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Mucopolysaccharidosis 4A

Mps IV a

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.

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Presentation

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) [6]. 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 [1]. 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 [11]. With regards to the respiratory tract, snoring, sleep apnea, recurrent upper respiratory infection, and dyspnea may occur.

Short Stature
  • Short stature, skeletal dysplasia, dental anomalies and corneal clouding are the hallmarks of MPS-IVA.[symptoma.com]
  • Clinical findings Short stature, skeletal dysplasia, dental anomalies, and corneal clouding. Intelligence is normal; no CNS involvement, except where skeletal changes compress anatomic structures and cause neurologic complications.[medical-dictionary.thefreedictionary.com]
  • Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal clouding.[uniprot.org]
  • Signs and symptoms include various skeletal abnormalities such as short stature, knock knees, pectus carinatum, and malformations of the spine, hips and wrists.[rarediseases.info.nih.gov]
Pain
  • Typical signs of anaphylaxis include cough, rash, throat tightness, hives, flushing, changes in skin color, low blood pressure, shortness of breath, chest pain, and gastrointestinal symptoms such as nausea, abdominal pain, retching, and vomiting.[vimizim.com]
  • Brand new chapters provide up-to-date, comprehensive coverage of topics relevant to current practice: -First Trimester Fetal Anatomy -Obstetric Ultrasound and the Obese Patient -Evaluation of Pelvic Pain in the Reproductive Age Patient -Gynecologic Ultrasound[books.google.com]
  • Progressive bone and joint involvement leads to short stature, and eventually to disabling pain and arthritis.[ncbi.nlm.nih.gov]
Falling
  • 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.[symptoma.com]
  • MyBioSource and its authorized distributors reserve the right to refuse to process any order where we reasonably believe that the intended use will fall outside of our acceptable guidelines.[mybiosource.com]
  • […] abnormalities Dental abnormalities Marked disproportionate short stature with short trunk and normal limbs Skeletal abnormalities including ulnar deviation of the wrists, pectus carinatum, kyphosis, scoliosis Hypermobile joints and waddling gait with frequent falls[centogene.com]
  • Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.[invitae.com]
  • Affected individuals exhibit a waddling gait with frequent falls. Early development and intelligence are typically normal, unlike other MPS storage disorders. High frequency hearing impairment is common.[rarediseases.org]
Recurrent Upper Respiratory Infections
  • 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.[symptoma.com]
Sleep Apnea
  • 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.[symptoma.com]
  • Respiratory Upper-airway obstruction and obstructive sleep apnea are managed by removal of enlarged tonsils and adenoids (average age 7 years [ Montaño et al 2007 ]).[ncbi.nlm.nih.gov]
  • Adequate spontaneous ventilation was a primary objective, as face mask ventilation was also likely to be very difficult because of the continuous deposition of glycosaminoglycans , disturbed anatomy and sleep apnea.[omicsonline.org]
  • Recurring respiratory infections are common, as are obstructive airway disease and obstructive sleep apnea. Many affected individuals also have heart disease, often involving enlarged or diseased heart valves.[en.wikipedia.org]
  • The airway may become narrow in some people with MPS IV, leading to frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea).[ghr.nlm.nih.gov]
Snoring
  • 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.[symptoma.com]
  • History of snoring, daytime somnolence and stridor may indicate airway obstruction [10] . History of snoring was present in our case.[ijaweb.org]
  • […] suggestive laboratory findings 4 : No distinctive clinical findings at birth History of adenoidectomy, tonsillectomy, hernia repair, ear ventilation, cervical spine decompression Respiratory abnormalities including sleep apnea, endurance limitations, snoring[centogene.com]
  • Airway evaluation: abnormal neck anatomy, short neck with limited mobility, hyromental and thyromentonian distance less than 6 cm, severely limited jaw protrusion, mouth opening inferior to 6 cm, mallampati IV and snoring.[omicsonline.org]
  • Parents did not reveal any history of snoring or apneic episodes while sleeping. Patient had virilization of the external genitalia with hirsutism and masculine voice. Patient had ambiguous genitalia.[joacp.org]
Dyspnea
  • 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.[symptoma.com]
  • Because of persistent dyspnea and poor exercise tolerance (New York Heart Association class III), he was investigated for cardiac disease.[ahajournals.org]
Respiratory Distress
  • Additionally, MPS-IVA patients may present with visual and hearing impairment, respiratory distress and heart disease.[symptoma.com]
Hepatomegaly
  • Affected people may also experience involvement of other organ systems such as respiratory problems, valvular heart disease, hearing impairment, corneal clouding, dental abnormalities, hepatomegaly, and spinal cord compression. 0000670 Cervical myelopathy[rarediseases.info.nih.gov]
