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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