Information

Explanation of the 'cherry red spot' in Tay Sachs disease

Explanation of the 'cherry red spot' in Tay Sachs disease


We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

In Tay Sachs disease, a hallmark symptom is a cherry red spot in the macula of the eye surrounded by a halo of white.

I understand that the ganglion cells, which are higher in numbers around the macula rather than in the macula, accumulate gangliosides due to the hexosaminidase deficiency, and thus cause the surroundings of the macula to appear white, but I don't understand why the macula is red.

It is said that in Tay Sachs disease, the macula is the only normal region of the eye, but isn't the macula supposed to be yellow, as it is referred to as the yellow spot?

Moreover, I've read that the red color comes from the choroid blood vessels, but isn't the choroid black? It contains blood vessels, yes, but it is pigmented. The hindmost layer of the retina also happens to be a pigmented epithelium. So what is the explanation of a cherry red spot?


Short answer

  1. The fovea centralis is colored red in both the healthy retina and Tay-Sachs affected retinae. The macular region around the fovea has a yellowish hue. You are confusing fovea and macula in your question.
  2. The reddish hue from the fovea comes from the well-vascularized choroid layer below. The choroid is not black, it is colored red due to the presence of many blood vessels. You are confusing choroid with the retinal pigment epithelium, which is indeed black.

Background
The macula includes the fovea at the center, also called the fovea centralis, which forms the very center of the retina. The macular region around the fovea includes the perifoveal and parafoveal areas. The macular region around the fovea has a slight yellowish appearance to it due to yellowish pigments present in the cone axons (Fig. 1) (Kolb, 2012).


Fig. 1. Healthy retina. The macular region is seen in the center, The parafoveal region has a slight yellow/orange hue to it. Note that the landmark yellow circle at 4 o'clock, with the vessels sprouting from it, is the optic nerve head. source: Webvision.

Below a Tay-Sachs affected retina showing the hallmark cherry red spot (Fig. 2):


Fig. 2. Tay-Sachs affected eye. The fovea centralis appears red. source: Prezi

The only normal part is the fovea centralis, appearing in its native red color, i.e. the cherry red spot.

The choroid plexus is well-perfused and is, therefore, red. You are confusing it with the pigment epithelium, which is pigmented (Fig. 3).


Fig. 3. Layers of the eye. RPE = Retinal Pigment Epithelium. source: Retina Eye Specialists

Reference
- Kolb (2012), Simple anatomy of the retina. In: Kolb et al. (eds.), Webvision. The organization of the retina and visual system. Salt Lake City, UT, Moran Eye Center


The black RPE contributes to the "normal" color of the eye fundus in photos of the retina. Albinism is a condition of absence of black pigment, and then you can see the eye fundus without pigment. Compare the two images below


Very rare metabolic disease

Tay-Sachs disease (TSD) is a very rare inherited metabolic disease. Tay-Sachs disease has a deficiency of the enzyme ß-hexosaminidase A. This causes an accumulation of certain fats, the GM2 gangliosides, in the brain and other body cells. This accumulation reaches a level where it becomes toxic. The disease is very rare and affects 1 in 320,000 children.

The disease was first described by the ophthalmologist Warren Tay who discovered a remarkable red spot in the center of the retina (the macula) in 1881 and the neurologist Bernard Sachs who described body cell changes in 1887 that mainly affect Jews of Eastern European descent, the Ashkenazi Jewish community.


A cherry-red spot at the macula is a rare finding, and the epidemiology depends on the cause. Tay-Sachs disease is estimated to affect 1 in 320000 newborns. The true epidemiology of central retinal arterial occlusion is unknown. A study estimated thatꂬute central retinal arterial occlusion (duration less than 48 hours) affects approximately 0.85 per 100000 per year or 1.13 per 10000 outpatient visits.[12]

The macula is characterized histologically by an area with more than one layer of ganglion cell layers, and the ganglion cell layer is thick at the macula. In diseases causing loss of transparency (whitening or opacification) of the inner retina, the reddish color of the vascular choroid and pigmentation of retinal pigment epithelium (RPE) is not seen through the opacified retina. However, foveola is devoid of the inner retinal layer. The retinal layers present at the foveola are (from inside outwards)- internal limiting membrane, outer nuclear layer, external limiting membrane, photoreceptor layer, and RPE. Inner retinal layers are absent in mature foveola. The vascular supply of the fovea is from the choroid, and in the occlusion of retinal vessels, it does not get hampered. Thus foveola, the thinnest part of the central retina, does not lose its transparency in inner retinal ischemia.

