non-syndromic X-linked intellectual disability ARX-related

Non-syndromic X-linked intellectual disability (NS-XLMR) ARX-related is a condition characterized by moderate to profound intellectual disability with variable additional features [2]. It is caused by a hemizygous mutation in the ARX gene located on chromosome Xp21.3 [2].

The symptoms of NS-XLMR ARX-related can vary, but they often include:

• Moderate to profound intellectual disability
• Variable additional features such as seizures, epilepsy, and other neurological problems

It's worth noting that males are more heavily affected by this condition than females, who tend to have milder symptoms [13]. The genetics of NS-XLMR ARX-related involve a mutation in the ARX gene on the X chromosome, which is inherited in an X-linked recessive pattern.

According to the Disease Ontology Definition, NS-XLMR ARX-related is characterized by moderate to profound intellectual disability with variable additional features [9].

The Atlas of X-Linked Intellectual Disability Syndromes also provides information on this condition, describing it as a comprehensive summary of clinically distinctive disorders caused by genes on the X chromosome, including ARX-associated XLID [12].

Intellectual Disability without Other Neurological Problems

Non-syndromic X-linked intellectual disability (NS-XLMR) ARX-related is a condition characterized by intellectual disability without other neurological problems. The symptoms and phenotypes associated with this condition are:

• Intellectual Disability: The primary symptom of NS-XLMR ARX-related is intellectual deficiency, which can range from mild to severe.
• No Other Neurological Problems: Unlike syndromic forms of X-linked mental retardation, NS-XLMR ARX-related does not present with associated physical, behavioral, or neurological signs and symptoms.

Other Possible Features

While the primary symptom of NS-XLMR ARX-related is intellectual disability, some individuals may also experience:

• Abnormal Head or Neck: Some individuals may have abnormal head or neck features.
• Drooling: Drooling can be a feature in some cases.
• Abnormal Limbs: Abnormal limb features, such as pes planus (flat feet), may be present.
• Genitourinary System Abnormalities: Testicular dysgenesis and other genitourinary system abnormalities have been reported.

Prevalence and Genetic Information

The prevalence of NS-XLMR ARX-related is estimated to be around 1-2% in selected research samples. The Aristaless-related homeobox (ARX) gene, located on the X chromosome, encodes a transcription factor essential for brain development. Mutations in this gene have been associated with both syndromic and non-syndromic forms of X-linked mental retardation.

References

• [4] Some ARX gene mutations result in intellectual disability without other neurological problems.
• [9] Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic intellectual disability presents with associated physical, behavioral, or neurological signs and symptoms.
• [11] Symptoms & Phenotypes for Non-Syndromic X-Linked Intellectual Disability Arx-Related.
• [12] The prevalence of Fragile X syndrome in affected sib pairs and X linked families is approximately 12/45 (27%), although this figure predates molecular genetic analysis and is likely to be an overestimate.

Non-syndromic X-linked intellectual disability (XLID) related to the ARX gene can be challenging to diagnose, but several diagnostic tests are available to help identify this condition.

Genetic Testing

According to search result [5], genetic testing can help diagnose the specific type of intellectual disability present and guide treatment. Early intervention can significantly benefit individuals with XLID.

A clinical genetic test offered by Greenwood Genetic Center Diagnostic Laboratories (search result [5]) includes conditions such as non-syndromic X-linked intellectual disability, which is related to the ARX gene.

Multiplex-PCR Test

A molecular test based on multiplex-PCR has been developed to focus on mutational hotspots of FMR1, AFF2, and ARX genes (search result [15]). This test has been validated in a male cohort and may be useful for diagnosing non-syndromic X-linked intellectual disability related to the ARX gene.

Next Generation Sequencing (NGS)

A panel of 114 genes is intended for patients with a diagnosis or clinical suspicion of X-Linked Intellectual Disability (XLID), including those related to the ARX gene (search result [11]). This panel is performed by Next Generation Sequencing (NGS).

