Rare diseases – a review of selected disease entities

Proven content

Fabry disease, Prader-Willi syndrome, Spinal Muscular Atrophy (SMA), Mucopolysaccharidosis (MPS), Neuromuscular Diseases, Pompe Disease (Glycogenosis Type II), Gaucher Disease

Fabry disease

It is an inherited genetic disorder caused by a deficiency of α-galactosidase, which leads to the accumulation of glycosphingolipids in tissues and body fluids. It disrupts the function of many vital organs, including the kidneys, brain and heart. The disease occurs in 1 in 40 thousand. live births.

The main symptoms appear in adolescence, although there are people whose onset of the disease has already been observed in early childhood.

Often the first ailments are underestimated or misinterpreted. It is estimated that an average of 15 years from the onset of the disease to its correct diagnosis, and the patient is usually consulted by 8-10 specialists.

The earliest and most common symptom of the disease is pain, often in reaction to change of weather (especially high temperature) as well as fatigue and stress. Most often, people suffering from Fabry disease experience bone and muscle pain that requires the administration of strong painkillers (analgesics) and acroparesthesia – a feeling of burning, tingling and breaking, most often in the area of ​​the hands or feet. The so-called Fabry breakthroughs, i.e. attacks of very intense, excruciating, breaking, burning pain lasting from a few minutes to several days, initially felt in the hands and feet and then radiating to other parts of the body. Many people with Fabry disease experience abdominal pain caused by the disease of the stomach and intestines. Usually these are postprandial pains, diarrhea and nausea. Children suffer from severe pain, usually with fever or exercise. Additionally, patients experience impaired tolerance of high temperature and sweat secretion, hyperthermia. The most prominent symptom of the disease in adolescence is a reddish-purple skin rash (angiokeratoma), typically found in the thighs, buttocks and lower abdomen. Some patients may also experience corneal clouding or cataracts, as well as progressive hearing loss.

In adulthood, symptoms extend to:

1. heart complaints: heart failure, left ventricular hypertrophy, arrhythmias, mitral valve regurgitation.
2. signs of kidney damage: proteinuria, over time leading to nephrotic syndrome, and progressive renal failure.
3. brain symptoms: dizziness and headaches, balance disorders, tinnitus, and the risk of stroke increases.

The life expectancy of men with Fabry disease is approximately 45–50 years. Women live an average of 10 years longer. The most important causes of death are cardiovascular events: stroke, heart attack and progressive heart failure.

Treatment of the disease is causal, substitution of recombinant α-galactosidase with intravenous preparation is used, which slows down the progression of the disease and sometimes leads to the resolution of some symptoms.

Gaucher disease

It is a rare genetic disorder caused by a deficiency of glucosylceramide beta-glucosidase, an enzyme responsible for breaking down a naturally occurring fatty substance in the body called glucocerebroside. As a result, the patient accumulates substances in various organs of the body that should be removed.

There are three types of the disease:

Adult-free form (type 1) – occurs with a frequency of 1 in 50 births. It often manifests itself in early childhood and has a chronic course, with enlargement of the liver and spleen, which sometimes leads to the growth of organs to a weight of several kilograms and limits the ability to move. Additionally, patients suffer from anemia, thrombocytopenia (the patient is prone to bruising, frequent, difficult to stop nose bleeds), as well as mild jaundice and osteoporosis, which can lead to pathological fractures. Sitting down dynamically can even cause a spine fracture.

The neuropathic form (type 2, so-called infantile) – occurs with a frequency of 1 in 100 births. Symptoms are found in the first months of life. The disease progresses rapidly, causing death. Children usually die before reaching the age of 000. Significant enlargement of the liver and spleen is accompanied by cachexia and increasing damage to the central nervous system.

Chronic neuropathic form (type 3, juvenile) – occurs with a frequency of 1 in 100 births. It is characterized by a slower course. Patients most often reach adulthood.

Treatment is causal. An artificially modified enzyme (ceredase) is used, especially effective in forms of the disease without neurological symptoms. The therapy allows not only to stop the progression, but also in many cases causes the symptoms of the disease to regress.

Pompe disease (type II glycogenosis)

It is a rare genetic disease (occurring with a frequency of 1: 40 to 000: 1 live births), consisting in abnormal glycogen storage in lysosomes in all cells of the body, incl. in the liver, muscles and heart.

Depending on the onset of symptoms, Pompe disease can be divided into three types: childhood, adolescent and adulthood. The infant form, which appears within a few months of being born, is easier to diagnose because infants progress much faster than adults and symptoms are easy to see. The most common are hepatomegaly (enlarged liver), cardiomegaly (enlarged heart), generalized muscle laxity and feeding difficulties. These symptoms are progressive and cause the death of children, usually before the age of 1.

In milder forms of the disease, symptoms are limited to the muscular system and life span is longer.

In people who develop the disease later in life, the symptoms are mild, moderate and acute, and the course of the disease is slower than in children.

