Mucopolysaccharidoses

The mucopolysaccharidoses, a subset of the lysosomal storage diseases, are a group of inherited disorders characterized by absent or defective enzymes needed to break down carbohydrate chains called glycosaminoglycans (GAGs), previously known as mucopolysaccharides. These disorders lead to the accumulation of GAGs within cell lysosomes Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles, resulting in a variety of health problems. Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship appear healthy at birth, but physical and/or mental function deteriorates as accumulation progresses. With disease progression, multiple organ systems may be affected. The diagnosis can be made by measuring urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat GAG concentrations and by performing enzyme assays to identify the enzyme deficiency. Management depends on the specific disorder, degree of GAG accumulation, and degree of deformity Deformity Examination of the Upper Limbs.

Last updated: 13 Apr, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Mucopolysaccharidoses (MPSs) are a group of genetic metabolic diseases due to absent or defective enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes needed to break down carbohydrate chains called glycosaminoglycans (GAGs).

Etiology and classification

The MPSs are all inherited and classified on the basis of the enzyme deficiency.

  • MPS I:
  • MPS II:
    • Also known as Hunter syndrome
    • X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) 
    • Deficiency of iduronate sulfatase
  • MPS III:
    • Also known as Sanfilippo syndrome
    • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance
    • Divided into 4 clinical entities on the basis of distinct enzyme deficiencies that are needed to break down heparan sulfate carbohydrate chains:
      • MPS IIIA: deficiency of heparan N-sulfatase
      • MPS IIIB: deficiency of alpha-N-acetylglucosaminidase
      • MPS IIIC: deficiency of heparan sulfate acetyl coenzyme A ( acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle):alpha-glucosaminide acetyltransferase
      • MPS IIID: deficiency of N-acetylglucosamine 6-sulfatase
  • MPS IV:
    • Also known as Morquio syndrome
    • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance
    • Divided into 2 clinical entities on the basis of distinct enzyme deficiencies that are needed to break down keratan sulfate carbohydrate chains:
      • MPS IVA: deficiency of N-acetylgalactosamine-6-sulfatase
      • MPS IVB: deficiency of beta-galactosidase
  • MPS VI:
  • MPS VII:
    • Also known as Sly syndrome
    • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance 
    • Deficiency of beta-glucuronidase
  • MPS IX:
  • Note: MPS V and MPS VIII are no longer recognized as distinct entities.

Epidemiology

  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 25,000 live births 
  • Based on type:
    • Severe MPS I: 1 in 100,000 
    • Attenuated MPS I: 0.2–1 in 100,000 live births 
    • MPS II: approximately 1 in 100,000 live male births
    • MPS III (all 4 types combined): 1 in 70,000 live births
    • MPS IV: 1 in 200,000 live births
    • MPS VII: 1 in 250,000 live births
    • MPS IX: exceedingly rare

Pathophysiology

  • Lysosomes Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles:
    • Cytoplasmic organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles containing degradative enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes enclosed in a membrane
    • Degradative enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes target specific proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance, carbohydrates Carbohydrates A class of organic compounds composed of carbon, hydrogen, and oxygen in a ratio of cn(H2O)n. The largest class of organic compounds, including starch; glycogen; cellulose; polysaccharides; and simple monosaccharides. Basics of Carbohydrates, or lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids.
  • Lysosomal storage diseases:
    • Deficiency of these degradative enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes halts processing and/or destruction of these target molecules.
    • Molecular accumulation in tissues leads to disease.
  • MPSs:
    • Deficiency of lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes needed to metabolize GAGs
    • GAGs are long carbohydrate chains made up of repeating disaccharide units attached to a protein core.
    • GAGs are present in several tissues: 
      • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types
      • Cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage: Histology
      • Tendons
      • Synovial fluid
      • Corneas
      • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
      • Connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue: Histology
      • Solid and luminal organs
    • The 4 main categories of GAGs include:
      • Hyaluronic acid Hyaluronic acid A natural high-viscosity mucopolysaccharide with alternating beta (1-3) glucuronide and beta (1-4) glucosaminidase bonds. It is found in the umbilical cord, in vitreous body and in synovial fluid. A high urinary level is found in progeria. Connective Tissue: Histology 
      • Heparan sulfate
      • Chondroitin sulfate Chondroitin sulfate Derivatives of chondroitin which have a sulfate moiety esterified to the galactosamine moiety of chondroitin. Chondroitin sulfate a, or chondroitin 4-sulfate, and chondroitin sulfate c, or chondroitin 6-sulfate, have the sulfate esterified in the 4- and 6-positions, respectively. Chondroitin sulfate B is a misnomer and this compound is not a true chondroitin sulfate. Connective Tissue: Histology
      • Keratan sulfate
    • Glycosaminoglycans and/or metabolites accumulate in cells or connective tissues.
      • Progressive cellular damage ensues.
      • Appearance and physical, mental, organ, and system functions may be affected.

