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Mucopolysaccharidoses: Complications

Mucopolysaccharidoses: Complications
Literature review current through: Jan 2024.
This topic last updated: May 04, 2021.

INTRODUCTION — The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by the deficiency of enzymes required for the stepwise breakdown of glycosaminoglycans (GAGs), also known as mucopolysaccharides. These conditions are differentiated by their clinical features and age of presentation (table 1). The MPS can affect many different systems, including the respiratory, cardiovascular, skeletal, and neurologic systems (table 2). Enzyme replacement therapy (ERT) is available for some MPS. Other therapies focus on treatment of symptoms.

The complications associated with the MPS and their management are reviewed here. The clinical features, diagnosis, and treatment of these disorders are discussed separately. (See "Mucopolysaccharidoses: Clinical features and diagnosis".)

RESPIRATORY COMPLICATIONS — Respiratory complications affect patients with all types of MPS and contribute to death and disability as their disease progresses. Respiratory abnormalities result from airway obstruction, excessive secretions, skeletal restriction, organomegaly, frequent infections, and neurologic compromise [1-3]. These problems can lead to progressive respiratory insufficiency, severe obstructive sleep apnea, and sudden death from central apnea.

Central apnea from cord compression — MPS IV A and IV B patients are especially prone to high cord compression due to atlantoaxial instability and odontoid dysplasia, although this complication also occurs in other types. This condition may result in depressed respiration or sudden respiratory arrest [4-7]. Early cervical fusion is recommended in MPS IV patients and in other patients with cervical instability. (See 'C1-C2 subluxation' below and 'Odontoid hypoplasia' below.)

Airway obstruction — Patients with MPS I, II, VI, and VII often develop upper airway obstruction due to an enlarged tongue, thickened gums, and engorged soft tissues of the nasopharynx [1-3,8-11]. Increased tonsillar and adenoid size due to storage of glycosaminoglycans (GAGs) in lymphatic tissue also contributes to obstruction. Upper airway obstruction may be exacerbated in certain positions (eg, raising the arms may result in obstruction of the thoracic inlet, causing facial plethora, distension of the neck veins, and shortness of breath) [12]. Airway problems may be worsened by excessive thick secretions due to chronic or recurrent ear and sinus infections. Progressive obstruction can result in sleep apnea with severe hypoxemia and right heart failure [1,2,13,14]. (See "Mechanisms and predisposing factors for sleep-related breathing disorders in children" and "Evaluation of suspected obstructive sleep apnea in children".)

Tracheal or lower airway obstruction can result from malformed and floppy tracheal cartilage, redundant respiratory epithelium, or pedunculated nodules [10,15-17]. Wheezing due to narrowed airways from increased mucus production and airway inflammation is common. In the setting of airway compromise, minor upper respiratory infections or pneumonia can cause severe reactive airway disease and airway edema. In patients with advanced disease, this may lead to sudden respiratory arrest [1]. (See 'Pulmonary function abnormalities' below.)

Interventions — Interventions are primarily directed at maintaining a stable airway. Removal of the tonsils and adenoids can temporarily reduce airway obstruction and sleep apnea, but these problems often recur [8,13,18]. (See "Adenotonsillectomy for obstructive sleep apnea in children", section on 'High-risk populations'.)

Upper airway obstruction, especially when associated with sleep apnea, may be improved by continuous positive airway pressure (CPAP) applied at night [8]. Younger patients seem to adapt better to CPAP than older ones. However, facial dysmorphism may make it difficult to achieve the proper fit of masks. Bilevel positive airway pressure ventilators (BiPAP devices), which decrease pressure during exhalation and increase pressure during inhalation, may be better tolerated by some patients. (See "Continuous positive airway pressure (CPAP) for pediatric obstructive sleep apnea".)

Supplemental oxygen at low flow rates can be used to treat arterial desaturation during sleep. However, oxygen therapy should be used with caution to avoid suppressing hypoxic respiratory drive. Patients with severe hypoxemia, hypercapnia, and sleep disturbance may require tracheotomy. Tracheotomy or tracheal T tubes are options in patients with signs of right heart failure and severe sleep apnea that cannot be improved with BiPAP or who have critical airway stenosis. If surgery or airway support with BiPAP is not possible, palliative care is given. (See "Adenotonsillectomy for obstructive sleep apnea in children", section on 'Adjuvant surgical procedures'.)

