Sanfilippo disease

Sanfilippo disease

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Sanfilippo disease

The Sanfilippo syndrome

Sanfilippo disease, also known as Sanfilippo syndrome, is a type of mucopolysaccharidosis known as MPS III. It manifests in children who have a deficiency in one of four digestive proteins, resulting in the accumulation of heparan sulfate in cellular compartments called lysosomes. Heparan sulfate, a macromolecule belonging to the mucopolysaccharide family, is vital for normal cell function.

Primarily accumulating in brain cells, heparan sulfate also accumulates in the lungs and bones, where it becomes toxic. This accumulation causes severe damage to the nervous system, respiratory issues, and bone deformities.

Depending on the enzyme deficiency involved, the disease is classified into four categories: MPS III A, B, C and D.

The course of the disease varies from child to child, but on average, life expectancy is very limited, typically between 15 and 20 years. Despite promising advances in medical research, Sanfilippo disease remains an orphan disease for which only palliative treatments are available.

Symptoms of the disease

Sanfilippo disease is often diagnosed late, with children typically showing no apparent symptoms at birth. The first signs of the disease usually manifest between the ages of 2 and 4. These initial symptoms, such as ear infections, colds, and diarrhea, are common in young children, so pediatricians may not be initially alarmed. It is only when significant psychomotor delays occur that doctors conduct more extensive investigations.

Diagnosis relies on urine tests to measure heparan sulfate, blood tests to detect the missing digestive protein, genetic tests to identify mutations, and prenatal diagnosis for parents who already have an affected child.

Genetic transmission

Sanfilippo disease is an autosomal recessive genetic disorder for all four forms of MPS III, with an estimated prevalence of 1 in 70’000 births.

Healthy carriers of the mutation can pass the disease on to their children, with a 25% risk for each pregnancy.


Direct administration of a substance into the cerebrospinal fluid by injecting it into the space surrounding the spinal cord. This method bypasses the blood-brain barrier.


Acid found in the nucleus of living cells, an essential component of chromosomes and serves as the carrier of genetic characteristics.


Version of a gene located at a specific position on a chromosome, which can vary from one individual to another.


Anemia is a blood disorder that impacts the quantity and quality of red blood cells (erythrocytes) in the bloodstream. It may result from an enzyme deficiency.


Graphical examination representing the hearing capacity of each ear.


Natural physiological mechanism by which cells initiate a cleansing program to eliminate or recycle damaged, dysfunctional, or pathogenic substances.


The term "autosomal" indicates that the genetic abnormality is located on a non-sexual chromosome.


Biotherapy refers to all treatments that utilize organisms or substances derived from living organisms, such as microbes, genes, cells, tissues, organs etc.


A catalyst is a substance that accelerates the rate of a chemical reaction. It participates in the reaction, but is not consumed or altered by it, thus not appearing in the reaction equation.


The deficiency of a lysosomal enzyme has a genetic cause, occurring when an individual’s genetic makeup lacks genes capable of producing a functional form of the enzyme in question. 

Our genetic makeup comprises 23 large books, known as chromosomes, containing approximately 25’000 chapters, or genes. Most of our genes exist in duplicate, meaning we possess two copies of the genes encoding each lysosomal enzyme. Sometimes, one copy of a gene (an allele) becomes inactive due to a typing error in the gene’s text, known as a mutation in the DNA of the gene. If both alleles of the same gene are rendered inactive by mutations, cells will no longer produce the lysosomal enzyme encoded by the gene, leading to the onset of the corresponding disease. For instance, inactivation of both alleles of the lysosomal glucocerebrosidase gene by mutation results in the Gaucher disease.


A cell is the fundamental building block of a living organism. The body consists of billions of cells, each serving unique functions: skin cells, neurons, white and red blood cells, among others.


A stem cell is an undifferentiated cell with the ability to multiply into cells that remain undifferentiated (self-renewal) and into differentiated cells, contributing to the formation of tissues or organs.


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A chromosome is a microscopic element composed of DNA molecules. It houses the genes, which carry genetic information that can be passed on to offspring. Chromosomes are present in pairs, with each healthy individual possessing 23 of them. The chromosomes within the same pair are identical, carrying the same genes. Thus, there are two versions of the same gene, known as alleles. Recessive inheritance occurs when the genetic defect responsible for a disease affects both copies of the involved gene. In other words, an individual can carry the abnormality (in one of the two copies of the gene) without it being expressed. The disease only manifests when both copies are abnormal.


