Acatalasemia - A Journey to Discovering Rare Diseases

Introduction

Acatalesemia, also known as acatalasia or Takahara's disease, is a rare autosomal recessive hereditary disorder that is caused due to mutations in the gene responsible for the formation of the enzyme: catalase. Catalase is responsible for the decomposition of hydrogen peroxide into water and oxygen. This lack of catalase results in an abnormal accumulation of hydrogen peroxide in the tissues.

Who Is Susceptible to Acatalesemia?

Worldwide, more than 100 cases have been reported especially in Japan, Hungary, and Sweden with a prevalence of one in every 12500, 20000, and 25000 of their respective population. It is also seen among the Israeli population.

What Causes Acatalesemia?

Acatalesemia caused due to mutations in the CAT gene (chloramphenicol acetyltransferase gene) present in the short arm of chromosome 11 (11p13 region) by the following:

• Homozygous splice mutation.

• 1-bp (base pair/2 nucleotides) deletion.

• Homozygous insertion mutation.

CAT gene stores the data required to synthesize the 4 heme-bound (iron-containing) subunits of the enzyme catalase. The mutations to the gene result in the deficiency of the enzyme.

Since acatalasemia shows an autosomal recessive pattern of inheritance, both parental copies of the gene need to show mutations to show the symptoms of acatalasemia, which decreases the amount of catalase by 90%. The presence of a single mutant CAT gene results in hypocatalasemia which does not usually cause any health problems.

What Is the Pathophysiology of Acatalesemia?

Various mutations to the CAT gene result in deficient amounts of catalase enzyme which is required to decompose the harmful hydrogen peroxide, formed by immune cells, into harmless water and oxygen.

Hydrogen peroxide, at low concentrations, acts as a chemical messenger, an agent of the immune response, and signals various physiological processes like cell proliferation, apoptosis, carbohydrate metabolism, and platelet activation; but is toxic at high concentrations. Accumulation of hydrogen peroxide leads to the liberation of ROS (reactive oxygen species) that can impair DNA, proteins, and cell membranes.

What Are the Signs and Symptoms of Acatalesemia?

Accumulation of hydrogen peroxide and lack of catalase enzyme leads to damage to the soft tissues. The clinical manifestations also develop due to oxidative stress in the body which essentially is the accumulation of ROS (reactive oxygen species).

Some of the symptoms are:

• Oral ulcerations.

• Oral gangrene.

• Altered lipid metabolism.

• Altered carbohydrate metabolism.

• Altered homocysteine metabolism.

• Oxidative damage to beta-cells of the pancreas results in diabetes mellitus.

• Tonsillar ulcers.

• Tooth mobility.

• Dental caries.

• Alveolar bone resorption.

• Deep necrotic periodontal ulcers.

• Gingivorrhagia (bleeding gums).

• Gingivitis (inflamed gums).

• Microcytic anemia (smaller RBCs with reduced oxygen-carrying capacity)

• Presbycusis (age-related hearing loss).

• Arteriosclerosis (artery walls get hardened).

• Neoplasm of the larynx (laryngeal cancer).

• Pain.

• Parkinsonism (central nervous system disorder characterized by nerve damage).

• Premature exfoliation of permanent dentition.

• Schizophrenia (mental disorder).

• Vitiligo (patchy pale regions on the skin).

• Non-alcoholic fatty liver.

How to Diagnose Acatalesemia?

A simple test can be performed to determine the lack of catalase enzyme activity. A swab with hydrogen peroxide can be applied over the oral lesion or gangrene. The lack of frothing indicates the absence of catalase enzymes.

Other tests can be performed like:

• Prenatal sequencing and analysis of all coding exons.

• Postnatal sequencing and analysis of all coding exons.

• Peroxisomal disorders panel.

• Peroxisomal disorders sequencing panel.

• ACGH (Array-based comparative genomic hybridization) analysis.

• CAT single gene test.

• Panel massive sequencing (NGS).

How to Treat Acatalesemia?

There is no cure for acatalesemia but there are management protocols in place to counteract the symptoms. Since the primary symptoms are oral ulcerations, periodontitis, and gangrene; regular dental and surgical consultation is important to keep the symptoms in check.

Oral hygiene maintenance and prophylactic treatment of caries and gum diseases may help in the reduction of oral symptoms. Gangrenes developed in the other body parts should be looked upon by a specialist surgeon. Regular debridement and dressing can hasten the healing process. An endocrinologist should be consulted to manage diabetes and its shortcomings.

Limited animal studies have indicated implantation of artificial cells containing exogenous catalase can take over the catalase demand of the body and help take down the symptoms.

What Is the Prognosis of Acatalesemia?

With regular consultations and lifestyle changes, a good prognosis is achieved against acatalasemia. Early intervention and management protocol implementation can prevent the complications of acatalasemia, thus preventing fatality.

What Are the Complications of Acatalesemia?

Acatalesemia, by itself, is not fatal. Unchecked, undiagnosed, and mismanaged acatalasemia can lead to the over-accumulation of hydrogen peroxide and reactive oxygen species (ROS).

Accumulation of ROS results in oxidative stress in the body which is the primary reason for complications. Complications can be seen in almost all organ systems which may eventually prove to be fatal.

Some of the complications include:

• IDDM (insulin-dependent diabetes Mellitus or gestational diabetes).

• Hypertension (increased blood pressure).

• Osteonecrosis (death of bone).

• Malnutrition.

• Asthma.

• NOMA (Necrotizing ulcerative gingivitis).

• Breast cancer.

• Hepatocellular carcinoma (primary liver cancer).

• Nerve damage.

• Blindness.

• Stroke (rupturing cranial blood vessels)

• Alzheimer's (progressive degeneration of neurons).

• Parkinson's (reduced dopamine in the brain results in tremors and other complications).

• Schizophrenia (a mental disorder that alters the reality of the patients).

• Bipolar disorder (a mental disorder of extreme mood swings).

• Wilson’s disease (excessive accumulation of copper).

• Impaired glucose tolerance.

• Insulin resistance.

• Ischemia (improper oxygen supply to any organ).

• Cardiomyopathy (heart muscles become incapable of pumping sufficient blood).

• Cardiac hypertrophy (thickening of the muscles of the heart).

• Congestive heart failure (improper output of heart with fluid build-up in lungs).

• Amyotrophic lateral sclerosis-ALS (nerve breakdown that affects the muscles).

• Multiple sclerosis (an autoimmune disorder of the myelin sheath-covering of neurons).

• Depression.

• Memory loss.

• Chronic obstructive pulmonary disease-COPD (inflammation of the lungs that causes respiratory blockage).

• Rheumatoid arthritis (an autoimmune disorder of the joints).

• Glomerulonephritis (inflammation of the glomerulus which is the filter of the nephron).

• Tubule-interstitial nephritis (inflammation of the tubules and peritubular structures of the nephron).

• Renal failure.

• Proteinuria (excretion of proteins through urine).

• Uremia (excessive build-up of toxins).

• Delayed sexual maturation.

• Delayed onset of puberty.

Conclusion

Acatalasemia, by itself, is not a fatal condition. With proper and timely intervention, the complications can be easily prevented. Due to limited research on the condition, proper pharmacotherapy is not established against acatalasemia, yet if results achieved in animal trials are to be considered, the development of a proper drug or therapy is not too far away.