Anesthesia — Patients with MPS often have complications during general anesthesia. These are primarily due to the presence of airway obstruction, excessive secretions, a large tongue, and abnormal airway anatomy, resulting in extreme difficulty in endotracheal intubation [10,19-24]. Older patients or those with sleep apnea or other signs of airway obstruction are at increased risk for difficult intubation. (See "The difficult pediatric airway for emergency medicine".)

In one report in 30 MPS patients who were anesthetized 141 times, preoperative signs of airway obstruction were present more often in patients with moderate to severe postoperative airway complications compared with those with mild or no complications (78 versus 23 percent) [10]. Extension of the neck may cause spinal cord injury due to instability of the cervical spine, increasing the difficulty of intubation [5,25].

These problems should be weighed carefully in making decisions about surgical procedures. Anesthesia should be administered at centers experienced in the management of MPS patients. A comprehensive plan should be made before performing general anesthesia, including management options if complications develop. Local or regional anesthesia should be used whenever possible [10,19,20,24,26,27].

If general anesthesia is unavoidable, fiberoptic intubation with an endotracheal tube smaller than indicated by the patient's age or weight may help with airway management [10,28]. Attempts to intubate without adequate visualization can lead to injury of the laryngeal tissue and airway edema.

Extubation may also be difficult in MPS patients. Glucocorticoids or other medications may be needed to reduce airway edema. In general though, earlier extubation is recommended if at all possible.

Sinopulmonary infections — MPS patients have frequent or chronic pulmonary infections, otitis media, and sinusitis in the first few years after birth [1,3,8,13,18]. The associated thick and copious secretions can worsen airway obstruction. Minor respiratory infections often progress to pneumonia with consolidation and require hospitalization.

Obstruction of the Eustachian tubes and sinus ostia contribute to the persistence of infections. Another possible mechanism for increased infection is abnormal immune function. T cell proliferative response and antibody production were decreased in a murine model of MPS VII after antigen challenge, and a quantitative defect in natural killer (NK) and B cells with normal immunoglobulin levels and function was identified in a family with MPS II [29,30].

The antimicrobial management of infections is similar to those without associated MPS. However, recovery time may be longer for MPS patients, and bronchodilators may be needed to treat reactive airway disease. Otitis media may also be more difficult to treat, and tympanostomy tubes may be required. Tube placement should be considered more readily than in patients without MPS. (See "Acute otitis media in children: Treatment", section on 'Initial antibiotic therapy'.)

Preventive measures include influenza vaccine in addition to standard childhood immunizations. Prophylactic antibiotic treatment has been used, especially during the winter, and nebulized gentamicin has been used for prophylaxis in patients with tracheotomies. However, the efficacy of these approaches in MPS is unknown. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups' and "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)

Pulmonary function abnormalities — Patients with MPS also have pulmonary function abnormalities that can be multifactorial [31]. They are a clinically important cause of morbidity and mortality. However, many MPS patients have trouble performing traditional pulmonary function testing to the standard guidelines because they cannot blow out sufficiently for long periods of time, making assessment difficult.

The restrictive disease is most likely related to their skeletal abnormalities and enlarged liver and spleen and not to interstitial disease. Although obstructive disease may be less important, it is not uncommon for these patients to be treated with bronchodilators as part of their general care.

In one series of 35 patients with MPS I, II, IV A, or VI, 48 percent had restrictive lung disease based upon spirometry, and 9 percent had obstructive lung disease [32]. In another series, 12 of 15 patients with MPS II had a mean forced expiratory volume in 1 second (FEV1) below 80 percent predicted [33].