Thus, when there is inner retinal opacification, the reddish color of the vascular choroid and the RPE is still seen through the foveola, which is surrounded by an area of the white/opacified retina this gives rise to the typical cherry-red spot. The size of the cherry-red spot depends on the size of the foveola. 

As the color of choroid and RPE varies with racial variation, the color of foveola or the central dot may change according to race. A true cherry-red spot presents in whites. The color of foveola was brown, causing a cherry brown spot in a Canadian aboriginal child with Sandhoff disease and black in a patient of east Indian race creating a cherry black spot in Sandhoff disease.[13] Thus an alternate name of 'perifoveal white patch' has been suggested.[13]

Therefore for a cherry-red spot to be seen, the vascularity of choroid needs to be intact. In cases of ophthalmic artery occlusion, there is a compromise to the vascular supply to retina, choroid, and optic nerve head circulation. There is retinal opacification without a cherry-red spot and severe vision loss, which might cause no perception of light or inaccurate projection of rays.

The opacification of inner retinal may be due to:

Sphingolipidoses are disorders of lysosomal metabolism, which involve conjugated products of ceramide and sugar or phospholipids. Sphingolipidoses include gangliosidosis, Niemann-Pick disease, Farber disease, and metachromatic leukodystrophy.


Tay–Sachs Disease

Inheritance, Distribution, and Frequency

TSD is inherited with an autosomal recessive pattern of transmission. Heterozygote carriers are entirely normal. TSD has been described in infants of all racial and ethnic groups, but historically has been identified predominantly among children of Central/Eastern European Jewish ancestry (Ashkenazim). The heterozygote frequency for TSD among Ashkenazi Jews is between 1/25 and 1/30 individuals, with a disease incidence of about 1 in 3000 births (1/27×1/27×1/4). Among general non-Jewish populations, the TSD carrier rate is approximately 1 in 300, making the disease incidence approximately 1 in 360000 births (1/300×1/300×1/4). Certain non-Jewish isolates with increased TSD have been found among the Pennsylvania-Dutch, the Cajuns of Louisiana, and some French Canadians from Quebec, Canada. Other non-Jewish isolates with TSD in China, Japan, and Morocco, also have been identified, all probable examples of genetic founder effect and drift.


Explanation of the 'cherry red spot' in Tay Sachs disease - Biology

Tay-Sachs disease (or GM2 gangliosidosis) is a genetic disorder: a rare autosomal recessive disorder that results in the accumulation of ganglioside material in neural tissue, leading to progressive mental and physical disability and death. The disorder results in the destruction of nerve cells in the brain and spinal cord.

The common infantile form starts at the age of six months and leads to death before the age of four, with the baby losing the ability to turn over, sit, or crawl this is followed by seizures, hearing loss, and inability to move. A less common juvenile form starts between the ages of two and 10 and is similarly fatal. A rare late-onset form may not be fatal, but is associated with severe disability.
The treatment is supportive in nature. This may involve multiple specialities as well as psychosocial support for the family.

The disease is named after English ophthalmologist, Waren Tay, who described the pathognomonic red spot ("cherry-red macula") in 1881, and American neurologist Bernard Sachs who described the cellular changes in 1887. Both recognized the familial nature of the condition in families with a Jewish heritage. Sachs proposed the condition be called amaurotic familial idiocy.


Classification

Medical Term Other Names Description
Seizures Epilepsy Seizures are an intermittent abnormality of the central nervous system due to a sudden, excessive, disorderly discharge of cerebral neurons and characterized clinically by some combination of disturbance of sensation, loss of consciousness, impairment of psychic function, or convulsive movements. The term epilepsy is used to describe chronic, recurrent seizures.
Ataxia Cerebellar ataxia Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Metatarsus adductus Metatarsus adductovarsus, Metatarsus varus, Forefoot varus, Intoe [more] The metatarsals are deviated medially (tibially), that is, the bones in the front half of the foot bend or turn in toward the body.
Muscle weakness Muscular weakness Reduced strength of muscles.
Hearing impairment Congenital deafness, Hypoacusis, Deafness, Hearing defect, Hearing loss, Congenital hearing loss [more] A decreased magnitude of the sensory perception of sound.
Paralysis Inability to move Paralysis of voluntary muscles means loss of contraction due to interruption of one or more motor pathways from the brain to the muscle fibers. Although the word paralysis is often used interchangeably to mean either complete or partial loss of muscle strength, it is preferable to use paralysis or plegia for complete or severe loss of muscle strength, and paresis for partial or slight loss. Motor paralysis results from deficits of the upper motor neurons (corticospinal, corticobulbar, or subcorticospinal). Motor paralysis is often accompanied by an impairment in the facility of movement.
Intellectual disability Nonprogressive intellectual disability, Poor school performance, Mental-retardation, Dull intelligence, Nonprogressive mental retardation, Mental deficiency, Mental retardation, nonspecific, Low intelligence [more] Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.

