Neonatal Adrenoleukodystrophy: Types, Causes, Symptoms, and Diagnosis

Introduction:

Neonatal adrenoleukodystrophy is a rare progressive genetic disorder of autosomal recessive inheritance that is a genetic condition passed from parents to the child. It is a part of the Zellweger spectrum. Neonatal adrenoleukodystrophy causes damage to the myelin sheath in the brain. Myelin sheath is a membrane that insulates nerve cells in the brain. It affects the brain and adrenal gland as the body cannot break very long chain fatty acids (VLCFAs), which results in the saturation of VLCFAs. The condition is present from birth. Affecting males more than females. Approximately affecting one in 15000 newborns. Cases are observed all over the world.

What Is the Genetics of Neonatal Adrenoleukodystrophy?

Neonatal adrenoleukodystrophy is an X-linked genetic disorder that means women are the carrier. The ABCD1 gene is located on the X chromosome. Males have one X and one Y chromosome. Females have two X chromosomes. Hence, if the offspring is a boy, he will experience the symptom of neonatal adrenoleukodystrophy as there is no other X chromosome for protection. If the offspring is a girl, she will experience fewer symptoms than a male, as females carry two X chromosomes. The presence of cells that express a healthy copy of the ABCD1 gene will protect females from developing cerebral adrenoleukodystrophy.

What Are the Types of Adrenoleukodystrophy (ALD)?

• Childhood Onset ALD: Onset is at four to ten years of age. It damages the white matter of the brain. Symptoms progress rapidly and worsen over time. If an early diagnosis is not made, it may lead to death within five to ten years.

• Addison's Disease: Adrenal gland does not produce the hormone, resulting in adrenal insufficiency. Adrenal insufficiency may cause X-linked ALD, also known as Addison's disease.

• Adrenomyeloneuropathy: Adrenomyeloneuropathy is an adult-onset of X-linked ALD, less severe and mild. Symptoms such as stiff gait and improper bladder and bowel functioning are seen.

What Are the Causes of Neonatal Adrenoleukodystrophy?

Symptoms may appear from birth till childhood. Mutation in genes causes neonatal adrenoleukodystrophy. Adrenoleukodystrophy is caused by pathological variation in the ABCD1 gene, which produces the adrenoleukodystrophy protein. The following genes can show mutation PEX2 (paroxysmal biogenesis factor 2), PEX1, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, PEX26, PEX3, PEX5, PEX6, PEX11B. Also, neonatal adrenoleukodystrophy is hereditary. It is passed from parents to offspring.

What Are the Signs and Symptoms of Neonatal Adrenoleukodystrophy?

• Unusual body movement is characterized by loss of coordination and speed.

• Adrenal insufficiency (decreased production of adrenal hormone).

• The palate (roof of the mouth) is abnormal.

• The forehead is high and has an abnormal shape of the skull.

• Low muscle tone.

• The anterior fontanelle is wide.

• Eye problems like optic nerve degeneration lead to vision loss, eyelid ptosis, misalignment of eyes known as strabismus, cataract (opacity or haziness in eyes), rhythmic eye movement is often involuntary, and retinal pigmentation is not normal.

• Macrocephaly (enlarged brain).

• Single transverse palmar crease (it is a single line that runs across the palm).

• Abnormal neuronal migration (a process in which neurons travel from origin to final position).

• Increased width and breadth of the nasal bridge.

• Hyperactive muscles.

• Height is shortened.

• Delayed achievements of milestones.

• Ears are low set.

• Abnormal ear functioning resulting in hearing loss.

• Increased frequency of seizures.

• Paralysis.

• Anteriorly faced nostrils.

• Associated liver disease or abnormality in the liver.

• Behavior changes.

• Low performance in school.

Do Women With Adrenoleukodystrophy Experience Symptoms?

Yes, women will also experience the signs and symptoms. But there is a delayed onset as compared to males. General onset in females is around 40 to 50 years of age. It can be misdiagnosed as multiple sclerosis. Symptoms are generally milder as compared to males.

How to Diagnose Neonatal Adrenoleukodystrophy?

Early diagnosis is essential because if the disease progresses, the damage done cannot be reversed.

• Detailed Family History: Most of the time, women are carriers and do not recognize them. They pass on the disease to their sons, and the symptoms are misdiagnosed.

• Blood Test: Includes blood test to determine the defect in genes by elevated levels of certain proteins.

• Genetic Testing: Genetic testing can identify defective genes. The defective gene is mostly the ABCD1 gene or PEX gene.

• Newborn Screening: It is also useful in detecting defective genes and identifying the cause.

• Other Tests: Other diagnostic tests include MRI (magnetic resonance imaging) to detect any damage to the brain and a specific blood test to measure the concentration of very long chain fatty acids, which are increased or elevated in boys.

What Are the Treatment Options for Neonatal Adrenoleukodystrophy?

• Stem Cell Transplant or Bone Marrow Transplant: The only effective treatment for neonatal adrenoleukodystrophy is stem cell transplant from a genetically matched donor. It can arrest the progression of cerebral demyelination, provided it is done in the early stages.

• Gene Therapy: Gene therapy may be beneficial for children who do not have any symptoms other than cerebral neonatal adrenoleukodystrophy. Newborn screens can help with defective genes, thus creating a small window to minimize neonatal adrenoleukodystrophy.

• Adrenal Steroid Replacement Therapy: Males with neonatal adrenoleukodystrophy will develop adrenal insufficiency in later life, and this therapy can be life-saving.

• Dietary Restrictions: Though it is of some use, dietary restrictions alone do not affect plasma VLCFA.

• Medications: Lorenzo's oil, docosahexaenoic acid (DHA), and Lovastatin can be used to treat by decreasing the blood plasma VLCFA.

• Multi-Specialist Treatment: The treatment plan involves many doctors, like ophthalmologists, cardiologists, kidney specialists, nutritionists, and dieticians. Follow the treatment plan provided by the doctor.

• Coping Up: It can be extremely difficult to get a diagnosis of this rare disease and very overwhelming for parents and children to live with it. Children and their families must learn to live with the disease as normal.

What Is the Role of Parents?

Getting a diagnosis of neonatal adrenoleukodystrophy can be extremely difficult for parents. But it is necessary to remember that early diagnosis can help minimize some symptoms. All prenatal and postnatal tests should be performed without fail. Caring for a child with neonatal adrenoleukodystrophy is never easy. Parents must take help from various support groups. Very limited treatment options are available, and participating in research programs might help increase the treatment options.

Conclusion:

Newborn screening is the key to saving a life in neonatal adrenoleukodystrophy. Early diagnosis and intervention can improve the quality of life. Care and support from parents and the medical team will facilitate positivity in children.