CARDIAC COMPLICATIONS — Cardiac abnormalities may result from the underlying MPS disorder or as a complication of severe pulmonary disease and associated chronic hypoxemia [34]. Cardiomyopathy and endocardial fibroelastosis occur rarely in young, severely affected patients with Hurler syndrome (MPS I) and MPS VI [35-37]. Cardiac problems may be complicated by coronary artery and other vascular diseases. (See "Definition and classification of the cardiomyopathies".)

Valvular disease — Progressive thickening of the mitral and aortic valves causing insufficiency occurs often in MPS, especially in types I, II, and VI, and less commonly in MPS III A to D [2,8,38]. In one series of 84 MPS patients, mitral and aortic regurgitation were detected in 64 and 41 percent, respectively [39]. Tricuspid and pulmonic valve regurgitation also occur and may be exacerbated by pulmonary hypertension. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation" and "Aortic regurgitation in children".)

Although regurgitation can be detected in young patients, progressive worsening of valvular competence typically results in heart failure in late school age or in the teens [1,39,40]. Severely affected patients may require valve replacement [41-43].

In patients with valvular insufficiency, systemic hypertension due to aortic coarctation and other vascular diseases can result in further compromise and should be treated [44]. It is uncertain whether prophylactic afterload reduction is beneficial in patients with moderate regurgitation and without hypertension. This approach has been used successfully to treat the cardiovascular manifestations of Marfan syndrome. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

Vascular disease — Storage cells accumulate in the walls of arterial blood vessels, including the coronary arteries, leading to impaired flow and ischemia [45,46]. The coronary lesions involve the entire course of the vessels. Obstruction may result in sudden death [45]. Vigilance is required to detect coronary disease as it is usually unexpected in young children. Furthermore, the clinical presentation may not be typical, and coronary angiography may not predict the severity of the disease [45].

Intimal lesions can result in narrowing of the abdominal aorta, causing hypertension and poor perfusion of the lower extremities [44]. Arteriopathy also affects other vessels, including the renal, mesenteric, and iliac arteries. Narrowing can be detected by arteriography, ultrasound, and magnetic resonance imaging (MRI).

Pulmonary hypertension — Chronic hypoxemia due to airway obstruction and pulmonary disease can lead to pulmonary hypertension [1,10]. Pulmonary hypertension may exacerbate right heart failure caused by mitral valve regurgitation. Therapy should be directed at maintaining a secure airway and avoiding hypoxemia, especially during the night. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis" and "Pulmonary hypertension in children: Management and prognosis".)

Myocardial infarction and stroke — Later complications in adults include myocardial infarction and stroke [47].

SKELETAL AND CONNECTIVE TISSUE COMPLICATIONS — Storage material in cells that form the connective tissues leads to abnormalities in bone, joints, and ligaments. These problems interfere with growth, cause dysmorphism, impair mobility, and cause pain.

Dysostosis multiplex — The constellation of characteristic bony abnormalities is known as dysostosis multiplex. This condition occurs in MPS I, II, IV, VI, and VII and is less extensive in MPS III and attenuated variants [2,8,48]. The radiographic findings of dysostosis multiplex are reviewed in detail separately. (See "Mucopolysaccharidoses: Clinical features and diagnosis", section on 'Radiologic findings'.)

The bone disease in Morquio patients (MPS IV A and IV B) begins with ovoid vertebrae and typical features of dysostosis multiplex and progresses with age to appear similar to spondyloepiphyseal dysplasia [49]. The ovoid vertebrae flatten and collapse, resulting in distinctive platyspondyly (thin, flat vertebral bodies). Patients can also have beaking of the anterior margin (central for MPS IV and lower third for MPS I) of the lumbar vertebrae.

Abnormalities of the vertebral bodies can result in spinal instability and kyphoscoliosis and lead to neurologic deficits. Circumferential arthrodesis is the preferred approach to severe thoracolumbar kyphoscoliosis [50]. Early spinal cord decompression may prevent or potentially reverse neurologic compromise [51]. Deficient ossification of the superior acetabulum may result in progressive dislocation of the hip joint and erosions of the femoral neck. Joint replacement surgery is possible using a standard prosthesis [52].

