He Zellweger's syndrome , Also known as Cerebro-Hepato-Renal syndrome, is a type of metabolic pathology classified within the peroxisomal diseases (Cáceres-Marzal, Vaquerizo-Madrid, Girós, Ruiz and Roels, 2003).
This disease is characterized by abnormal processing or accumulation of various compounds, phytanic acid, cholesterol or bile acids, in various areas such as the brain, liver or kidneys (Hospital Sant Joan de Déu, 2016).
At the clinical level, Zellweger syndrome is defined by the presentation of various medical signs and symptoms related to abnormalities and facial malformations, hepatomegaly and severe neurological dysfunction (Rodillo et al., 1996).
In addition, the etiologic origin of this disease is in a genetic anomaly that results in a poor production or activity of the peroxisome. A cellular component with a prominent role in the metabolism of various biochemical substances in our organism (Girós, López Pisón, Luisa Serrano, Sierra, Toledo and Pérez-Cerdá, 2016).
In addition to physical examination and identification of clinical manifestations, Zellweger syndrome includes a wide variety of laboratory tests: biochemical analysis, histological studies, neuroimaging, ultrasound, Electroencephalography , Ophthalmic examination, cardiac function analysis, etc. (Cáceres-Marzal, Vaquerizo-Madrid, Girós, Ruiz and Roels, 2003).
Current experimental studies have yet to identify a cure for Zellweger syndrome. All therapeutic interventions are based mainly on symptomatic and palliative treatment (Hospital Sant Joan de Déu, 2016).
In most cases, people affected by Zellweger syndrome do not usually exceed 2 years of life, due to the significant medical complications it entails.
Characteristics of Zellweger syndrome
Zellweger's syndrome is a congenital pathology of genetic origin that is classified within the so-called Peroxisomal diseases Or peroxisome biogenesis disorders (National Institute of Neurological Disorders and Stroke, 2016).
Peroxisomal disorders or diseases constitute a large group of metabolic pathologies caused by an abnormality in the formation or function of peroxisome (Hospital Sant Joan de Déu, 2016):
The peroxisome is a Cellular organelle Which contains various proteins responsible for performing numerous metabolic functions, such as the degradation or synthesis of biochemical substances.
This organelle or cellular compound, can be localized in almost all the tissues of the organism, however, it is more habitual that predominates in Brain areas , Renal or hepatic.
In addition, they can be formed by a division and multiplication of the existing cells or by new processes of proliferation, synthesized by diverse proteins located in the cellular nuclei.
Therefore, the biogenesis or production of peroxisome is influenced by the activity of various proteins, coded at the genetic level by approximately 16 different genes, whose alteration can cause important anomalies in this cellular compound.
In the case of Zellweger syndrome, an anomaly occurs in the biogenesis of the peroxisome that results in a pathological accumulation of diverse compounds that are toxic or they have not been degraded of correct form.
Biochemical analyzes performed within the Zellweger syndrome research field have shown high concentrations of phytanic acid, polysaturated acids, urine cholesterol, bile acids, etc.
In addition, these types of alterations can also have a significant impact on the synthesis of plasmids, a fundamental substance in brain development.
Consequently, people affected by Zellweger syndrome present a wide variety of neurological symptoms, craniofacial anomalies, renal and hepatic abnormalities that severely compromise their survival (Cáceres-Marzal, Vaquerizo-Madrid, Girós, Ruiz and Roels , 2003).
This disease was first described by Hans Zellweger (1964), who receives his name and his work group (Valdez Geraldo et al., 2009).
In his clinical report, Zellweger referred to two sibling patients whose clinical status was characterized by a multifunctional failure, associated with the absence of peroxisomes.
Subsequently, in 1973, Goldfischer and colleagues located the absence of these cellular organelles at a specific level in the kidneys and liver (Prudencio Beltrán, Coria Miranda, Nubela Salguero, Pemintel Zárate, 2009).
Zellweger syndrome is currently defined as one of the most serious variants of the peroxisomal diseases, whose clinical characteristics will lead to a systematic deterioration of the person affected (Braverman, 2012).
