Meckel syndrome
Encyclopedia
Meckel syndrome is a rare, lethal, ciliopathic
, genetic disorder
, characterized by renal
cystic dysplasia
, central nervous system
malformations, polydactyly
, hepatic
developmental defects, and pulmonary hypoplasia
due to oligohydramnios
.
Meckel-Gruber syndrome is named for Johann Meckel and Georg Gruber.
in 95% to 100% of all identified cases. When this occurs, microscopic
cyst
s develop within the kidney and slowly destroy it, causing it to enlarge to 10 to 20 times its original size. The level of amniotic fluid
within the womb may be significantly altered or remain normal, and a normal level of fluid should not be criteria for exclusion of diagnosis.
Occipital
encephalocele
is present in 60% to 80% of all cases, and post-axial polydactyly
is present in 55% to 75% of the total number of identified cases. Bowing or shortening
of the limbs are also common.
Finding at least two of the three features of the classical triad, in the presence of normal karyotype
, makes the diagnosis solid. Regular ultrasound
s and pro-active prenatal care can usually detect symptom
s early on in a pregnancy
.
Meckel–Gruber syndrome (MKS) is an autosomal recessive lethal malformation. Recently, two MKS gene
s, MKS1
and MKS3, have been identified. A study done recently has described the cellular
, sub-cellular
and functional characterization of the novel protein
s, MKS1
and meckelin, encoded by these genes. The malfunction of this protein production is mainly responsible for this lethal disorder.
s, both genetic syndromes
and genetic diseases
, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical
root cause of the widely-varying, phenotypically
-observed disorders. Thus, Meckel–Gruber syndrome is a ciliopathy
. Other known ciliopathies include primary ciliary dyskinesia
, Bardet–Biedl syndrome, polycystic kidney
and liver disease
, nephronophthisis
, Alstrom syndrome
, and some forms of retinal degeneration
.
The MKS1 gene has been explicitly identified as a ciliopathy.
, according to Bergsma, for Meckel syndrome is 0.02 per 10,000 births. According to another study done six years later, the incidence rate could vary from 0.07 to 0.7 per 10,000 births.
This syndrome is a Finnish heritage disease
. Its frequency is much higher in Finland
, where the incidence is as high as 1.1 per 10,000 births. It is estimated that Meckel syndrome accounts for 5% of all neural tube defects there.
Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function.Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated...
, genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
, characterized by renal
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
cystic dysplasia
Dysplasia
Dysplasia , is a term used in pathology to refer to an abnormality of development. This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells. Dysplasia is often indicative of an early neoplastic process...
, central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
malformations, polydactyly
Polydactyly
Polydactyly or polydactylism , also known as hyperdactyly, is a congenital physical anomaly in humans, dogs, and cats having supernumerary fingers or toes....
, hepatic
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
developmental defects, and pulmonary hypoplasia
Pulmonary hypoplasia
Pulmonary hypoplasia is incomplete development of the lungs, resulting in an abnormally low number or size of bronchopulmonary segments or alveoli. A congenital malformation, it most often occurs secondary to other fetal abnormalities that interfere with normal development of the lungs...
due to oligohydramnios
Oligohydramnios
Oligohydramnios is a condition in pregnancy characterized by a deficiency of amniotic fluid. It is the opposite of polyhydramnios.-Diagnosis:Diagnosis is made by ultrasound measurement of the amniotic fluid index...
.
Meckel-Gruber syndrome is named for Johann Meckel and Georg Gruber.
Diagnosis
Dysplastic kidneys are prevalentPrevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
in 95% to 100% of all identified cases. When this occurs, microscopic
Microscopic
The microscopic scale is the scale of size or length used to describe objects smaller than those that can easily be seen by the naked eye and which require a lens or microscope to see them clearly.-History:...
cyst
Cyst
A cyst is a closed sac, having a distinct membrane and division on the nearby tissue. It may contain air, fluids, or semi-solid material. A collection of pus is called an abscess, not a cyst. Once formed, a cyst could go away on its own or may have to be removed through surgery.- Locations :* Acne...
s develop within the kidney and slowly destroy it, causing it to enlarge to 10 to 20 times its original size. The level of amniotic fluid
Amniotic fluid
Amniotic fluid or liquor amnii is the nourishing and protecting liquid contained by the amniotic sac of a pregnant woman.- Development of amniotic fluid :...
within the womb may be significantly altered or remain normal, and a normal level of fluid should not be criteria for exclusion of diagnosis.
Occipital
Occipital
The word occipital, in zoology, pertains to the occiput .Occipital is a descriptor for several areas of animal & human anatomy.*External occipital protuberance* Internal occipital crest* Greater occipital nerve...
encephalocele
Encephalocele
Encephalocele, sometimes known by the Latin name cranium bifidum, is a neural tube defect characterized by sac-like protrusions of the brain and the membranes that cover it through openings in the skull. These defects are caused by failure of the neural tube to close completely during fetal...
is present in 60% to 80% of all cases, and post-axial polydactyly
Polydactyly
Polydactyly or polydactylism , also known as hyperdactyly, is a congenital physical anomaly in humans, dogs, and cats having supernumerary fingers or toes....
is present in 55% to 75% of the total number of identified cases. Bowing or shortening
Shortening
Shortening is any fat that is solid at room temperature and used to make crumbly pastry. The reason it is called shortening is because it prevents cross-linkage between gluten molecules. Cross linking is what causes doughs to be sticky. Seeing as cake is not meant to be sticky, shortening is used...
of the limbs are also common.