Odontoid hypoplasia — Hypoplasia or dysplasia of the odontoid (a tooth- or peg-like projection from the second cervical vertebra) is a characteristic finding in MPS IV A and IV B and is common in the severe forms of MPS I and VII. Hypoplasia is due in part to inadequate ossification, although reossification may occur after cervical fusion. Odontoid hypoplasia can lead to atlantoaxial instability, which can result in subluxation of the first and second cervical vertebrae (C1-C2 subluxation) and high spinal cord compression [4,53,54]. (See 'C1-C2 subluxation' below.)

Subluxation and kyphoscoliosis — Vertebral subluxation and kyphoscoliosis can occur throughout the spinal column, although they usually occur at points of transition (cervicothoracic, thoracolumbar, and lumbosacral junctions). The causes of kyphoscoliosis include dysplastic vertebral bodies (beaked vertebrae), subluxation (which results in part from ligamentous laxity), and compression or deformation of the vertebral bodies. Subluxation can compromise the cord at any level.

Patients with Hurler syndrome (MPS I) often develop a gibbus deformity of the lumbar spine, characterized by anterior wedging and posterior displacement of the vertebrae at the peak of the curve (picture 1), resulting in a beaked appearance on lateral radiographs (image 1) [55]. The causes of gibbus formation include incomplete ossification of the abnormal vertebrae, poor truncal tone, disturbed growth, anterior disc herniation, and weight bearing. Spondylolisthesis (forward slippage of the fifth lumbar vertebra [L5] over the first sacral vertebra [S1]) occurs in the majority of patients with less severe forms of MPS I.

The goal of treatment is to stabilize the spine with the minimum necessary intervention. Spinal fusion surgery may be required [56,57]. However, MPS patients may not heal well and often have complications from surgical procedures. Thus, fusion surgery should be performed only when necessary. Orthotic bracing may be used early on as a temporizing measure, allowing the patient to grow more before proceeding with definitive surgery.

Genu valgum — Abnormalities in the growth plates and epiphyses are caused by glycosaminoglycan (GAG) storage in the chondrocytes. In the knee, storage may lead to inadequate growth in the medial part of the tibial growth plate, causing genu valgum, or knock-knee deformity. This abnormality occurs in the majority of patients with MPS IV A and IV B but also can occur in other types. Severe cases require osteotomy and straightening procedures [58,59]. Early operative intervention while the child is growing includes epiphysiodesis (fusion of the growth plate). (See "Approach to the child with knock-knees", section on 'Pathologic knock-knees'.)

Short stature — The extensive skeletal abnormalities impair growth and result in short stature. Growth hormone resistance may also play a role in patients with MPS I [60]. Although patients with severe MPS I may have accelerated growth in the first year, height attained is typically less than the fifth percentile. Less severely affected children may reach normal or near-normal heights. Patients with MPS II have accelerated growth in the first three years of life but subsequently have decreased growth velocity [61]. The adolescent growth spurt occurs earlier in boys with MPS II. Enzyme replacement therapy (ERT) may improve growth in patients with MPS II, particularly if therapy is started before 10 years of age [62].

Joint stiffness and degenerative disease — Joint stiffness associated with pain on movement occurs in nearly all MPS patients. The etiology of the stiffness includes inflammatory changes, engorgement of the synovial and other connective tissues of the joint, and abnormalities of the cartilage and epiphyseal bone [63-65]. Pain and decreased movement can lead to development of contractures (picture 2). This progression may be hastened in some patients by poor neurologic function.

Physical therapy can improve flexibility of the joints and help maintain function. However, it cannot prevent the inexorable decline in joint mobility. Wheelchairs are often needed for mobility, even in patients who can walk, because of pain and/or limited endurance. Animal studies suggest a possible therapeutic role for tumor necrosis factor (TNF) alpha antagonists, but additional studies are necessary [63].

Patients can develop painful and debilitating degenerative hip disease due to abnormalities in the femoral epiphyses. The optimal management for hip disease in MPS patients is unclear, and attempts to reach consensus have been challenging due to a poor evidence base and divergent practice [66]. Common approaches focus on exercise recommendations, physical therapy, adequate analgesia, and surgery where possible and probably provide functional benefit. There is anecdotal evidence for an increase in total hip replacements in adolescents and young adults with MPS diseases.

