Mucopolysaccharidosis (MPS)

Metabolic storage disease with multiorgan involvement.

MPS.

MPS I H:Hurler Syndrome (Hurler-Pfaundler Syndrome; Johnie McL Syndrome; Thompson Syndrome; Hurler-Scheie Syndrome; Mucopolysaccharide Storage Disease I; α-L-Iduronidase Deficiency Syndrome; Dysostosis Multiplex; Dysostotic Idiocy; Hurler-Pfaundler Syndrome; Gargoylism; Lipochondrodystrophy; Pfaundler-Hurler Syndrome)

MPS I S: Scheie Syndrome

MPS I H/S: Hurler-Scheie Syndrome

MPS II:Hunter Syndrome (Hurler-Hunter Disease; Mucopolysaccharide Storage Disease II)

MPS III: Sanfilippo Syndrome (Mucopolysaccharide Storage Disease III; Heparitinuria; HS-Mucopolysaccharidosis; Polydystrophic Oligophrenia)

• Type A: Sanfilippo Syndrome A (Heparan Sulfate Sulfatase Deficiency)
• Type B: Sanfilippo Syndrome B (N-Acetyl-Alpha-D-Glucosaminidase [NAG] Deficiency)
• Type C: Sanfilippo Syndrome C (Acetyl-Coa:Alpha-Glucosamide N-Acetyltransferase Deficiency)
• Type D: Sanfilippo Syndrome D (N-Acetylglucosamine-6-Sulfate Sulfatase Deficiency)

MPS IV:Morquio Syndrome (Mucopolysaccharide Storage Disease IV; Morquio-Brailsford Syndrome; Morquio-Ullrich Syndrome; Atypical Chondrodystrophy; Dysotosis Enchondralis Metaepiphysaria; Eccentrochondrodysplasia; EccentroOsteochondrodysplasia; Familial Osseous Dystrophy; Hereditary Chondrodysplasia; Hereditary Osteochondrodystrophy; Hereditary Polytopic Enchondral Dysostosis; Keratansulfaturia; KS Mucopolysaccharidosis; Osteochondrodystrophia Deformans; Osteochondrodystrophy; Spondylo-Epiphyseal Dysplasia; Silfverskiold Syndrome; Morquio-Silfverskiold Syndrome)

• Type A: Morquio Syndrome A (Galactosamine-4-Sulfatase [GALNS] Deficiency)
• Type B: Morquio Syndrome B (Morquio-Like Syndrome; β-Galactosidase Deficiency)

MPS V: Obsolete, previously known Ellis-Sheldon Syndrome

MPS VI: Maroteaux-Lamy Syndrome (Mucopolysaccharide Storage Disease VI; Arylsulfatase B [ARSB] Deficiency; N-Acetylgalactosamine-4-Sulfatase Deficiency; Polydystrophic Dwarfism; Pyknodysostosis of Maroteaux-Lamy)

MPS VII: Sly Syndrome (Mucopolysaccharide Storage Disease VII; Beta-Glucuronidase Deficiency; Beta-Glucuronidase Deficiency Mucopolysaccharidosis; GUSB Deficiency)

MPS VIII:Diferrante Syndrome.

NB: DiFerrante Syndrome should not be used as a term to describe MPS VIII because it has been proved that the author committed fraud based on observation obtained from only one patient.

MPS F:Fucosidosis (Mucopolysaccharide Storage Disease F; α-L-Fucosidase [FUCA] Deficiency)

The incidence of MPS is estimated at 0.04-0.3% of living births and considered 1.5% of all congenital disorders. The average surviving for these patients is around 20-30 years and cardiac failure or infections to the gastrointestinal tract cause death. The instability to the atlantoaxial joint is also implicated as cause of death.

MPS I and III are autosomal recessive; MPS II is X-linked with locus at Xq27-q28; MPS IV is autosomal recessive and located on chromosome 16 long-arm; MPS VI is autosomal recessive; MPS VII is autosomal recessive, with GUSB locus on long arm of chromosome 7; fucosidosis is an autosomal recessive trait with occasional parental consanguinity, located on the short arm of chromosomes 1 and 2.

MPS I: Inborn error of mucopolysaccharide metabolism with α-l-iduronidase deficiency in leucocytes and fibroblasts and abnormal mucopolysaccharide incorporation and degradation by fibroblasts. Three types are recognized. All three types have similar laboratory findings, except the fibroblasts differ.

MPS I-H (Hurler Syndrome): Most severe of the three types with coarse (gargyloid) facies, accelerated growth from infancy followed by progressive decline in rate of development, mental retardation, dysostosis multiplex, corneal clouding, and death before age 10 years as a consequence of pneumonia and heart failure. Some symptoms (hernia, macrocephaly, respiratory infections, and limited hip abduction) become apparent early in infancy, but the complete clinical picture develops during the second year of life.