  • Hepatomegaly and peripheral corneal deposits resembling arcus senilis were present. Peripheral leukocytes contained basophilic granulation.[annals.org]
  • Affected people may also experience involvement of other organ systems such as respiratory problems,valvular heart disease, hearing impairment, corneal clouding, dental abnormalities, hepatomegaly, and spinal cord compression.[checkorphan.org]
  • Extra-skeletal manifestations include respiratory problems, hepatomegaly, valvulopathies, hearing loss and corneal clouding. Intelligence is normal.[orpha.net]
Flushing
  • Serious and severe reactions can happen with VIMIZIM treatment, including life-threatening allergic reactions (anaphylaxis), hives, swelling, cough, shortness of breath, and flushing.[vimizim.com]
  • Serious and severe reactions can happen with Vimizim treatment, including life-threatening allergic reactions (anaphylaxis), hives, swelling, cough, shortness of breath, and flushing.[biomarin.com]
Hearing Impairment
  • Additionally, MPS-IVA patients may present with visual and hearing impairment, respiratory distress and heart disease.[symptoma.com]
  • Affected people may also experience involvement of other organ systems such as respiratory problems, valvular heart disease, hearing impairment, corneal clouding, dental abnormalities, hepatomegaly, and spinal cord compression. 0000670 Cervical myelopathy[rarediseases.info.nih.gov]
  • Affected people may also experience involvement of other organ systems such as respiratory problems,valvular heart disease, hearing impairment, corneal clouding, dental abnormalities, hepatomegaly, and spinal cord compression.[checkorphan.org]
Hearing Problem
  • Recurrent upper airway infections and hearing problems. Mild hepatosplenomegaly.[patient.info]
  • Pediatricians, surgeons, specialists who assess and treat heart problems (cardiologists), specialists who assess and treat hearing problems (audiologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat[rarediseases.org]
Visual Impairment
  • 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.[symptoma.com]
  • Involvement of other organ systems can lead to respiratory complications, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly.[centogene.com]
  • Visual impairment: corneal clouding. Dental caries (enamel abnormalities).[patient.info]
  • Ocular complications caused by anterior segment abnormalities commonly cause visual impairment in MLS. Angle-closure glaucoma is one such complication, but there are limited data on presentation, workup, and management of this condition.[thepermanentejournal.org]
  • Involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly[ncbi.nlm.nih.gov]
Genu Valgum
  • 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.[symptoma.com]
  • Skeletal deformities (platyspondyly, kyphosis, scoliosis, pectus carinatum , genu valgum , long bone deformities) become more pronounced as the child grows. Joint hyperlaxity is accompanied by frequent luxations (hips, knees).[orpha.net]
  • valgum Knock knees 0002857 Grayish enamel Gray colored tooth enamel Greyish enamel [ more ] 0000683 Hearing impairment Deafness Hearing defect [ more ] 0000365 Hepatomegaly Enlarged liver 0002240 Hyperlordosis Prominent swayback 0003307 Hypoplasia of[rarediseases.info.nih.gov]
  • Genu valgum (knock-knee) results from distal femoral and proximal tibial involvement and joint laxity.[ncbi.nlm.nih.gov]
  • 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.[icd10data.com]
Platyspondyly
  • 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.[symptoma.com]
  • Characteristic findings included hypoplasia of odontoid peg, universal platyspondyly, gibbus and kyphosis of the dorsal region with widening of disk spaces.[cjhr.org]
  • Skeletal deformities (platyspondyly, kyphosis, scoliosis, pectus carinatum , genu valgum , long bone deformities) become more pronounced as the child grows. Joint hyperlaxity is accompanied by frequent luxations (hips, knees).[orpha.net]
  • Clinical manifestations include: Platyspondyly of vertebrae. Dysplasia of the long bones. Atlanto-occipital instability. Genu valgum. Gait abnormalities. Corneal clouding. Differential diagnosis Multiple epiphyseal dysplasia.[patient.info]
  • Increased size of lower jaw Large lower jaw Prominent chin Prominent lower jaw [ more ] 0000303 Metaphyseal widening Broad wide portion of long bone 0003016 Opacification of the corneal stroma 0007759 Osteoporosis 0000939 Ovoid vertebral bodies 0003300 Platyspondyly[rarediseases.info.nih.gov]
Coxa Valga
  • valga 0002673 Disproportionate short-trunk short stature Disproportionate short-trunked dwarfism Disproportionate short-trunked short stature Short-trunked dwarfism [ more ] 0003521 Epiphyseal deformities of tubular bones 0003053 Flaring of rib cage[rarediseases.info.nih.gov]
  • Radiological findings in Morquio's syndrome include odontoid hypoplasia, atlanto-axial subluxation, flared ribs, short thorax, flattened capital femoral epiphyses, coxa valga, universal platyspondyly, anterior beaking of vertebrae and short ulna.[patient.info]
  • valga Qualitative urine glycosaminoglycan (GAG) analysis, which uses thin layer chromatography or electrophoresis to identify specific types of GAG, was commonly used for MPS IVA diagnostics 4.[centogene.com]
Arthritis