Cardiological Aspects of Systemic Disease

Robert F. English , José A. Ettedgui , in Paediatric Cardiology (Third Edition) , 2010

GM2 Gangliosidoses

The GM2 gangliosidoses result in variable deficiency of hexosaminidase, the locus for which has been mapped to the q arm of chromosome 5. This enzyme, which is composed of alpha and beta subunits, comes in two forms. Hexosaminidase A, found in the central nervous system, is composed of an alpha and beta subunit, while hexosaminidase B, found in peripheral tissues, is composed of two beta subunits. Thus, the GM2 gangliosidoses result from a defect in either the alpha subunit, producing Tay-Sachs disease and severe deficiency of hexosaminidase A, or the beta subunit, which produces Sandhoff’s disease, with severe deficiency of both types A and B of the enzyme. The juvenile and adult chronic GM2 gangliosidoses result from less severe deficiencies of hexosaminidase A. Treatment for these disorders is still under investigation and has included gene therapy, substrate reduction, and transplantation of bone marrow. 99–101

Tay-Sachs Disease

Tay-Sachs disease is the most common of the gangliosidoses. It presents with motor weakness in the first 6 months of life. There is progressive motor and mental deterioration, with convulsions, spasticity, and decerebrate rigidity. Death usually occurs by the age of 3 years, the most frequent cause being bronchopneumonia. The children have doll-like facies. Examination of the retina shows the typical cherry red macula, which later becomes brown. Cardiac accumulation of substrate is usual. Save for a prolonged QT interval and non-specific T wave changes, however, cardiac manifestations are rare. While the hallmark of the disease is accumulation of GM2 ganglioside in the central nervous system, evidence of involvement of the peripheral and autonomic nervous system has been reported in patients with chronic disease. 102

Sandhoff’s Disease

Sandhoff’s disease is similar to Tay-Sachs disease in its presentation and course, but is biochemically distinct. Clinically relevant cardiac involvement is rare, but a cardiomyopathy has been described, along with thickening of the mitral valve and its tension apparatus. 103 Another separate report described a case of congestive cardiac failure due to aortic and mitral valvar thickening with severe mitral regurgitation. 104 The coronary arteries may also be narrowed. 105 As for GM1 gangliosidoses, inheritance is autosomal recessive.


Neurologic Diseases

Tay-Sachs Disease and Sandhoff Disease

Tay-Sachs disease occurs with a deficiency of the lysosomal enzyme hexosaminidase A and results in the accumulation of GM 2 gangliosides. These gangliosides accumulate in all tissues, but the clinical symptoms are seen in those cells with the greatest accumulation. As expected from the discussion above, these cells are neurons and specifically those of the central and autonomic nervous systems as well as retinal cells.

Pathology & Histology

Histiocytes

Histiocytes are fixed cells of the immune system found in many organs and connective tissue. They are phagocytic cells of the reticuloendothelial system and may also be known as macrophages or mononuclear phagocytes. Examples include: ▪

Gaucher cells: uniformly vacuolated mononuclear, kerasin-containing cells present in the bone marrow, spleen, liver, and lymph nodes in patients afflicted with Gaucher disease

Kupffer cells: phagocytes located within the sinusoids of the normal liver

Dust cells: macrophages located in the alveoli and interalveolar spaces of the lung

Langerhans cells: dendrite-shaped cells found in the stratum spinosum of skin

Biochemistry

Gangliosides

Gangliosides are the most complex group of glycosphingolipids. These ceramide (a family of lipids composed of sphingosine and fatty acid) oligosaccharides are composed of a sugar and at least one sialic acid residue. They are the primary component of cell membranes and make up 6% of brain lipids.

Three gene products are required to form a complex resulting in the degradation of GM2 gangliosides. Hexosaminidase A is composed of an α and a β subunit and an activator—each expressed from different genes. Proper binding of this complex to the ganglioside causes hydrolysis between N-acetylgalactosamine and galactose ( Fig. 8-7 ). A mutation of the α subunit leads to a deficiency of hexosaminidase A activity. The mutation has an autosomal recessive mode of inheritance.

Normal at birth, these children develop mental and physical deterioration, blindness, deafness, and muscle atrophy followed by paralysis. A cherry-red spot of the macula is present in Tay-Sachs just as in other lipid storage diseases ( Fig. 8-8 ). In this classic presentation that begins around the fifth or sixth month, death usually occurs by age 5. Tay-Sachs disease is common in the Ashkenazi Jewish population and French Canadians. Ninety-eight percent of Tay-Sachs cases result from one of three mutations in the Ashkenazi Jewish population, thus providing a basis for carrier screening within this population.