Doctor who diagnoses conditions through direct examination of patients.


Most cells share relatively similar structures, consisting of three elements:

  • A nucleus, which contains the genetic makeup of every individual in the form of 23 pairs of chromosomes, each of them containing a long DNA molecule;
  • A cell membrane, surrounding the cell and regulating all exchanges between the cell’s contents and the outside world
  • A cytoplasm, a liquid inside the cell containing various organelles, each of which perform functions necessary for the cell’s life.

Cystinosis is a condition associated with a defect in cystine transport out of lysosomes, leading to lysosomal accumulation of this amino acid in various organs. The degradation product of the amino acid cysteine is utilized in the treatment of cystinosis under the trade name of Cystagon.


When both copies of a gene encoding a lysosomal enzyme are inactivated by a mutation, the lysosomal digestion process within the cell is disrupted, leading to the accumulation of molecules in the lysosomes. This accumulation causes the number and size of lysosomes in the cell to increase, resulting in cellular malfunction or death. 

This mechanism underlies the appearance of symptoms in lysosomal diseases. 

Lysosomal diseases vary in:

  • Affected organs
  • Severity
  • Onset time, ranging from early childhood to adulthood
  • Manifestation differences among patients

*Article written in collaboration with Pr Marc Abramowicz (Hôpital Érasme).


An enzyme is a protein that acts as a biological catalyst, facilitating biochemical reactions without altering the products. It lowers the activation energy of a reaction, speeding up metabolic chemical reactions by millions of times without affecting the equilibrium.


Use of enzymes for therapeutic purposes.


This therapy involves replacing the missing or deficient enzyme with a ‘recombinant’ enzyme, produced through genetic engineering.


Study of various factors likely involved in the onset and development of one or more diseases.


A multiplex family is characterized by several family members being affected by a disease.


Complete genetic material, comprising DNA molecules, of a cell.


Entirety of an individual’s genetic constituents.


Carbohydrates constitute a class of organic molecules, containing a carbonyl group (either aldehyde or ketone) and multiple hydroxyl groups (-OH). Historically, carbohydrates were known as saccharides.


Glucosamine serves as the primary monomer in mucopolysaccharides, including hyaluronic acid (found in connective tissue), keratan (in skin) and heparin (in blood). It promotes the synthesis of proteoglycans and collagen while inhibiting collagenase activity. Glucosamine also possesses anti-inflammatory properties by reducing free radical production by macrophages.


Linear polysaccharide consisting of repeating disaccharide units, with one sugar being an amino acid (N-acetylglucosamine or N-acetyl galactosamine) and the other a uronic acid. Hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, and keratan sulfate are distinguished types. These can combine with proteins to form proteoglycans, except for hyaluronic acid. Glycosaminoglycan was previously synonymous with mucopolysaccharide. 


Glycosylation is an enzymatic process that involves the covalent attachment of a carbohydrate to a peptide chain, protein, lipid, or other molecules. In biological contexts, glycosylation primarily refers to the enzymatic addition of glycans to proteins or other organic molecules.


Please navigate to the ‘Sanfilippo disease’ tab for more information.


A nucleus, cell, or individual with two dissimilar genes at the same location on the two homologous chromosomes of a pair (each inherited from one parent).


Description of a disease’s various manifestations and its progression over time in the absence of treatment.


A nucleus, cell, or individual with two identical genes at the same position on the two homologous chromosomes of a pair.


Hydrolases constitute a class of enzymes that catalyze the hydrolysis of molecules.


Number of new cases appearing in a population within a year.


This treatment aims at partially inhibiting the production of metabolites that, due to a genetic defect, are not recycled by cells. Such treatment reduces metabolite accumulation and cell congestion.


Precise location of a gene (or series of genes) on a chromosome.


Lysosomal Storage Diseases (LSDs) are a group of inherited metabolic disorders mostly caused by enzyme deficiencies in the lysosome, leading to an accumulation of undegraded substrate. This storage process results in a wide spectrum of clinical manifestations depending on the specific substrate and site of accumulation.


To dissolve a cell or bacteria.


The lysosome is a eukaryotic cell organelle acting as a cellular waste bin where non-functional molecules are eliminated by digestion. It contains hydrolases, enzymes designed to break down intracellular molecules.