MPS I-S (Scheie Syndrome): More moderate autosomal recessive form caused by deficiency of α-l-iduronidase leading to accumulation of dermatan sulfate in tissues. It is marked by corneal opacities, clawhand, aortic valve disease, normal stature, mild or absent intellectual impairment, and nearly normal lifespan, depending on cardiac complications. The condition is seldom recognized during infancy or early childhood.

MPS H/S (Hurler-Scheie Syndrome): Intermediate form between the previous two variants, which includes short stature, dysostosis multiplex, hepatosplenomegaly, corneal clouding, umbilical or inguinal hernia, generally normal mental development with psychotic symptoms later in life, and death by age 25 years caused by acute or chronic cardiac failure (cor pulmonale). Symptoms are usually apparent by age 2 years.

Clinical characteristics and demonstration of α-l-iduronidase deficiency, abnormal deposits of mucopolysaccharides, and increasing urinary heparan sulfate and dermatan sulfate.

Coarse (gargyloid) facies, macrocephaly with frontal bulging, scaphoidocephaly, premature closure of sagittal and metopic sutures, J-shaped sella turcica, full cheeks, and prominent nasolabial fold. Thick earlobes. Prominent lower eyelids, shallow orbits, corneal opacity, glaucoma, and synophrys. Flat philtrum, wide and anteverted nares, broad tip and depressed bridge of nose. Wide mouth with protruding tongue, big lips, and widely spaced teeth. Short neck. Stiff rib cage with pectus excavatum or carinatum. Prominent abdomen with hernia. Stiff fingers with clawhand. Joint contractures, long bone deformities, genu valgum, and hip deformities. Kyphosis, dysplastic (hook-shaped) vertebral bodies, lumbar lordosis. May have hypoplastic odontoid with atlantoaxial subluxation. Dysostosis multiplex. Dry, pale, coarse skin with hypertrichosis. Hydrocephalus. Arteriosclerosis with coronary artery narrowing, valvular defects, mainly mitral valve thickening. Hepatosplenomegaly. Recurrent chest infections. Early accelerated growth followed by failure with mental and motor retardation. Poor gag and swallowing reflexes, rhinorrhea, noisy respiration, and sleep apnea syndrome, deafness (sensorineural and conductive), blindness, and psychosis.

Full motor and mental milestones as well as medical history. Note respiratory status, arterial blood gases where indicated, and chest radiographs; pulmonary function tests where possible; treat infection before anesthesia. C1-C2 subluxation is frequent so neck instability must be ruled out. Spinal cord compression may occur as a consequence of thickening of the dura and odontoid hypoplasia, so preoperative MRI of the spinal cord is suggested. Cardiac investigation (echocardiography) is necessary to evaluate cardiac involvement: valves, myocardial function, coronary arteries. Rule out sleep apnea syndrome with polysomnography or night oximetry: sleep apnea syndrome, if present, should be treated preoperatively (i.e., nasal continuous positive airway pressure).

There are copious oral secretions: anticholinergic premedication is very helpful. A standard facial mask might be difficult to fit to the patient's face because of facial deformities; try placing the mask upside-down. Thickening of the tongue and oropharyngeal soft tissues, the presence of a short neck, and the limited mobility of the cervical spine and temporomandibular joint make direct laryngoscopy and tracheal intubation extremely difficult. A laryngeal mask airway and a fiberoptic laryngoscope should be ready for use. A nasopharyngeal airway can be useful but might be difficult to insert because of choanal narrowing by accumulation of mucopolysaccharide deposits; moreover, it might induce bleeding. An oral airway is often difficult to insert and can displace the tip of epiglottis downward. Poor gag and swallowing reflexes are present so a rapid-sequence induction is theoretically necessary, but careful inhalational induction or awake fiberoptic intubation in a cooperative patient is the safest option. Stiff chest wall with prominent abdomen could lead to difficulty with ventilation. Mental retardation, psychosis, and short stature with contractures may make IV access and patient control difficult. Hydrocephalus cases have raised intracranial pressure, so appropriate precautions are essential. Anesthetic management should take into account the presence of coronary and/or valvular disease.

Although there are no specific pharmacological implications, each condition might have specific limitations. For instance, the use of sedative medications in the Hunter and Hurler patient may lead to airway obstruction. In the presence of cardiac anomalies, the pharmacological implications are those associated with the anomaly. Antibiotic prophylaxis in case of valvular involvement.

