What Is Adult Metachromatic Leukodystrophy (AMLD)?
It is a neurodegenerative genetic condition that destroys the protective layer around the nerves in the central and peripheral nervous systems. Symptoms include loss of intellectual and motor function. It is generally caused due to mutations in the ARSA gene and occasionally in the PSAP gene. These mutations should be present in both parents for the child to have them. Although it is present at birth, the symptoms can start at any age. The condition is called metachromatic because the accumulated fats (sulfatides), when observed under the microscope, will appear in a different color than the regular cellular material (which shows the usual metachromatism).
What Causes AMLD?
AMLD is caused due to mutations in the genes ARSA and PSAP (rarely). A mutation is a change in the genetic structure; it can happen due to a myriad of reasons like exposure to ionizing radiation, lifestyle changes, mistakes during cell division, etc.
AMLD is an autosomal recessive disorder. The human body has two types of chromosomes-
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Autosomes - These are responsible for carrying the entire genetic information except for determining the sex. The genes ARSA and PSAP are both autosomal.
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Allosomes - These carry the information which will determine the sex of the individual.
For every trait that is passed on to the next generation, there are two versions- dominant and recessive. If the individual has both the dominant and the recessive variants, the dominant variety of the gene will express its traits, and the traits of the recessive gene will be masked. The recessive variant will only express its traits in the total absence of the dominant traits. AMLD is a recessive trait.
It means the individual affected with AMLD has two copies of recessive genes. This is possible only when both the parents of the individual are carriers of the recessive trait, meaning each parent has one mutated copy and one normal copy of the genes (ARSA). When these two carrier parents have children, the risk of the child inheriting the mutated genes is 25%; the other 75 % will result in a carrier child (50 %) or the one with both normal genes (25 %).
What Happens in AMLD?
Individuals with mutated ARSA genes will have excessive amounts of fats stored in their body which leads to dysfunction in normal brain activities. The fats that we consume need to be broken down for further use; this is done by enzymes. Different enzymes metabolize different types of fats, the fats which contain sulfates are metabolized by an enzyme called arylsulfatase A. This enzyme is not produced in sufficient quantities in AMLD. As a result, the sulfate-containing fats do not get metabolized, and they start accumulating in the brain, kidneys, testes, etc. In the brain, these fats will destroy the myelin sheath, which will cause neuro physical and neuropsychological problems.
The myelin sheath is a protective layer that is wrapped around the neuron (the fundamental unit of the nervous system); it insulates the nerves from external shocks and allows the transmission of electrical impulses from one neuron to the other. If the myelin sheath is destroyed, the nerve impulses will not be transmitted, and the body will shut down eventually.
What Are the Signs and Symptoms of AMLD?
The symptoms depend on the extent of the conditions; they are-
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Dysesthesias- It means abnormal sensations like burning, pricking, or aching without any underlying cause.
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Psychosis - The term psychosis translates to an impaired relationship with reality.
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Schizophrenia - A mental abnormality where people interpret reality abnormally; this will result in hallucinations, delusions, disordered thinking, etc.
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Dementia - Dementia is a term used to describe the group of symptoms that affect memory, thinking, and social ability.
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Disinhibition - Patients with AMLD lack restraint which is not under their control.
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Impulsiveness - This is a symptom only if the patient affected is not normally an impulsive person.
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Loss of Motor Function - These include speech, walking, grasping, etc.
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Optic Atrophy - This is an end-stage symptom that will ultimately lead to blindness.
How Is AMLD Diagnosed?
After physical examination, the clinician will obtain family history, which plays a crucial role in the initial diagnosis because the symptoms of AMLD are non-specific and mimic bipolar disorder. Detailed family history helps the clinician out rule other conditions.
After the family history, the clinician will request the following investigation-
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Laboratory Tests - These include urine tests (to check for sulfatide levels), radiolabeled sulfatide fibroblast loading, and DNA mutation analysis.The sulfatide levels will help to distinguish AMLD from arylsulfatase A pseudo deficiency that has the same symptoms as AMLD but the normal concentration of urine sulfatide.
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Imaging Tests - A brain MRI (magnetic resonance imaging) is done to examine the characteristic striped pattern (tigroid) that occurs in the white matter of the brain in patients with AMLD.
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Additional Tests- These include nerve conduction tests and neurocognitive and neuropsychological testing.
What Is the Treatment for AMLD?
This includes the standard symptomatic treatment and investigational treatment.
Symptomatic Treatment - Managing the symptoms is the main focus of this treatment; it is done by various methods, some of which are-
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Seizures - Are managed with antiepileptics like Levetiracetam, Lacosamide, etc.
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Spasticity - It can be reduced with Botox toxin A, Cyclobenzaprine, etc.
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Dystonia - It is managed with Botox toxin A.
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Dysautonomia - Anticholinergic therapy is effective in controlling the excessive drooling and orthostasis seen in dysautonomia.
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Pain - The usual NSAIDs and the serotonin-norepinephrine reuptake inhibitors, which are successful in reducing pain in other conditions, are also effective for pain caused by AMLD.
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Nutrition - Feeding tube and bowel regimen with docusate sodium with senna extracts will provide the necessary nutrition and aid in elimination, respectively.
Investigational or Experimental or Emerging Treatment - These include gene therapy- where the defective gene is replaced with a normal gene, and hematopoietic stem cell therapy (HSTC) - which involves transplantation of stem cells from a healthy individual called the donor. These are effective in patients in whom the neurodegenerative symptoms have not yet started. The effectiveness and the long-term safety of these treatments are yet to be determined.
Conclusion:
AMLD is a progressive autosomal recessive disorder that is passed through generations. It is imperative that the clinician opts for a multidisciplinary approach while managing a patient with AMLD. This will help in the diagnosis, evaluation options, and treatment plan. The family members of the patient should also be part of the team to manage the emotional emergencies of the patient. Long-term follow-up with the medical team will prevent complications to a certain extent and provide the needed support.