Ligamentous laxity — Although lysosomal storage causes some joints to be stiff, GAG accumulation in ligaments can lead to laxity of other joints. This is seen most often in MPS IV A and IV B [67]. Ligamentous laxity contributes to atlantoaxial instability and the development of kyphoscoliosis. (See 'Central apnea from cord compression' above and 'Odontoid hypoplasia' above.)

Hernias — Inguinal and umbilical hernias resulting from connective tissue abnormalities are common, especially in MPS I, II, VI, and VII [2,48,68]. They may occur early on as part of the initial presentation and can become quite large [69]. Hernias can also occur at the incision site following abdominal surgery. Hepatosplenomegaly may contribute to increased intra-abdominal pressure and lead to hernia formation.

Surgical repair of inguinal hernias may fail and need to be repeated. Hepatosplenomegaly and the weak connective tissues may contribute to poor results. Thus, in some patients, management with trusses is a temporary option that may be preferable to the risk of anesthesia and surgical repair. However, large umbilical hernias that occur in MPS I should be repaired when possible since their size can lead to breakdown of the overlying skin.

NEUROLOGIC COMPLICATIONS — Neurologic complications can result from storage in cells in the brain; in supporting structures, such as the meninges or spinal column; or directly in sensory organs, such as the eye. Characteristic findings on cranial magnetic resonance imaging (MRI) include arachnoid cysts, enlarged cisterna magna, cerebellar hypoplasia, encephaloceles, and linear cyst-like structures in the subcortical white matter and corpus callosum [70-76]. These cysts are due to storage in the Virchow-Robin spaces around the blood vessels and are not associated with cognitive defects (image 2) [71,77]. Alterations of myelination may occur. Patients with increased intracranial pressure (ICP) can have significant ventriculomegaly, although some have minimal or no ventricular enlargement associated with transependymal fluid shifts in the periventricular areas.

Patients initially may be misdiagnosed as having idiopathic developmental delay, autism spectrum disorders, and/or attention deficit hyperactivity disorder [78]. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis" and "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis" and "Attention deficit hyperactivity disorder in adults: Epidemiology, clinical features, assessment, and diagnosis".)

Developmental delay and neurologic decline — Developmental delay and progressive decline occur in severe forms of MPS I, II, III, and VII [2,48,79-81]. Patients with MPS IV and VI usually have normal intellectual development. In Hurler syndrome (MPS I), delay that begins during the first year of life is often not appreciated until the second year. In most cases, affected children begin to walk and speak short sentences before reaching a developmental plateau. They then decline slowly so that the average intelligence quotient (IQ) is 50 by age three to four years [82].

Abnormal behavior — Patients with Hurler syndrome (MPS I) tend to be pleasant, good-natured children with excellent behavior during the early stages of the disease but often become unresponsive as the disease progresses to its final stages. In severe Hunter (MPS II) and Sanfilippo (MPS III) syndromes, developmental delay typically is noted at two to six years of age and is accompanied by hyperactive and aggressive behavior [80,83-86]. Patients have short attention spans, do not respond to instructions, and have no sense of danger. The aggressive behavior appears to improve with age as overall function progressively declines, usually reaching a neurologically devastated and unresponsive state in the early teenage years. Abnormal behavior in some patients may be caused by hydrocephalus with increased ICP, although the prevalence of this problem in MPS III is unknown. Patients with MPS II can have meningeal obstruction and high-pressure hydrocephalus, causing severe headaches that may in some cases worsen the behavior problems.

Management consists primarily of ensuring that the home environment is safe. Attempts to treat the abnormal behavior with medications have been limited by their side effects [68,87]. Medications that are sometimes used include neuroleptics (eg, risperidone, olanzapine), which may cause excessive sedation; benzodiazepines, which may increase secretions and cause respiratory compromise in patients with airway problems, bulbar palsy, and decreased swallowing; tricyclic antidepressants; selective serotonin reuptake inhibitors (eg, fluoxetine), which should be avoided in patients with seizures; and anticonvulsants (eg, carbamazepine). Methylphenidate is usually not helpful [87,88].

