Pompe Disease- Infants and Adults

Pompe disease is alleged caused by genetic inheritance, but is it, in all cases? Might it be tipped by a predisposition caused by care during and after the child's birth? This would be by lowering the baby's red cell count, white cells, and platelets. Drugs given the mother during birth can change the mother's and the child's pH. Any upset can be devastating to both.

The lowering of the child's blood nutrients and cell count is being caused by the babies being harvested at birth for their stem cell. This is being allowed presently by the Federal and State, Provincial and Territories. This is obvious political financial policies of allowing immediate and umbilical cord clamping. This unnecessary harvesting of the baby's stem cells is a local issue that every City needs to be aware of to protect the children from harm in their own medical birth centers and hospitals. This harvesting the newborn by immediate umbilical cord clamping is a violation of duty to the child and in breach of the Human Rights Declarations. It is likely a criminal offense being protected by bogus political policies and personal interest in shares in private cord stem cell blood banks and in drug companies that make new products from the nutrients of the blood, enzymes, hormones, and so forth. Your politicians, at all levels of government, and medical institutions, colleges and universities need to be questioned. Our due process law means that this concern on a world wide public violation of trust should be in a court of law, as to the government's nations involved in this disregard to the human child.

See Red Title, "What is Pompe" below. Research by Donna Young (revised, March 2, 2004)

Pronounced: (po'm-pah or pom-pa'y) LINKS of research below. Emphasis are by the researcher, Donna

Glossary which may be of interest from World Book Dictionary, Thorndike Barnhart, 1979 :

autosomal ( o to so mal) adj. of or having to do with an autosome or autosomes.

autosome (o to som) n. Genetics, any chromosome that is not a sex chromosome (auto - Greek soma body)

chromosome (kro mo som), n. any one of the rod-shaped bodies found in the nucleus of a cell that appear when the cell divides. Chromosomes are derived from the parents and carry the genes that determine heredity, controlling the development of the organism and determining its nature. They are of a definite number for each species and occur in pairs in most organisms, except in the germ cells ( (gamete (reproduction cell), egg or sperm cells). The genetic material in each chromosome is a long polynucleotide strand, usually of deoxyribonucleic acid (DNA) but sometimes of ribonucleic acid (RNA), set in a protein matrix. (Note: Mice have an equal chromosome number to man).

chromosome number, Biology. the number of chromosomes present in a given species or organism,normally constant for each species: A recount indicates that the human chromosome number ordinarily is 46 (44 autosomes plus 2 sex chromosomes) and not 48 as believed for so long (Lorus and Margery Milne) p. 366, Vol A-K, World Book Dictionary, ed, 1979.

glycogen (gli ko jen). n. a starchlike carbohydrate stored in the liver and other animal tissues. It is changed into glucose when the body needs energy. Glycogen . . . represents chemical energy in a stored form (Harbaugh and Goodrich). French glycogene < Greek glykys sweet + French gene -gen).

glyucogenosis n. a condition affecting metabolism in young children, in which excess glycogen accumulates in one or more organs such as the liver or kidneys, making them expand greatly.

glycol. Glycol is obtained from various ethylene compounds and is used as an antifreeze for automobiles, as a solvent, and in making lacquers.

glycolate a salt or ester of glycolic acid.

glycolic acid, a colorless crystalline acid found in unripe grapes and also made synthetically, used as a catalyst.

glycosuria a condition in which glucose is present in the urine, as in diabetes; glucosuria. Greek glykys sweet + English -uria)

lecithin (les i thin). n. any one of a group of fatty substances found in plant or animal tissues. Lecithin is composed of nitrogen and phosphorus and is found especially in nerve cells and brain tissue. It is obtained from egg yolk, soybean, and corn. (Greek lekithos egg yolk + English -in)

lysis (li sis) 1. the destruction of a cell by dissolution of the cell membrane, as by a lysin or a virus.

lysogenic (li so jen ik) 1. causing the destruction of cells by dissolution of the cell membrane. 2. carrying a prophage within the cell: a lysogenic bacterium.

lysogenization n. the process of lysogenizing; fusion of the genetic material of a virus with that of a host bacterium.

lysogenize to make lysogenic, causing (bacteria) to carry a prophage within the cell.

lysolecithin n. a substance that is highly destructive of red blood cells, obtained by the action of snake venom (virus poison) on lecithin.

