Mucopolysaccharidosis 4A is a lysosomal storage disease caused by sequence anomalies of the gene encoding for N-acetylgalactosamine-6-sulfatase. In affected individuals, glycosaminoglycan degradation is impaired, which frequently leads to a variety of musculoskeletal symptoms but may comprise organ systems like the cardiovascular and respiratory system as well as the central nervous system.
Short stature, skeletal dysplasia, dental anomalies and corneal clouding are the hallmarks of MPS-IVA. While birth lengths of affected individuals are generally normal (52±5 cm), final adult heights for males and females are far below average (123±23 and 117±21 cm, respectively) . First anomalies are usually noted in early childhood, generally, before a child becomes three years old. MPS-IVA commonly manifests in form of kyphosis or gibbus, scoliosis, pectus carinatum, genu valgum, gait disturbances and frequent falls, but the clinical presentation varies with disease severity . Symptoms like back, leg, and hip pain or malformations of the upper limbs more often introduce mild forms of the disease. Short neck, cervical spine instability, and generalized platyspondyly may also be noted. Ligamentous laxity contributes to joint instability and hypermobility, and may be detrimental in patients suffering from dysplasia of the vertebral column. As has been described above, this condition may cause spinal cord compression and paraplegia. Fortunately, this complication is rare. In general, MPS-IVA patients show normal intelligence, but visual impairment and hearing loss are regularly reported. Besides corneal clouding, vision may also be compromised due to astigmatism or retinopathy. MPS-IVA patients frequently suffer from valvular heart disease . With regards to the respiratory tract, snoring, sleep apnea, recurrent upper respiratory infection, and dyspnea may occur.
Anamnestic data may substantiate a tentative diagnosis of MPS-IVA. On the one hand, there may be a family history of similar complaints and consanguineous marriage increases the likelihood of hereditary disorders to manifest. On the other hand, considerable shares of MPS-IVA patients present with a medical history of ear tube placement, tonsillectomy, adenoidectomy or dental problems. Patients may also have undergone orthopedic surgery without a proper investigation as to the causes of skeletal anomalies.
If anamnestic data, clinical presentation, ophthalmological and radiographic findings are consistent with MPS-IVA, the following measures should be undertaken to confirm the diagnosis :
Of note, radiographic anomalies like odontoid hypoplasia, spinal curvature, and epiphyseal dysplasia may be detected in the neonatal period, possibly before the onset of clinical symptoms .
Specific treatment is limited and thus, supportive care is provided and adjusted to the needs of an individual patient. Traditionally, the latter comprised physiotherapy, orthopedic interventions, and provision of orthopedic aids, psychological support for the patient and their family. Furthermore, therapy aims at symptom relieve and avoidance of complications due to lesions of the nervous system, heart and respiratory tract, which may be achieved by means of surgery, administration of non-steroidal anti-inflammatory drugs, prophylactic application of antibiotics, and supplementation of oxygen, among others. While these measures are still of major importance, approval of elosulfase alfa (Vimizim®) for enzyme replacement therapy in MPS-IVA patients gave rise to new hope for an improvement of life quality and endurance  . Elosulfase alfa is typically administered intravenously, at a weekly dose of 2 mg/kg. Patients should be prepared for drug administration by previous application of an antihistamine. Long-term outcomes of elosulfase alfa therapy have not yet been published. Regular follow-ups are recommended in any case. Here, particular attention should be paid to a possible progression of cardiac and pulmonary disorders as well as spinal cord compression.
Symptom onset generally occurs early in life, and the disease follows a progressive course. While morbidity and mortality largely depend on the severity of the disease, Morquio A is a serious illness often associated with severely reduced quality of life, disability and long-term needs for care. Patients diagnosed with mild MPS-IVA have a near-to-normal life expectancy, but moderate to severe forms of the disease cause premature death. Respiratory failure and heart failure have recently been reported to be the most common causes of death in MPS-IVA patients, which occurs at a mean age of 25 years .
MPS-IVA is a hereditary disease caused by mutations in the gene encoding for GALNS, which is located on the long arm of chromosome 16. It encompasses almost 50 kb and comprises 14 exons that are assembled to a 522-amino acid protein. Several hundred mutations have been related with MPS-IVA so far, and still, as-of-yet undescribed gene variants are discovered periodically . Either one of the three most common mutations may be encountered in only about 20% of MPS-IVA patients. With regards to the nature of mutations, missense mutations prevail and account for more than three-fourths of known gene defects. Nonsense mutations as well as deletions and insertions of varying size account for the remaining variants . Recently, the three-dimensional structure of this glycosaminoglycan-degrading enzyme has been disclosed by means of crystallography . This knowledge allowed for mapping known mutations to substructures of the homodimeric glycoprotein and revealed that MPS-IVA-related variants either present a disruption of the active site, inadequate folding or loss of surface exposure of certain amino acids.
Estimates regarding the prevalence of MPS-IVA range from 1-10 per 1,000,000 inhabitants, with slightly higher prevalence rates, reported among neonates . The International Morquio A Registry provides further epidemiological data regarding race, gender, and age of affected individuals . The majority of patients registered were Caucasians, but most questionnaires were filled out by North Americans and Europeans, so it is not possible to deduce a possible predilection for a race. Blacks and Asians were included in this study, indicating that MPS-IVA may affect people of all races, though. Men and women accounted for 53% and 47% of study participants, respectively, implying an equal prevalence in both genders. This result is consistent with the autosomal mode of inheritance described for the disease. The patients' mean age at symptom onset was 2.1 year, with less than 10% of affected individuals experiencing first symptoms beyond the age of 5 years. Of note, eldest study participants were older than 70 years, thus showing that mild MPS-IVA does not necessarily provoke premature death.