Seizures — Seizures may occur in Hunter (MPS II) and Sanfilippo (MPS III) syndromes but are rarely seen in other MPS disorders [70]. Electroencephalographic data in a few MPS patients with seizures demonstrate irregular slow wave activity and typical epileptiform discharges [70,83,89]. Seizures are managed with anticonvulsant medications similar to patients without MPS. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)

Sleep disturbance — Sleep disturbance is common, especially in Sanfilippo (MPS III) syndrome [87,88]. Sleep becomes progressively fragmented [90], and patients become active around the clock.

A padded bedroom is usually required to keep the child contained and avoid injury during the night. Restraints are generally not effective. Medications, including melatonin or sedatives, may improve sleep. Melatonin is estimated to be successful in approximately 75 percent of patients within three to four days of use. The authors start with a dose of 2 to 3 mg and increase if necessary after one to two weeks to 4 to 6 mg, with further increases as clinically indicated. Children with MPS frequently require treatment with the maximum dose of 10 mg. Melatonin is used with a strict regimen of sleep time and a darkened bedroom. Benzodiazepines, antihistamines, and chloral hydrate are overall reported as less efficacious [91].

Sleep disturbances contribute to exhaustion of the caretakers. Respite care should be made available for the parents.

Hydrocephalus — Communicating hydrocephalus may develop in MPS I, II, III, VI, and VII [2,8,92-95]. In MPS I, II, VI, and VII, the mechanism is engorgement of the arachnoid granulations by storage material, impeding resorption of cerebrospinal fluid (CSF), and increasing ICP (image 3) [96]. In MPS III patients, ventricular enlargement may be due to hydrocephalus but more commonly is due to atrophy in the later stages of the illness. Acute increases in ICP may present with severe headaches, visual disturbances, altered mental status, and rapidly progressive developmental decline [92]. However, the process may be insidious and without typical signs [48,97]. Papilledema is not a reliable indicator and is often not present in patients with increased ICP. Swelling of the optic nerve head is frequently a precursor of optic atrophy, rather than a sign of increased ICP [48,98]. Another diagnostic pitfall is the interpretation of modest ventriculomegaly seen on MRI as cerebral atrophy rather than high-pressure communicating hydrocephalus.

The diagnosis of hydrocephalus is confirmed by lumbar puncture with measurement of opening pressure. The disorder is usually managed by placement of a ventriculoperitoneal shunt.

Cervical cord compression — Compression of the cervical spinal cord can result from pachymeningitis cervicalis or vertebral subluxation.

Pachymeningitis cervicalis — Pachymeningitis cervicalis is the progressive thickening and scarring of the meninges around the cervical spinal cord caused by glycosaminoglycan (GAG) storage in MPS (image 4A-B). The thickened meninges may form a tight sleeve around the spinal cord that impedes the flow of CSF and progressively compresses the cervical cord. This process may be compounded by a spinal canal that has been narrowed by bone disease. Pachymeningitis cervicalis was originally described in Maroteaux-Lamy syndrome (MPS VI) but has been reported in MPS I, II, and VII [99-101].

The clinical course is insidious. Patients may complain of fatigue in their legs and gradually have decreased movement and prefer sedentary activities. Occasional "buckling" of the knees may be attributed to a joint problem. Patients typically present to the clinician for evaluation as weakness or sensory loss becomes more evident. The constellation of motor and sensory defects depends upon the extent and location of the compression and may affect breathing or bowel and bladder control.

Management of this condition is difficult. The pressure can often be relieved by laminectomy with incision and removal of meningeal tissue [99,102-104]. In patients with accompanying subluxation, fusion of the vertebrae is needed. Surgical treatment may be the only option in many cases. However, these procedures have high surgical and anesthesia risks and may not offer significant benefit in some patients. To prevent serious cervical cord accidents in these patients, it is extremely important to assure that the neck is appropriately protected at all times and is not flexed or extended during intubation or surgery. Presurgical conferences to discuss management with the anesthesiologist and surgeon are necessary to assure that the neck is protected during surgical decompression.