lysosomal (li s so mal) adj. of or having to do with lysosomes: The membrane severs to protect the rest of the cell from the contents of lysosomes, because uninhibited action of lysosomal enzymes causes cell death (London Time).

lysosome n. a particle in the cytoplasm of most cells that contains destructive, hydrolytic enzymes: The lysosomes function in many ways as the digestive system of the cell (Scientific American), (Greek lysis a loosening + soma body).

lysostaphin n. an enzyme that destroys staphylococcal bacteria by disintegrating the bacterial cell wall.

lysozyme n. a enzymelike substance that is capable of destroying many kinds of bacteria. It is found in egg white, human tears, and most body fluids. As early as 1922, researchers have known that the enzyme lysozyme, found in nasal secretions , has important bacteria-destroying powers. (Science News Letter).

NOTE : newborns are aggressively, today, syringed of their nose, for meconium or mucus. This is more than a gentle wiping down. Perhaps, this natural lysozyme defense is destroyed by the re-used syringe bulbs, or removed, altogether by the agressive syringing. Then, more harm then good, may be taking away a healthy enzyme and leaving a harmful one. Who knows? Staph infections can be spread by the cutting knives. What diseases can be spread by rubber syringe bulbs, if reused over and over again? How clean might they be? We are seeing babies with low immune system to day, and more ear and throat infections. More brain cancers, more autism, more of everything and much of the increased disorders involving the children are not being commuicated to the public as well as they ought to be.

prophage (pro faj), n. a fusion of the genetic material of a virus with that of a host bacterium, capable under certain circumstances of becoming a group of viral particles; provirus. (pro + Greek phagein eat).

prophylactic (pro fi lati tick) adj. n. adj. 1. protecting from disease:

(Donna Young's comments: To have a "natural" birth, is now considered prophylactic rather than a hospital's or medical person's often imposed, "active management". Natural birth is described as birth without drugs accepted by the mother, her choice;gravity or forward sitting or sideways birth position, not on the back or in semi-sitting birth positions; no cutting of her body, an episiotomy, or a c-section birth; but to birth in warm water (if a warm room is not assured or wrapping the baby in a warmed towel); and no clamping or cutting off the placenta and cord . . . also wrapped in a warm towel and kept close to baby. No needles of any kind inserted into the baby, for blood samples taken (such insertion allows entry of a virus even in the cleanest of hospitals). All these are the mother's right and to have these all put in a "signed" birth contract.

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In researching the pompe disease, I am wonder, if it is possible, that if the parents both have an alleged genetic disorder, if other factors of risk taking during child birth, may then lead to a predisposition to cause the child to develop the pompe disease.

Not all parents who both have the gene defect always have children who later get this disorder. Those that do, might we not investigate what of common factors during the birth of the child may have led a predisposition to then develop into pompe?

Thanks to Internet, lay persons could organize, themselves, and start to compare the birth process. They need not have a doctor head their organization, or control it. But simply organize, themselves, as doctors self-governed and organized, but as parents who are wanting to find out if anything in their or their child's birth experience, they shared in common.

Such as a common drug, for example, used in birth, is a common factor; like oxytocin. Or, early umbilical clamping that may deplete the child's enzymes in the blood; or cutting of the mother's body. A cutting will allow the risk of a virus entry. Or, did the mother have an added distress of birth positions, flat on the back and semi-sitting, this can bruise the child, cause broken ribs, and even result in a broken collar bone. What about early vaccinations, to the child, and while anemic or in distress after birth? It could be one or a combination of such unnecessary birth interventions and risk taking that is done in "active management" choices imposed on the trusting mother.

IATROGENIC DISORDERS ARE NOT TAKEN INTO CONSIDERATION IN SURVEYS:

It is interesting, all research on internal disorders, are tried to be associated with genes, or life style of the mother or father. This can be found true at any Child Development Center, or children's hospitals that are dealing with compromised children. In most instances, if there is a questionnaire, almost NEVER do the inquiries go back to review the birth care and treatment of the birthing mother and care and treatment of the neonate. Why not?

Research: If you read in between the lines of any research, ask yourself what is missing? Or, is there a conflict of interest setting one "active management" against one drug over another, but never drugs over undrugged birth choices.