Mucopolysaccharidosis I: Characterized by a wide range of phenotypic involvement with three major recognized clinical entities: Hurler (MPS IH), Scheie (MPS IS), and Hurler-Scheie (MPS IH/S) syndromes. All three variants are caused by a deficiency of α-l-iduronidase. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS I clinical spectrum, respectively, and Hurler-Scheie syndrome is intermediate in phenotypic expression. MPS I is more frequent than MPS II (Hunter syndrome), which has no corneal clouding and pursues a slower course. The clinical characteristics are discussed under Mucopolysaccharidoses.

MPS II (Hunter Syndrome): Caused by a deficiency of iduronate sulfatase with storage of dermatan sulfate and heparan sulfate in many tissues. It is similar to MPS I, except for the absence of corneal clouding and slower progression of the course of the disease and central nervous system deterioration. Two types are recognized, both of which are normal at birth: severe (MPS IIA), which is characterized mainly by mental retardation and progressive physical deterioration and early death, and a mild form (MPS IIB), in which patients may survive into adulthood. Onset of MPS IIA occurs between 2 and 4 years of age; deterioration, chronic diarrhea, recurrent ear infections, hearing impairment, and communicating hydrocephalus with increased intracranial pressure are progressive features, with death occurring between the ages of 10 and 15 years. Obstructive airway disease caused by hypertrophied adenoids and tonsils. Cardiac valvular dysfunction, myocardial thickening, pulmonary hypertension, coronary disease, and myocardial dysfunction may complicate the illness. MPS IIB is milder without mental retardation. Symptoms include hearing impairment, carpal tunnel syndrome, joint stiffness, discrete corneal opacities, and papilledema. Death may occur in young adulthood and can be caused by airway obstruction or cardiac failure. Laryngoscopy and tracheal intubation are usually very difficult.

MPS III (Sanfilippo Syndrome): Autosomal recessive inheritance inborn error of metabolism with a deficiency of the intralysosomal enzymes involved in heparan sulfate (HS) degradation. Affected infants appear normal at birth, with slowing of development taking place at about 1 to 2 years of age, occasionally not becoming apparent until early school age. Behavioral disorders, mental deterioration, and loss of motor skills are the principal features, with hirsutism, macrocephaly, and limited joint movements. Four biochemically distinct types, each with a different enzyme deficiency, are recognized: A, B, C, and D. The phenotype is similar in all four types and consists mainly of some facial coarsening with dull appearance, slightly sunken nasal bridge, and abundant scalp hair. Early development is usually normal, followed between the ages of 2 and 6 years by mainly behavioral disorders with progressive loss of mental and motor skills with spastic diplegia. The patient eventually becomes bedridden. Death usually occurs between 10 and 20 years of age. Type A has the most severe course with the earliest onset and mortality. Type A is caused by heparan sulfatase (EC 3.10.1.1) deficiency. Type B is caused by N-acetyl-alpha-d-glucosaminidase (EC 3.2.1.50) deficiency. Type C is caused by acetyl-CoA:alpha-glucosamide N-acetyltransferase (EC 2.3.13) deficiency. Type D is caused by N-acetylglucosamine-6-sulfate sulfatase (EC 3.1.6.14) deficiency. Behavioral problems can make induction and awakening from anesthesia problematic. Even though the incidence of difficult tracheal intubation is much less than in the other mucopolysaccharidoses, it is still very important to assess the airway carefully. Assess cardiorespiratory status carefully. Younger children with Sanfilippo syndrome often have only mild physical abnormalities. Severe mental retardation and aggressive behavior may cause problems during induction of anesthesia, and the presence of a parent may be helpful. Difficulty with airway management is less likely than in other forms of mucopolysaccharidosis.

MPS IV (Morquio Syndrome): Inborn error of metabolism characterized by faulty degradation of keratan sulfate in cartilage and lysosomal accumulation. Clinical features include short trunk dwarfism, dysostosis multiplex, progressive spinal deformity, short neck, pectus carinatum, genu valgum, pes planus, and odontoid hypoplasia with varying degrees of severity. Mental development is usually normal, but progressive intellectual deterioration is reported in type B. Two types are recognized according to the enzymes involved. Type A is caused by galactosamine-6-sulfate sulfatase (EC 3.16.4) and is more severe than type B. It is marked by shortness and hyperextension of the neck causing the head to appear as if it were resting directly on the shoulders; short trunk; long extremities with excessive joint mobility; kyphosis or kyphoscoliosis; pectus carinatum; the sternum extending from clavicular junction and angling downward in midsection; spinal cord compression associated with atlantoaxial dislocation (they often require posterior cervical fusion at a young age) and thoracolumbar gibbus; protruding abdomen; and clouding of the cornea. Aortic valve insufficiency is common late in the disease. Type B is caused by β-galactosidase (EC 3.2.1.23) deficiency and is marked a milder phenotype consisting of dysostosis multiplex, pectus carinatum, odontoid hypoplasia, kyphosis, genua valga, platyspondyly, and corneal clouding. Direct laryngoscopy and intubation are usually very difficult because of cervical spine instability or previous fusion. Endotracheal tube size may be smaller than predicted.

