Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

infants with milder symptoms living longer. One infant with MGS lived until four months of age. Another lived to seven months of age after surgical repair of a small encephalocele. At birth he had cystic kidneys but normal kidney function. These two case reports show that longer survival is rare but possible because of the variable expression of MGS.

Resources

PERIODICALS

Salonen, R. and P. Paavola. “Meckel Syndrome.” Journal of

Medical Genetics 35 (1998): 497–502.

ORGANIZATIONS

Meckel-Gruber Syndrome Foundation. http://www.meckelgruber.org .

Amie Stanley, MS

Mediterranean anemia see

Beta-thalassemia

Medium-chain acyl-coenzyme A see

MCAD deficiency

Melnick-Fraser syndrome see

Branchiootorenal syndrome

I Menkes syndrome

Definition

Menkes syndrome is a sex-linked recessive condition characterized by seizures and neurological deterioration, abnormalities of connective tissue, and coarse, kinky hair. Affected males are often diagnosed within the first few months of life and die in early childhood.

Description

Menkes syndrome is also known as Menkes disease and “kinky hair syndrome.” It was originally described in 1962 based on a family of English and Irish descent who had five male infants with a distinctive syndrome of progressive neurological degeneration, peculiar hair, and failure to thrive. Each of the boys appeared normal at birth but, by the age of several months, developed seizures and began to regress in their physical skills. Each child died at an early age, with the oldest surviving only until three-and-a-half years. In 1972, Menkes syndrome was linked to an inborn copper deficiency. It is now clear that this lack of copper, an essential element

for normal growth and development, inhibits the work of specific enzymes in the body. The clinical signs and symptoms of Menkes syndrome are a direct result of these biochemical abnormalities.

Approximately 90–95% of patients with Menkes syndrome have a severe clinical course. This represents classical Menkes syndrome. Males with milder forms of Menkes syndrome have also been described. The mildest presentation is now known as occipital horn syndrome (OHS), which is allelic to Menkes syndrome: both conditions are due to different mutations in the same gene. Mutations responsible for OHS primarily cause connective tissue abnormalities and have significantly milder effects on intellectual development. Individuals with OHS also live longer than those with classical Menkes syndrome.

Genetic profile

Menkes syndrome is an X-linked recessive condition. The gene, which was identified in 1992, is located on the long arm of the X chromosome at band 13.3 (Xq13.3). It is extremely unusual for a female (with two X chromosomes in her cells) to be affected, although it has been reported. Males, who have only one X chromosome, make up the overwhelming majority of patients.

Approximately one-third of affected males are due to a new mutation in the mother’s egg cell. There is usually a negative family history, or no other affected male family members. When the mutation occurs as an isolated, random change, the mother’s risk of having another affected son is low.

On the other hand, the remaining two-thirds of affected males are born to carrier mothers. Often, there is a family history of one or more affected male relatives (e.g., uncle, brother, cousin), all of whom are related to one another through the maternal side. Carrier females are normal but face a risk of passing on the gene for Menkes syndrome to their children. A carrier mother has a 25% risk of having an affected son, 25% risk of having an unaffected carrier daughter, 25% risk of having a normal son, and a 25% risk of having a normal, non-carrier daughter. These risks apply to each pregnancy.

The Menkes syndrome gene, also known as MNK or ATP7A, is a large gene known to encode a copper-trans- porting protein. Individuals with Menkes syndrome have low levels of copper in their blood. Their cells are able to take in copper but the metal is unable to leave the cell and be delivered to crucial enzymes that require copper in order to function normally. As a result, copper accumulates in the body tissues, and clinical abnormalities occur. Most symptoms of Menkes syndrome, such as skeletal changes and abnormal hair, may be explained by the loss

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of specific enzymes. However, the reasons for the brain degeneration are still not entirely clear.

A variety of mutations that cause Menkes syndrome have been identified in the MNK gene. Unfortunately, almost every family studied has had a unique mutation. This makes genetic testing difficult, particularly if the mutation in the family has not yet been determined. OHS is also due to mutations in the MNK gene.

