Homozygous familial hypercholesterolemia


HoFH (homozygous familial hypercholesterolemia) is a very rare genetic disorder with life-threatening consequences for those affected. It is the most severe form of familial hypercholesterolemia, which is characterised by extremely high LDL (low-density lipoprotein) cholesterol levels. 

The long-term exposure to significant elevated LDL-C levels in patients with HoFH can lead to premature atherosclerosis and increased risk of cardiovascular events such as acute coronary syndrome, heart attack, and stroke.

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Cause

The cause of familial hypercholesterolemia can be traced to a mutation (a defect) in the LDL (low-density lipoprotein) receptors, which are responsible for transporting cholesterol from the blood to the cells. 

Heterozygous familial hypercholesterolemia

In the case of heterozygous familial hypercholesterolemia (HeFH), only one parent passes on a pathogenic genetic change. This means that the activity of the LDL receptors is reduced by around 50 percent. Cholesterol levels in this (more common) form are between 300 and 500 mg/dl. One in 500 people is affected by HeFH. Although extremely rare, it is possible that both parents suffer from HeFH and both pass down their pathogenic gene to a child. The combination of pathogenic genetic alterations then produces a clinical picture that does not differ from that of HoFH and must be also treated in the same way.    

Homozygous familial hypercholesterolemia

In the extremely rare case of homozygous familial hypercholesterolemia (HoFH), the mutation of the LDL (low-density lipoproteins) receptors is passed on by both parents. This leads to a very steep rise in the level of LDL-C in the blood, ranging between 500 and 1200 mg/dl. Only one in one million people is affected by HoFH. This makes it one of the rarest diseases.

Symptoms

Atherosclerosis

The symptoms of homozygous familial hypercholesterolemia can be traced back to the very high cholesterol levels experienced since birth. The role of LDL-C should be especially noted. An extended surplus of LDL-C in the blood causes fat and calcium to accumulate on vessel walls, causing them to narrow or close up. This process is known as atherosclerosis. In addition to coronary heart disease and strokes, generalised atherosclerosis can cause chronic arterial circulatory disorders that can also seriously damage muscles and organs. 

Depending on the severity and duration of the LDL-C burden, even young HoFH patients may suffer from heart attacks or strokes that are caused by a highly accelerated ageing process (before the age of 20!) in the vessels. 

Xanthomas

The high cholesterol level may result in the build-up of cholesterol deposits in the skin and tendons as well – xanthomas.

  • Skin xanthomas (cutaneous xanthomas): particularly on eyelids and between the fingers.
  • Tendon xanthomas: develop primarily on the Achilles tendon and finger extension tendons

These skin alterations may already exist from birth or develop in early childhood. 

The disease often goes undetected for an extended period of time because the patients do not display any apparent symptoms.