Mucopolysaccharidoses

Key Points:

  • Mucopolysaccharidoses (MPSs) are caused by enzyme mutations that limit the regular degradation of glycosaminoglycans (GAGs) within lysosomes.
  • GAGs accumulate in cells, where they cause progressive cellular and organ dysfunction.
  • Skeletal deformities, including scoliosis, kyphosis, hip dysplasia, and genu valgum are common in MPSs.
  • Atlantoaxial instability and spinal stenosis are critical conditions that should be identified and monitored closely in patients with MPS.

Description:

The MPSs, part of a larger group of disorders known as lysosomal storage disorders, are a group of related conditions that result from deficiencies in enzymes that control the intracellular degradation of GAGs. Accumulation of GAGs within cells causes progressive destruction of tissues. The named disorders include Hurler (MPS I H), Scheie (MPS I S), Hunter (MPS II), Sanfilippo (MPS III), Morquio (MPS IV), Maroteaux-Lamy (MPS VI), and Sly (MPS VII). Scheie was formerly known as MPS V, until it was reclassified due to sharing the same enzyme defect as Hurler (Vijay, 2005). The classification is based on the combination of GAGs that are excreted in the urine of patients, including dermatan sulfate, heparin sulfate, chondroitin sulfate, and keratin sulfate.

Epidemiology:

MPSs are rare, with a combined incidence of only 1 out of 25,000 live births (Baehner, 2005; Nelson, 2003). Sanfilippo (MSP III) has four subtypes, and is the most common MPS (Malm, 2010; White, 2011).

Clinical Findings:

Though caused by different single gene mutations, all MPSs share some of the same clinical manifestations (White, 2013). Patients typically appear normal at birth, and may grow normally for several years before showing signs of MPS (Kircher, 2007; Gardner, 2011). Musculoskeletal abnormalities can include spinal stenosis at the occipitocervical junction (Thomas, 1985), atlantoaxial instability (White, 2009), focal thoracolumbar kyphosis (gibbus deformity) (Mundada, 2009; Levin, 1997), thoracic or lumbar spinal stenosis (Levin, 1997), scoliosis (Tandon, 1996), hip dysplasia and osteonecrosis (Taylor, 2008; Masterson, 2009), genu valgum (Odunusi, 1999, Dhawale, 2012), carpal tunnel syndrome (Yuen, 2007; Van Heest, 1998; White 2010), Madelung wrist deformities, short metacarpals, and broad clavicles (Mundada, 2009; Simonaro, 2010). Other findings may include coarsened facial features, hydrocephalus, corneal clouding, inguinal or umbilical hernias, hepatosplenomegaly, conductive hearing loss, upper airway obstruction, chronic bronchitis, recurrent respiratory tract infections, and cardiac disease (Braunlin, 2006; Kircher, 2007). Neurocognitive involvement is fairly heterogeneous and can affect patients with any type of MPS, though behavioral changes and cognitive delay seem to be more common in Hurler and Sanfilippo (Kircher, 2007; Malm, 2010).

Imaging Studies:

Skeletal surveys are useful to diagnose and classify MPSs. Periodic screening should be performed for atlantoaxial instability using flexion-extension lateral X-Rays of the cervical spine, and is especially important before any planned surgical procedures. Suspected cervical stenosis can be confirmed by MRI (Stevens, 1991; White, 2009). Screening and monitoring for scoliosis and thoracolumbar gibbus deformities can be done with sitting or standing PA and lateral scoliosis X-Rays. AP pelvis X-Rays are appropriate to screen and monitor for hip dysplasia and osteonecrosis, and standing AP X-Rays of the legs can be used to monitor the hips, as well as limb deformities such as genu valgum.

Etiology:

All of the MPSs are single gene mutations in enzymes that control the degradation of GAGs within lysosomes. The gene mutations are inherited in an autosomal recessive pattern. The GAGs (dermatan sulfate, heparin sulfate, chondroitin sulfate, and keratin sulfate) accumulate within cells, including those in the brain, viscera, and joints. The physical space taken up by the gradual accumulation of the GAGs, such as within the intramedullary space and the spinal canal, leads to many of the clinical manifestations. Additionally, a secondary inflammatory reaction to the GAG fragments appears to exacerbate destruction within cells (Simonaro, 2010).

Treatment:

Hematopoietic stem cell transplantation (HSCT) and intravenous enzyme replacement therapy (ERT) are modern treatments that have led to significant improvement in the somatic manifestations of MPS (Gardner, 2011; White, 2010). However, HSCT and ERT have no effect on established skeletal manifestations of MPS, and therefore, many patients will still require orthopedic care (Masterson, 1996; Kircher, 2007). Patients with signs of myelopathy related to cervical instability or stenosis (unsteady gait, weakness, dysesthesia, urinary retention) are candidates for decompression and fusion, usually from the occiput to C2 (Tandon, 1996; Sitoula, 2014). Spine deformities may be treated conservatively with casting or bracing, though the benefits of these methods in the MPS population are not well-established, and may only be delaying tactics. For progressive deformities, spine fusion is typically required. Due to hypoplastic spinal elements, patients may benefit from combined anterior-posterior fusions with instrumentation and protective postoperative bracing (Tandon, 1996; Mut, 2005). Progressive hip dysplasia can be treated surgically with femoral and pelvic osteotomies (White, 2010). Patients with severe hip arthritis related to dysplasia or osteonecrosis can be treated with total hip arthroplasty (Lewis, 2010). Treatment of genu valgum is individualized, but guided growth can be performed in younger patients (Cooper, 2016). In older patients, tibial or fibular osteotomy may be required (Dhawale, 2012). Open carpal tunnel release with tenosynovectomy is recommended for carpal tunnel syndrome (White, 2010).

Complications:

Anesthesia is complicated in patients with MPSs, not only due to possible cervical instability, but also due to potential upper airway obstruction, tracheomalacia, and tracheal stenosis (Belani, 1993). Surgeons should work closely with their anesthesiologists, and recognize the need for possible fiberoptic intubation, proper positioning, emergency tracheostomy, and postoperative ICU care. Routine intraoperative spinal cord monitoring should be considered for surgical procedures more than 45 minutes in length (White, 2013).

References:

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Top Contributors:

Kevin M. Neal MD