Active management is time efficiency, controlled by drugs. It is the first and often the only choice of many hospital and doctors preferences. What is not offered and reasons for patience in child birth is a natural child birth: no drugs, rather a warm water birth to control labor discomfort and the mother in control of her birth position, and she catches her own baby. The mother does not permit anyone to handle the infant's umbilical cord in an invasive manner, clamping for example. She does not allow the baby out of her sight or her birth witness, and does not allow injections or blood samples taken from the baby vein. She may, allow a bit of blood from the placenta's vein, but not from the cord.

Conflict of interest is some research I have read, have left out drugs used when comparing a study with a controlled group and not allowed a controlled group who took no drugs, but had water births. Or for a blood condition present in the child, like jaundice, they attributed it to delayed clamping and left out if the mother was sick with a diabetic condition. In choosing the time period of clamping off a pulsating cord, they may only offer immediate cord clamping and 30-second clamping and not tell the mother of the fact, no harm done and she can have no clamping or cutting of the cord, at all, now called the Lotus Birth. In the event the placenta and cord were cut, the research does not state what the hospitals does with the placenta or how much blood was trapped in the placenta after it was drained out. Or report that the medicalpersons or institution was claiming the ownership of the trapped blood in the placenta, or the placenta to be sold to drug companies, research, and cosmetic companies. Why is that?

SEPARATION OF CHURCH AND STATE HAS BEEN FORGOTTEN

BY PERHAPS MANY NOW INVOLVED IN PUBLIC SERVICES SUCH AS MEDICAL SERVICES:

When selling the placenta and its contents are done, generally, without informed guardian consent, it is a violation of privacy. In some cases, it violates separation of Church and State as to government controlled hospitals and medical practices. This is because there are some with a religious conviction not to donate blood components or receive them. All persons have right of informed consent and the right to protect their baby or babies from being exploited and harvested for stem cell blood banks. That is going on, apparently, in all Nations. Governments are involved in this concealment for they have on all University Board that train doctors, on all hospital boards, and at all College of Midwives, Physicians and Surgeons, representatives of the public, that we are not violated or that best practice possible with informed consent is upheld. That is not happening in most instances in child birth, a natural event, and not a sickness, not requiring, in 93 to 95 percent of all births a hand on the birthing mother.

The hospitals and doctors, who are involved in taking the placenta and the blood trapped in it are being paid by government controlled research programs. This involves the stem cell research, governed, for example by the grant money managed by the Tri-Council of Canada, and by likely, various Provincial medical plans and grants.

Drugs are being offered to the birthing-mother without all their harmful side effects and the ingredients in them shared:

The drugs accepted or unknowingly given the mother during labor and birth must be investigated. The drugs or their ingredients or preservatives may have dissolved enzymes or the cells abilities to use enzymes. This may cause diseases like pompe.

There are so many various proteins and hormones naturally present in the blood which were created there by various glands. This presence of any drug and with low blood volume by hasty clamping, may trigger and set off the disease of those with a predisposition to developing the disease, their cell membranes vulnerable to destruction, if they already carry a defective gene.

ACCESS TO INFORMATION:

All persons have a legal right to check the hospitals records on themselves and their children. They have a legal right to get a copy of the billings for drugs and where the discarding of the placenta went. Was it burned or sent to research? What, then was the amount of blood deprived the child.

The mother can get the information to confirm facts about the drugs used, like oxytocin, pitocin. Were, these drugs or others given sometime in the child's birth process? And if, so, why were they given without informed consent. Appropriate care forms are not informed consent. They only mean a form was signed. They are nothing more.

IMPOSING DRUGS ON THE BIRTHING MOTHER:

Generally, when the baby's head is born, many doctors routinely inject the mother with oxytocins. This is sometimes done without her informed consent. The reasons to use this drug are only to cut down the third stage of labor. It is the wrong drug to stop bleeding. Other hormones do that. In fact this drug is more to increase the fear of bleeding in the mother because of harsher muscle contractions.

When done, the injection of oxytocin is then followed with 30-second umbilical cord clamping. This deprives the child of nutrients, enzymes and hormones that were in his/her placenta blood. This can be significant to put a child to the disposition of being enzyme short because of low blood volume, the nutrients and enzymes of the blood now trapped in the placenta.