Fabry disease is an X-linked recessive inherited disorder of glycosphingolipid metabolism caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. This enzyme defect leads to the accumulation of undegraded substrate in tissues and plasma. 

In its classic form, the disease affects hemizygous males more severely, with clinical signs typically beginning in childhood, including pain in the extremities and dermatological manifestations. Heterozygous women often exhibit symptoms, albeit in a more variable manner and generally less severe than in men. Diagnosis is definitively confirmed by assaying enzyme activity in men and identifying GLA gene mutations in women. 

Replagal® (agalsidase alpha), produced by Shire (Cambridge, Massachussets), is used in the treatment of Fabry disease.

Author: Dr D. Germain (September 2022)

Le Replagal® (agalsidase alpha), produit par Shire (Cambridge, Massachusetts) est utilisé dans le traitement de la maladie de Fabry.

*Auteur : Dr D. Germain (septembre 2002).


Gaucher's disease is a rare genetic disorder inherited from both parents, affecting major organs. It is caused by a defect in a lysosomal enzyme called beta-glucocerebrosidase.

The absence or malfunction of this enzyme leads to the accumulation of glucosylceramide (or glucocerebroside). Typically, symptoms do not manifest at birth but may appear after several months, years, or even adulthood. Effective treatments are available for types 1 and 3 of the disease, including VPRIV® (velaglucerase alpha), produced by Shire, for a long-term treatment in patients with type 1 Gaucher disease.


Genetic disease that is transmitted from generation to generation.


Hunter disease is attributed to a deficiency in iduronate 2-sulphatase (IDS), leading to the buildup of dermatan sulphate (DS) and heparan sulphate (HS) in the lysosomes of different tissues.


Hurler's disease stems from a deficiency in alpha-L-iduronidase. Treatment for this condition typically involves enzyme replacement therapy.


Lysosomal diseases result from deficiencies in specific lysosomal enzymes. With approximately fifty distinct lysosomal enzymes, each serving a unique role in degradation, there are likewise about fifty known lysosomal diseases.


Morquio's disease, also known as mucopolysaccharidosis type IV (MPS IV), is a lysosomal overload disorder within the mucopolysaccharidosis group. It is characterized by spondyloepiphyso-metaphyseal dysplasia. A recombinant enzyme infusion therapy tailored to target bone tissue is currently under development.


Niemann-Pick disease is an autosomal recessive lysosomal disorder resulting from a deficiency in the activity of acid sphingomyelinase, the enzyme responsible for hydrolyzing sphingomyelin into ceramide. This deficiency leads to cellular overload with sphingomyelin.


Pompe disease, also known as glycogenosis type II (GSD II), is a lysosomal overload disease causing skeletal and respiratory muscle damage of varying severity, often accompanied by hypertrophic cardiomyopathy in its infantile form. Treatment for Pompe disease involves Myozyme®, an enzyme replacement infusion manufactured by Genzyme.


A rare disease is defined by its frequency. A disease is considered rare when it affects less than one out of 2000.


Sanfilippo disease arises from a genetic defect causing a metabolism deficiency in a mucopolysaccharide, now termed glycosaminoglycan. Specifically, heparan sulphate fails to be adequately broken down in the cell's lysosomes, which typically serve as the cell's "waste dump". The accumulation of heparan sulphate within the lysosomes leads to the characteristic disorders of this disease, categorized as a lysosomal overload disorder. There are four types of MPS III, each linked to the deficiency of one of four heparan sulphate-degrading enzymes: MPS type IIIA, MPS type IIIB, MPS type IIIC, and MPS type IIID.


Scheie's disease is a progressive hereditary lysosomal storage disorder caused by a deficiency in the enzyme alpha-L-iduronidase. It represents an attenuated form of mucopolysaccharidosis type 1. Since 2003, an enzyme replacement therapy called laronidase (Aldurazyme MD) has been available to mitigate the disease's progression.


Sly disease is an inherited metabolic disorder characterized by a deficiency in β-glucuronidase, a lysosomal enzyme.


Metabolism encompasses all the transformation reactions occurring in the body. It consists of two main processes: anabolism, involving reactions leading to synthesis or manufacture, and catabolism, involving reactions leading to degradation and/or the release of energy.