Demographics

Menkes syndrome is relatively rare, with an estimated incidence of one in 100,000–250,000 male births. To put this into a different perspective, among the 3.5 million infants born annually in the United States, approximately 15–35 males would have Menkes syndrome.

Signs and symptoms

Infants with classical Menkes syndrome appear normal at birth and continue to develop normally for roughly the first eight to ten weeks of life. At approximately two to three months of age, affected infants begin to lose previously attained developmental milestones, such as head control and a social smile. They lose muscle tone and become hypotonic, or floppy, develop seizures, and begin to fail to thrive. Changes in the appearance of their face and hair become more apparent. A diagnosis of Menkes syndrome is often made around this time.

The clinical features of Menkes syndrome include:

Neurologic

•Mental deterioration and handicap due to structural and functional brain abnormalities

•Seizures

•Inability to regulate body temperature (hypothermia)

•Feeding and sleeping difficulties

Connective tissue

•Decreased muscle tone

•Tortuous blood vessels due to abnormal formation of blood vessel walls

•Abnormalities of bone formation, as noted by x ray (skull, long bones, and ribs)

•Bladder diverticulae

•Loose skin, particularly at the nape of neck, under the arms, and on the trunk

•Loose joints

Other

•Unusual facial features (jowly, pudgy cheeks, large ears)

•Abnormal hair, including the eyelashes and eyebrows

•Light, even for family, skin and hair coloring (hypopigmentation)

•Delayed eruption of teeth

•Impaired vision

•Normal hearing

The hair of individuals with Menkes syndrome deserves special discussion, particularly since this condition is sometimes also called kinky hair syndrome. Abnormal hair is not typically evident during the first few months of life. However, around the time that the other physical signs of the disorder become more apparent, the hair takes on an unusual appearance and texture. On magnified inspection, it is short, sparse, coarse, and twisted. It has been likened to the texture of a steel wool cleaning pad. It shows an unusual orientation, referred to as pili torti, a 180 degree twist of the hair shaft. It is usually fragile and breaks easily. The hair of all affected individuals shows these characteristic changes; it is likewise present in some women who are known gene carriers.

Death occurs early in males with Menkes syndrome, often by the age of three years in classical disease. However, longer survival is not unusual and is most likely due to more recent improvements in medical care. Severity of disease and its rate of progression are fairly consistent among untreated males in a single family.

Diagnosis

An initial diagnosis of Menkes syndrome is usually suspected based on the combination of physical features. However, as these features are generally subtle in the newborn period, they may be missed, particularly if there is no prior family history of the condition.

A somewhat common prenatal and newborn history has been recognized among affected infants. The histories often include: premature labor and delivery; large bruises on the infant’s head after an apparently normal, uncomplicated vaginal birth; hypothermia; low blood sugar (hypoglycemia); and jaundice. Hernias may be present at either the umbilicus or in the groin area. These findings are non-specific and occur in normal pregnancies and unaffected infants. However, their presence may alert a knowledgeable physician that Menkes syndrome should be considered as a possibility, especially when other clinical signs are also present.

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A clinical diagnosis is strongly supported by decreased serum levels of copper and ceruloplasmin, a protein in the blood to which the majority of copper is attached. Abnormal results, however, do not confirm the diagnosis since both copper and ceruloplasmin levels may also be low in normal infants during the first few months of life. A definitive diagnosis of Menkes syndrome is possible by either specific biochemical analysis to measure the level of copper accumulation in the cells or by identification of the responsible mutation in the MNK gene. Both types of analysis represent highly specialized testing and are available only through a limited number of laboratories in the world.

Prenatal diagnosis, in the context of a family history of the disorder, is possible. Ideally, a woman’s carrier status will have been determined prior to a pregnancy as carrier detection may be difficult and time-consuming. Mutation analysis is the most direct and accurate way to determine carrier status. In order for this to be possible, the MNK mutation in an affected family member must have been previously determined. Linkage analysis is another possibility but requires blood samples from other family members, including the affected relative, to facilitate interpretation of results. If the affected relative is deceased, a stored DNA sample may be used.