Also, the child's lungs are weakened as they did not get filled up with oxygenated blood. And pompe disorder is weakness of the lungs and heart, in the infant. There is risk of IRDS, and lurking viruses by the injections to the small infant. And, perhaps, the pompe disorder too, since it deals with brain, lung and heart dysfunction in the infant.

DEPRIVATION OF PLACENTA BLOOD AND ALL ITS COMPONENTS AND NUTRIENTS --

CAN CAUSE IATROGENIC DISORDERS:

Early umbilical cord clamping is factually known to cause blood deprivation of up to 50 percent total blood volume. The baby, now anemic of nutrients and low blood volume is under distress to replace the blood volume, deprived, which can be 4 to 6 ounces deprived a 9-pound baby's 10 ounces total blood volume supply. Replacement of the blood may take 2 weeks and longer to deal with an jaundice condition, and 6 weeks to 9 months to deal with an anemic disorder. The child may never make up the means to replace the proper enzymes and the proteins and other substances of the blood for the muscles to use and release sugar. (ref: Policy #71, December 1998, SOGC).

How can we say for sure Pompe or any other internal disease is genetic, only? Question always and compare when you organize into into discussion groups what you can find out as a etiology, or common theory, or similar experiences, at birth. All research and probable cause of any internal disorder must go back to distress in child birth. Long term effects of active management in child birth is long over due.

Other LINKS are provided on the history of this disease that kills by destroying the lungs and hearts capacity to function.

What is Pompe?

Pompe is one of several diseases that stem from a genetically inherited defect of an enzyme that breaks down animal starch (glycogen) into sugar. Cells use sugar for energy. When cells break down glycogen into glucose fuel, the buildup of waste material is normally cleaned up by cell components known as lysosomes. They're like the vacuum cleaners of every cell, keeping the cell clean and uncluttered inside. Absence of this enzyme results in excess glycogen's building up in the cells as waste. Eventually, all that waste kills the muscle cell. Since the cells in children with Pompe lack the ability to readily break down glycogen into glucose sugar for energy, the cells are essentially lacking in fuel.

The cells that are most notably affected are in the heart, skeletal (especially limbs), and breathing (diaphragm) muscles. Early on, by the time the baby is observed to have weak arms and legs, the heart muscle is already severely damaged and enlarged. Eventually, the heart and muscles used for breathing weaken to the point where the child can't survive. Since this affects every muscle cell in the body, it's devastating.

The most promising research in Pompe disease is using gene therapy to get the body to produce the missing enzyme. Where did it go? Likely it was in the placenta blood deprived the baby?

Y.T. Chen of Duke University is leading the fight to produce a treatment. Early identification of a child with Pompe disease is difficult but critical to saving the child's life. By the time the diagnosis is made, much of the muscle damage, particularly of the heart, is irreversible.

The Web site http://www. pompe.org.uk has more information on Pompe disease.

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Mitchell Hecht is a physician specializing in internal medicine. Send questions to: Ask Dr. H, Box 767787, Atlanta, Ga. 30076. Due to the volume of mail, personal replies are not possible.

http://www.philly.com/mld/philly/living/columnists/mitchell_hecht/5247969.htm

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How Do You Get Pompe Disease?

http://www.unitedpompe.com/about_Pompe_disease.htm

Pompe disease is an alleged inherited as an autosomal recessive disorder. The term autosomal implies that males and females have an equal chance of being affected.

Recessive means that in order to get Pompe disease, an individual has to inherit two faulty copies of the Pompe disease (GAA) gene. Children usually inherit 1 copy of any particular gene from each parent.

The mutant GAA gene (trait) can be passed on from unaffected parents (carriers) to their children. The likelihood of children born from Pompe disease carrier parents to suffer the disease is 25% (1 out of 4). Parents who carry a faulty copy of the GAA gene also have a normal copy of the gene. One normal copy of the gene generates enough GAA activity to prevent excess storage of lysosomal glycogen.

Incidence (Frequency):

Pompe disease is very rare. The incidence, or the chance of being born with Pompe disease, is estimated at about one in every forty thousand live births. The estimated frequency of Pompe disease may vary among different ethnic groups and nationalities:

Holland: 1 in 40,000. (Adults: 1 in 57,000; Infantile: 1 in 138,000)

Southern China and Taiwan: 1 in 50,000 births

African-Americans: 1 in 14,000 births

Caucasian: 1 in 100,000

Assuming a disease frequency of 1 in 40,000 births, the number of people with Pompe disease worldwide is estimated to be somewhere between 5,000 and 10,000 cases.

