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Storage disorders in children Dr Vidyut Bhatia Pediatric Gastroenterologist Indraprastha Apollo Hospital, New Delhi Editor: Celiac Focus
A B
D
Toxic!!
C Not enough, substrate insufficiency/deficit
Substrate excess
Inborn error of metabolism—Garrod’s hypothesis
Storage within the cell
Lysosomal: Lysosomal storage disorders
Cytoplasmic: Glycogen storage disorders
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
Glycogen polymer
Cont.
Glycogenesis:
The conversion of excess glucose to glycogen for storage
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
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.
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.
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
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
Symptoms of type I and III
Poor physical growth
Hypoglycemia
Hepatomegaly
Abnormal biochemical parameters especially for cholesterol and triglycerides
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
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
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”
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
Lysosomal Storage Disorders
Metachromatic Leukodystrophy
8%
Sanfilippo A 7%
Krabbe 5%
Morquio 5%
Cystinosis 4%
Tay-Sachs 4%
Sanfilippo B 4%
Niemann Pick C 4%
Gm1 Gangliosidosis 2%
Sandoff 2%
Niemann Pick A/B 3%
Mucolipidosis II/III 2%
Maroteaux-Lamy 3%
MPS I H/S 9%
Fabry 7%
Pompe 5% Hunter
6% (For Australia1980-1996; Meikle et al., JAMA 281;249-254
Gaucher 14%
MPS 34%
Lysosomal storage disorders general principles
The single most common LSD is Gaucher disease
Most LSDs are autosomal recessive
A few are X-linked
Patients are normal at birth
Manifestations of neurological disease begin in infancy or childhood Initially, there is delay and then arrest of psychomotor development, neurological regression, blindness, and seizures. Progression leads to a vegetative state
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
Presentation and Progression
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
"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
"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
Umbilical hernia
Corneal clouding
Coarse facial features
Skeletal Abnormalities
MPS I Gaucher
Angiokeratoma
Visceromegaly
Joint deformities
"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.
Kyphosis Cystine crystal deposits
Lymphadenopathy
Farber
Cystinosis Aspartylglycosaminuria
Ataxia Hypertonia
Krabbe Disease
Strabismus
Infantile Sialic acid SD
Retinitis pigmentosa
Neuronal ceroid lipofuscinosis
Small jaw
Macroglossia
Picnodysostosis
Cardiomegaly
GM2 Gangliosidosis
Cherry red spot
Muscle wasting
Pompe
Hypotonia
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
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.
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
I - Defective metabolism of glycosaminoglycans " the mucopolysaccharidoses"
Aspartylglucosaminuria
Fucosidosis, type I and II
Mannosidosis
Sialidosis, type I and II
II - Defective degradation of glycan portion of glycoproteins
III - Defective degradation of glycogen Pompe disease
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
IV - Defective degradation of sphingolipid components
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
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
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
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
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
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
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
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
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)
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