Other, non-molecular methods of carrier detection include analysis of hair samples to look for areas of pili torti, increased fragility, or hypopigmentation. Skin cells cultured in the laboratory may be used to measure the accumulation of radioactive copper. However, these approaches are not always reliable, even in known carriers.

If a woman is found to be a non-carrier, prenatal testing for Menkes syndrome is generally not necessary in any of her pregnancies. However, in the event that a woman is a confirmed carrier, prenatal testing such as chorionic villus sampling (CVS) or amniocentesis may be offered. Ultrasound examinations alone will not assist in making a diagnosis. CVS or amniocentesis will determine the fetal sex: if female, additional testing is usually not recommended since carrier daughters would be expected to be normal. Carrier testing on the daughter may be performed after birth, if desired, or postponed until later in life.

Further testing is offered when a fetus is male. If mutation studies cannot be performed because the mutation in the family is unknown, biochemical analysis may be attempted. Biochemical testing has serious drawbacks, and a correct diagnosis may not always be possible. Tissue obtained during CVS normally has a very low copper content and is also very susceptible to contamination by maternal tissue or by outside sources, such as laboratory instruments or containers. As a result, if the

K E Y T E R M S

Catecholamines—Biologically active compounds involved in the regulation of the nervous and cardiovascular systems, rate of metabolism, body temperature, and smooth muscle.

Connective tissue—A group of tissues responsible for support throughout the body; includes cartilage, bone, fat, tissue underlying skin, and tissues that support organs, blood vessels, and nerves throughout the body.

Diverticulae—Sacs or pouches in the walls of a canal or organ. They do not normally occur, but may be acquired or present from birth. Plural form of diverticula.

Enzyme—A protein that catalyzes a biochemical reaction or change without changing its own structure or function.

Jaundice—Yellowing of the skin or eyes due to excess of bilirubin in the blood.

Linkage analysis—A method of finding mutations based on their proximity to previously identified genetic landmarks.

Tortuous—Having many twists or turns.

copper level exceeds a certain level, an unaffected pregnancy could potentially be falsely identified as affected. Specific handling precautions are necessary to minimize this risk.

Similar concerns exist for a sample obtained by amniocentesis. Ordinarily, the cells obtained from this procedure are cultured and grown in the laboratory. A measurement is taken of the total amount of accumulated copper over a certain period. The timing of amniocentesis in the pregnancy is critical because the amniotic fluid cells do not grow as rapidly after a gestational age of 18 weeks. Problems in cell growth cause significant difficulties in the interpretation of the biochemical results.

Other methods of diagnosis are being investigated. Two that hold some promise are assessment of the concentration of copper in a sample of the placenta (extremely high in affected pregnancies) and the level of catecholamines (low) in a sample of blood from the umbilical cord. Both methods, which are fast, reliable, and performed immediately after delivery, clearly require a high level of suspicion of the disorder. In most cases, this will be based on a history of a previous affected son, abnormal or unclear prenatal testing results, or both.

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Women who do not have a family history of Menkes syndrome and are therefore not expected to be at-risk, are not offered this testing.

Treatment and management

The underlying, critical problem for patients with Menkes syndrome is an induced copper deficiency. Copper uptake is normal but the gene abnormality prevents the release of copper to the appropriate enzymes in the cells. Copper accumulates in the intestinal system, and patients are unable to meet their most basic nutritional needs. The most serious effects are apparent during the first year of life when growth of the brain and physical development are occurring most rapidly. Copper is required in order for both of these processes to occur normally.