Clinical Presentation

Affected individuals are usually not affected at birth, but they experience disease progression as they age. Clinical features vary based on the MPS type.

MPS I

Results in a continuous spectrum of disease that is divided into 3 clinical entities based on disease severity (less severe forms referred to as attenuated):

  • Hurler syndrome (most severe):
    • Developmental delay by 1 year of age
    • Arrested development between ages 2 and 4 years
    • Frequently, death by age 10 (usually from cardiopulmonary complications)
  • Hurler-Scheie syndrome (intermediate severity):
    • Symptom onset between 3 and 8 years
    • Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids: late teens to early 20s
  • Scheie syndrome (least severe):
    • Symptom onset between 5 and 10 years
    • Can live into adulthood

Distinguishing clinical features (more or less pronounced depending on severity):

  • Neurological, psychiatric, and developmental issues:
    • Mental/cognitive impairment
    • Language limitation
    • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    • Spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy compression Compression Blunt Chest Trauma (pachymeningitis cervicalis) → muscle weakness and/or paralysis
    • Peak in development (e.g., walking, short sentences), followed by decline
    • Growth retardation Growth Retardation Failure of a fetus to attain expected growth. Fetal Alcohol Spectrum Disorder and short stature
  • Poor vision Vision Ophthalmic Exam:
    • Corneal clouding
    • Retinal degeneration
  • Dysostosis multiplex (characteristic skeletal abnormalities):
    • Compressed spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types/joint abnormalities
    • Joint restriction and contractures Contractures Prolonged shortening of the muscle or other soft tissue around a joint, preventing movement of the joint. Wound Healing (painful and progressive)
    • Carpal tunnel syndrome Carpal Tunnel Syndrome Carpal tunnel syndrome (CTS) is a complex of signs and symptoms caused by compression of the median nerve as it crosses the carpal tunnel. Presentation is with pain and paresthesia of the dermatomal target tissues innervated by the median nerve as well as weakness and atrophy of the nerve’s myotomal targets. Carpal Tunnel Syndrome
  • Distinct facial features:
    • Coarse features
    • Flat midface
    • Depressed nasal bridge
    • Bulging forehead Forehead The part of the face above the eyes. Melasma
    • Small jaws
    • Widely spaced teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth: Anatomy
    • Peg-shaped teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth: Anatomy
    • Macroglossia Macroglossia The presence of an excessively large tongue, which may be congenital or may develop as a result of a tumor or edema due to obstruction of lymphatic vessels, or it may occur in association with hyperpituitarism or acromegaly. It also may be associated with malocclusion because of pressure of the tongue on the teeth. Wilms Tumor (enlarged tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy)
  • Organomegaly:
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
    • Spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy
  • Cardiovascular disease:
    • Cardiomegaly Cardiomegaly Enlargement of the heart, usually indicated by a cardiothoracic ratio above 0. 50. Heart enlargement may involve the right, the left, or both heart ventricles or heart atria. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (heart failure) or several forms of cardiomyopathies. Ebstein’s Anomaly
    • Valve disease
    • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
    • Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR)
  • Obstructive airway Airway ABCDE Assessment disease:
    • Thick mucus
    • Enlarged tonsils Tonsils Tonsillitis and abnormal tracheal cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage: Histology → may lead to progressive airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction
    • Noisy breathing
    • Frequent respiratory infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Tendency to develop abdominal and inguinal hernias Inguinal Hernias An abdominal hernia with an external bulge in the groin region. It can be classified by the location of herniation. Indirect inguinal hernias occur through the internal inguinal ring. Direct inguinal hernias occur through defects in the abdominal wall (transversalis fascia) in Hesselbach’s triangle. The former type is commonly seen in children and young adults; the latter in adults. Inguinal Canal: Anatomy and Hernias

MPS II

  • Attenuated cases are less severe but are not designated as distinct entities.
  • X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) trait → primarily a disease in males
  • Disease progression:
    • Symptom onset between ages 2 and 4 years
    • Frequently, death by age 15 years (usually cardiopulmonary complications)
    • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with attenuated cases may live into their 50s.
  • Similar clinical features as for MPS I but milder presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor, including:
    • Neurocognitive decline
    • Abnormal facies
    • Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus
    • Cardiomegaly Cardiomegaly Enlargement of the heart, usually indicated by a cardiothoracic ratio above 0. 50. Heart enlargement may involve the right, the left, or both heart ventricles or heart atria. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (heart failure) or several forms of cardiomyopathies. Ebstein’s Anomaly
    • Dysostosis multiplex with dwarfism
  • Distinguishing characteristics:
    • Absence of corneal clouding
    • Aggressive behavioral tendencies
    • Communicating hydrocephalus Communicating Hydrocephalus Hydrocephalus in Children
    • Chronic diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • White lesions on limbs and trunk

