Hurler's disease

The Hurler disease (Syn .: Pfaundler Hurler syndrome, Hurler-Pfaundler's disease) is the severe form of the lysosomal storage disease mucopolysaccharidosis type I (MPS I). The name is derived from the German pediatrician Gertrud Hurler (1889–1965), who described this form of the disease for the first time.

MPS I is caused by a defect in the enzyme alpha-L-iduronidase. This leads to an accumulation of glycosaminoglycans (GAG; formerly known as mucopolysaccharides ) and a disruption of the cellular metabolism. The enzyme defect is based on various mutations, so the clinical picture of the disease is different. Clinically, MPS I can be divided into three forms (phenotypes):

Progressive form	Expression
Hurler's disease (Hurler disease)	Heavy
Hurler / Scheie disease (Hurler / Scheie disease)	Attenuated (medium)
Scheie's disease (M. Scheie)	Attenuated (light)

Compared to the other two forms, the symptoms are most pronounced in M. Hurler and the disease progresses quickly.

A distinction is now made more frequently between MPS I with involvement of the central nervous system (CNS) and MPS I without CNS involvement. In the severe form, the Hurler disease, the CNS is always affected. In comparison, there is no CNS involvement in M. Scheie.

Epidemiology

MPS I is a rare disease. The frequency is estimated at 1: 145,000 births. The M. Hurler is the most common MPS I form with a frequency of 1: 100,000.

root cause

Like all MPS I phenotypes, the severe form, Hurler's disease, is based on a defect in the enzyme alpha-L-iduronidase. Due to the enzyme defect, glycosaminoglycans can no longer be sufficiently broken down and broken down. Instead, they are stored in the lysosomes of the body's cells. In the process, dermatan sulfate and heparan sulfate in particular accumulate. As a result, the function of the cells is severely impaired, which ultimately leads to the symptoms of the disease.

Symptoms

The symptoms appear in infancy and are very pronounced.

The main symptoms of M. Hurler are:

Short stature
Facial dysmorphia
Give it / kyphosis
Recurring otitis
Obstructive and restrictive airway problems
Recurrent pulmonary infections
Umbilical and inguinal hernias, also recurrent
Mental retardation
Hip dysplasia (bilateral)
Gibbus
Joint contractures and joint stiffness
Carpal tunnel syndrome, often bilateral and in childhood
Corneal opacity
Hearing loss
Enlarged tongue (macroglossia)
Sleep apnea
Compression of the spinal cord in the area of the upper cervical spine (craniocervical junction)

Due to the narrowing of the airways, the reduced elasticity of the lung tissue and the enlarged tongue, breathing is severely restricted. Increasing corneal opacity can also lead to visual disturbances and even blindness. In addition, patients are very susceptible to otitis media, which, due to the accumulation, can lead to impaired hearing. In addition, the central nervous system is affected in patients and without early treatment with stem cell transplantation, intellectual development is increasingly restricted.

Appearance

Patients with Hurler's disease have a typical appearance for the disease. They have a short neck, rough facial features, an enlarged tongue, wide-set eyes, and a deep bridge of the nose. Up to the age of three, the patients usually grow normally, but growth is increasingly restricted by the severe skeletal changes. Often, patients with Hurler's disease do not grow taller than 1.20 m and show a characteristic gait pattern due to the misalignment.

In the past, the disease was also called gargoylism , as the coarse facial features (so-called gargoyle faces ) of the people affected were reminiscent of gargoyles .

diagnosis

If MPS-I is suspected, the enzyme activity of alpha-L-iduronidase in the blood is determined in the laboratory. If it is reduced, the MPS-1 diagnosis is usually confirmed. In addition, a genetic analysis is almost always carried out today.

A dry blood test (Dried Blood Spot, DBS) that can be easily integrated into everyday practice is available both for measuring enzyme activity and for genetic analysis: a few drops of blood are placed on a dry blood card for this purpose. After they have dried, the card is mailed to a specialized laboratory. There the blood is removed from the filter card and processed for the following tests.

To determine the enzyme activity, a defined amount of substrate is added to a defined amount of blood. After a certain time z. B. analyzed by mass spectroscopy how much product was created by the enzyme reaction. This shows how active the enzyme is. It is important that a certified assay is used to ensure the reliability of the readings.

For genetic analysis, the alpha-L-iduronidase gene is sequenced. Both tests - the measurement of the enzyme activity and the genetic analysis - can - depending on the laboratory - be carried out from the material of a dry blood card.

forecast

In contrast to patients with M. Scheie, patients with M. Hurler have a significantly lower life expectancy. If left untreated, patients usually die before the age of 10.

therapy

Bone marrow or hematopoietic stem cell transplantation (BMT) is the treatment of choice for patients with Hurler disease up to about 2.5 years of age. By transplanting bone marrow from a suitable donor, the patient receives blood cells that can produce the enzyme alpha-L-iduronidase. These cells release part of the formed, intact enzyme into the environment, which can be taken up by other body cells and transported into their lysosomes. This allows the stored glycosaminoglycans to be broken down again. However, only cognitive development and life expectancy can be positively influenced by the transplant. However, BMT cannot cure the disease.