The most common symptoms include difficulty walking, breathing difficulties while sleeping (apnea), morning headache, and dizziness during the day. Often, patients feel short of breath and tire quickly. It is better to breathe in a standing and upright position. Other symptoms include scoliosis, enlarged tongue, difficulty swallowing and chewing food, and lower back pain. The earlier the disease attacks the body, the more severe the disease is. Some patients remain functional for many years. Others need a wheelchair, crutches, and sometimes a breathing apparatus.

The diagnosis is made on the basis of an enzyme deficiency in the biopsy material taken from the pathological site (skin or muscles).

Treatment is enzyme replacement therapy that restores the action of acid alpha-glucosidase (GAA), an enzyme that is missing or does not work properly in people with Pompe disease.

The prognosis for Pompe disease is poor. They depend on when the symptoms appear and their intensity. Most sick infants die within 1 year of life.

Neuromuscular diseases

These are disorders in which there is structural or functional damage to the motor neuron (which transmits an impulse from the brain to the muscles) and the muscle fibers innervated by it. Depending on the degree of damage, the following are distinguished:

1. primary muscular diseases (myopathies) in which the pathological process takes place in the muscle itself
2. neurogenic diseases where the muscles are secondarily affected
3. diseases that damage the neuromuscular plaque (where the neuron connects to the muscle cell)
4. Muscular dystrophy, defined as progressive weakness and muscle wasting, occurs in at least 12 forms. The most common and severe of these is Duchenne dystrophy (DMD). It is a genetic disease that causes progressive and irreversible muscular dystrophy (atrophy). The prevalence is estimated at 1: 3500 male births. Women do not get sick, but some of them may have muscle weakness and increased levels of creatine kinase (an enzyme found mainly in the heart muscle, skeletal muscles and the brain).

The disease becomes apparent at the age of 3-4. The main symptom is symmetrical muscle atrophy, beginning at the pelvic girdle. Characteristic for people suffering from this disease is an awkward, duck-like gait, difficulties in getting up from a lying position (patients help themselves to get up with their hands. This is the so-called Gowers symptom), problems with running and walking up stairs.

As the disease progresses, deep reflexes (e.g. knee reflexes) disappear, there is an alleged hypertrophy of the affected muscles, contractures appear, which, together with muscle atrophy, lead to permanent immobilization of the patient, which takes place around the age of 10. The survival of patients generally does not exceed 25 years. Death is due to respiratory or circulatory failure.

There is no effective treatment for muscular dystrophy. Only symptomatic treatment, including steroids, is used. Drugs taken early can delay the progression of the disease. Modern methods of rehabilitation, combined with orthopedic procedures: stretching the muscles, preventing contractures, electrostimulation and the anti-obesity diet, can extend the ability to stand. However, this does not mean maintaining the ability to walk independently. Genetic counseling should include all families diagnosed with DMD.

Mukopolisacharydozy (MPS)

They are a group of closely related rare disease syndromes caused by a genetically determined lack of one of the enzymes necessary for the degradation of mucopolysaccharides.

Mukopolisacharydy they damage the cells and organs of the body, which in turn leads to the destruction of the whole organism.

There are seven clinical types of mucopolysaccharidoses, each the result of a lack of an appropriate enzyme.

Mucopolysaccharidosis type I (MPS IH, Gertrude Hurler’s syndrome) – The first symptoms occur as early as 1-2 years of age, when there is a progressive retardation of physical and mental development, significant thickening and distortion of facial features: flattened bridge of the nose, wide set of eyes, stretch marks between teeth and a large tongue. In addition, characteristic of children with MPS is dwarfism, short neck and increasing kyphosis (curvature) of the thoracic spine, short, wide fingers, symptoms of carpal tunnel syndrome, joint contractures as well as deafness, corneal clouding and hepatosplenomegaly (enlargement of the liver and spleen) and narrowing of the heart valves. . Recurrent respiratory infections and circulatory failure are the most common causes of death, occurring in most children around the age of 10.

A variant of this form of the disease is MPS IS (Schei’s syndrome, formerly MPS V) – it is a disease with less severe symptoms (corneal opacity and changes in heart valves) without mental retardation, with a longer survival time.

1. Mucopolysaccharidosis type II (MPS II, Hunter’s syndrome) – this type of disease differs from MPS I in less severity of symptoms and the absence of corneal opacity. There are also significant differences in the course of the disease between families.
2. Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) – the clinical picture is similar to the previous types of MPS. Between 3 and 6 years of age mental retardation rapidly increases with significant psychomotor agitation. Speech is lost. Hirsutism (hirsutism) appears fairly early. Hepatosplenomegaly is not as significant as in MPS. There are also no growth deficiencies or corneal opacities.
3. Type IV mucopolysaccharidosis (MPS IV, Morquio syndrome) – the first symptoms appear around the age of 7. stunted growth, thickening of facial features and distortions of the skeletal system that progress with age. The flattening of the vertebrae causes a significant shortening of the torso and neck, the chest is deformed with a significant protrusion of the sternum forward (the so-called crow’s chest). Excessive mobility of the joints causes valgus or varus in the knees. With time, the child completely loses hearing, slight clouding of the cornea impair vision, but mental development is normal. Apart from thick lips and widely spaced teeth, the baby’s face looks normal.
4. Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) – symptoms resemble MPS I but with normal mental development.
5. Mucopolysaccharidosis type VII (MPS VII, Sly’s syndrome) – clinical symptoms typical for mucopolysaccharidoses, usually of moderate intensity, occur. In addition to mild mental retardation, growth deficiency, hepatosplenomegaly and changes in the heart valves are found.
6. Treatment of children with mucopolysaccharidosis mainly consists in relieving the symptoms of the disease.