Under physiological conditions, glycosaminoglycans chondroitin 6-sulfate and keratan sulfate are subjected to degradation by GALNS. This lysosomal enzyme catalyzes the hydrolytic cleavage of the sulfuric ester bonds in these macromolecules. In MPS-IVA patients, functional deficiencies of GALNS result in an intralysosomal accumulation of glycosaminoglycans, which is primarily observed in cartilaginous and osseous tissues as well as in the cornea . In general, this condition is referred to as a lysosomal storage disorder, and ensuing pathophysiological events are similar to those observed in other entities of this group of diseases: Progressive enlargement of lysosomes initially interferes with the function of these cell organelles, but eventually, cellular, tissue and organ function are compromised. Nevertheless, detrimental consequences of glycosaminoglycan accumulation are likely to go beyond mere mechanical effects. In this context, it has been suggested that keratan sulfate inhibits osteoblast activity at low concentrations and directly mediates bone toxicity at higher concentrations . With regards to neurological deficits observed in some MPS-IVA patients, these are not usually due to lysosomal defects in neurons or glia cells. They rather constitute complications of the disease arising from bone deformities that hinder development, growth and function of the central nervous system. For instance, odontoid hypoplasia and atlantoaxial subluxation or instability, as well as extradural deposition of glycosaminoglycans, may result in spinal cord compression, cervical myelopathy, and myelomalacia . This condition is life-threatening.
Affected families may benefit from genetic counseling. Due to the severity of the disease, prenatal screens are indicated upon suspicion of inheritance. Similar to the postnatal assessment of enzymatic activity in leukocytes or fibroblasts, tests may be performed to evaluate GALNS activity in cultured chorionic villus cells or amniocytes . Specimens obtained by chorionic villus sampling or amniocentesis may also be utilized for genetic screens. Possibly, a delay of symptom onset and a reduction of the disease' severity may be achieved by an early diagnosis and initiation of treatment, if parents-to-be decide against a premature termination of pregnancy.
Mucopolysaccharidosis 4A or mucopolysaccharidosis IVA (MPS-IVA) is a rare lysosomal storage disease that has first been described by the Uruguayan pediatrist Luis Morquio and James Brailsford from England in 1929. The disease is also referred to as Morquio A many times. It is inherited as an autosomal recessive trait and provoked by mutations of the gene encoding for the enzyme N-acetylgalactosamine-6-sulfatase (GALNS), which catalyzes the degradation of glycosaminoglycans like chondroitin 6-sulfate and keratan sulfate. Deficiency of GALNS results in the accumulation of these substrates in lysosomes. This condition eventually interferes with cellular, tissue and organ function.
MPS-IVA is generally described as a musculoskeletal disorder since most patients present with short stature and progressive skeletal dysplasia. However, compromise of the cardiovascular system or respiratory tract, as well as visual and auditory impairment, may also be observed . Although sequence anomalies of a single gene account for MPS-IVA, manifold mutations have been described and are possibly related to clinical heterogeneity. While symptom onset typically occurs in infancy or early childhood, the severity of the disease varies largely. Unfortunately, severe MPS-IVA is still associated with considerable morbidity and mortality. In contrast, most patients suffering from mild MPS-IVA survive into adulthood and may even have a near-to-normal life expectancy. Life-long enzyme replacement therapy is the treatment of choice.
Mucopolysaccharidosis 4A (MPS-IVA) is a rare hereditary disease. It is triggered by mutations in the gene encoding for the enzyme N-acetylgalactosamine-6-sulfatase (GALNS), which catalyzes the degradation of glycosaminoglycans like chondroitin 6-sulfate and keratan sulfate. In patients suffering from MPS-IVA, GALNS activity is severely reduced. Consequently, chondroitin 6-sulfate and keratan sulfate accumulate within cells forming the cartilage, bones, and cornea and interfere with cellular, tissue and organ function. Accordingly, short stature, skeletal dysplasia, dental anomalies and corneal clouding are the hallmarks of MPS-IVA. Affected individuals are born apparently healthy, but symptom onset occurs in early childhood. By the age of three, children may have developed considerable deformities like spinal curvature, pectus carinatum, and knock-knee. In milder forms of the disease, gait disturbances and dysplasia of upper and lower limbs may be most striking. Additionally, MPS-IVA patients may present with visual and hearing impairment, respiratory distress and heart disease.
Diagnostic measures to confirm a tentative diagnosis of MPS-IVA include laboratory analyses of urine samples (to demonstrate abnormal excretion of chondroitin 6-sulfate and keratan sulfate), assessment of GALNS activity and the application of molecular biological techniques to identify gene defects. The only proof of reduced enzymatic activity or positive results of genetic tests are considered diagnostic, though, since people suffering from other types of mucopolysaccharidosis may also excrete glycosaminoglycans in their urine.
Unfortunately, causative therapy is not available. Enzyme replacement therapy has recently been approved for the treatment of MPS-IVA and may improve life quality and endurance. Otherwise, affected individuals and their families are offered personalized supportive care that may comprise physiotherapy, orthopedic interventions and provision of orthopedic aids, psychological support, drug therapy and surgery.