HANAC Syndrome - A Rare Multisystemic Disease

What Is HANAC Syndrome?

Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) is a rare genetic disorder. It occurs due to a mutation (alteration) in the COL4A1 gene, which codes for a collagen protein component. This syndrome is characterized by disorders of the blood vessels (angiopathy) that affect several body parts.

The inheritance pattern of HANAC syndrome is autosomal dominant, which means that a single copy of the defective gene is enough to cause the condition. A family history of this syndrome is the single most significant risk factor for developing the condition.

Who Gets HANAC Syndrome?

• HANAC syndrome is a rare genetic disorder whose prevalence rate is unknown.

• Some reports suggest that the prevalence of HANAC syndrome is one in a million individuals.

• HANAC syndrome is reported to be manifested during childhood. However, most of the signs and symptoms may develop later in life.

• Both genders may be equally affected, and no preference is seen.

• There is also no preference for any race or ethnic group.

What Are the Risk Factors for HANAC Syndrome?

A family history of HANAC syndrome is the single most significant risk factor for developing HANAC syndrome. It is essential to remember that having a risk factor does not guarantee the development of the condition. However, a person with a risk factor has a higher risk of developing a condition than someone without the risk factors. Some risk factors are more important than others. Also, just because a person does not have a risk factor does not mean they would not get the disease. Therefore, discussing the effect of risk factors with the healthcare provider is always important.

What Are the Causes of HANAC Syndrome?

Mutations in the COL4A1 gene cause HANAC syndrome. Under normal circumstances, a component of type IV collagen is typically encoded by the COL4A1 gene.

• Basement membranes are formed by the type IV collagen molecules joining together to provide structural integrity and cell separation in nearly all body tissues, including blood vessels.

• When the mutation occurs in the COL4A1 gene, the resultant mutated component of collagen IV does not allow binding with other molecules, compromising the structural integrity of the basement membrane.

• The weakened basement membranes get more susceptible to breaking, causing angiopathy (blood vessels disorder) and weakening of other tissues and organs, resulting in HANAC syndrome.

The inheritance pattern of HANAC syndrome is autosomal dominant, meaning a single copy of the defective gene is enough to develop the condition.

In these conditions, the individual has the gene with one normal copy and one mutant copy. The abnormal copy of the gene dominates, which then masks the effects of the correctly functioning gene. Individuals with an autosomal dominant condition have a 50 percent chance of passing the abnormal gene on to their offspring. However, the condition will not be passed on to their offspring or developed by children who do not inherit the abnormal gene.

What Are the Signs and Symptoms of HANAC Syndrome?

HANAC syndrome is primarily a blood vessels disorder (angiopathy) that also has the potential to affect multiple tissues. Consequently, the affected organ-specific signs and symptoms of HANAC Syndrome are listed below:

1. Kidneys

• Blood is seen in the urine.

• Formation of cysts in either one or both kidneys.

• Kidney disease (nephropathy).

2. Heart

• Supraventricular arrhythmia (irregular heartbeats because the lower chambers of the heart beat so quickly).

3. Brain

• Headaches.

• Intracranial aneurysms (enlargement of one or several blood vessels in the brain).

• In rare cases, hemorrhagic stroke (bleeding in the brain).

• Leukoencephalopathy or change in the white matter of the brain leads to various neurological signs and symptoms.

4. Eye

• Abnormal arterial structure within the eyes (arterial retinal tortuosity).

• Bleeding occurs due to any minor injury or trauma to the eye.

• Cataracts (clouding of the normal eye lens).

• Abnormal positioning of the pupil and tearing of the iris in the eye. This is collectively known as the Axenfeld-Rieger anomaly.

5. Muscle-Related

• Cramping due to exercise.

• Cramps that last for up to several minutes.

6. Fingers and Toes

• Raynaud phenomenon, in which temperature changes bring upon a narrowing of blood vessels in the fingers and toes. This may lead to tingling or throbbing sensations. There might also be bluish discoloration of the fingers and toes for a short period.

HANAC syndrome may initially manifest only as muscle cramps during childhood. However, additional symptoms may develop later in life.

How Is HANAC Syndrome Diagnosed?

The diagnosis of HANAC syndrome can be made based on the following procedures-

• A thorough physical examination.

• An assessment of all the symptoms.

• An evaluation of the family medical history.

• Blood test to check for the concentration of serum creatine kinase (to evaluate muscle breakdown and renal issues).

• Magnetic resonance imaging (MRI) scan of the kidneys and brain.

• Examination of the eyes and vision tests.

• Prenatal genetic testing of fetal cells may be done if there is a family history of the condition.

Signs and symptoms may be the same for many medical conditions. To arrive at a definitive diagnosis, the healthcare provider may order additional tests to rule out any other clinical conditions.

What Are the Possible Complications of HANAC Syndrome?

Some potential complications from HANAC syndrome may include the following-

• Muscle cramps last for hours.

• Stroke (damage to the brain due to interruption of blood supply).

• Changes in the white matter of the brain resulting in severe neurological symptoms.

• Temporary loss of vision.

• Kidney cysts may become enlarged, leading to mild renal failure.

• Cardiac arrhythmia (irregular heartbeat).

• The use of blood thinners may result in bleeding disorders.

How Is HANAC Syndrome Treated?

Currently, no treatments are available to cure HANAC syndrome. However, symptomatic treatments can be done, and certain medications may help resolve symptoms for the following conditions-

• Arrhythmia and hypertension (high blood pressure).

• Headaches.

• Muscle cramps.

Other treatment measures may include:

• Treating any abnormalities in kidney function.

• Treating any neurological signs and symptoms that a brain stroke may cause.

How Can HANAC Syndrome Be Prevented?

• Currently, no specific methods or guidelines are available to prevent HANAC syndrome since it is a genetic condition.

• Prenatal diagnosis (molecular testing of the fetus) and genetic testing of the expecting parents (and related family members) may aid in better understanding the risks associated with pregnancy.

• Genetic counseling will help determine the risks before making plans to have a child if there is a history of the condition in the family.

• Currently, active research is being conducted to investigate the treatment and prevention options for inherited and acquired genetic disorders like HANAC Syndrome.

Nevertheless, the following steps may help prevent the worsening of the condition-

• Avoiding activities that could cause head trauma.

• Quitting smoking.

• Avoiding blood thinners.

• Avoiding excessive and strenuous physical activity.

Regular medical screening with periodic tests and physical examinations is strongly recommended.

What Is the Prognosis (Outcome) Of HANAC Syndrome?

• The prognosis of HANAC syndrome is not reported since it is a sporadic disorder.

• The types and severity of signs and symptoms in the affected individuals may dictate the outcome. Individuals with mild signs and symptoms have a better prognosis than those with severe signs and symptoms.

Conclusion:

Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is a rare inherited disorder with no cure. However, the signs and symptoms of the disorder may be managed with symptomatic treatment options. Also, genetic testing at the time of conceiving or during pregnancy may help determine any associated risk factors, especially when there is a family history of this condition.