Alpha Thalassemia X-Linked Intellectual Disability Syndrome - An Overview

Introduction:

Alpha thalassemia X-linked intellectual disability syndrome is a rare genetic disorder that mostly affects males. Though the genetic condition is present in females, the clinical presentation is not so discrete in females. Almost every organ system in the human body is affected due to this syndrome, and treatment is necessary with the help of early diagnosis. Initial diagnosis can be made by evaluating the clinical symptoms, and it can be confirmed with the help of a genetic test which can also predict the risk of disease in the entire family. This article elaborates on various causes, diagnoses, and treatments of this condition.

What Is Alpha Thalassemia X-Linked Intellectual Disability Syndrome?

Alpha thalassemia X-linked intellectual disability syndrome (ATR-X) is a genetic disorder affecting various body organ systems. Due to the varied clinical findings, it becomes difficult to diagnose the disease. It can be characterized by decreased or disordered intellectual ability, distinct facial features, genitourinary tract abnormalities, and alpha thalassemia (defective production of hemoglobin) can be noticed in almost every patient. It is an X- linked, recessively inherited genetic disorder.

What Are the Causes of Alpha Thalassemia X-Linked Intellectual Disability Syndrome?

• An abnormal gene present on the X chromosome, which manifests in males inherited as a recessive X-linked genetic condition, causes this syndrome. Clinical presentation is seen in males. Females with an abnormality on the X chromosome serve as carriers.

• Changes or disruptions in the gene ATRX which is present on the X chromosome, lead to this syndrome.

• Marked skewing of the X chromosome is a process that makes females carriers and does not present as any clinical findings.

Who Are the Most Affected Populations of Atrx Syndrome?

Males are the most affected part of the population. Upon conducting molecular genetic testing, more than 200 cases. Most of the time, this syndrome goes undiagnosed or underdiagnosed, which makes reporting the statistics difficult. Mutated genes can be present in females, which act as carriers and do not show any clinical presentations.

What Are the Clinical Findings Associated With Alpha Thalassemia X-Linked Intellectual Disability Syndrome?

The symptoms' appearance and severity differ from person to person. These are mostly seen during the infancy phase.

• Craniofacial Findings: Decreased head circumference, increased space between eyes, thick lower lip, and short triangular nose. Disordered anatomy of the ear, increased spaces in the teeth, along with continuous protrusion of the tongue. Oral findings can appear after a few years of birth.

• Impairment of Growth: Short stature.

• Genital Anomalies: Undescended testes, abnormal genitalia, urinary opening placement unusually, and underdevelopment of the scrotum.

• Delayed Development: Disabled intellectual ability.

• Skeletal System Anomalies: Short fingers (brachydactyly), fixed fingers in a bent position (clinodactyly), and abnormal curvature of the spine (kyphoscoliosis).

What Are the Other Disorders Associated With Alpha Thalassemia X-Linked Intellectual Disability Syndrome?

Coffin-Lowry Syndrome: RPS6KA3 gene mutations occur as an X-linked dominantly inherited genetic condition that leads to Coffin-Lowry syndrome. This syndrome presents with intellectual disability, craniofacial (head and face) abnormalities, abnormalities of fingers, and other skeletal malformations such as upper jawbone under development can occur.

Smith-Fineman-Myers Syndrome: It is an inherited X-linked recessive inherited genetic disorder. It is a rare genetic condition that leads to intellectual disability, decreased muscle tone, distinct features of the face, micrognathia (small jaw), cryptorchidism (testes failure to descend into the scrotum), along with delayed milestones development.

Alpha Thalassemia: Also called intellectual disability of chromosome 16 is a rare condition that occurs due to mutations (deletion of genes on chromosome 16) that presents more severely than ATRX syndrome.

What Are the Diagnostic Methods Associated With Alpha Thalassemia X-Linked Intellectual Disability Syndrome?

• Clinical Findings: This syndrome can be detected at the time of birth or after birth based on clinical examination and identification of certain characteristics such as abnormal facial features, disturbance in the genitourinary tract, etc.

• Laboratory Findings: It includes blood tests demonstrating hemoglobin h inclusion bodies in RBCs (red blood cells) to help in diagnosing the condition. It should be noted that it is a variable finding, and the absence of this finding does not eliminate ATRX syndrome.

• Red Blood Cell Indices: Hypochromic anemia in an individual with alpha thalassemia can be seen. Upon screening in newborns for hemoglobinopathies( inherited diseases of the blood), detection of Hgh has been identified, which helps in the diagnosis of ATRX syndrome.

• Molecular Genetic Testing: It is a diagnostic method that confirms the presence of mutation of the ATRX gene. Alterations in the pathogenesis and mutations can be identified with the help of a specific DNA (deoxyribonucleic acid) methylation profile. Molecular genetic testing includes targeted gene testing and comprehensive genomic testing.

• Single Gene Testing: It is a part of targeted gene testing which requires the clinician to determine which gene is involved in causing the disease.

• Multi-Panel Gene Testing: This helps in identifying the cause of the condition and also identifying similar variants in the gene which can be the cause of the genetic condition.

• Comprehensive Genomic Testing: The exact location of the mutation on the gene is identified by genome sequencing (a process in which the entire gene is studied), which is done in comprehensive genomic testing that does not require a clinician.

What Is the Treatment for Alpha Thalassemia X-Linked Intellectual Disability Syndrome?

After the initial diagnosis following evaluations is made:

• Growth Evaluation: Evaluation that checks height, weight, and circumference of the head in infants and children.

• Evaluation of Development: Assessing the development of speech, intellectual, education, and developmental milestones.

• Neurologic Evaluation: This helps in assessing muscle tone.

• Gastrointestinal Evaluation: Evaluation of the nutritional status, constipation, difficulty in swallowing, or vomiting.

• Genital Abnormalities: A physical examination of the genital regions to evaluate the condition.

• Musculoskeletal Evaluation: Mobility of the limbs, the spine's position, and motor skills are evaluated.

Treatment is mainly based on symptoms or clinical presentations in the individual.

• Seizures are treated by consulting a neurologist and taking anti seizures medication.

• Gastrointestinal abnormalities are treated by maintaining proper methods of feeding and other methods and medication as advised by a gastroenterologist.

• Drooling can be treated with the help of Botulinum toxin and anticholinergic.

• Abnormalities associated with genital regions are to be treated under the consultation of a urologist.

• Orthopedics and rehabilitation, along with the use of certain medical equipment and devices, can help in relieving and treating musculoskeletal abnormalities.

• Alternative ways of communication are evaluated, and speech therapy can be initiated for those having communication issues.

• Proper surveillance of an individual during the treatment and recovery, along with genetic counseling, is necessary for the proper outcome of the treatment.

Conclusion:

ATR-X syndrome can occur rarely, and genetically acquired characteristics or disorders are undeniable. Though this condition does not lead to a fatal situation, delay or missing the clinical features can worsen the situation that hampers the individual's life. This syndrome presents with symptoms that affect every system in the human body. Symptomatic treatment is given according to the clinical condition described in the article. Consulting and obtaining a proper treatment plan from experienced healthcare professionals helps increase the efficiency of the treatment outcome.