Disease characteristics. L1 syndrome is characterized by hydrocephalus, mental retardation, spasticity of the legs, and adducted thumbs. The phenotypic spectrum of L1 syndrome includes X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome [mental retardation, aphasia (delayed speech), spastic paraplegia (shuffling gait), adducted thumbs], SPG1 (X-linked complicated hereditary spastic paraplegia type 1), and X-linked complicated corpus callosum agenesis. Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; mental retardation is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; mental retardation ranges from mild (IQ of 50-70) to moderate (IQ of 30-50).
Diagnosis/testing. The diagnosis of L1 syndrome can be established in males with characteristic clinical and neuropathologic findings and a family history consistent with X-linked inheritance. Of note, bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding. L1CAM is the only gene associated with L1 syndrome. Clinically available molecular genetic testing can be used to confirm the diagnosis in suspected cases when clinical findings alone are insufficient to establish the diagnosis.
Management. Treatment of L1 syndrome involves a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics. Shunting of the cerebrospinal fluid (CSF) should be performed as needed to reduce intracranial pressure. Surgery for adducted thumbs is not indicated; in some milder cases, tendon transfer and/or splint may improve thumb function. Surveillance includes monitoring of developmental progress and neurologic findings.
Genetic counseling. L1 syndrome is inherited in an X-linked manner. Women who are carriers have a 50% chance of transmitting the disease-causing mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation will be carriers. Affected males do not reproduce. Carrier testing of at-risk female relatives and prenatal testing are available if the L1CAM disease-causing mutation has been identified in an affected family member.
L1 syndrome involves a phenotypic spectrum ranging from severe to mild. Before the availability of molecular genetic testing, several of the phenotypes were thought to be distinct entities. These phenotypes, which are useful in facilitating clinical diagnosis and providing prognosis, have traditionally comprised the following:
X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS). Signs present in affected males:
Severe hydrocephalus, often of prenatal onset. The clinical criteria for hydrocephalus:
Increased intraventricular fluid volume evidenced by an increased occipital-frontal circumference and imaging findings such as increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid
Increased intraventricular pressure based on: (1) specific clinical signs and symptoms depending on age, such as progressive increase of OFC (occipital frontal circumference), headache, nausea and vomiting, irritability; and/or (2) ultrasound and/or brain imaging; or (3) intracranial pressure measurements with ventricular catheter or lumbar puncture [Schrander-Stumpel & Fryns 1998]
Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [Schrander-Stumpel & Fryns 1998]
Spasticity evidenced by brisk tendon reflexes and extensor plantar responses
Severe mental retardation
MASA syndrome [mental retardation, aphasia (delayed speech), spastic paraplegia (shuffling gait), adducted thumbs] [Bianchine & Lewis 1974, Schrander-Stumpel et al 1990]. Findings in affected males:
Mild to moderate mental retardation
Delayed onset of speech
Hypotonia progressing to spasticity
Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles
Variable dilatation of the third ventricle
SPG1 (X-linked complicated hereditary spastic paraplegia type 1). Findings in affected males:
Spastic paraplegia
Mild to moderate mental retardation
Normal MRI of the brain
X-linked complicated corpus callosum agenesis [Willems et al 1987, Boyd et al 1993, Schrander-Stumpel 1995, Yamasaki et al 1995]. Findings in affected males:
Variable spastic paraplegia
Mild to moderate mental retardation
Corpus callosum dysplasia, hypoplasia, or aplasia
Neuropathology and neuroimaging reveal hydrocephalus with or without stenosis of the aqueduct of Sylvius in combination with corpus callosum agenesis/hypogenesis and/or cerebellar hypoplasia, small brainstem, and agenesis of the pyramids (corticospinal tracts) [Willems et al 1987, Yamasaki et al 1995]. Bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding [Chow et al 1985; Schrander-Stumpel et al 2000]. Aqueductal stenosis is not a constant feature of L1 syndrome [Landrieu et al 1979, Varadi et al 1987, Yamasaki et al 1995].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. L1CAM is the only gene associated with L1 syndrome.
Molecular genetic testing: Clinical uses
Confirmation of diagnosis
Carrier detection of at-risk female relatives
Prenatal diagnosis
Preimplantation genetic diagnosis
Molecular genetic testing: Clinical methods
Sequence analysis. Mutation detection rates using sequence analysis have not been reported in the literature. Sequence analysis may have a slightly greater sensitivity than mutation scanning, and thus a higher detection rate.
Mutation scanning. Finckh et al (2000) used mutation scanning to provide data on the detection of L1CAM mutations in probands as related to clinical features and family history (Table 2).
