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MASA syndrome

Medically Reviewed

A condition with intellectual disability, spasticity, and hydrocephalus.

Overview

MASA syndrome is a rare X-linked genetic disorder that affects the development of the central nervous system and is named after its core features: Mental retardation (now more accurately referred to as intellectual disability), Aphasia (language difficulties), Shuffling gait, and Aducted thumbs. It primarily affects males, though female carriers may show mild symptoms. MASA syndrome is part of a spectrum of conditions associated with mutations in the L1CAM gene and shares overlapping features with X-linked hydrocephalus.

First described in the 1980s, MASA syndrome is now known to fall within the broader category of L1 syndrome—a group of disorders caused by mutations in the same gene. These disorders affect neuronal development and communication, leading to a wide range of neurological and developmental impairments. The severity of MASA syndrome can vary, even within the same family.

Causes

MASA syndrome is caused by mutations in the L1CAM gene located on the X chromosome (Xq28). This gene encodes the L1 cell adhesion molecule, a protein essential for proper development of the nervous system, including neuronal migration, axon guidance, and myelination.

Because it is an X-linked recessive disorder, MASA syndrome primarily affects males, who have only one X chromosome. Females, with two X chromosomes, may be carriers of the mutation and either remain asymptomatic or display mild neurological signs due to random X-chromosome inactivation.

Mutations in L1CAM can lead to a range of conditions collectively known as L1 syndrome, including MASA syndrome, X-linked hydrocephalus (HSAS), spastic paraplegia type 1 (SPG1), and agenesis of the corpus callosum with hydrocephalus.

Symptoms

The hallmark features of MASA syndrome form the basis of its acronym, but affected individuals may present with a broader range of symptoms. Common clinical manifestations include:

  • Intellectual disability: Varying degrees of cognitive impairment, typically mild to moderate.

  • Aphasia or delayed speech development: Difficulty with language acquisition or verbal expression, often noticeable in early childhood.

  • Shuffling gait: Abnormal, unsteady, or spastic walking pattern due to lower limb spasticity or weakness.

  • Adducted thumbs: Thumbs that are held in toward the palm due to joint contractures; often present at birth and may be bilateral.

  • Spasticity or increased muscle tone: Especially in the lower limbs.

  • Hydrocephalus: May be present in some cases and can cause increased head circumference in infants.

  • Seizures: Reported occasionally in some individuals.

  • Behavioral issues: May include hyperactivity, attention deficits, or social interaction challenges.

  • Variable dysmorphic features: Such as a prominent forehead, flat nasal bridge, or mild facial asymmetry.

Female carriers may have subtle signs such as mild learning disabilities or gait abnormalities, but most remain unaffected.

Diagnosis

Diagnosis of MASA syndrome involves a combination of clinical assessment, neuroimaging, family history, and genetic testing. The key diagnostic steps include:

  • Clinical evaluation:

    • Assessment of developmental delays, speech issues, gait, and thumb positioning.

    • Family history suggesting an X-linked inheritance pattern.

  • Neuroimaging:

    • MRI or CT scan may reveal structural brain abnormalities such as hypoplasia of the corpus callosum, ventriculomegaly, or hydrocephalus.

  • Genetic testing:

    • Sequencing of the L1CAM gene to identify pathogenic mutations.

    • Carrier testing and prenatal diagnosis are possible in at-risk families.

  • Neurodevelopmental assessment:

    • Standardized tests to evaluate intellectual functioning, motor skills, and language development.

Early diagnosis enables timely intervention and genetic counseling for affected families.

Treatment

There is no cure for MASA syndrome, but treatment focuses on managing symptoms, maximizing developmental potential, and improving quality of life. A multidisciplinary approach is essential. Key management strategies include:

  • Speech and language therapy: To support communication skills and address aphasia or delayed language development.

  • Physical therapy: Helps improve muscle tone, balance, and coordination, especially for those with gait abnormalities or spasticity.

  • Occupational therapy: Aids in developing fine motor skills and enhancing independence in daily activities.

  • Educational support: Individualized education programs (IEPs) tailored to cognitive and learning needs.

  • Orthopedic interventions:

    • Surgical correction of adducted thumbs if they interfere with function.

    • Bracing or mobility aids as needed for spasticity-related gait issues.

  • Management of hydrocephalus: Ventriculoperitoneal (VP) shunting may be required in severe cases.

  • Behavioral therapy: For attention deficits, emotional regulation, and social development.

Regular monitoring by neurology, orthopedics, physical medicine, and developmental specialists is important for comprehensive care.

Prognosis

The prognosis for individuals with MASA syndrome depends on the severity of symptoms and the presence of complications like hydrocephalus. While intellectual disability and motor challenges are lifelong, many affected individuals can achieve partial independence with supportive care and therapies.

Most patients do not experience progressive neurological deterioration. With early intervention, improvements in communication, mobility, and daily living skills are possible. Life expectancy is generally normal unless complicated by severe hydrocephalus or recurrent infections.

Ongoing research into L1CAM mutations and related syndromes may improve understanding of disease mechanisms and lead to new therapies. Genetic counseling is strongly recommended for families with a known history of MASA syndrome.

Medical Disclaimer

The information provided on this page is for educational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.