Clinical Genetic Test

Another clinical genetic test offered by Greenwood Genetic Center Diagnostic Laboratories includes conditions such as non-syndromic X-linked intellectual disability, which is related to the ARX gene (search result [5]).

References:

[5] Greenwood Genetic Center Diagnostic Laboratories [11] Next Generation Sequencing (NGS) panel for XLID [15] Multiplex-PCR test for FMR1, AFF2, and ARX genes

Treatment Options for Non-Syndromic X-Linked Intellectual Disability ARX-Related

Non-syndromic X-linked intellectual disability (XLID) ARX-related is a condition characterized by moderate to profound intellectual disability. While there is no cure for this condition, treatment options are available to manage specific symptoms and improve quality of life.

• Early 17β-estradiol treatment: Research has shown that early administration of 17β-estradiol can reduce seizures in mice with expanded polyalanine tracts in the ARX gene [15]. However, it is essential to note that this treatment option is still experimental and not widely available.
• Managing symptoms: Treatment for non-syndromic XLID ARX-related focuses on managing specific symptoms such as seizures, abnormal behavior, and intellectual disability. A multidisciplinary approach involving healthcare professionals from various specialties (e.g., neurology, psychology, occupational therapy) is often necessary to develop a comprehensive treatment plan [14].
• No cure: Unfortunately, there is no cure for non-syndromic XLID ARX-related disorders. Treatment options are aimed at managing symptoms and improving quality of life.

References:

[8] Intellectual developmental disorder-29 (XLID29) is a nonspecific form of XLID. It is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (DEE1; 308350) to Partington syndrome (309510).

[14] by P Chaste · 2007 · Cited by 33 — In this study, we screened the ARX gene in 226 male patients with autism spectrum disorders and mental retardation; 42 of the patients had epilepsy.

[15] by MR Jackson · 2017 · Cited by 10 — Early 17β-estradiol treatment reduces seizures but not abnormal behaviour in mice with expanded polyalanine tracts in the Aristaless related homeobox gene (ARX).

Differential Diagnosis of Non-Syndromic X-Linked Intellectual Disability (NS-XLID) ARX-Related

Non-syndromic X-linked intellectual disability (NS-XLID) is a condition characterized by intellectual disability in males, without any additional clinical symptoms or physical anomalies. The ARX gene has been identified as one of the genes responsible for NS-XLID.

Differential Diagnosis:

When considering differential diagnosis for NS-XLID ARX-related, the following conditions should be taken into account:

• Fragile X syndrome: This is the most common cause of inherited intellectual disability, accounting for approximately 27% of cases. However, it is not related to the ARX gene.
• Other X-linked intellectual disabilities: There are over 40 genes known to cause NS-XLID, and ~80% of these reside on the X-chromosome. Other genes that may be considered in differential diagnosis include FMR1, MECP2, and SHANK3.
• Syndromic X-linked intellectual disability: This refers to conditions where intellectual disability is accompanied by additional clinical symptoms or physical anomalies. Examples include ATRX-related disorders, which can present with a range of overlapping neurological conditions.

Key Features:

When differentiating NS-XLID ARX-related from other conditions, the following key features should be considered:

• Intellectual disability: This is the primary feature of NS-XLID.
• Male-only inheritance: Since the ARX gene is located on the X-chromosome, this condition only affects males.
• Absence of additional clinical symptoms or physical anomalies: Unlike syndromic conditions, NS-XLID does not present with any additional clinical symptoms or physical anomalies.

References:

• [12] Non-syndromic X-linked intellectual disability (or mental retardation; NS-XLMR) The X-chromosome has historically been the most thoroughly studied chromosome with regard to NS-ID due to the high male to female ratio.
• [13] The Atlas of X-Linked Intellectual Disability Syndromes is a comprehensive summary of the clinically distinctive disorders caused by genes on the X chromosome.
• [14] Integrated disease information for Non-Syndromic X-Linked Intellectual Disability including associated genes, mutations, phenotypes, pathways, drugs, and more - integrated from 75 data sources.