Diagnosis

Pompe disease, like many other LSDs, is a rare disorder. Therefore consultation with specialists that are more familiar with this disease who use qualified laboratories to perform diagnostic tests may expedite the diagnostic process and the implementation of symptom management. Pompe disease diagnosis is usually based on, but not restricted to, the following criteria:

1. Natural history

Progressive generalized muscle weakness (All types)

Heart hypertrophy and macroglossia (Early onset)

Motor developmental delay (Prominent in Early onset) or regression of acquired motor skills (All types)

Previously diagnosed or symptomatic siblings or other relatives

2. Decreased/absent GAA activity in muscle or skin biopsies by qualified laboratories

3. Histopathology: Multivesicular PAS (+) storage in muscle tissue

4. GAA gene mutation(s) in patient's DNA .

What is Pompe Disease?

(po'm-pah or pom-pa'y)

Pompe disease is a rare genetic disorder in which a progressive muscle weakness of all muscles in the body develops as a result of glycogen accumulation or storage in cell vesicles named lysosomes.

For this reason, it is considered a Lysosomal Storage Disease or LSD.

In unaffected individuals, glycogen in the lysosomes is broken down by acid alpha-glucosidase (GAA), an important and unique lysosomal enzyme that reduces large molecules of glycogen to glucose. Individuals with Pompe disease have very little or no activity of this enzyme because of defects or mutations in the GAA gene.

Onset and Symptoms

There are two major forms of Pompe disease based on age of symptom onset, and on level of enzyme activity:

Early Onset (Infantile)

Symptoms appear shortly after birth and include an enlarged heart and liver and a severe lack of muscle tone

GAA activity in fibroblasts and muscle less than 1% of normal

Most patients die from cardiorespiratory failure or respiratory infection in the first year of life

A non-classical infantile variety is also described in which enzyme activity may be somewhat higher and heart enlargement may be present but is not generally symptomatic

Late Onset (Juvenile and Adult)

Symptoms appear in early-to-late childhood or even much later in life (between 20 to 60 years of age)

GAA activity (average relative to normal). In fibroblasts: Juveniles 4%, Adults 18% (Range 1 - 40%). In muscle: Juveniles 5%, Adults: 8% (Range 3 - 12 %)

Progression of the disease is generally slow, and the primary symptom is muscle weakness in the trunk, lower limbs and diaphragm

Some adults live their lives without major symptoms or limitations

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http://www.emedicine.com/PED/topic1866.htm

Background: Glycogen storage disease type II (GSDII), also referred to as Pompe disease, is an autosomal recessive disorder that results from the deficiency of acid alpha-glucosidase, a lysosomal hydrolase.

The disease was first described by Pompe in 1932 when he was presented with a 7-month-old girl who died after developing idiopathic hypertrophic cardiomyopathy. Pompe observed the abnormal accumulation of glycogen in all tissues examined and described the cardinal pathologic features.

There are 3 major forms of the disorder: infantile, juvenile, and adult-onset. The infantile form usually presents by age 6 months and is marked by a progressive and rapidly fatal course. In this form, involvement of cardiac, skeletal, and respiratory muscles exists. Respiratory and cardiac failure are the usual proximate causes of death.

Adult Form:

The adult form is a slowly progressive disease in which the heart is not affected. Patients with adult-onset GSDII typically present with proximal muscle weakness between the second and sixth decades of life. Similar to the infantile form, patients with the adult form ultimately succumb to respiratory failure.

The juvenile (intermediate) form includes infants and children older than 6 months who present with weakness but generally have no cardiac disease, and the clinical features overlap those of the other forms. In general, the older the age of onset, the less the likelihood of cardiac involvement.

Excessive glycogen storage within lysosomes may interrupt normal functioning of other organelles and leads to cellular injury. In turn, this leads to enlargement and dysfunction of the entire organ involved (eg, cardiomyopathy).

In the infantile form, clinically significant storage occurs in the heart, resulting in progressive cardiomegaly with left ventricular (LV) thickening that eventually leads to outflow tract obstruction.

Storage in skeletal muscle leads to hypotonia (less then normal muscle tone) and weakness.

The respiratory muscles are also affected, resulting in hypoventilation and progressive respiratory compromise.