Finding at least two of the three features of the classical triad, in the presence of normal karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
, makes the diagnosis solid. Regular ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
s and pro-active prenatal care can usually detect symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s early on in a pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
.
Pathophysiology
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, MKS1
MKS1
Meckel syndrome, type 1 also known as MKS1 is a protein that in humans is encoded by the MKS1 gene.- Function :The MKS1 protein along with meckelin are part of the flagellar apparatus basal body proteome and are required for cilium formation....
and MKS3, have been identified. A study done recently has described the cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
, sub-cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
and functional characterization of the novel protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, MKS1
MKS1
Meckel syndrome, type 1 also known as MKS1 is a protein that in humans is encoded by the MKS1 gene.- Function :The MKS1 protein along with meckelin are part of the flagellar apparatus basal body proteome and are required for cilium formation....
and meckelin, encoded by these genes. The malfunction of this protein production is mainly responsible for this lethal disorder.
| Type | OMIM | Gene |
|---|---|---|
| MKS1 | MKS1 MKS1 Meckel syndrome, type 1 also known as MKS1 is a protein that in humans is encoded by the MKS1 gene.- Function :The MKS1 protein along with meckelin are part of the flagellar apparatus basal body proteome and are required for cilium formation.... |
|
| MKS2 | TMEM216 TMEM216 Transmembrane protein 216 is a protein that in humans is encoded by the TMEM216 gene.- Clinical significance :Mutations in this gene may be associated with Meckel syndrome or Joubert syndrome.... |
|
| MKS3 | TMEM67 TMEM67 Meckelin is a protein that in humans is encoded by the TMEM67 gene.- Function :The protein encoded by this gene localizes to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium... |
|
| MKS4 | CEP290 CEP290 Centrosomal protein of 290 kDa is a protein that in humans is encoded by the CEP290 gene.-External Links:* -Further reading:... |
|
| MKS5 | RPGRIP1L RPGRIP1L RPGRIP1L is a human gene.-Function:The protein encoded by this gene is localized to primary cilia and centrosomes in ciliated human epithelial kidney cells... |
|
| MKS6 | CC2D2A CC2D2A Coiled-coil and C2 domain-containing protein 2A that in humans is encoded by tbe CC2D2A gene.-Function :This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation.... |
Relation to other rare genetic disorders
Recent findings in genetic research have suggested that a large number of genetic disorderGenetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
s, both genetic syndromes
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
and genetic diseases
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
root cause of the widely-varying, phenotypically
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
-observed disorders. Thus, Meckel–Gruber syndrome is a ciliopathy
Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function.Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated...
. Other known ciliopathies include primary ciliary dyskinesia
Primary ciliary dyskinesia
Primary ciliary dyskinesia , also known as immotile ciliary syndrome or Kartagener Syndrome ', is a rare, ciliopathic, autosomal recessive genetic disorder that causes a defect in the action of the cilia lining the respiratory tract and fallopian tube, and also of the flagella of sperm in...
, Bardet–Biedl syndrome, polycystic kidney
Polycystic kidney disease
Autosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
and liver disease
Polycystic liver disease
Polycystic liver disease usually describes the presence of multiple cysts scattered throughout normal liver tissue, in association with polycystic kidney disease.-Pathophysiology:Associations with PRKCSH and SEC63 have been described....
, nephronophthisis
Nephronophthisis
Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease.The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure.It is a form of...
, Alstrom syndrome
Alstrom syndrome
Alström syndrome is a rare genetic disorder caused by mutations in the gene ALMS1. It is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and over 501 known cases in 47 countries. It was first described by Carl-Henry Alström in...
, and some forms of retinal degeneration
Retinopathy
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
.
The MKS1 gene has been explicitly identified as a ciliopathy.
Incidence
While not precisely known, it is estimated that the general rate of incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
, according to Bergsma, for Meckel syndrome is 0.02 per 10,000 births. According to another study done six years later, the incidence rate could vary from 0.07 to 0.7 per 10,000 births.
This syndrome is a Finnish heritage disease
Finnish heritage disease
A Finnish heritage disease is a genetic disease or disorder that is part of the Finnish disease heritage. Finnish heritage diseases are significantly more common in people whose ancestors were ethnic Finns, natives of Finland and Sweden. About 40 rare diseases are regarded as Finnish heritage...
. Its frequency is much higher in Finland
Finland
Finland , officially the Republic of Finland, is a Nordic country situated in the Fennoscandian region of Northern Europe. It is bordered by Sweden in the west, Norway in the north and Russia in the east, while Estonia lies to its south across the Gulf of Finland.Around 5.4 million people reside...
, where the incidence is as high as 1.1 per 10,000 births. It is estimated that Meckel syndrome accounts for 5% of all neural tube defects there.