  • Arthritis Rheum 2006;55:709–16. (30) Doherty M, Dacre J, Dieppe P, Snaith M. The ‚GALS‘ locomotor screen. Ann Rheum Dis 1992;51:1165–69. (31) Chan MO, Sen ES, Hardy E, Hensman P, Wraith E, Jones S, et al.[revista.spr.org.py]
  • Joint replacement surgery may be needed in adults with severe arthritis and pain. A number of treatments have shown benefit in other types of mucopolysaccharidoses. However, their use in Morquio's syndrome is still in an experimental stage.[patient.info]
  • Arthritis Rheum 50:1650–1654 CrossRef PubMed Google Scholar 22. Farahmand P et al (2011) Epidemiologie des Morbus Paget. Osteologie 20:114–118 Google Scholar 23. Feng X et al (2011) Disorders of bone remodeling.[link.springer.com]
  • Progressive bone and joint involvement leads to short stature, disabling pain and arthritis.[centogene.com]
  • Progressive bone and joint involvement leads to short stature, and eventually to disabling pain and arthritis.[ncbi.nlm.nih.gov]
Back Pain
  • Signs of spinal cord injury include back pain, numbness and paralysis, and loss of bladder and bowel control. Contact your doctor immediately if you develop any of these symptoms.[vimizim.com]
  • Anterior and posterior circumferential spinal fusion are indicated if one or more of the following are present: Progressive thoracolumbar kyphosis greater than 70 degrees Uncontrolled back pain Neurologic changes related to spinal stenosis Cardiac Elevated[ncbi.nlm.nih.gov]
Withdrawn
  • , Trial Phase, Sponsor Type and End point status The report reviews top companies involved and enlists all trials (Trial title, Phase, and Status) pertaining to the company The report provides all the unaccomplished trials (Terminated, Suspended and Withdrawn[gii.co.jp]
Short Neck
  • 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.[symptoma.com]
  • Airway evaluation: abnormal neck anatomy, short neck with limited mobility, hyromental and thyromentonian distance less than 6 cm, severely limited jaw protrusion, mouth opening inferior to 6 cm, mallampati IV and snoring.[omicsonline.org]
  • This child also presented with most of the features such as short stature, pectus carinatum, short neck, knock knees, kyphosis, projecting jaw, broad mouth, and flat feet with an abnormal gait.[cjhr.org]
  • 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.[icd10data.com]
  • Clinical manifestations include: Short stature (flat vertebrae cause a short trunk), short neck, moderate kyphosis or scoliosis, and mild pectus carinatum (pigeon chest).[patient.info]
Pelvic Pain
  • Brand new chapters provide up-to-date, comprehensive coverage of topics relevant to current practice: -First Trimester Fetal Anatomy -Obstetric Ultrasound and the Obese Patient -Evaluation of Pelvic Pain in the Reproductive Age Patient -Gynecologic Ultrasound[books.google.com]
Waddling Gait
  • The combined abnormalities usually result in a duck-waddling gait. Mid-face hypoplasia and mandibular protrusion. Thin teeth enamel. Corneal clouding affecting vision. Recurrent upper airway infections and hearing problems. Mild hepatosplenomegaly.[patient.info]
  • gait with frequent falls Visual impairment secondary to corneal clouding, astigmatism, and/or retinopathy Frequent findings on skeletal radiographs in MPS IV-affected children include the following 2, 4 : Kyphosis and gibbus (structural kyphosis) Odontoid[centogene.com]
  • The patient may have a waddling gait. Pectus carinatum (horizontal and protuberant sternum) and a shortened neck with clouding of the cornea, ligamentous laxity, and joint stiffness are also seen.[cjhr.org]
  • Affected individuals exhibit a waddling gait with frequent falls. Early development and intelligence are typically normal, unlike other MPS storage disorders. High frequency hearing impairment is common.[rarediseases.org]
  • The patient had a waddling gait. Clinical examination of cardiovascular and respiratory systems did not reveal any other abnormality. The abdomen appeared protuberant. At the umbilicus, there was a swelling 6x6 cm in size.[ijaweb.org]
Abnormal Gait
  • This child also presented with most of the features such as short stature, pectus carinatum, short neck, knock knees, kyphosis, projecting jaw, broad mouth, and flat feet with an abnormal gait.[cjhr.org]
  • Treatment is based on the signs and symptoms present in each person. 0002750 Gait disturbance Abnormal gait Abnormal walk Impaired gait [2] Last updated: 7/24/2017 Mucopolysaccharidosis type IV is inherited in an autosomal recessive manner. [1] This means[rarediseases.info.nih.gov]
  • The most prevalent clinical manifestations were kyphosis (100%), pectus carinatum (96%), abnormal gait (93%), striking short trunk dwarfism (92%), genu valgum (92%), and valvular heart disease (91%).[ojrd.biomedcentral.com]
Average Intelligence
  • On clinical examination, the child appeared to have a less than average intelligence but was placid and cooperative. He was short statured (height 99.5 cm, expected height 115 cm), weighed 19.5 kg (expected weight 24 kg) and had a short neck.[ijaweb.org]
Cerebellar Disease
  • Entries on cerebellar diseases, peripheral neuropathies, various dementias, diagnostic tests (both clinical and laboratory), forms of cerebral edema, dissociative signs and syndromes - all these and many more have been added, expanded, updated or clarified[books.google.com]
Somnolence
  • History of snoring, daytime somnolence and stridor may indicate airway obstruction [10] . History of snoring was present in our case.[ijaweb.org]

