%
Niemann Pick C
4%
Sanfilippo B
4% Metachromatic
Leukodystrophy
Tay-Sachs 8%
4%
Cystinosis
4% Sanfilippo A
7%
Morquio
5%
Pompe Fabry
5% 7%
Krabbe Hunter
5% 6% MPS
(For Australia1980-1996; Meikle et al., JAMA 281;249-254
34%

18. Lysosomal storage disorders
general principles
The single most common Manifestations of neurological
disease begin in infancy or
LSD is Gaucher disease childhood
Most LSDs are autosomal Initially, there is delay and then
recessive arrest of psychomotor
development, neurological
A few are X-linked regression, blindness, and
Patients are normal at birth seizures.
Progression leads to a vegetative
state

19. Presentation and Progression
Heterogeneous presentation across the LSD categories and
often even within a single disease
Wide clinical variability according to different types of
substrate stored and locations of storage
Clinical manifestations tend to be progressive, as more waste
substrate accumulates over time

20. Presentation and Progression

21. Presentation and Progression
As a group, LSDs affect nearly every bodily system
Symptoms vary in severity from relatively mild to severe
somatic and rapidly progressive neurologic
manifestations.
Even those without formal sub-types based on age of
onset, affected organs/systems, and severity generally
encompass a spectrum of clinical manifestations

22. "Red Flag" Symptoms
While no single symptom is an LSD hallmark, several
frequently present across enough of the disorders that
they can raise a physician's suspicion and prompt further
investigation
LSD symptoms often present in clusters, so the
appearance of more than one of these is even more
suggestive

23. "Red Flag" Symptoms
Coarse facial features (sometimes with macroglossia)
Corneal clouding or related ocular abnormalities
Angiokeratoma
Umbilical/inguinal hernias
Short stature
Developmental delays
Joint or skeletal deformities
Visceromegaly (especially liver and spleen)
Muscle weakness or lack of control (ataxia, seizures, etc.)
Neurologic failure/decline or loss of gained development

24. Coarse facial features
Corneal clouding
Umbilical hernia

25. Skeletal
Abnormalities
Gaucher
MPS I

26. Angiokeratoma Joint deformities
Visceromegaly

27. "Red Flag" Symptoms
Particularly noteworthy are the following signs:
Loss of motor skills,
Increasing dementia or behavioural abnormalities,
Muscular or neurologic deterioration,
That suggest a progressive/degenerative disorder.

28. Kyphosis Cystine crystal deposits
Aspartylglycosaminuria
Cystinosis
Lymphadenopathy Ataxia Hypertonia
Farber Krabbe Disease

29. Strabismus Retinitis pigmentosa
Cherry red spot
Neuronal ceroid lipofuscinosis
Infantile Sialic acid SD
Small jaw GM2 Gangliosidosis
Cardiomegaly
Macroglossia
Pompe
Picnodysostosis
Muscle wasting Hypotonia

30. LSD Sub-Categories
When a lysosomal enzyme (or another protein that
directs it) is deficient or malfunctioning, the substrate it
targets accumulates, interfering with normal cellular
activity
Healthy cell vs. LSD cell with accumulated substrate

31. LSD Sub-Categories
Sub-categories are based on the type of enzymatic defect
and/or stored substrate product.
For example, the mucopolysaccharidoses (MPS) are
grouped together because each results from an enzyme
deficiency that causes accumulation of particular
glycosaminoglycan (GAG) substrates.

32. I - Defective metabolism of glycosaminoglycans
" the mucopolysaccharidoses"
MPS I (Hurler, Hurler-Scheie, Scheie)
MPS II (Hunter)
MPS III (San filipo Types A,B,C and D)
MPS IV (Morquio type A and B)
MPS VI (Maroteaux-Lamy)
MPS VII (Sly)
MPS IX (Hyaluronidase deficiency)
Multiple Sulfatase deficiency

33. II - Defective degradation of glycan portion
of glycoproteins
Aspartylglucosaminuria
Fucosidosis, type I and II
Mannosidosis
Sialidosis, type I and II
III - Defective degradation of glycogen
Pompe disease

34. IV - Defective degradation of sphingolipid
components
Acid sphingomyelinase deficiency (Niemann-Pick A & B)
Fabry disease
Farber disease
Gaucher disease, type I, II and III
GM1 gangliosidosis, type I, II and III
GM2 gangliosidosis (Tay-Sachs type I, II, III and Sandhoff
Krabbe disease
Metachromatic leukodystrophy, type I, II and III

35. V - Defective degradation of polypeptides
Pycnodysostosis
VI - Defective degradation or transport of
cholesterol, cholesterol esters, or other complex
lipids
Neuronal ceroid lipofuscinosis, type I, II, III and IV

36. VII - Multiple deficiencies of lysosomal enzymes
Galactosialidosis
Mucolipidosis, type II and III
VIII - Transport and trafficking defects
Cystinosis
Danon disease
Mucolipidosis type IV
Niemann-Pick type C
Infantile sialic acid storage disease
Salla disease

37. Progression and
outcome
The LSDs with neurologic involvement can often be the
most severe, marked by rapid decline and high mortality
rates
But generally, predicting LSD progression and outcome
is challenging, especially in later-onset patients

38. Prognosis of LSDs
Early identification and diagnosis is essential for
appropriate management
Early intervention is mandatory for the most
serious and debilitating symptoms (particularly
neurologic and skeletal)
Once established these often will not respond to
even disease-specific therapies

39. Disease Management
For most LSDs, no disease-specific therapy is available
Clinical manifestations can only be addressed through
palliative measures such as physical therapy, dialysis or
surgery
These methods can be effective in managing
symptoms, but they do not affect the biochemical
cause of the disease

40. Disease-Specific Treatment Options
Hematopoietic stem cell transplant (HSCT)
Healthy stem cells (from bone marrow or cord blood)
are transplanted i.v. to the patient to provide new
healthy cells that produce the missing enzyme
Enzyme replacement therapy (ERT)
A recombinant form of the deficient enzyme is infused
i.v. at definite intervals

41. Disease-Specific Treatment Options
Enzyme enhancement therapy (EET)
Misfolded enzyme is stabilized during its synthesis by
the use of small chemical chaperones
Substrate reduction therapy (SRT)
The rate of production of the substrate is slowed by
drug therapy

42. Bone marrow transplant
First attempted in the 1980s and has been most used for MPS I
Positive results when performed early in a disease's course,
despite its challenges and risks
transplant failure or rejection
toxicity of the conditioning regimen
difficulty finding a good donor match
Improved chance for success in newborns with naturally
suppressed immune systems

43. Enzyme Replacement Therapy
The first ERT for Gaucher type I went on the market
in 1991
ERT is a treatment option for 6 LSDs
Gaucher Type I, Fabry, MPS I (Hurler/Scheie) and
MPS II (Hunter) Pompe (GSD type II) and MPS VI
(Maroteaux-Lamy)

44. Thank You