Treatment of Menkes syndrome has focused on providing patients with an extra source of copper to try to deliver it to the enzymes that need it for normal function. Studies at the National Institutes of Health (NIH) have focused on the use of a copper-histidine compound in affected males. Copper-histidine is normally present in human serum and is most likely the form in which copper is absorbed by the liver. Also, in the laboratory, the presence of histidine in serum has been shown to increase the uptake of copper. Daily injections are the most successful form of treatment to date.

Two conclusions have been drawn from this work:

(1) Treatment is more successful when started at an early age. Most, but not all, treated boys have achieved more normal developmental milestones and have had milder mental impairment. (2) Treatment is much less effective if started after the age of several months, or when neurologic symptoms have already begun. While milder improvements in the areas of physical development, personality, and sleeping habits have been reported in boys whose treatment started later, the degree of mental handicap has not been significantly altered.

A separate study in 1998 lent further support to these results. This study followed four affected males with classical Menkes syndrome, all of whom were started on copper-histidine treatment soon after birth. Three of the four males were born into families with other affected relatives; the fourth child was diagnosed at the age of three weeks. All four showed significant improvements in their development and clinical course. None were completely normal but their remaining clinical abnormalities were similar to those seen in patients with occipital horn syndrome. The oldest survivor of the group was 20 years old at the time of this publishing.

This information strongly supports the importance of nutritional therapy in the care of patients with Menkes

syndrome. Early treatment is best but requires early diagnosis. It should also not be seen as a “cure.” It has been shown to lessen the severity of the syndrome but not eliminate it. Thus, prenatal diagnosis, and its possible limitations, should continue to be discussed with prospective parents known to be at risk. Mutation studies should be performed, whenever possible, to increase the accuracy of testing results.

Prognosis

Death often occurs by the age of three years in untreated males with classical Menkes syndrome, although longer-term survivors have been reported. Treatment with supplemental copper has resulted in improved physical development, milder mental handicap, and extended lifespan in some affected males. However, not all patients have responded to the same extent. Additionally, patients treated after the onset of symptoms have done worse than those treated before symptoms occur. Research is continuing to refine the best dosage of copper-histidine, determine the optimal timing and route of treatment, and develop newer treatment strategies.

Resources

BOOKS

Jones, Kenneth L., ed. Smith’s Recognizable Patterns of Human

Malformations. 5th ed. Philadelphia: W.B. Saunders Company, 1997.

PERIODICALS

Christodoulou, John, David M. Danks, Bibudhendra Sarkar, Kurt E. Baerlocher, Robin Casey, Nina Horn, Zeynup Tumer, and Joe T.R. Clarke. “Early treatment of Menkes disease with parenteral copper-histidine: Long-term fol- low-up of four treated patients.” American Journal of Medical Genetics 76, no. 2 (March 5, 1998): 154–64.

Kaler, Stephen G. “Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency.” American Journal of Clinical Nutrition 67 supplement(1998): 1029S–34S.

Kaler, Stephen G. and Zeynup Tumer. “Prenatal diagnosis of Menkes disease.” Prenatal Diagnosis 18 (1998): 287–89.

Tumer, Zeynup and Nina Horn. “Menkes disease: Underlying genetic defect and new diagnostic possibilities.” Journal of Inherited Metabolic Disease 21, no. 5 (August 1998): 604–12.

ORGANIZATIONS

Corporation for Menkes Disease. 5720 Buckfield Court, Fort Wayne, IN 46814. [phone].

WEBSITES

“Menkes syndrome.” U.S. National Library of Medicine. National Institutes of Health. http://www.nlm.nih.gov/ mesh/jablonski/syndromes/syndrome422.html .

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“NINDS Menkes Disease Information Page.” National Institute of Neurological Disorders and Stroke. http://www.ninds

.nih.gov/health_and_medical/disorders/menkes.htm . Online Mendelian Inheritance in Man.

http://www.ncbi.nlm.nih.gov .