C1-C2 subluxation — Odontoid dysplasia and ligamentous laxity can result in subluxation of the first cervical vertebra (C1) on the second cervical vertebra (C2) and cause cord compression [54,105-108]. The instability and frequent movement may impair ossification of the odontoid and result in thickened fibrocartilaginous tissue anterior to the cord, causing further compression [4,6,109]. This problem is common in MPS IV A and IV B but also occurs in MPS I, VI, and VII [4,70,110].

Cord compression due to subluxation is often anterior and predominantly causes motor dysfunction. Onset of motor dysfunction can be insidious, with slowly progressive and nonspecific fatigue followed by decreased activity and preference for sedentary play. If untreated, the cord compression can result in progressive ascending paresis and paralysis. Compression can be visualized with MRI and cord injury confirmed by the presence of abnormal T2-weighted signal in the cord. Somatosensory evoked potentials of the median or posterior tibial nerves have been used to evaluate functional impairment [111].

Management includes posterior cervical fusion to stabilize the neck and reduce cord compression injury [4,21,104,105]. Concomitant decompression of excess tissue anterior to the cord may be needed. This procedure should be performed early in MPS IV A and IV B to avoid sudden high cord compression and respiratory arrest following a minor fall in those patients with radiologic instability [4,6,112,113]. Surgery should be performed at centers experienced in the management of MPS. To prevent serious cervical cord accidents in these patients, it is extremely important to assure that the neck is appropriately protected at all times and is not flexed or extended during intubation or surgery. Other MPS patients, especially those with MPS I and MPS VII, should be evaluated with annual radiographs in flexion and extension as well as MRI scans. If cervical instability is present, fusion should be performed. (See 'Pachymeningitis cervicalis' above.)

Carpal tunnel syndrome — Nerve compression disorders, such as carpal tunnel syndrome, resulting from bone disease and soft tissue storage, are common in MPS [2,8,114-118]. The onset of symptoms can be insidious. Specific symptoms of median nerve compression, such as pain, paresthesias, or weakness, occur rarely in affected children, leading to under-recognition of the disorder [115,119-123]. Signs including thenar atrophy, decreased sweating, claw hand deformity, and weakness are more common.

All MPS patients should be evaluated for carpal tunnel syndrome using standard methods, such as nerve conduction studies. Treatment by carpal tunnel release results in functional improvement [115]. However, additional accumulation of storage material in soft tissues can lead to recurrence. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis" and "Surgery for carpal tunnel syndrome".)

Entrapment of other peripheral nerves, such as the ulnar nerve, may occur [124,125]. Treatment is similar to patients without MPS. Trigger finger (flexor tendon entrapment of the digit, typically due to thickening of the digit's first annular pulley) is common [114,126].

Diarrhea — MPS II and III patients may develop recurrent or chronic diarrhea. The mechanism is thought to be GAG storage in the neurons of the myenteric plexus, leading to abnormal motility [127]. Although motility has not been directly studied, storage in these cells has been demonstrated in biopsies of the intestinal wall [87]. Diarrhea can be improved with medications that decrease bowel motility (eg, loperamide) [87].

OPHTHALMOLOGIC COMPLICATIONS — Vision-impairing ophthalmologic complications of MPS include corneal clouding, glaucoma, optic neuropathy, and degeneration of the retina [128,129]. Corneal clouding is uncommon in MPS II. These complications seem to develop early in the course and often are present at the time of initial diagnosis. Retinopathy may be a later change.

OTOLARYNGOLOGIC COMPLICATIONS — Hearing loss is common in all forms of MPS [130]. It is caused by storage of glycosaminoglycans (GAGs) within the oropharynx, dysostosis of the ossicles of the middle ear, and damage to the eighth nerve and may be made worse by frequent ear infections.

DENTAL COMPLICATIONS — Unerupted teeth and enamel hypoplasia are common. Many patients present with flattening of the mandibular condyle with decreased mobility of the temporomandibular joint [131].