Compound resulting from the biochemical transformation of an initial molecule by the metabolism.


In biology, a monomer (or subunit) serves as the building block of polymers such as proteins (e.g., hemoglobin and albumin), nucleic acids (e.g., DNA), and polysaccharides (e.g., mucopolysaccharides).


Mucopolysaccharide, also known as glycosaminoglycan, is a type of glycoprotein formed by the linkage between a protein (chain of amino acids) and a polysaccharide (sugar molecule).


Mucopolysaccharidoses include several types:

  • Mucopolysaccharidosis type I (associated with Hurler’s disease and Scheie’s disease)
  • Mucopolysaccharidosis type II (related to Hunter’s disease)
  • Mucopolysaccharidosis type III (linked to Sanfilippo disease)
  • Mucopolysaccharidosis type IV (characteristic of Morquio’s disease)
  • Mucopolysaccharidosis type VI (see Maroteaux-Lamy syndrome)
  • Mucopolysaccharidosis type VII (connected with Sly disease)
  • Type IX mucopolysaccharidosis is caused by a deficiency in hyaluronidase. As of July 2012, there is currently no treatment available.

N-acetylglucosaminidase alpha is a protein encoded by the NAGLU gene in humans.


Odiparcil is a small molecule taken orally with the potential to reduce the accumulation of chondroitin sulphates (CS) and dermatan sulphates (DS) in the lysosomes of patients with certain subtypes of MPS.


In cell biology, organites (sometimes called organelles) are specialized structures contained in the cytoplasm and separated from the rest of the cell by a phospholipid membrane. Phospholipids, which are lipids with a phosphate group, consist of two fatty acids, glycerol, and phosphate.


Oses, also known as monosaccharides, are the monomers of carbohydrates.


Stable nucleic acid lipid particles are nanoparticle-sized lipid particles capable of containing and delivering various types of nucleic acid molecules into cells.


The phenotype encompasses all observable characteristics of an individual. It reflects gene expression as well as the influence of environmental factors.


See organites


Study of the mechanisms underlying the development of a disease.


A healthy carrier is an individual who is heterozygous for a defective recessive gene and, as a result, is not affected by the genetic disease in question.


ST-920 is an experimental gene therapy aiming to provide a fully functioning version of the GLA (Galactosidase alpha) gene to the liver, which would then release alpha-GalA into the bloodstream


Constituent of the living cells, comprising the cytoplasm and the nucleus.


Translational research bridges the gap between basic research and clinical applications, facilitating the rapid implementation of therapeutic innovations for patient benefit.


Gene sequencing involves determining the nucleotide sequence of the DNA present in each cell of a given organism.


Splenomegaly refers to an enlargement of the spleen.


Maroteaux-Lamy syndrome, also referred to as mucopolysaccharidosis type VI, is a rare inherited metabolic disorder characterized by dwarfism, deafness, and progressive skeletal deformities. It is treated with the medication Naglazyme®.


Cellular therapies involve transplanting cells to restore deficient biological functions in a tissue or organ.


Enzyme replacement therapy (ERT) is a therapeutic approach for administering a defective or absent congenital enzyme. This can be done directly by coupling the enzyme to a carrier molecule or through organ transplantation, or indirectly by introducing the gene into the recipient.


Gene therapy entails replacing a defective or missing gene with a correct version or over-expressing a therapeutic protein.


Tralesinidase alfa is an investigational enzyme replacement therapy (ERT) developed to replace the defective NAGLU enzyme in individuals with Sanfilippo type B disease. This therapy involves a healthy version of the human NAGLU enzyme fused with a small protein derived from insulin growth factor 2 (IGF2), enhancing the enzyme’s ability to enter cells and perform its function.


Autosomal recessive inheritance occurs when a genetic trait is carried by an autosome, which is a non-sex chromosome (neither X nor Y). The phenotype associated with this trait is recessive, requiring the presence of two identical alleles for expression. One allele is inherited from the male gamete, and the other one from the female gamete.


Natural sugar synthesized by certain bacteria, fungi, plants and animals.


Trombocytopenia refers to a blood platelet count of less than 150’000 per cubic millimeter of blood.


In gene therapy, a lentiviral vector utilizes lentiviruses rendered non-pathogenic for humans. This method allows for the insertion, modification, or deletion of genes in cells. Lentiviruses belong to the group of retroviruses.