In patients with Hurler's disease, enzyme replacement therapy is often used before or after a bone marrow or hematopoietic stem cell transplant. The defective enzyme is replaced by a biotechnologically produced form of the human enzyme and the pathological storage of glycosaminoglycans can be broken down again. However, due to the blood-brain barrier, the enzyme replacement does not reach the CNS, so that this therapy cannot have any direct influence on the cognitive and motor symptoms of Hurler's disease. At the moment, this is only possible with early stem cell transplantation. Before BMT, enzyme replacement therapy can improve the general condition of the patient. In addition, enzyme replacement therapy can aid the transplant and relieve symptoms, since BMT cannot cure MPS I. For M. Hurler patients who are diagnosed later than 2.5 years and for whom a bone marrow or stem cell transplant is no longer an option, enzyme replacement therapy is available to treat the non-neurological manifestations of the disease.

Individual evidence

↑ ^a ^b ^c ^d ^e J. Muenzer. In: Rheumatology (Oxford), 2011, 50 Suppl 5, pp. V4-12
↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j C. Lampe: Lysosomal storage diseases . In: Thieme-Refresher internal medicine , 2014, pp. R35 – R54
↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r Gesellschaft für Mukopolysaccharidose e. V. - mps-ev.de subpages: Characteristics - Causes - Frequency - Therapy - Enzyme replacement therapy - Life expectancy - Bone marrow transplantation - accessed on November 23, 2015.
↑ G. Hurler et al .: About a type of multiple variations predominantly on the skeletal system . In: Z Kinderheilk. , 24, 1919, 220-234
↑ KE Mengel: Mucopolysaccharidosis type I - Rare lysosomal storage disease - Deficiency of the lysosomal enzyme α-L-iduronidase . In: Clinic Doctor . 2008, S02, pp. S2-26
↑ P. Biro et al .: Anesthesia for rare diseases . 4th edition. Springer Verlag, Heidelberg 2011
↑ ^a ^b K D'Aco, L Underhill, L Rangachari et al .: Diagnosis and treatment trends in mucopolysaccharidosis I: findings from the MPS I registry . In: Eur J Pediatr . tape 171 , no. 6 , 2012, p. 911 .
↑ MH. de Ru et al. In: Orphanet J Rare Dis. , 2011, doi: 10.1186 / 1750-1172-6-55
↑ LA. Clarke. In: Expert Rev Endocrinol Metab. , 2011, 6, pp. 755-768
↑ Michael Beck et al .: The natural history of MPS I: global perspectives from the MPS I Registry . In: Genet Med . tape 16 , no. 10 , October 2014, p. 759-765 .

[Muenzer-1] J. Muenzer. In: Rheumatology (Oxford), 2011, 50 Suppl 5, pp. V4-12

[Lampe-2] ↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j C. Lampe: Lysosomal storage diseases . In: Thieme-Refresher internal medicine , 2014, pp. R35 – R54

[mps-ev.de-3] ↑ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r Gesellschaft für Mukopolysaccharidose e. V. - mps-ev.de subpages: Characteristics - Causes - Frequency - Therapy - Enzyme replacement therapy - Life expectancy - Bone marrow transplantation - accessed on November 23, 2015.

[Hurler-4] G. Hurler et al .: About a type of multiple variations predominantly on the skeletal system . In: Z Kinderheilk. , 24, 1919, 220-234

[Mengel-5] KE Mengel: Mucopolysaccharidosis type I - Rare lysosomal storage disease - Deficiency of the lysosomal enzyme α-L-iduronidase . In: Clinic Doctor . 2008, S02, pp. S2-26

[Biro-6] P. Biro et al .: Anesthesia for rare diseases . 4th edition. Springer Verlag, Heidelberg 2011

[Aco-7] K D'Aco, L Underhill, L Rangachari et al .: Diagnosis and treatment trends in mucopolysaccharidosis I: findings from the MPS I registry . In: Eur J Pediatr . tape 171 , no. 6 , 2012, p. 911 .

[8] MH. de Ru et al. In: Orphanet J Rare Dis. , 2011, doi: 10.1186 / 1750-1172-6-55

[Clarke-9] LA. Clarke. In: Expert Rev Endocrinol Metab. , 2011, 6, pp. 755-768

[10] Michael Beck et al .: The natural history of MPS I: global perspectives from the MPS I Registry . In: Genet Med . tape 16 , no. 10 , October 2014, p. 759-765 .