MONITORING — Additional studies are needed when the diagnosis of MPS disease is made to evaluate for complications:

An ophthalmologic examination should be performed as part of the initial review and then as needed as determined by the ophthalmologist to assess corneal clouding and glaucoma. Glaucoma is most common in MPS I, II, VI, and VII. (See "Overview of glaucoma in infants and children" and 'Ophthalmologic complications' above.)

A cardiac evaluation, including electrocardiogram (ECG) and echocardiography, should be performed at the time of diagnosis and then annually to assess valvular disease, cardiomyopathy, cor pulmonale, and heart failure [38].

A comprehensive neurologic examination is done at presentation and then annually or when new symptoms occur to detect carpal tunnel syndrome, spinal cord compression, or communicating hydrocephalus. These conditions can be further evaluated with electromyography, somatosensory evoked potentials, and lumbar puncture with measurement of opening pressure. Neuroimaging should be performed if hydrocephalus is suspected and in patients with developmental delay.

Radiographic studies of the neck in flexion and extension (plain films) should be obtained to assess cervical instability and magnetic resonance imaging (MRI) of the craniocervical junction for compression. These studies are obtained annually initially, but the frequency can be reduced in those without significant abnormalities. Plain films may not be required if MRI in flexion and extension is possible. Evaluation of the spine for vertebral slippage and kyphoscoliosis should be performed annually.

Patients who have breathing problems at night or daytime somnolence should have oximetry or polysomnography to evaluate obstructive sleep apnea [132]. (See "Evaluation of suspected obstructive sleep apnea in children".)

Hearing should be tested annually, or more frequently if there is a clinical change, in all patients with MPS.

Orthopedic evaluation should be performed every 6 to 12 months, depending upon disease severity, to monitor patients for hip and other joint disease.

Dental evaluation should be performed every 6 to 12 months.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mucopolysaccharidoses".)

SUMMARY

The mucopolysaccharidoses (MPS) are lysosomal storage disorders that are differentiated by their clinical features and age of presentation (table 1). These disorders can affect many different systems, including the respiratory, cardiovascular, skeletal, and neurologic systems (table 2). (See 'Introduction' above.)

Respiratory complications of MPS may include central apnea, airway obstruction, sleep apnea, and frequent or chronic sinopulmonary infections or otitis media. (See 'Respiratory complications' above.)

Cardiac complications of MPS may include cardiomyopathy, endocardial fibroelastosis, valvular disease, vascular disease, and pulmonary hypertension. (See 'Cardiac complications' above.)

Skeletal and connective tissue complications of MPS may include dysostosis multiplex (the constellation of characteristic bony abnormalities) (image 5 and image 1 and image 6 and image 7 and image 8), spine abnormalities, hip dysplasia, genu valgum (knock knees), short stature, joint stiffness, ligamentous laxity, and inguinal and umbilical hernias. (See 'Skeletal and connective tissue complications' above.)

Neurologic complications of MPS may include developmental delay or neurologic decline, abnormal behavior, seizures (in Hunter [MPS II] and Sanfilippo [MPS III] syndromes), sleep disturbance, hydrocephalus, cervical cord compression, carpal tunnel syndrome, and diarrhea (thought to be related to abnormal motility). (See 'Neurologic complications' above.)

Ophthalmologic complications of MPS may include corneal clouding, glaucoma, optic neuropathy, and degeneration of the retina. (See 'Ophthalmologic complications' above.)

Patients with MPS should also undergo periodic evaluation for (see 'Monitoring' above):

Corneal clouding (picture 3) and glaucoma

Valvular disease, cardiomyopathy, cor pulmonale, and heart failure

Carpal tunnel syndrome, spinal cord compression (image 4A and image 4B), communicating hydrocephalus

Cervical instability, vertebral slippage, and kyphoscoliosis (picture 4)

Organomegaly

Obstructive sleep apnea

Hearing

Hip dysplasia and other orthopedic complications

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ed Wraith, MD; Emil Kakkis, MD, PhD; Robert Wynn, MD, MRCP, FRCPath; and Simon Jones, MD, who contributed to earlier versions of this topic review.

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Topic 2932 Version 29.0

References

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