Terri A. Knutel, MS, CGC

Mental retardation see Smith-Fineman-

Myers syndrome

Mental retardation X-linked, syndrome 3 (MRXS3) see Sutherland Haan X-linked mental retardation syndrome

Mermaid syndrome see Sirenomelia

I Metaphyseal dysplasia

Definition

Metaphyseal dysplasia is a very rare disorder in which the outer part of the shafts of long bones is unusually thin with a tendency to fracture. Aside from valgus knee deformities (commonly known as knock-knee), many patients with metaphyseal dysplasia exhibit few or no symptoms. However, the disorder comes in a variety of forms, some of which cause serious problems including mental retardation, blindness, and deafness.

Description

Metaphyseal dysplasia is frequently mistaken for craniometaphyseal dysplasia, a disorder characterized by the thickening of the bones of the head. Metaphyseal dysplasia is genetically distinct from craniometaphyseal dysplasia and has only mild effects on the skull. In fact, metaphyseal dysplasia is so subtle, often it cannot be detected by clinical observation and is uncovered only when x rays are taken for another purpose. The signs are immediately visible on x rays, however, particularly the cone-like flaring that occurs on the tubular bones of the leg. This flaring is similar in shape to the Erlenmeyer glass flasks used in laboratories.

Another name for metaphyseal dysplasia is Pyle’s disease, after Edwin Pyle (1891-1961), an orthopedic surgeon in Waterbury, CT who first described it in 1931.

There are eight varieties of metaphyseal dysplasia. They are classified as: Jansen type, Schmid type, McKusick type, metaphyseal anadysplasia, Shwachman Diamond metaphyseal dysplasia, adenosine deaminase

deficiency, Spahr type metaphyseal chondrodysplasia, and metaphyseal acroscyphodysplasia.

Genetic profile

Inheritance of metaphyseal dysplasia is autosomal recessive, meaning that both parents are carriers of an abnormal gene when a child exhibits symptoms. Children inheriting the gene from one parent become carriers. When both parents are carriers, each child has a 25% chance of having the disorder and a 50% chance of being a carrier. In the case of Jansen-type metaphyseal dysplasia, the chromosomal gene locus is 3p22-p21.1. In Schmid type metaphyseal dysplasia, the locus is 6q21q22.3. For McKusick type (cartilage-hair hypoplasia), it is 9p13. In adenosine deaminase deficiency, the locus is 20q-13.11. The modes of inheritance for Jansen type, Schmid type, and adenosine deaminase deficiency are all autosomal dominant, meaning that a child may inherit the disorder if just one parent is a carrier. For all other varieties of metaphyseal dysplasia the modes are autosomal recessive, with the possible exception of metaphyseal anadysplasia, which may be X-linked recessive. In that case, whenever one parent is a carrier of the disorder, each child would have a chance of either inheriting it or being a carrier.

Demographics

This disorder is very rare, and the number of recorded cases is too small to draw firm demographic conclusions. There appears to be no preference based on sex.

Signs and symptoms

The characteristic sign of metaphyseal dysplasia is splaying of the long bones, more severely than in craniometaphyseal dysplasia. Gross Erlenmeyer flask flaring is seen in the tubular bones of the leg, particularly in the femur. Unlike craniometaphyseal dysplasia, few signs occur in the skull in metaphyseal dysplasia, apart from protrusions over the eye sockets.

Metaphyseal dysplasia is also marked by expanded bones of the rib cage and pelvis, and by changes in the angle of the lower jaw. The humerus bone of the arm tends to be unusually broad. Other signs include scoliosis (a sideways curvature of the spine) and osteoporosis (a condition that makes bones brittle). Patients may complain of muscle weakness or joint pain. Dentists may notice malocclusion, an inability of the teeth to properly close. Some spinal changes are possible, associated with the flaring of tubular bones. These may include platyspondyly, a broadening of the vertebrae.

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K E Y T E R M S

Carrier—A person who possesses a gene for an abnormal trait without showing signs of the disorder. The person may pass the abnormal gene on to offspring.

Dysplasia—The abnormal growth or development of a tissue or organ.

Splay—Turned outward or spread apart.

