Morquio Syndrome: Symptoms, Types, Causes and Treatment

Morquio syndrome, also known as mucopolysaccharidosis type IV (MPS IV), is a rare genetic disorder with profound impacts on affected individuals and their families. Characterized by a wide spectrum of symptoms, this condition can affect multiple parts of the body, particularly the skeleton, but also involves other organ systems. Understanding Morquio syndrome is crucial for early detection, effective management, and supporting those living with the disease.

Symptoms of Morquio Syndrome

Morquio syndrome presents with a range of symptoms that can vary greatly in severity and onset. Many symptoms are skeletal, but the disorder also affects other organs and overall quality of life. Early recognition is vital for timely intervention and improved outcomes.

Symptom	Description	Impacted Systems	Source(s)
Short stature	Marked reduction in height, evident early	Musculoskeletal	1 3 5 6 8
Skeletal deformities	Abnormal bone shape, dysostosis multiplex	Skeleton, joints	3 4 5 6
Joint laxity	Hypermobile joints, frequent dislocations	Musculoskeletal	3 4 5
Gait abnormality	Waddling gait, walking difficulties	Musculoskeletal, motor	3 6 8
Corneal clouding	Hazy cornea, visual issues	Eyes	1 5
Hearing loss	Diminished hearing, may be progressive	Ears	1
Respiratory issues	Sleep apnea, airway obstruction	Respiratory	1 3 5
Cardiac problems	Valve thickening, regurgitation	Cardiovascular	1 5
Dental anomalies	Misshapen teeth, frequent cavities	Dental	1 5
Hepatomegaly	Enlarged liver	Digestive	1
Normal intelligence	Cognitive development unaffected	Neurological	5 6

Table 1: Key Symptoms

Skeletal and Musculoskeletal Manifestations

The most prominent symptoms of Morquio syndrome are skeletal. Children often present with short stature that becomes more pronounced with age. Typical bone deformities include:

• Kyphoscoliosis: Abnormal curvature of the spine
• Pectus carinatum: Protruding chest
• Genu valgum: Knock-knees
• Coxa valga/vara: Deformities of the hip joints
• Odontoid hypoplasia: Underdeveloped bone at the top of the spine, increasing risk of spinal instability and compression 3 4 5 6

Joint hypermobility is common, leading to frequent joint dislocations and abnormal gait patterns such as waddling. These orthopedic challenges often necessitate multiple surgeries, especially in childhood and adolescence, to maintain mobility and function 5 6 8.

Non-Skeletal Symptoms

Morquio syndrome also affects several other organ systems:

• Eyes: Corneal clouding, astigmatism, and sometimes glaucoma impair vision 1 5
• Ears: Progressive hearing loss can occur, often requiring hearing aids 1
• Respiratory: Obstructive sleep apnea and airway obstruction are common, contributing to fatigue and, in severe cases, life-threatening complications 1 3 5
• Cardiovascular: Heart valve thickening and regurgitation can develop, sometimes necessitating surgical intervention 1 5
• Dental: Dental anomalies, including misshapen teeth and frequent cavities, are typical and require ongoing dental care 1 5
• Digestive: Hepatomegaly (enlarged liver) and frequent hernias may be observed 1
• Cognitive: Unlike some other mucopolysaccharidoses, intelligence and cognitive development remain normal 5 6

Quality of Life and Disease Progression

The severity and progression of symptoms can vary widely, even between individuals with the same genetic subtype. Some experience rapid progression with early loss of mobility, while others maintain function into adulthood. The most critical complications, such as spinal cord compression and respiratory failure, are the leading causes of morbidity and mortality 3 5.

Types of Morquio Syndrome

Morquio syndrome is classified into two main types based on the specific enzyme deficiency involved, although both share many clinical features.

Type	Enzyme Deficiency	Genetic Cause	Clinical Course	Source(s)
MPS IVA	N-acetylgalactosamine-6-sulfate sulfatase (GALNS)	Mutations in GALNS gene	Severe to mild, early onset	3 4 6 7 8 9
MPS IVB	Beta-galactosidase	Mutations in GLB1 gene	Generally milder, variable	3 6

Table 2: Morquio Syndrome Types

MPS IVA (Morquio A)

Morquio A, or MPS IVA, is caused by a deficiency of the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), resulting in the accumulation of glycosaminoglycans (keratan sulfate and chondroitin-6-sulfate) primarily in cartilage and bone 3 4 6 7. This is the more common and typically more severe form, with symptoms often appearing in early childhood or even at birth 4 6 8.

Key Features of MPS IVA:

• Earlier onset and more severe skeletal involvement
• Greater risk of spinal cord compression and respiratory complications
• Marked short stature and progressive skeletal dysplasia
• Broad spectrum: from severe, rapidly progressive cases to milder, slowly advancing forms 8

MPS IVB (Morquio B)

Morquio B, or MPS IVB, is due to beta-galactosidase deficiency caused by mutations in the GLB1 gene. This subtype generally presents with a milder phenotype than MPS IVA, with later onset and slower progression 3 6. However, clinical symptoms can overlap, making biochemical and genetic testing essential for precise diagnosis.

Key Features of MPS IVB:

• Mild to moderate skeletal abnormalities
• Fewer systemic complications
• Later onset of symptoms in some cases

Phenotypic Spectrum and Genotype-Phenotype Correlation

Both types can present with a spectrum ranging from severe to mild symptoms. Recent research underscores that even within MPS IVA, the clinical course depends on the specific genetic mutations, residual enzyme activity, and other modifying factors 7 8 9. This complexity can challenge diagnosis and management.