MPS V (Scheie Syndrome, now MPS I-S): Autosomal recessively inherited disease that presents with the same deficient enzyme as observed in Hurler syndrome, but in this case it is specific for dermatan sulfate. The clinical manifestations are milder than in Hurler syndrome and do not appear until age 5 years. Patients have normal intelligence with mild facial coarsening and skeletal abnormalities. Corneal clouding leads to visual impairment. Aortic insufficiency is common. Patients reach normal height and have a near-normal life expectancy. Assess airway for evidence of aortic regurgitation. These children are less severely affected than are children with Hurler syndrome but may still present difficulty with airway management. Obstructive sleep apnea has been reported. Children with cardiac valve abnormalities should receive antibiotic prophylaxis for endocarditis.

MPS VI (Maroteaux-Lamy Syndrome): Inborn error of metabolism characterized by arylsulfatase B (EC 3.1.6.12) deficiency preventing degradation of mucopolysaccharides, with their accumulation in soft tissues causing obstruction and compression of the blood vessels, trachea, and peripheral nerves, and disruption of normal bone development. It is associated with the phenotype similar to that in MPS I, but generally patients are of normal intelligence (mental retardation has been reported in a few isolated cases). Three basic types are recognized. The mild type (type B) is marked by usually normal childhood until approximately 6 years of age, when short stature, Legg-Perthes-like changes of the hips, aortic stenosis, spinal deformities, and corneal clouding begin to appear; survival is into adulthood. The intermediate type has a phenotype similar to that in mucolipidosis III with coarse Hurler-like facies, stiff joints with decreased mobility, and short stature. The severe type (sometimes designated Maroteaux-Lamy syndrome type A) is usually associated with onset of symptoms in early childhood, a rapidly progressive course, and death in adolescence. Short stature, coarse facies, hyperextended head, corneal clouding, defective hearing, heart abnormalities, and musculoskeletal anomalies are the main characteristics. Direct laryngoscopy and tracheal intubation are usually very difficult. Beware of cardiac involvement.

MPS VII (Sly syndrome): Autosomal recessive inborn error of metabolism characterized by beta-glucuronidase (EC 3.2.1.31) deficiency leading to accumulation of chondroitin 4/6 sulfate, with abnormal storage of mucopolysaccharides in various tissues. The phenotype consists mainly of short stature, hepatosplenomegaly, dysostosis multiplex, and mild mental retardation. Type I is the most severe, with hydrops fetalis, coarse facies with hypertelorism and depressed nasal bridge, cloudy cornea, and onset of symptoms at birth. TypeII has a less severe course, with moderate Hurler facies and hypertelorism, and onset at age 2 to 3 years. Type III has the mildest symptoms, with onset during adolescence. Mitral and aortic valve involvement. Intubation may be difficult. Assess cardiorespiratory status carefully and obtain appropriate investigations (e.g., chest radiograph, echocardiogram). Assess airway and cervical spine. Check history for evidence of obstructive sleep apnea. Difficulty with airway management should be anticipated in more severely affected patients. Spontaneous respiration should be preserved until the airway is secure.

MPS VIII: Inborn error of mucopolysaccharide metabolism with glucosamine-6-sulfate sulfatase deficiency and characteristics similar to those of mucopolysaccharidosis II and IV. Delayed physical and mental development, hypertrichosis, hepatosplenomegaly, dysostosis multiplex, and mild deafness are the main symptoms.

Fucosidosis: Lysosome storage disease caused by α-l-fucosidase (EC 3.2.1.51) deficiency in leukocytes manifested by abnormal accumulation in tissues and urinary excretion of partially catabolized oligosaccharides, glycoasparagines, and glycolipids with α-linked fucose at the nonreducing end of the glycogen chain. The phenotype is variable and may include delayed growth and mental development, progressive neurologic deterioration, Hurler-like (mucopolysaccharidosis I-H) coarse facies, recurrent infections, visceromegaly, skeletal abnormalities, joint contractures, deafness, and angiokeratoma corporis diffusum. Several types are recognized by different researchers. The form exhibiting a longer survival, mild neurologic manifestations, and angiokeratoma is sometimes referred to as fucosidosis type II. In a different scheme, three different types are recognized according to their age of onset. Types I and II are the most severe, with onset at 10 and 18 months, respectively, with a life expectancy of 6 years. Type III is a juvenile form marked by a milder expression of psychomotor retardation and a slower deterioration of neurologic activities. Hurler-like gargyloid facies occurs mainly in types I and II and is less common in type III (for further information see Fucosidosis).

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