Jansen type

In addition to the above-mentioned signs, Jansentype metaphyseal chondrodysplasia is characterized by short arms, legs, and stature (short-limbed dwarfism), which become apparent during early childhood. Affected children experience a gradual stiffening and swelling of their joints. Often, they develop a characteristic “waddling gait” and a stance that appears as if they were squatting. Some facial abnormalities may be evident at birth. These include prominent, widely spaced eyes, a receding chin, or a highly arched palate. Some affected adults develop unusually hardened bones in the back of the head, which sometimes results in deafness and/or blindness. Abnormal cartilage development may harden into rounded bone masses that may be noticeable on the hands, feet, and elsewhere. Other signs and symptoms associated with Jansen-type metaphyseal chondrodysplasia include clubbed fingers, a fifth finger permanently fixed in a bent position, fractured ribs, mental retardation, psychomotor retardation, and high blood levels of calcium. Curvature of the spine in these patients may be front-to-back as well as sideways. Testing the blood and urine for calcium can assist in confirming a diagnosis. Jansen-type metaphyseal chondrodysplasia was formerly referred to as metaphyseal dysostosis.

Schmid type

Like Jansen-type metaphyseal chondrodysplasia, Schmid type metaphyseal chondrodysplasia is also characterized by short-limbed dwarfism. Other special features may include an outward “flaring” of the lower rib cage, bowed legs, leg pain, a normal spine, and a hip deformity that causes the thigh bone to angle toward the body’s center. Schmid type metaphyseal chondrodysplasia was first discovered in 1943 in a family of Mormons that had experienced 40 cases of the disorder over four generations. The first affected ancestor was traced back to 1833.

McKusick type

Like Jansen type and Schmid type, McKusick type metaphyseal chondrodysplasia is marked by short-limb dwarfism. Other features include thin, light-colored hair, loose-jointed fingers, elbows that cannot be fully extended, Hirschsprung disease (a birth defect in which the usual nerve network fails to develop around the rectum, and in some cases, the colon), and abnormalities of the immune system. In the shin, the tibia bone is uncharacteristically shorter than the fibula. Patients are at increased risk of developing cancers, especially of the skin and the lymph nodes. McKusick type metaphyseal chondrodysplasia is also known as cartilage hair hypoplasia syndrome. The disorder was first recognized in 1965 among the Old Order Amish. Billy Barty (19242000), the actor who founded the dwarfism advocacy group Little People of America, had McKusick type metaphyseal chondrodysplasia.

Metaphyseal anadysplasia

First noticed in 1971, metaphyseal anadysplasia is a form of metaphyseal dysplasia that starts early. Instead of appearing after puberty, some signs were found to be present at birth, but disappeared after two years. For example, parts of the long bones were irregular. In the thigh bones of these patients, there was an unusually low level of red blood cell production.

Shwachman-Diamond syndrome

In addition to the skeletal system, ShwachmanDiamond syndrome also affects the pancreas. It is characterized by inadequate absorption of fats because of abnormal pancreatic development and bone marrow dysfunction. Other unusual symptoms and signs include short stature, liver abnormalities, and low levels of any or all blood cells. Reduced levels of white blood cells may cause these patients to be vulnerable to repeated bouts with pneumonia, otitis media, and other bacterial infections. Shwachman-Diamond syndrome is also referred to as Shwachman-Bodian syndrome, Shwachman-Diamond- Oski syndrome, Shwachman syndrome, and congenital lipomatosis of the pancreas. Some researchers call it pancreatic insufficiency and bone marrow dysfunction.

Adenosine deaminase deficiency

A deficiency of Adenosine deaminase (ADA), an essential, broadly distributed enzyme, causes severe combined immunodeficiency disease. This can bring about a wide range of effects, including asthma, pneumonia, sinusitis, diarrhea, problems with the liver, kidneys, spleen and skeletal system, and failure to thrive. ADA deficiency is similar to McKusick type metaphyseal

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chondrodysplasia in that both disorders include skeletal changes and problems with cellular immunity. ADA deficiency earned a special place in genetics history in 1990, when, in the first application of gene therapy in humans, it was corrected using genetically engineered blood.