Sandhoff disease results from a mutation in the β subunit and thus causes a deficiency in hexosaminidase A and hexosaminidase B complexes, the latter being composed of two β subunits and an activator. Tay-Sachs and Sandhoff diseases have similar presentations however, individuals with Sandhoff disease have hepatosplenomegaly and the disease is not predominant in any particular population.


The Embryo Project Encyclopedia

In 1881 British ophthalmologist Warren Tay made an unusual observation. He reported a cherry-red spot on the retina of a one-year-old patient, a patient who was also showing signs of progressive degeneration of the central nervous system as manifested in the child’s physical and mental retardation. This cherry-red spot is a characteristic that would eventually come to be associated with metabolic neurological disorders like Sandhoff, GM-1, Niemann-Pick, and, in recognition of Tay, the lysosomal storage disorder known as Tay-Sachs Disease. Tay shares the disease’s title with New York neurologist Bernard Sachs, who described the cellular changes present in the disease as well as its potential for heritability, shortly after Tay’s observation. Sachs also noted the higher occurrence of the disease in Jews of eastern and central European descent as well as the typical pattern of the disease, including early blindness, severe retardation, and death in early childhood.

Tay-Sachs disease can manifest itself in the classic infantile form or as juvenile or late-onset Tay Sach’s (LOTS) disease, both of which are less common and less severe. A single-gene disease, Tay-Sachs results in an individual who has not met certain developmental milestones, depending on the expression of the gene the disease affects. In the Classic Infantile form, the destructive process begins in the fetus early in pregnancy, though children with Tay-Sachs appear normal at birth. By the age of six months, however, development noticeably slows, with seizures and decreased mental function typically occurring by age two. A pattern of regression follows, in which the child loses the ability to crawl, sit, turn over, or reach out and becomes paralyzed, blind, cognitively impaired, and non-responsive. Additional symptoms of the disease include poor feeding, retarded development and regression, overactive reflexes (hyperreflexia), lethargy, opisthotonos (severe rigidity of the body and arching of the back), the cherry-red spot on the retina, seizures, blindness, deafness, and spasticity. In this form of the disease, death typically occurs before age five.

Individuals with the juvenile or late-onset forms of the disease do produce the enzyme that is missing in the classic infantile form, but in less than normal amounts. Thus, while the classic infantile form is characterized by a high level of GM2 ganglioside accumulation, this accumulation is less pronounced in the juvenile and LOTS forms of the disease and is restricted to the hippocampus, granular cells of the cerebellum, the nuclei of the cells of the brainstem and spinal cord, and the retina. Individuals with the juvenile form tend to develop symptoms similar to the classic infantile form between ages two and ten with death almost always occurring by age fifteen. In contrast, individuals with LOTS experience symptoms that are less severe than both the class infantile and juvenile forms. They tend to occur between adolescence and the mid-30’s and typically do not include vision or hearing loss. Symptoms of LOTS vary and can include loss of mental function, speech difficulties, muscle weakness or cramping, issues with gait, or sometimes mental illness. Life expectancy is also variable and sometimes even unaffected.

These symptoms result from the accumulation of a fatty substance in the brain due to the absence or suppression of an important enzyme known as hexosaminidase A, or Hex-A, that is a result of a mutation on both copies of the hexosaminidase A (alpha polypeptide), or HEXA, gene. As its name implies, the HEXA gene is essential to the production of the Hex-A enzyme, which is further comprised of alpha and beta subunits. Located on the long arm of chromosome 15, the HEXA gene contains genetic information that encodes for a particular protein involved in the formation of the enzyme’s alpha subunit. In 1969, Shintaro Okada and John S. O’Brien discovered that Tay-Sach’s disease was in fact linked to diminished Hex-A activity and that this event was connected to a disturbed alpha subunit, which could be identified with an enzyme assay.

The hexosaminidase A enzyme forms a complex within the lysosomes of cells that acts to break down a fatty substance known as GM2 ganglioside. This ganglioside was first characterized in the late 1930s and early 1940s by Ernst Klenk and his colleagues as an acid-containing glycosphingolipid. The inability to suppress ganglioside levels results in toxic accumulation of GM2 in the nerve cells of the brain and spinal cord, ultimately leading to their destruction and to the symptoms associated with the disease. This is why Tay-Sachs Disease is also known as GM2 gangliosidosis type 1. In 1960, Robert Terry and Saul Korey identified membranous bodies within the neurons of Tay-Sachs patients that were filled with gangliosides. The membranous bodies possessed qualities similar to lysosomes, the cellular structures responsible for degrading toxic substances. Additionally, some of the first reports of Tay-Sachs were characterized by observations of cells swollen with lipid-filled cytoplasm in the postmortem brains of affected children.