CNS involvement primarily is limited to the anterior horn cells of the spinal cord and brain stem nuclei, although intellectual performance remains normal.

While skeletal and respiratory involvement is frequently present in the juvenile form, cardiac involvement is variable. Cardiac involvement does not exist in the adult form.

Frequency:

In the US: Frequency is estimated at 1 per 40,000 people (total) for all 3 variants of GSDII. This calculation is from estimated gene frequencies in healthy individuals from various ethnic groups.

Internationally: The frequency in Taiwan and southern China is estimated at 1 per 50,000 individuals. The frequency in the Dutch population is estimated at 1 per 40,000 individuals (1:138,000 for the infantile category). In this population, 63% carry at least 1 of the 3 common mutations.

Mortality/Morbidity:

The infantile form usually is fatal during the first year of life. As the weakness progresses, patients develop feeding difficulties and respiratory insufficiency. Enlargement of the left ventricle leads to outflow tract obstruction and ventricular failure. Death results from cardiopulmonary failure.

The juvenile (intermediate) form progresses more slowly and is uniformly fatal. Patients generally do not survive beyond the second or third decade of life. All patients have involvement of respiratory muscles, and most die of respiratory failure. Several patients are reported to have died of basilar artery aneurysm. All were found to have abnormal storage within the lysosomes of arterial smooth muscle fibers. Age of onset does not predict age of death.

Patients with the adult form may survive for decades following diagnosis. Muscle weakness may interfere with normal daily activities, and respiratory insufficiency often is associated with sleep apnea. Death usually results from respiratory failure.

Race:

Although specific alleles are identified in certain ethnic groups, no definite genotype-phenotype correlation is present.

Sex:

This is an autosomal recessive disease; therefore, it affects males and females equally.

Age:

As noted above, age of onset usually distinguishes the 3 types. Age of onset in the juvenile form may overlap both the adult and infantile forms

Complications:

The major complication among infant patients is aspiration pneumonia.

Ausems MG, Verbiest J, Hermans MP, et al: Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 1999 Sep; 7(6): 713-6[Medline].

Ausems MG, Lochman P, van Diggelen OP, et al: A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology 1999 Mar 10; 52(4): 851-3[Medline].

Bulkley BH, Hutchins GM: Pompe's disease presenting as hypertrophic myocardiopathy with Wolff- Parkinson-White syndrome. Am Heart J 1978 Aug; 96(2): 246-52[Medline].

Engel AG, Hirschhorn R: Acid maltase deficiency. In: Engel AG, Franzine-Armstrong C, eds. Myology: Basic and Clinical. New York: McGraw-Hill; 1996: 1533-53.

Engel AG, Gomez MR, Seybold ME, Lambert EH: The spectrum and diagnosis of acid maltase deficiency. Neurology 1973 Jan; 23(1): 95-106[Medline].

Hirschhorn R: Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver CR, Beaudet AL, Sly W, Valle E, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill; 1995: 2443-64.

Isaacs H, Savage N, Badenhorst M, Whistler T: Acid maltase deficiency: a case study and review of the pathophysiological changes and proposed therapeutic measures. J Neurol Neurosurg Psychiatry 1986 Sep; 49(9): 1011-8[Medline].

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Background: A glycogen storage disease (GSD) is the result of an enzyme defect.

These enzymes normally catalyze reactions that ultimately convert glycogen compounds to glucose.

Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.

Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, GSD type 0 also is described, which is due to defective glycogen synthase.

These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations recently have been reported for each disorder.

Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.

Diagnosis depends on findings from muscle biopsy, electromyography, ischemic forearm testing, creatine kinase testing, patient history, and physical examination. Biochemical assay for enzyme activity is the method of definitive diagnosis.

Phosphofructokinase catalyzes the rate-limiting step in glycolysis. Phosphofructokinase deficiency leads to muscle pain and exercise-induced fatigue and weakness. Tarui disease resolves with rest, and, although no specific treatment exists, the condition may not progress to severe disability.

Pathophysiology: With an enzyme defect, carbohydrate metabolic pathways are blocked and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect, and each enzyme is in specific or most body tissues. Phosphofructokinase catalyzes the rate-limiting step in glycolysis.

Enzyme deficiency decreases the rate of conversion of fructose-6-phosphate to fructose-1,6-diphosphate.

