Clinical Guidance

In their review, noted that pathogenic missense variants in extracellular domains or pathogenic variants in cytoplasmic regions cause milder phenotypes than those resulting from truncation in extracellular domains or from nondetectable L1 protein. Pathogenic missense variants that affect "key amino acid residues" are most likely to result in a severe phenotype. Key amino acid residues are those crucial for the structure of the immunoglobulin or fibronectin type III-like domains of the L1 protein . A statistical analysis was performed on 33 individuals with L1 syndrome in whom a pathogenic variant was identified to detect any possible genotype-phenotype correlation.

Source: GeneReviews — "L1 Syndrome"

Diagnostic Criteria

Suggestive Findings

L1 syndrome involves a phenotypic spectrum ranging from severe to mild. L1 syndrome should be suspected in individuals with any of the following clinical phenotypes or neuroimaging findings and supportive family history.

Clinical Phenotypes

X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS). Signs present in affected males:

Source: GeneReviews — "L1 Syndrome"

Differential Diagnosis

The differential diagnosis of males with developmental delay or intellectual disability and early hypotonia evolving into spastic paraplegia during childhood, with or without adducted thumbs, includes many conditions. See OMIM Autosomal Dominant, Autosomal Recessive, and Nonsyndromic X-Linked Intellectual Developmental Disorder Phenotypic Series. Nonsyndromic congenital hydrocephalus. Individuals with L1 syndrome and hydrocephalus do not have major additional physical anomalies. Other single-gene causes of nonsyndromic congenital hydrocephalus include biallelic pathogenic variants in CCDC88C, MPDZ, and WDR8 (see OMIM PS236600). Nonsyndromic congenital hydrocephalus may also occur as part of (or secondary to) the following:

Source: GeneReviews — "L1 Syndrome"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with L1 syndrome, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with L1 Syndrome

Source: GeneReviews — "L1 Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "L1 Syndrome"

Surveillance Guidelines

Table 5.

Recommended Surveillance for Individuals with L1 Syndrome

System/Concern | Evaluation | Frequency

Hydrocephalus

| Neurologic eval | At regular intervals per individual patient

DD/ID

Spastic paraplegia

DD = developmental delay; ID = intellectual disability

Source: GeneReviews — "L1 Syndrome"