Spahr type metaphyseal chondrodysplasia

This is one of several disorders that used to be called metaphyseal dysostosis. It is extremely rare, and its features include severely bowed legs and short-statured dwarfism. In some cases, the bowing of the knees is so severe as to require surgical correction. Spahr type is very similar to Schmid type metaphyseal chondrodysplasia, except that inheritance is believed to be autosomal recessive in Spahr type, unlike Schmid type, which is autosomal dominant.

Metaphyseal acroscyphodysplasia

This variety is also referred to as wedge-shaped epiphyses of the knees. Its special features include severely retarded growth, psychomotor retardation, abnormally small arms and legs, extremely short fingers, and curvature of the knees.

Diagnosis

Diagnosis is usually by x ray, in which the bone deformities of metaphyseal dysplasia are very noticeable, even if not apparent in a normal clinical examination. A medical doctor will look for valgus knee deformities. A radiologist will look for Erlenmeyer-flask shaped femur bones and ensure that any deformities to cranial bones are minor, to rule out craniometaphyseal dysplasia. The radiologist will also watch for abnormally broad humerus, radius, and ulna bones.

Treatment and management

Metaphyseal dysplasia cannot be directly treated, but some individual symptoms, such as osteoporosis or joint problems, may be treated or surgically corrected.

Prognosis

In many cases, patients with metaphyseal dysplasia may be symptomless and very healthy. Other patients, including those with Jansen-type metaphyseal chondrodysplasia, may have more severe complications including blindness, deafness, or mental retardation.

Resources

PERIODICALS

Pyle, E. “Case of unusual bone development.” Journal of Bone and Joint Surgery (1931): 3: 874-876.

Raad, M. S., and P. Beighton. “Autosomal recessive inheritance of metaphyseal dysplasia (Pyle disease).” Clinical Genetics (1978) 14: 251-256.

Turra. S., C. Gigante, G. Pavanini, C. Bardi. “Spinal involvement in Pyle’s disease.” Pediatric Radiology (January 2000) 25-27.

David L. Helwig

I Methylmalonic acidemia

Definition

Methylmalonic acidemia (MMA) is a group of disorders characterized by the accumulation of methylmalonic acid in the fluids of the affected individual. The first recognized cases of these disorders were described in 1967. All known genetic forms of MMA are non-sex linked (autosomal) and recessive. Some non-genetic cases have been reported in which the affected individuals were vegetarians who had been on prolonged cobalamin (vitamin B12) deficient diets.

Description

Methylmalonic acidemia (MMA) is characterized by an accumulation of methylmalonic acid in the blood stream, which leads to an abnormally low pH (high acidity) in nearly every cell in the body (metabolic acidosis). A higher than normal accumulation of ketones in the blood stream (ketosis) similar to that seen in instances of diabetes mellitus is also associated with MMA. If left untreated, metabolic acidosis is often fatal.

Methylmalonic acid is an intermediate in the metabolism of fats and proteins. This chemical accumulates in the bodies of individuals affected with MMA because of a partial or complete inability of these individuals to convert methylmalonyl-CoA to succinyl-CoA in the tricarboxlic acid (TCA) cycle.

MMA is one of the genetic disorders that cause problems with mitochondrial metabolism. The mitochondria are the organelles inside cells that are responsible for energy production and respiration at the cellular level. One of the most important processes in the mitochondria is the TCA cycle (also known as the Krebs cycle). The TCA cycle produces the majority of the ATP (chemical energy) necessary for maintenance (homeostasis) of the cell. When blood sugar (glucose) is broken down in preparation to enter the TCA cycle, it is broken down into a chemical known as acetyl-CoA. It is this acetyl-CoA that is then further broken down in the TCA cycle to yield

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K E Y T E R M S

Apoenzyme—An enzyme that cannot function without assistance from other chemicals called cofactors.