Causes of Morquio Syndrome

Morquio syndrome is an inherited lysosomal storage disorder caused by specific genetic mutations that impair the breakdown of certain complex sugars (glycosaminoglycans) within cells.

Cause	Description	Inheritance	Source(s)
Enzyme deficiency	Lack of GALNS or beta-galactosidase	Autosomal recessive	3 4 6 7 9
Mutation in GALNS gene	Over 400 variants identified	Both parents must be carriers	7 9
Mutation in GLB1 gene	Causes MPS IVB	Autosomal recessive	6
GAG accumulation	Build-up of keratan sulfate and chondroitin-6-sulfate damages tissues	Cellular/biochemical	3 4 6 7

Table 3: Causes of Morquio Syndrome

Genetic and Biochemical Basis

• MPS IVA: Caused by mutations in the GALNS gene, which encodes the enzyme N-acetylgalactosamine-6-sulfate sulfatase. More than 400 unique GALNS gene variants have been identified, most of which are missense mutations. The high diversity of mutations explains the variability in symptoms and disease progression 7 9.
• MPS IVB: Caused by mutations in the GLB1 gene, leading to deficiency of beta-galactosidase 6.

Both forms are inherited in an autosomal recessive manner, meaning a child must receive a defective gene from both carrier parents to manifest the disease.

Pathophysiology

The enzyme deficiency prevents the normal breakdown of glycosaminoglycans, specifically keratan sulfate and chondroitin-6-sulfate, causing these substances to accumulate within lysosomes. This accumulation is particularly damaging to cartilage and bone, disrupting normal skeletal development and leading to the characteristic features of Morquio syndrome 3 4 6.

Genetic Testing and Counseling

Due to the heterogeneity of mutations, genetic testing is crucial for confirming diagnosis, predicting disease course, and providing family counseling. Prenatal and preimplantation genetic diagnosis is possible for families with a known mutation 7 9.

Treatment of Morquio Syndrome

While there is currently no cure for Morquio syndrome, several treatment strategies can help manage symptoms, slow disease progression, and improve quality of life. Advances in therapy are ongoing, offering hope for better outcomes.

Treatment	Description	Effectiveness/Limitations	Source(s)
Enzyme Replacement Therapy (ERT)	Intravenous GALNS (elosulfase alfa)	Improves endurance, limited effect on bone	11 12 13 14
Hematopoietic Stem Cell Transplantation (HSCT)	Bone marrow transplant	Some improvement, best if early	10 11 14
Orthopedic surgery	Corrects skeletal deformities	Symptomatic, multiple procedures	5 6 11
Supportive care	Physical therapy, respiratory, cardiac care	Multidisciplinary, essential	1 14
Emerging therapies	Gene therapy, improved enzyme delivery	Preclinical/developmental stage	3 12 14

Table 4: Morquio Syndrome Treatments

Enzyme Replacement Therapy (ERT)

The most significant development in recent years is the approval of enzyme replacement therapy with recombinant human GALNS (elosulfase alfa) 11 13. Administered intravenously, ERT can:

• Improve endurance and functional capacity
• Reduce levels of accumulated glycosaminoglycans in the body

Limitations:

• ERT has limited impact on bone and cartilage abnormalities because the enzyme has difficulty penetrating these tissues 11 12.
• Lifelong weekly infusions are required.
• Individual response varies, and predicting benefit remains challenging 13.

Research is underway to improve enzyme delivery, including nanoparticle-based systems, which may enhance uptake into cartilage 12.

Hematopoietic Stem Cell Transplantation (HSCT)

HSCT involves the transplantation of healthy bone marrow cells capable of producing the missing enzyme. It has shown:

• Some improvement in respiratory function and daily living activities, especially when performed early in life 10
• Potential to slow disease progression and reduce need for orthopedic surgery

Limitations:

• HSCT carries risks such as graft-versus-host disease and requires a matched donor.
• Its effect on established skeletal dysplasia is limited 10 11.

Surgery and Supportive Care

Because of the extensive skeletal involvement, many patients require multiple orthopedic surgeries to correct spine, hip, and leg deformities 5 6 11. Other supportive interventions include:

• Physical and occupational therapy to maintain mobility
• Respiratory therapy and management of sleep apnea
• Cardiac evaluations and interventions as needed
• Dental care for frequent dental issues 1 14

A multidisciplinary team approach is essential for optimal care.

Emerging and Future Therapies

• Gene therapy: Promising but in early stages of research, with potential to correct the underlying genetic defect 3 14
• Novel ERT delivery systems: Nanostructured carriers may increase the effectiveness of enzyme delivery to skeletal tissue 12
• Prenatal and newborn screening: May enable earlier intervention and improved outcomes 9

Conclusion

Morquio syndrome is a complex and multisystemic condition that requires lifelong, comprehensive management. While challenges remain, advances in diagnosis and therapy are improving the outlook for affected individuals.

Key points:

• Morquio syndrome features a combination of severe skeletal abnormalities and multi-organ involvement, with preserved intelligence.
• Two main types exist: MPS IVA (GALNS deficiency) and MPS IVB (beta-galactosidase deficiency).
• The condition results from inherited enzyme deficiencies leading to accumulation of glycosaminoglycans, particularly damaging bone and cartilage.
• Early and accurate diagnosis is essential to guide management and genetic counseling.
• Treatment is multidisciplinary, including enzyme replacement therapy, stem cell transplantation, surgery, and supportive care.
• New therapies, such as improved drug delivery and gene therapy, hold promise for the future.

By understanding Morquio syndrome’s symptoms, types, causes, and treatment options, healthcare professionals and families can work together to provide the best possible care and hope for improved quality of life.