Duplication/deletion analysis. The frequency of deletions and duplications is unknown. In two different families, two males had a large deletion; in another family, duplication of part of the gene was identified [Vits et al 1994, Van Camp et al 1993; author, personal observation].
Note: In males, deletions are detected by absence of a PCR product in mutation scanning and sequence analysis; duplication analysis by quantitative PCR is possible but much more difficult and time consuming.
Table 1 summarizes molecular genetic testing for this disorder.
Test Method | Mutations Detected | Mutation Detection Rate | Test Availability |
---|---|---|---|
Sequence analysis | L1CAM sequence alteration | Unknown | Clinical |
Duplication/deletion analysis | L1CAM duplication or deletion |
Family History | Clinical Findings | ||
---|---|---|---|
Atypical 1 | Typical 2 | ||
1 | >1 | ||
Negative | 1/35 | 8/43 | 7/24 |
2 affected family members | 0/6 | 3/8 | 4/6 |
>2 affected family members | 2/4 | 7/12 | 14/15 |
Adapted from Finckh et al 2000, using mutation scanning based on 153 probands
1. May have cleft palate, brain hemorrhage, metabolic disorder, heart malformation, esophageal atresia, and/or club feet in addition to hydrocephalus
2. Includes hydrocephalus, adducted thumbs, spastic paraplegia, mental retardation, agenesis or hypoplasia of the corpus callosum
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
No other phenotypes are associated with mutations of L1CAM.
Affected males. In L1 syndrome, the major features are hydrocephalus, mental retardation, spasticity of the legs, and adducted thumbs. Hydrocephalus may be present prenatally and result in stillbirth or death in early infancy. Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs. Seizures may occur. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay. Mild-to-moderate ventricular enlargement is compatible with long survival.
In HSAS, mental retardation is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus. In MASA syndrome, mental retardation ranges from mild (IQ of 50-70) to moderate (IQ of 30-50). The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe mental retardation and a normal head circumference have been reported.
Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life. In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group. Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait.
All phenotypes can be observed in affected individuals in the same family.
Other findings of unknown significance in individuals with L1CAM mutations and L1 syndrome
Seven individuals with an L1CAM mutation and a combination of L1 syndrome and Hirschsprung disease (HSCR) have been reported [Okamoto et al 1997, Vits et al 1998, Parisi et al 2002, Okamoto et al 2004, Basel-Vanagaite et al 2006]. HSCR is characterized by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. It has been suggested that failure of migration of the neural crest cells underlies aganglionosis. Parisi et al (2002) hypothesized that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause aganglionosis. An L1CAM mutation alone does not cause HSCR.
Another report presents an association between X-linked hydrocephalus and a specific form of congenital idiopathic intestinal pseudo-obstruction (CIIP) in an infant [Bott et al 2004] in whom an L1CAM mutation had been detected.
Carrier females. Females may manifest minor features such as adducted thumbs and/or subnormal intelligence. Rarely do females manifest the complete L1 syndrome phenotype.
In their review, Weller & Gärtner (2001) noted that missense mutations in extracellular domains or mutations in cytoplasmic regions cause milder phenotypes than those resulting from truncation in extracellular domains or to nondetectable L1 protein.
Missense mutations 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 [Bateman et al 1996].
The above generalizations about genotype-phenotype correlations notwithstanding, clinical findings in L1 can range from mild to severe even in the same family, indicating that other factors must influence the clinical presentation [Finckh et al 2000].
The acronym 'CRASH syndrome' was first used in 1995 [Fransen et al 1995]. This acronym was not causally focused and had the potential to be offensive [Schrander-Stumpel 1998]; thus, L1 syndrome is the preferred name.
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS or hydrocephalus with stenosis of the aqueduct of Sylvius) is the most common genetic form of congenital hydrocephalus, with a prevalence of approximately one in 30,000.
This accounts for approximately 5%-10% of males with nonsyndromic congenital hydrocephalus [Schrander-Stumpel & Fryns 1998, Finckh et al 2000].
In males with complicated spastic paraplegia, the prevalence of L1 syndrome is unknown.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The differential diagnosis of males with developmental delay or mental retardation and early hypotonia evolving into spastic paraplegia during childhood, with or without adducted thumbs, includes many conditions.
