H63D-Syndrome (English)

H63D syndrome (also known as Oslo Syndrome) is a very rare genetic disease, which is often the result of a homozygous mutation of the HFE gene H63D. This mutation can trigger or promote numerous disease patterns, but H63D syndrome is specific to this homozygous variant. A typical symptom is excessive transferrin saturation based on a relative lack of transferrin, which causes free iron of the NTBI type (labile iron pool) to invade certain tissues (especially parenchyma and brain cells) and other organs, where it can cause severe damage at the cellular level. In addition, many H63D syndrome patients suffer from an unspecific activation of the inert immune system, which leads to autoimmune reactions in addition to the iron-induced organ damage.

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1 Symptoms of H63D syndrome

Since it is a storage disease, the course is insidious and chronic. In most cases, the first symptoms appear in childhood or adolescence, but are so unspecific that they are usually not being looked into seriously at first. Often organs with the highest risk of NTBI accumulation (brain, heart, liver, testicles, skin) are already structurally severely damaged when the diagnosis is made based on significant symptoms.

2 Brain damage

The damage to the brain (degeneration) caused by NTBI in the context of H63D syndrome is caused by oxidative stress within the affected brain tissue, leading to cell death (scarring of brain tissue) with severely impaired neurotransmitter activity. These incurable processes include elevated cellular iron, free radical activity, disturbances in the brain's dopamine and glutamate balance, and abnormal levels of tau-proteins and alpha-synuclein, both of which lead to dementia, Parkinson's disease or similar disorders. The substantia nigra and basal ganglia with all their functions are particularly susceptible.

3 Iron deposition in the heart

Many patients with H63D syndrome suffer from conduction disorders, cardiomyopathies, cardiac dysrhythmia and especially disorders of the calcium channels.

4 Liver symptoms

A fatty liver (even at normal weight) as well as cryptic (non-specific) liver dysfunction and a metabolic syndrome are also typical for H63D syndrome.

5 Skin and other organs

Since NTBI iron cannot be stained in biopsies, the iron deposition in skin, liver, etc. is not histologically detectable. However, deposits visible to the naked eye are sometimes present, as are impetigo-like skin changes, blistering, itching, etc., rarely in the tissues of the eye. In men, slightly shrunken testicles are often found in H63D syndrome, sometimes with signs of degenerative changes in sonography. If there is already significant damage to the substantia nigra, H63D syndrome patients also suffer symptoms similar to those of the non-motor signs of Parkinson's disease. These include a loss of the sense of smell, a slowing down or partial paralysis of the gastrointestinal passage, cataplexies, narcolepsy, dementia, etc. Sensory disorders such as hearing loss and eye diseases can also occur from time to time.

6 Immune System

For reasons that are as yet completely unexplained, the inert immune system is overactive in many H63D syndrome patients, in the sense of passive autoaggressive dysfunctions, which are represented by a "colorful" symptom picture, occur highly acutely, can be dangerous in some cases, and regress after a certain time. A tipping point mechanism can be assumed, which is still completely unexplored.

7 Diagnosis and treatment of H63D syndrome

According to the current state of research, individuals with a homozygous HFE H63D mutation should be examined for syndromic symptoms affecting the brain, nervous system, heart, liver and, to a lesser extent, kidney function, skin diseases, blood formation and other susceptible organ systems. A transferrin value that is too low when saturation is far too high and ferritin is low is pioneering. Causal treatment is currently (2020) not available because non-protein-bound free iron (NTBI) cannot be removed from the cells by bloodletting or similar procedures. In the case of illness, at most some of the symptoms can be alleviated. In the case of a homozygous H63D mutation, a dietary control of iron intake should only be carried out under the supervision of a medical nutritionist, as an overload of the body with non-protein-bound iron (NTBI), for example due to hypotransferrinemia, can exist in parallel with a deficiency of ferritin.

8 Not curable

The H63D syndrome is incurable (2020). The various symptoms must be treated by experienced specialists in each case so that a patient with H63D syndrome does not suffer too much. In addition, a reduction in iron absorption, which must be monitored by a physician, should be aimed for.

9 Literature and scientific studies

Please visit the German version of this Article. There you’ll find relevant studies and sources.