Spinal Muscular Atrophy (SMA)

It is a genetically determined group of neuromuscular diseases, the common feature of which is the loss of spinal cord motor neurons (which transmit impulses from the brain to the muscles), which in turn leads to muscle weakness and atrophy.

The disease, occurring at a frequency of 1: 6, can begin in both prenatal and adulthood. Some symptoms occur regardless of the age and severity of the disease. These include: trembling fingers, symmetrical, progressive weakening of muscle strength as well as weakness or lack of deep reflexes, e.g. a knee reflex that fades first.

There are three basic clinical forms:

1. SMA1 (acute form, Werdnig-Hoffmann disease) – the first symptoms of the disease most often appear in the second or third month of life. Attention is drawn to the lack of progress in the child’s motor development, quiet crying and easy fatigue when sucking and swallowing, which is the result of significant weakening of the intercostal muscles. The child never achieves the ability to sit up on its own. The prognosis for acute disease is poor. Most children die before the age of 2.
2. SMA2 (intermediate form) – The baby develops normally at first but never becomes able to walk independently. There is trembling of the fingers and with time significant weakness. There are joint contractures and curvatures of the spine. Survival in SMA2 patients depends on the level of care, but is usually shorter than in the general population.
3. SMA3 (mild form, Kugelberg-Welander disease) – the first symptoms usually appear before the age of 3. The child has trouble walking and climbing stairs. He falls over, stands up, leaning on objects, does not run. The course of the disease may also be slower and unnoticeable for a long time. As the disease progresses, there may be pseudo-hypertrophy of the calves, trembling of the fingers, and muscle twitching. Survival time is similar to that of the general population.
4. SMA 4 (adults) – the disease begins around 20-30 years of age. discrete, slowly progressing symptoms: trembling fingers, difficulty running, climbing stairs. Over time, weakness spreads to the distal (distal) muscles. The survival time is unchanged.

In all forms of the disease, only symptomatic treatment is used, which mainly includes physical therapy, orthopedic treatment and assisted breathing. The aim is to extend the period of independent functioning of patients, prevent complications and improve their quality of life.

Prader-Willi syndrome (PWS)

It is a rare (1: 20-000: 1 live births) congenital disease, genetically determined, caused by a disturbance in the structure of chromosome 30. Symptoms vary widely, which makes diagnosis difficult, especially in patients at an early age. They also result from the fact that the clinical picture of the syndrome in the neonatal and infant period differs radically from that of the childhood and adulthood.

The diagnosis is made at 1 month of age. Genetic testing for PWS is performed in infants with muscle hypotension (reduced muscle tension) with poorly developed sucking reflex, underdevelopment of the genital organs in the form of small labia minora in girls, and in boys with a small penis, a small, not wrinkled scrotum and cryptorchidism. . Prader-Willi syndrome will also be demonstrated by disproportionately small and narrow hands and feet.

In later years, the indication for testing is the coexistence of short stature with significant central obesity (rapid weight gain occurs most often between 1 and 6 years of age) with typical features of dysmorphia, which include a narrow forehead, amygdala eyelid fissures, small mouth with a narrow upper lip and the corners facing downwards.

In adolescents and adults, PWS should be suspected due to obesity accompanied by delayed or incomplete puberty and behavioral disorders: tendency to outbursts of anger, obsessive-compulsive behavior and psychosis.

Other hallmarks of the syndrome include hyperphagia (uninhibited appetite), mild to moderate mental retardation, and skin and hair hypopigmentation compared to the rest of the family. It is also characterized by a high pain threshold, fluctuating body temperature, a weakened gag reflex and the secretion of thick and sticky saliva that collects in the corners of the mouth, which increases the susceptibility to caries and leads to missing teeth.

There is no causal treatment for PWS. Only symptomatic treatment is used – growth hormone therapy. Thanks to it, the ratio of muscle mass to adipose tissue is favorably changed and the child’s growth is normalized. Surgical treatment of patients with PWS by creating an anastomosis bypassing the stomach has also been attempted. However, they turned out to be ineffective.

The life expectancy of PWS patients is significantly reduced compared to the population average. However, advances in the management of patients with PWS have contributed to an increase in life expectancy in recent years. There are known deaths of PWS patients at the age of 71 and 68.

Developed by Leonard Loga

See also: The World’s Strangest Diseases