In newborns with hydrocephalus, other causes of hydrocephalus should be excluded [Schrander-Stumpel & Fryns 1998]. Hydrocephalus is often divided into nonsyndromic forms and syndromic forms:
Nonsyndromic congenital hydrocephalus
As part of a neural tube defect
Isolated hydrocephalus
Congenital aqueductal stenosis
X-linked hydrocephalus (L1 spectrum)
Autosomal recessive hydrocephalus
As part of a CNS malformation
Arnold-Chiari malformation
Dandy-Walker malformation
Hydranencephaly
Vein of Galen malformation
Midline hyperplasia with malformation of the fornical system
Congenital cyst
Other midline abnormalities
Congenital communicating hydrocephalus secondary to hemorrhage
Syndromic congenital hydrocephalus
Cytogenetic abnormalities
Trisomy 13
Trisomy 18
Trisomy 9 and 9p (mosaic)
Triploidy
Others
Mendelian (single gene) conditions
Walker-Warburg syndrome (see Congenital Muscular Dystrophy Overview)
Hydrolethalus syndrome
Meckel-Gruber syndrome
Mucopolysaccharidosis type II (Hunter syndrome)
Fanconi anemia syndrome (VACTERL with hydrocephalus)
Crouzon syndrome
Apert syndrome
Associations and disruptions
Oculoauricoluvertebral spectrum
Hydranencephaly
Porencephaly
VACTERL association
PLP1-related disorders (including SPG2). The PLP1-related disorders of central nervous system myelin formation caused by mutations in the PLP1 gene include the spectrum of phenotypes ranging from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. SPG2 can be "complicated" or "uncomplicated (pure)" spastic paraparesis. Complicated SPG2 often includes autonomic dysfunction (such as spastic urinary bladder), ataxia, and nystagmus; pure SPG2 does not have other significant CNS signs; however, autonomic dysfunction, such as spastic urinary bladder, may also occur. A wide range of phenotypes can be observed in members of the same family. Clinical diagnosis depends on the typical neurologic findings, X-linked recessive inheritance pattern, and, usually, diffusely abnormal myelin on MRI.
Because of clinical overlap between the SPG1 phenotype of L1 syndrome and the SPG2 phenotype of the PLP1-related disorders, it may be difficult to make the diagnosis of the L1 syndrome on clinical grounds alone especially when hydrocephalus is absent in affected males.
See also Hereditary Spastic Paraplegia Overview.
Head imaging study
Complete neurologic evaluation
Developmental evaluation
Optimal management involves a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics.
Hydrocephalus. Surgical treatment should be performed as needed. Shunting of the cerebrospinal fluid (CSF) is indicated to reduce intracranial pressure. Of note, prenatal shunting procedures offer no advantage [Pinckert & Golbus 1988].
Mental retardation. Developmental progress should be monitored and stimulated. Developmental outcome is variable and individual counseling important.
Adducted thumbs. Surgical intervention is not indicated. In some milder cases, tendon transfer may improve thumb function. A splint helps reduce the degree of adduction is some cases.
Spastic paraplegia. Neurologic features should be monitored. Follow-up and treatment is nonspecific; general guidelines can be followed.
Carrier testing of at-risk female relatives is available on a clinical basis if the mutation has been identified in a male relative.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
L1 syndrome is inherited in an X-linked manner.
Parents of a proband
The father of an affected male will not have the disease, nor will he be a carrier of the mutation.
In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
If a woman has more than one affected son and the disease-causing mutation cannot be detected in DNA extracted from her leukocytes, she has germline mosaicism.
When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:
He has a de novo disease-causing mutation in the L1CAM gene and his mother is not a carrier. Although uncommon, de novo disease-causing mutations have been reported [Jouet & Kenwrick 1995; author, personal observations].
His mother has a de novo disease-causing mutation in the L1CAM gene, either a) as a 'germline mutation' (i.e., present at the time of her conception and therefore in every cell of her body); or b) as 'germline mosaicism' (i.e., present in some of her germ cells only).
His mother has a disease-causing mutation that she inherited from a maternal female ancestor.
Sibs of a proband
The risk to sibs depends upon the carrier status of the mother.
If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%.
Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers.
If the proband's disease-causing mutation has not been identified in DNA extracted from the mother's leukocytes, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
Offspring of a proband. No males with L1 syndrome are known to have reproduced.
Other family members. Depending on the pedigree, related females may be at risk, e.g., the proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending upon their gender, may be at risk of being carriers or of being affected.
Carrier testing of at-risk female relatives is available on a clinical basis if the mutation has been identified in the proband.
Fewer than 5% of females who are carriers of an L1CAM mutation manifest clinical features. The features are usually minor symptoms of the clinical spectrum; however, severe hydrocephalus has been reported in a female carrier [Kaepernick et al 1994].
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Molecular genetic testing. Prenatal testing is possible for pregnancies of women who are carriers if the L1CAM disease-causing mutation has been identified in a family member. The usual procedure is to determine the fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15-18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation. While it is not possible to accurately predict the clinical course and phenotype in a male with an L1CAM mutation identified prenatally, a severe phenotype is generally expected. If the karyotype is 46,XX and the fetus is a carrier of an L1CAM mutation or the carrier status is unknown, serial ultrasound examination is offered at 20 weeks and 32 weeks to monitor for hydrocephalus.
