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L1 syndrome, also referred to as MASA, Crash syndrome or Gareis-Mason syndrome, is a rare inherited neurological disorder caused by a genetic mutation of the L1CAM gene located on the x chromosome.

This syndrome causes severe symptoms in males, while the majority of females are carriers of the syndrome and do not experience severe symptoms as only one X chromosome is affected.

An estimation of how many people are affected by this syndrome is unknown.

There is no cure for L1 syndrome, however treatment is used to improve individual’s symptoms.

Signs and Symptoms (Clinical features)
L1 syndrome has a spectrum of symptoms that individuals may experience, these physical manifestations can range in severity and can vary wildly within and between families.

In less affected individuals a diagnosis may occur later in life and may only be noticed due to developmental delay.

An L1 syndrome diagnosis is considered if individuals display any of the following symptoms :

X linked hydrocephalus with stenosis of the aqueduct of Silvius (HSAS)

 * Hydrocephalus (increased intraventricular fluid in the middle of the brain), mild and moderate cases are associated with an increased life expectancy, when compared to severe cases.
 * Adducted thumbs
 * Spasticity
 * Intellectual disability, usually severe and occurs regardless of treatments
 * Seizures may occur

MASA syndrome

 * Intellectual disability, this ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). The severity of an individual’s intellectual disability does not always predict or be caused by the size of the person's head or severity of their hydrocephalus
 * Aphasia
 * Hypotonia progressing to spasticity during the first year and gets progressively worse throughout adulthood.
 * Adducted thumbs
 * Enlargment of the third ventricle

SPG1 (X linked complicated hereditary spastic paraplegia type 1)

 * Spastic paraplegia
 * Intellectual disability
 * Normal MRI scan of the brain

X linked complicated corpus callosum agenesis

 * Spastic paraplegia
 * Intellectual disability

Female carriers
. Severe symptoms in females is extremely rare, only one case of a female carrier displaying such characteristics have been reported.
 * Females which have a mutation of the L1CAM are more likely to display less severe symptoms of L1 syndrome such as adducted thumbs or mild intellectual disability . It has estimated that only 5% of female carriers display clinical features from mild to severe

Genetics
Genetically, L1 syndrome is caused by the mutations in the L1CAM gene located on the X chromosome. Males with the syndrome display severe symptoms compared to females with the same mutations.

This mutation causes a lack of production of the L1 cell adhesion molecule (L1CAM), a protein which is used in the migration and creation of neurons in the central nervous system prenatally. The protein has also been linked with the creation of complex cognitive and memory processes .

To date around 240 different mutations of the L1CAM have been identified and can be sometimes exclusive to the family that was studied. The majority of the mutations published have been labelled as missense, nonsense and small insertions or deletions. Reports have been published where larger deletions and duplications of L1CAM have been detected, however these cases are rare.

Inheritance
L1 syndrome is inherited in an X linked recessive pattern, leading the syndrome to predominantly affect males. This is due to males typically not having an extra copy of the X chromosome, unlike females, confirming the mutated gene has to be used and expressed. Because of the recessive nature of the syndrome individuals may have L1CAM mutations, however they may not display the clinical features of the syndrome, these individuals are classed as carriers. .

If the mother is a carrier of or is affected by the mutated gene and the father is unaffected: If the father has the affected mutated gene, and therefore is affected, and the mother is unaffected: If both parents have a mutated gene: To date there have been no reported cases of affected males reproducing. However not all cases of L1 syndrome are inherited. 7% of L1 syndrome cases have been found to be due to new genetic mutations in families (De novo mutation).
 * Both male and female offspring have a 50% chance of inheriting her mutated L1CAM gene.
 * In typical males with one X chromosome, this means they have a 50% chance of displaying symptoms of L1 syndrome.
 * In typical females with two chromosomes, the likelihood of displaying L1 syndrome clinical features is further decreased due to the process of x inactivation; one of the two x chromosomes are silenced within the cell and therefore this chromosome will not express its genes and affect the system.
 * In typical males with one x chromosome, the chances of inheriting the mutated gene drops to 0%. In This scenario the father has to pass on his Y chromosome while the mother contributes one of her unaffected X chromosomes.
 * In typical females with two chromosomes, the likelihood of inheriting a mutated gene remains the same as if the mother was the sole carrier of the mutated gene
 * In typical males there is a 50% chance of inheriting one of the mothers mutated X chromosomes.
 * In typical females this increases to 100%.

Prevalence
The prevalence rate of L1 syndrome is currently unknown, due to a lack of reliable data ; However L1 syndrome, specifically HASA, has found to be the leading cause of hydrocephalus, affecting 1 in 30,000 male births and proximately 5-10% suffers

Some have suggested L1 syndrome is under diagnosed and should be considered if a child has an intellectual disability or shows any clinical signs of L1 syndrome. Another, perhaps less time consuming and more cost effective, solution proposed by researchers suggested that clinicians should consider testing for L1CAM mutations if patients display three or more clinical features associated with this syndrome. The probability of identifying an L1CAM mutation has been reported to increase up to 66% if such techniques are used. However the effectiveness of this type of diagnostic aid has yet to be thoroughly tested and similar results have only been replicated once before.

Diagnosis and Testing
To confirm a diagnosis of L1 syndrome, after identifying a number of physical symptoms, genetic testing is completed. Testing approaches can include screening multiple genes of interest (multigene panel) or focusing simply on a single gene (sequence analysis). Single gene analysis is usually followed by deletion/duplication analysis, a type of analysis used to determine if there is and absence or excessive amount of a particular gene within the chromosome ; this step is completed if a mutation of L1CAM is not found. Sequence analysis is the most commonly used technique and has been used to diagnose on average 99% of individuals with L1 syndrome.

In order to estimate the severity of the syndrome and the individual’s needs, after diagnosis a number of different evaluations are used. These include neuroimaging study, complete neurologic evaluation, developmental evaluation and consultation with a clinical geneticist. .

Management and Treatment
In order to meet the wide variety of needs of an individual with L1 syndrome a wide variety of expertise is needed such as paediatrics, child neurology, neurosurgery, rehabilitation and clinical genetics.

Hydrocephalus This symptom requires surgical treatment in order to elevate the increasing pressure within the skull. This is done through shunting of the cerebrospinal fluid. However performing shunting prenatally has been shown to have no significant effects on individual’s development .

Adducted thumbs Treatment for this symptom is possible but not commonly practiced. Individuals may use a splint to reduce the degree to which the thumb is curled to the palm. In order to improve overall thumb use, tendon transfer is available and shown to be sucessful for less extreme cases. .

Intellectual disability The individual’s developmental progress should be examined and accommodated for in order to optimise the patient’s growth. The advancement in the individual’s development is variable and subjective to the education package provided.

Spastic paraplegia To date no specific treatments have been developed which prevent, slow down or reverse the effects of spastic paraplegia. However pharmacological and physical therapy options are applied in order to manage patient’s symptoms.

In order to prevent secondary complications later in life physiotherapy is recommended.