Workup

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 [12]:

  • Qualitative and quantitative analysis of urine samples for glycosaminoglycan content. MPS-IVA patients test positive for urinary excretion of chondroitin 6-sulfate and keratan sulfate. Because the sensitivity of this assay is restricted, additional tests should be performed if there is a suspicion of MPS-IVA. Furthermore, urine analysis may not allow for a distinction between MPS-IVA and mucopolysaccharidosis 4B (MPS-IVB).
  • Assessment of GALNS activity in leukocytes or fibroblasts, which yields values below laboratory-specific reference ranges. In contrast, MPS-IVB patients suffer from a deficiency of β-galactosidase.
  • Identification of mutations affecting the gene encoding for GALNS.

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 [6].

Treatment

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 [13] [14]. 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.

Prognosis

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 [10].

Etiology

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 [2]. 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 [3]. Recently, the three-dimensional structure of this glycosaminoglycan-degrading enzyme has been disclosed by means of crystallography [4]. 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.

Epidemiology

Estimates regarding the prevalence of MPS-IVA range from 1-10 per 1,000,000 inhabitants, with slightly higher prevalence rates, reported among neonates [5]. The International Morquio A Registry provides further epidemiological data regarding race, gender, and age of affected individuals [6]. 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.

Sex distribution
Age distribution

Pathophysiology

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 [7]. 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 [8]. 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 [9]. This condition is life-threatening.

Prevention

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 [12]. 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.

Summary

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 [1]. 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.

Patient Information

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.

References

Article

  1. Hendriksz CJ, Harmatz P, Beck M, et al. Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA. Mol Genet Metab. 2013; 110(1-2):54-64.
  2. Morrone A, Tylee KL, Al-Sayed M, et al. Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations. Mol Genet Metab. 2014; 112(2):160-170.
  3. Tomatsu S, Montano AM, Nishioka T, et al. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Hum Mutat. 2005; 26(6):500-512.
  4. Rivera-Colón Y, Schutsky EK, Kita AZ, Garman SC. The structure of human GALNS reveals the molecular basis for mucopolysaccharidosis IV A. J Mol Biol. 2012; 423(5):736-751.
  5. Leadley RM, Lang S, Misso K, et al. A systematic review of the prevalence of Morquio A syndrome: challenges for study reporting in rare diseases. Orphanet J Rare Dis. 2014; 9:173.
  6. Montaño AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis. 2007; 30(2):165-174.
  7. Tomatsu S, Montaño AM, Oikawa H, et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment: a special review. Curr Pharm Biotechnol. 2011; 12(6):931-945.
  8. Fang-Kircher SG, Herkner K, Windhager R, Lubec G. The effects of acid glycosaminoglycans on neonatal calvarian cultures--a role of keratan sulfate in Morquio syndrome? Life Sci. 1997; 61(8):771-775.
  9. Möllmann C, Lampe CG, Müller-Forell W, et al. Development of a Scoring System to Evaluate the Severity of Craniocervical Spinal Cord Compression in Patients with Mucopolysaccharidosis IVA (Morquio A Syndrome). JIMD Rep. 2013; 11:65-72.
  10. Lavery C, Hendriksz C. Mortality in patients with morquio syndrome a. JIMD Rep. 2015; 15:59-66.
  11. Lin HY, Chuang CK, Chen MR, et al. Natural history and clinical assessment of Taiwanese patients with mucopolysaccharidosis IVA. Orphanet J Rare Dis. 2014; 9:21.
  12. Wood TC, Harvey K, Beck M, et al. Diagnosing mucopolysaccharidosis IVA. J Inherit Metab Dis. 2013; 36(2):293-307.
  13. Sanford M, Lo JH. Elosulfase alfa: first global approval. Drugs. 2014; 74(6):713-718.
  14. Hendriksz CJ, Burton B, Fleming TR, et al. Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis. 2014; 37(6):979-990.

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Last updated: 2019-07-11 20:34