Ultrasound examination. L1 syndrome cannot be reliably diagnosed on the basis of prenatal ultrasound only. A diagnosis of hydrocephalus often requires serial ultrasound examination and cannot be guaranteed before 20-24 weeks' gestation or even the third trimester of pregnancy. Furthermore, apparently normal ultrasound findings in a pregnancy with a priori increased risk are not reliable in ruling out L1 syndrome in the fetus.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) has been reported [Gigarel et al 2004; Sermon et al 2004] and may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
---|---|---|
L1CAM | Xq28 | Neural cell adhesion molecule L1 |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
303350 | MASA SYNDROME |
307000 | HYDROCEPHALUS DUE TO CONGENITAL STENOSIS OF AQUEDUCT OF SYLVIUS; HSAS |
308840 | L1 CELL ADHESION MOLECULE; L1CAM |
Gene Symbol | Locus Specific | Entrez Gene | HGMD |
---|---|---|---|
L1CAM | L1CAM | 3897 (MIM No. 308840) | L1CAM |
For a description of the genomic databases listed, click here.
Normal allelic variants: The L1CAM gene consists of 29 exons of which 28 include coding regions [Kallunki et al 1997]. The non-coding exon (exon 1A) of 125 bp is about 10 kb upstream of exon 1, the first coding exon. The mRNA has been shown to be alternatively spliced. The neuronal form of L1CAM contains exon 2 and exon 27, while they are excluded from the non-neuronal mRNA. Missense mutations that are non-pathogenic polymorphisms and mutations of unknown pathogenic relevance have also been reported [Finckh et al 2000, Weller & Gärtner 2001].
Pathologic allelic variants: The majority of L1CAM mutations appear to be private mutations and are scattered throughout the gene. All types of disease-causing mutations are found: nonsense, frameshift, splice site, and missense mutations. The nonsense and frameshift mutations lead to truncation of the L1 protein.
To date, 181 different mutations in more than 200 families with L1 syndrome have been reported [dnalab-www.uia.ac.be/dnalab/l1, Van Camp et al 1996, Weller & Gärtner 2001, Hubner et al 2004].
Normal gene product: The mature protein consists of 1256 amino acids with a molecular weight of 200 kd (including carbohydrates). The L1 cell adhesion molecule (L1CAM) is a cell surface (transmembrane) glycoprotein. It belongs to the large class of immunoglobulin superfamily proteins with an extracellular part consisting of six immunoglobulin-like (Ig-like) domains and five fibronectin type III-like (FNIII) domains, a single-pass transmembrane domain, and a short cytoplasmic domain [Weller & Gartner 2001].
L1 is expressed on neurons, both in the central nervous system and the peripheral nervous system. On differentiated neurons, L1 is found at regions of contact between neighboring axons and on the growth cones. The L1 protein mediates cell-cell adhesion through homophilic and heterophilic interactions with other L1 protein molecules and with various ligands. L1 ligand binding is linked to intracellular signaling pathways and the L1 protein is involved in modification of cytoskeleton interactions [Kenwrick et al 2000].
Abnormal gene product: Truncated proteins caused by a nonsense mutation in the extracellular part of the protein lack the transmembrane domain and thus contact between neurons is impaired. The truncated proteins are either secreted into the extracellular space or degraded quickly [Kamiguchi & Lemmon 1997, Brümmendorf et al 1998].
Truncating or missense mutations in the cytoplasmic domain act upon a highly conserved domain that contains binding and phosphorylation sites. Abnormal proteins caused by missense mutations in the extracellular domain may lose function by altered folding or trafficking or by altered ligand binding [Kenwrick et al 2000, De Angelis et al 2002, Rünker et al 2003].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
Hydrocephalus Association
870 Market Street Suite 705
San Francisco CA 94102
Phone: 888-598-3789; 415-732-7040
Email: info@hydoassoc.org
http://www.hydroassoc.org/
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Connie Schrander-Stumpel is a professor of clinical genetics in Maastricht, The Netherlands. She is head of the department of clinical genetics and head of the training program for clinical geneticists in Maastricht. She wrote her thesis on the X-linked type of hydrocephalus and is especially interested in dysmorphology, X-linked mental retardation, and preconception care.
Yvonne J Vos is a clinical molecular geneticist and head of the department of DNA diagnostics at the University Medical Center Groningen, The Netherlands.
20 October 2006 (me) Comprehensive update posted to live Web site
28 April 2004 (me) Review posted to live Web site
14 October 2003 (css) Original submission