Tay-Sachs is an autosomal recessive disorder, meaning both parents must be carriers for the disease in order for one or more of their children to be affected. A carrier for Tay-Sachs disease possesses one copy of the mutated HEXA gene but is phenotypically normal. If both parents are carriers, they have a one in four chance of producing a child who is homozygous for the trait, receiving both of the mutated HEXA genes, with any given pregnancy.

Tay-Sachs Disease can be diagnosed through enzymatic testing or DNA testing, including prenatal testing by amniocentesis or chorionic villus sampling. Carrier testing and aggressive community initiatives have been effective measures of prevention. The goal of such testing is to prevent the conception or birth of at-risk babies, with termination being a commonly chosen solution. For Tay-Sachs carriers who wish to bear a normal child, in vitro fertilization followed by testing of individual blastomeres and implantation of non-affected embryos is a reliable though expensive option. As of 2010, primary research initiatives include gene therapy, the development of ganglioside inhibitors, chaperone therapy, cord blood transplant, and enzyme replacement therapy. Though no current cures exist for those born with Tay-Sachs disease, progress in the search is promising.


Tay Sachs Disease Research Paper

A mutation (or mutating) is changing a structure of a gene. Tay Sachs disease is a lethal mutation inherited as an autosomal recessive disorder, it is also known as Hexosaminidase A deficiency, GM2-Gangliosidosis, or TSD. Tay Sachs is an extremely tragic disease that has no cure. Tay Sachs was named after and discovered by english ophthalmologist Warren Tay and Jewish-American neurologist Bernard Sachs. Tay and Sach’s development and research of the disease was around the 1860’s and 1870’s. As said earlier, Tay Sachs is an autosomal recessive disorder which means two copies of the mutated gene needs to be present in order to inherit the disease. If both parents are carriers.

Infants can be diagnosed if a doctor spots a cherry-red spot in the retina of their eye, it will most likely be Tay Sachs. There is a 50% chance in every pregnancy of having a child being a TSD carrier. Most people who suffer from Tay Sachs disease is discovered to have the mutation around six months when symptoms start showing. Ashkenazi Jews are especially affected by Tay Sachs. In the United States, approximately 1 out of 27 Jews are a Tay Sachs carrier. In the non-jewish population, about 1 out of 250 people are Tay Sachs carriers. Another ethnic group affected are the people with ancestry from Ireland, they are at a risk of 1 out of 50 people. To see if you have TSD or if you are a TSD carrier you can undergo a blood plasma assay that can see differences in Hex A activity. You can basically get the test whenever you want or you might be recommended one if severe symptoms start showing. After women becomes pregnant, a test can be done to see if the baby has Tay Sachs, and whether or not the fetus has TSD there can be counseling for the parents and counseling about therapeutic pregnancy termination. There is therapy available for people with Tay Sachs that is aimed towards making the child.

A neurologist or a geneticist often make the diagnosis. Late Onset Tay Sachs disease doesn’t always shorten the diagnosed patient’s life span unlike infants or children with Tay Sachs. When an adult is diagnosed with Late Onset Tay Sachs disease they should: understand Tay Sachs and their diagnosis, keep updated in recent research, and talk to their doctor about local support groups and counseling. As far as a cure goes for Tay Sachs disease, there is none. There is also no treatments available either, but there is therapy and some medications that can help with the symptoms such as seizures. Other therapies include gene therapy, stem cell therapy, bone marrow transplant, and pharmacological or molecular chaperone therapy. Current research for Tay Sachs Disease is developing more therapies and doctors are also researching on how to “stop or slow down disease progression, reverse damage, and timeline to market.” Something that is helpful to the diagnosed person and their family is a support groups. Support groups can help you with emotional support and give you encouragement and advice. Here are some disease organizations that can provide support groups: NTSAD, Genetic Alliance, March of Dimes, National Organization for Rare Disorders. Tay Sachs is.



Comments:

  1. Kigar

    What are yours in the head?

  2. Logen

    Interesting note

  3. Zulkijora

    I posted a link to this post on my people’s site. I think many will be interested!

  4. Vukree

    Bravo, remarkable phrase and is duly

  5. Sik'is

    Yes ... Probably ... The simpler, the better ... It's just really ingenious.



Write a message