About us
Zellweger's syndrome is considered a rare disease, rare in the general population (Genetics Home Reference, 2016).
Statistical studies have shown an approximate incidence of one case per 50,000 people (Genetics Home Reference, 2016).
As regards sociodemographic characteristics associated with the prevalence of this disease, current research has not found a higher incidence associated with gender, geographical origin or membership of particular ethnic and / or racial groups (National Organization for Rare Disorders, 2013 ).
Despite this, some authors (Braverman, 2012) point out the presence of a differential prevalence associated with different countries:
- United States: 1 case per 50,000 inhabitants.
- Japan: 1 case per 500,000 inhabitants.
- Saguenay-Lac Saint Jean (Quebec): 1 case per 12,000 inhabitants.
In addition, in many cases this pathology remains undiagnosed due to its rapid progression and high mortality, so statistical data regarding its prevalence may be underestimated (National Organization for Rare Disorders, 2013).
Signs and symptoms
The clinical characteristics of Zellweger syndrome will be classified into several groups: craniofacial alterations, neurological alterations and hepatic / renal abnormalities (Genetics Home Reference, 2016; National Organization for Rare Disorders, 2013).
Craniofacial Alterations
Many people with Zellweger syndrome have an atypical facial phenotype characterized by:
- Dolicocephaly : The overall cranial structure may have an abnormal structure, characterized by an elongation of the anterior and posterior regions.
- Flattened facial appearance : In general, all the structures that conform the face usually present a poor development. In this sense, they are usually smaller than normal or, on the contrary, develop incompletely. As a result, the visual sensation is a flattening of the facial area.
- Occiput flat: The back of the head, located between the end of the skull and the neck, may develop poorly, resulting in an abnormally flattened configuration.
- Bulky front, wide and wide : In general, the total size of the forehead or frontal area of the skull is usually larger than normal, showing a significant protrusion.
- Wide nasal root: The bony structure of the nose usually develops with a volume higher than normal or expected, so that it usually presents a broad and robust appearance. In addition, the presence of inverted nasal passages is usually another of the most frequent features in this syndrome.
- Ophthalmic anomalies: The ocular fossae are usually ill-defined. In addition, the development of corneal pathologies is frequent. Many affected individuals may have significantly reduced visual capacity.
- Micrognatia: In this case, both the chin and the rest of the jaw structure usually develop with a reduced volume, resulting in other secondary dental and dental alterations.
- Auditory malformation : The ears usually present malformed or with a very deficient development. In this sense, they not only translate into aesthetic malformations, but also the cases of hearing loss can be abundant.
- Oral anomalies: In the case of the internal structure of the mouth, it is common to see palatine crevices.
- Excess skin : Specifically, it is common to identify a significant excess of skin on the neck.
Neurological disorders
The pathologies related to Structure and function of the nervous system Are usually the most severe symptoms of Zellweger's syndrome.
In general, medical complications of a neurological nature are primarily due to altered neuronal migration, to the loss or injury of Myelin (Demyelination) and significant white matter atrophy ( Leukodystrophy ).
Consequently, it is also possible to observe the development of Macrocephaly (Abnormal increase of the cranial perimeter) or Microcephaly (Significant reduction of the cranial perimeter).
Therefore, some of the complications secondary to these neurological alterations are characterized by the presence of:
- Seizures: Structural and functional anomalies at the brain level can generate a deficient and asynchronous neuronal electrical activity. Therefore, it can give rise to the suffering of Recurrent episodes of spasms Sudden and uncontrollable muscles, muscle stiffness or periods of absence.
- Muscle hypotonia : In general, muscle groups usually present a reduced and less functional tone that makes it difficult to perform any type of motor activity.
- Hearing and visual loss : In addition to the additive and ophthalmologic malformations, it is possible that there is an alteration of the visual and auditory capacity secondary to a neurological anomaly, such as the injury of the peripheral nerve terminals.
- Intellectual disability : Multiple neurological abnormalities usually involve very limited intellectual and cognitive development.