Phosphofructokinase is found in muscle tissue and red blood cells.

Tarui disease is an autosomal recessive condition.

Frequency:

Internationally: Herling and colleagues studied the incidence and frequency of inherited metabolic conditions in British Columbia. GSDs are found in 2.3 children per 100,000 births per year.

Mortality/Morbidity:

As in McArdle disease, immediate morbidity arises from exercise intolerance.

Race:

The disease appears to be prevalent among people of Ashkenazi Jewish descent.

Age:

In general, GSDs present in childhood. Later onset correlates with a less severe form. Consider Pompe disease if onset is in infancy.

http://www.emedicine.com/med/topic913.htm

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There has been more than a one hundred-year history of the clinical evolution and delineation of lysosomal storage disorders.

The earliest report of the clinical features of a lysosomal storage disorder was in 1881 when the British ophthalmologist, Warren Tay, described symptoms of retinal abnormalities in a 12-month old infant with 'very little power of holding its head up and moving its limbs'.

In 1896 an American neurologist, Bernard Sachs, provided more detail of the neurological aspects of the disorder described earlier by Tay. This disorder soon became know as Tay-Sachs syndrome (or disease) and was identified as a lysosomal storage disorder in 1969.

One year after Tay's report of what we now believe was a patient with Tay-Sachs disease, Phillippe Gaucher described a condition he believed to be an epithelioma (cancer of the skin) of the spleen with manifestations in other organs that eventually became known as Gaucher disease. Charles Hunter described the first mucopolysaccharidosis patient in 1917, which subsequently became known as Hunter syndrome.

Throughout the early- and mid-1900s clinical observers continued to describe different syndromes that were later identified as lysosomal storage disorders. However, it was not until the 1960s and 70s that these syndromes were recognized as lysosomal storage disorders following the identification of deficiencies in the function of specific lysosomal enzymes and the subsequent storage of specific substrates in the lysosome.

Identification of the nature of these substrates aided the accurate diagnosis of each condition and led to the recognition that the number of lysosomal storage disorders differed from what was previously believed. For instance, Sanfilippo syndrome was first described as a single disorder in 1963, but was shown in the 1970s to be caused by a deficiency in functional activity in any one of four different enzymes.

Sanfilippo syndrome is now recognized as four distinct sub-types: types A, B, C and D. Another example, Hurler syndrome (first described in 1919), and Scheie syndrome (described in 1962) were thought to be separate diseases, but were shown in the 1970s to result from a deficiency in the same enzyme, a-L-iduronidase.

In many instances, the medical discovery of disorders now referred to as lysosomal storage disorders preceded the scientific identification of the lysosome as a recycling center and the specific protein deficiencies by more than 30 years. The term 'lysosomal storage disorder' was not recognized until the 1960s when the Dutch scientist, Hers, linked Pompe disease to a deficiency of a lysosomal protein called alpha-glucosidase, which is required to break down glycogen in the lysosome .

This connection was preceded by the work of De Duve and co-workers who first described lysosomes as sac-like structures containing a range of proteins or enzymes needed to break down complex materials.

This key observation in the development of the concept of lysosomes, together with the observations of Novikoff and others led to the recognition of an overall cellular network that includes the endoplasmic reticulum, the Golgi apparatus, endosomes, secretory vesicles and lysosomes. This network is involved in the assembly and maintenance of the lysosome.

These examples and many others provided a very productive period of investigation in the 1980s that led to a much clearer understanding of the clinical, biochemical and genetic nature of lysosomal storage disorders. Many of the specific proteins involved in disorders recognized as lysosomal storage disorders were purified and their genes isolated in the 1980s and 90s. The past 10 years have seen a rapid expansion of knowledge through the identification of mutations in the genes that lead to storage in lysosomes and cause the clinical problems associated with these disorders.

This last 10 years has also seen acceptance into clinical practice and trial, successful and potentially successful therapies (bone marrow transplantation and enzyme replacement therapy) for the treatment of some lysosomal storage disorders.

The next decade will see the introduction of a number of successful therapies into the clinic and the development of newborn screening to enable early detection of these disorders. Early detection of lysosomal storage disorders is an integral part of a process to maximize the benefits of effective therapies by having them introduced at a time before the onset of irreversible symptoms.

http://www.tkt5s.com/html/lysosomal/lys_history.html

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Contact for comments: Donna Young