MPS III

  • Disease progression:
    • Symptom onset after 1st year of life
    • Marked decline in learning between ages 2 and 6 years
    • Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables, from late teens to early 30s
  • There are few clinical differences among the 4 clinical entities.
  • Similar clinical features as for MPS I
  • Distinguishing characteristics: severe neurologic symptoms
    • Progressive dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders
    • Aggressive behavior
    • Hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Deafness
    • Vision Vision Ophthalmic Exam loss
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
    • Progressive unsteadiness on feet
    • Unable to walk by age of 10 years
Dysmorphic features in mps

Clinical features of mucopolysaccharidosis IIIA:
Facial dysmorphism (coarse facial features, slightly depressed nasal bridge, prominent eyebrows, low-set ears Low-set ears DiGeorge Syndrome, malocclusion, full cheeks Cheeks The part of the face that is below the eye and to the side of the nose and mouth. Melasma, wiry and dry hair, and short neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess) and skeletal symptoms (genu valga, varus feet, and stocky hands) are shown.

Image: “Dysmorphic features of our patient” by Department of Paediatrics, Medical University of Lublin, Racławickie 1, 20-059, Lublin, Poland. License: CC BY 4.0

MPS IV

  • Disease progression:
    • Symptom onset between ages 1 and 3 years
    • Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids to 20s or 30s, unless the severe form is present
  • Similar clinical features as for MPS I
  • Presentations are similar in both types, but appear more severe in MPS IVA.
  • Distinguishing characteristics:

MPS VI

  • Disease progression:
    • Normal growth and development to age 8 years
    • Development of truncal shortening, crouched stance, and joint restriction by age 10 years
    • Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables: late teens and 20s
  • Similar clinical features as for MPS I, but commonly with normal intellectual development
  • Distinguishing characteristics:
    • Neurologic complications include: 
    • Truncal shortening
    • Crouched stance (forward-curving spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy)
    • Joint restriction
    • Cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) valve disorders
    • Pulmonary hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
Mucopolysaccharidosis vi

Rapidly progressing MPS VI in a 16-year-old patient:
Face shows coarse facies Coarse facies Autosomal Dominant Hyperimmunoglobulin E Syndrome, with frontal Frontal The bone that forms the frontal aspect of the skull. Its flat part forms the forehead, articulating inferiorly with the nasal bone and the cheek bone on each side of the face. Skull: Anatomy bossing, enlarged tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, thick lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, abnormal dentition, and gingival hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation.

Image: “Rapidly progressing 16-year old MPS VI patient” by Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, Paris, France. License: CC BY 2.0

MPS VII

  • Disease progression:
    • Severe form causes hydrops Hydrops Cholecystitis fetalis:
      • Widespread fetal edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
      • Leads to infantile death
    • Most children are less severely affected:
      • Mild to moderate intellectual impairment by age 3 years
      • Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids to teens or 20s
  • Similar clinical features as for MPS I
  • Distinguishing characteristics:
    • Soft tissue Soft Tissue Soft Tissue Abscess and skeletal anomalies
    • Susceptibility to pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
    • Communicating hydrocephalus Communicating Hydrocephalus Hydrocephalus in Children

MPS IX

  • Nodular soft tissue Soft Tissue Soft Tissue Abscess masses located around joints
  • Episodes of painful swelling Swelling Inflammation of the joint masses
  • Mild facial changes
  • Short stature (as seen in other MPS disorders)
  • Normal joint movement
  • Normal intelligence

Diagnosis

Clinical history and examination:

Laboratory analysis:

  • Urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat GAG concentrations 
  • Enzyme assays to confirm the specific enzyme deficiency: 
    • Serum testing in suspected cases in infancy or early childhood
    • Prenatal diagnosis can be performed with the use of amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios and chorionic villus sampling. 
  • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies
  • Note: Newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn screening Screening Preoperative Care in the U.S. is only done for MPS I; screening Screening Preoperative Care is not available for other forms of MPS.

Management

There is no cure for MPS. Medical care Medical care Conflict of Interest is aimed at treating systemic conditions and at improving quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life. At this time, eventual decline in function is inevitable.

  • Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies for parents who have a family history Family History Adult Health Maintenance of MPS to determine if they are carrying a causative genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
  • Physical therapy Physical Therapy Becker Muscular Dystrophy to delay joint problems and improve mobility Mobility Examination of the Breast 
  • Surgery:
  • Enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID) therapies:
    • Currently in use for:
      • MPS I (laronidase)
      • MPS II (idursulfase)
      • MPS IVA (elosulfase alpha)
      • MPS VI (galsulfase)
      • MPS VII (vestronidase alfa)
      • Enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID) for other types is in development.
    • Therapy has proven useful in reducing:
      • Nonneurologic symptoms
      • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Bone marrow transplantation Bone marrow transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation (BMT) and umbilical cord Umbilical cord The flexible rope-like structure that connects a developing fetus to the placenta in mammals. The cord contains blood vessels which carry oxygen and nutrients from the mother to the fetus and waste products away from the fetus. Placenta, Umbilical Cord, and Amniotic Cavity blood transplantation (UCBT):
    • Limited success in treating MPSs
    • High-risk procedures usually performed only after extensive evaluation and parental counseling

Differential Diagnosis

  • Mucolipidosis: lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases with excessive storage of lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids. Children with mucolipidosis may share some clinical features associated with the MPSs (facial features, bony/structural abnormalities, brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification abnormalities). Diagnosis is made with laboratory testing to demonstrate enzyme deficiency. Management is supportive.
  • Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease: most common lysosomal storage disorder; results from glucocerebrosidase deficiency. The 3 types have varying presentations and severity. These presentations can include hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, easy bruising Easy bruising Chédiak-Higashi Syndrome, bone fractures Bone fractures Breaks in bones. Bones: Remodeling and Healing, and progressive neurologic deterioration. The diagnosis is made with DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure or enzyme analysis. Management depends on the type and includes enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID), glucosylceramide synthase inhibitors, splenectomy Splenectomy Surgical procedure involving either partial or entire removal of the spleen. Rupture of the Spleen, and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow or stem cell transplantation. 
  • Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease: lysosomal storage disorder resulting from hexosaminidase A Hexosaminidase A A mammalian beta-hexosaminidase isoform that is a heteromeric protein comprised of both hexosaminidase alpha and hexosaminidase beta subunits. Deficiency of hexosaminidase A due to mutations in the gene encoding the hexosaminidase alpha subunit is a case of Tay-sachs disease. Deficiency of hexosaminidase A and hexosaminidase B due to mutations in the gene encoding the hexosaminidase beta subunit is a case of Sandhoff disease. Tay-Sachs Disease deficiency. The 3 types have variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables onsets. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may present with macular cherry-red spots, blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity, deafness, cognitive and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology deterioration, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson’s Disease, spasticity Spasticity Spinal Disk Herniation, ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. The diagnosis is made with enzyme activity testing and molecular analysis. Management is supportive.
  • Niemann-Pick disease Niemann-Pick disease Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease ( NPD NPD Niemann-pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type a and type B result from mutations in the smpd-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type c results from npc1 or npc2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease): rare inherited, lysosomal storage disorder that is classified based on the genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations. Types A and B NPD NPD Niemann-pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type a and type B result from mutations in the smpd-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type c results from npc1 or npc2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease result in acid sphingomyelinase Acid sphingomyelinase Niemann-Pick Disease enzyme deficiency. Clinical manifestations may include failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, interstitial lung disease, cognitive and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology impairment, and macular cherry-red spots. The diagnosis can be confirmed by the measurement of sphingomyelinase activity or biomarkers, genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies, or biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Management is supportive.

References

  1. Mucopolysaccharidoses Face Sheet. (n.d.). National Institute of Neurological Disorders and Stroke. Retrieved May 22, 2021, from https://web.archive.org/web/20160818205908/http://www.ninds.nih.gov/disorders/mucopolysaccharidoses/detail_mucopolysaccharidoses.htm
  2. Sihoun, H. (2021). Mucopolysaccharidoses: clinical features and diagnosis. Retrieved May 22, 2021, from https://www.uptodate.com/contents/mucopolysaccharidoses-clinical-features-and-diagnosis
  3. Sihoun, H. (2021). Mucopolysaccharidoses: treatment. Retrieved May 22, 2021, from https://www.uptodate.com/contents/mucopolysaccharidoses-treatment
  4. Sihoun, H. (2021). Mucopolysaccharidoses: complications. Retrieved May 22, 2021, from https://www.uptodate.com/contents/mucopolysaccharidoses-complications

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