Hepatic and renal abnormalities
In spite of having a milder incidence, compared to the signs described above, some systems such as renal or hepatic can also be significantly impaired:
- Splenomegaly : The spleen and adjacent structures may grow more than usual, leading to different functional abnormalities.
- Hepatomegaly : The liver usually develops abnormally, reaching a larger size of normal or supported by the body structure.
- Cirrhosis : Due to metabolic disturbances, abnormal and pathological storage of fatty material in the liver may occur.
- Jaundice : As in other cases, metabolic deficiencies can lead to the presence of abnormally high levels of Bilirubin In blood, producing a yellow coloration at the cutaneous and ocular level.
Causes
As we pointed out in the initial description, Zellweger's syndrome has its origin in a deficient biogenesis of peroxoisoma (Girós, Lopez Pisón, Luisa Serrano, Sierra, Toledo and Pérez-Cerdá, 2016).
However, this anomalous metabolic mechanism finds its etiologic cause in a genetic alteration.
Specifically, different studies have identified specific mutations in a wide variety of genes, around 14-16 (Girós, López Pisón, Luisa Serrano, Sierra, Toledo and Pérez-Cerdá, 2016).
Although not all of the functions of these genes are known accurately, they have been shown to play a prominent role in the generation of biochemical instructions for the production of a group of proteins called peroxins (Genetics Home Reference, 2016).
These types of proteins are a basic component in the formation of the cellular organelles called Peroxisomes (Genetics Home Reference, 2016).
Consequently, these genetic mutations can lead to a poor development of the peroxisome biogenesis and hence its functional activity (Genetics Home Reference, 2016).
Diagnosis
Zellweger syndrome can be diagnosed during gestation or postnatal stage.
In the case of prenatal diagnosis, the Ultrasound Gestation control may show various abnormalities compatible with this pathology, such as intrauterine growth retardation or craniofacial malformations.
However, it is essential to perform a biochemical analysis through blood extraction and chorionic villus sampling to determine the presence of a metabolic disorder of genetic origin.
On the other hand, in the case of postnatal diagnosis, physical examination offers sufficient clinical findings to confirm its presence, although several tests are performed to rule out other types of pathologies.
Some of the laboratory tests used in the diagnosis are based on histological and biochemical tests or neuroimaging tests (Cáceres-Marzal, Vaquerizo-Madrid, Girós, Ruiz and Roels, 2003).
Treatment
As in other genetic disorders, a cure for Zellwerger syndrome has not yet been identified.
In this case, medical interventions are directed towards life support methods and pharmacological treatment.
Medical complications tend to progress exponentially, so worsening of the clinical status of those affected is inevitable.
The majority of those affected by Zellweger syndrome usually do not exceed 2 years of age.
References
- Braveman, N. (2012). Zellweger syndrome. Obtained from Orphanet:.
- Déu, H. S. (2009). Peroxisomal Diseases. Hospital Sant Joande Déu.
- Girós, M. L.; Et al. (2016). Protocol for the diagnosis and treatment of the peroxisomal disorders of the Zellweger spectrum and the rhizomelic chondrodysplasia punctata".
- NIH. (2016). Zellweger Syndrome. Retrieved from the National Institute of Neurological Disorders and Stroke.
- NIH. (2016). Zellweger Spectrum disorder. Retrieved from the Genetics Home Reference.
- NORD. (S.f.). Zellweger Spectrum Disorders. Retrieved from the National Organization for Rare Disorders.
- Prudencio Beltrán et al. (2010). Zellweger syndrome. Rev Soc Bol Ped, 22-4.
- Rodillo et al. (nineteen ninety six). Zellweger's cerebrohepatorenal syndrome: a peroxisomal disease. Rev. Chil. Pediatr. , 79-83.
- Valdez Geraldo, C., Martínez Jiménez, C., García-Arias, S., Mayeda Gaxiola, L., & Zavala Ruiz, M. (2009). Zellweger syndrome (brain-hepato-renal). Report of a case. Pediatrics Mex.