ATP—Adenosine triphosphate. The chemical used by the cells of the body for energy.

Cofactor—A substance that is required by an enzyme to perform its function.

Ketosis—An abnormal build-up of chemicals called ketones in the blood. This condition usually indicates a problem with blood sugar regulation.

Metabolic acidosis—High acidity (low pH) in the body due to abnormal metabolism, excessive acid intake, or retention in the kidneys.

Methylmalomic acid—An intermediate product formed when certain substances are broken down in order to create usable energy for the body.

Sudden infant death syndrome (SIDS)—The general term given to “crib deaths” of unknown causes.

TCA cycle—Formerly know as the Kreb’s cycle, this is the process by which glucose and other chemicals are broken down into forms that are directly useable as energy in the cells.

carbon dioxide, water, and ATP. When some fatty acids and certain amino acids from proteins (specifically isoleucine, valine, threonine, methionine, thymine, and uracil) are broken down in preparation to enter the TCA cycle, they are broken down into propionyl-CoA, rather than acetyl-CoA. This propionyl-CoA is then converted into methylmalonyl-CoA, which is next converted to suc- cinyl-CoA. It is succinyl-CoA that enters the TCA cycle to eventually yield carbon dioxide, water, and the ATP needed by the cells.

The conversion of methylmalonyl-CoA to succinylCoA involves the apoenzyme methylmalonyl-CoA mutase. An apoenzyme is an enzyme that cannot function without the aid of other chemicals (cofactors). One of the cofactors for this apoenzyme is cobalamin (vitamin B12). Genetic MMA is a result of either a deficiency in the methylmalonyl-CoA mutase apoenzyme or a defect in the mechanism inside the cells that converts dietary vitamin B12 into its useable form for this chemical reaction.

An enzyme is a chemical that facilitates (catalyzes) the chemical reaction of another chemical or of other chemicals; it is neither a reactant nor a product in the

chemical reaction that it facilitates. As a result, enzymes are not used up in chemical reactions; they are recycled. One molecule of an enzyme may be used to facilitate the same chemical reaction over and over again several hundreds of thousands of times. All the enzymes necessary for catalyzing the various reactions of human life are produced within the body by genes. In the case of the enzyme deficiency that causes MMA, the enzyme consists of a genetically produced apoenzyme and a cofactor (vitamin B12) that comes from dietary sources.

Genetic profile

The gene responsible for MMA has been mapped to 6p21.2-p12. At least 30 mutations in this gene have been identified which lead to a broad spectrum of clinical symptoms and severities.

Demographics

The exact frequency of MMA is not known. It is believed to occur with a frequency of approximately one in every 48,000 live births in the United States. As in all recessive non-sex linked (autosomal) genetic disorders, both parents must carry the gene mutation in order for their child to have the disorder. Therefore, in cases where the parents are related by blood (consanguineous), the occurrence rate is higher than in the rest of the population. Parents with one child affected by MMA have a 25% likelihood that their next child will also be affected with MMA.

No increased likelihood for the disease on the basis of sex or ethnicity has been observed in cases of MMA.

Signs and symptoms

The abnormally high levels of acid in the blood of individuals affected with MMA can produce drowsiness, seizures, and in severe cases, coma and/or stroke. Prolonged acidemia can cause mental retardation. In the very rare instances of a complete apoenzyme absence, MMA is associated with sudden infant death syndrome (SIDS) and at least one known case of sudden child death at an age of 11 months.

Dehydration and failure to thrive are generally the first signs of MMA. These symptoms are generally accompanied by lethargy, lack of muscle tone (hypotonia), and “floppiness” in newborns.

Developmental delay is typically experienced in all individuals affected with MMA if treatment is not instigated early in life.

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Some individuals affected with MMA have facial dysmorphisms. These include a broad nose, a high forehead, a skin fold of the upper eyelid (epicanthal folds), and a lack of the normal groove in the skin between the nose and the upper lip (the philtrum). In a few individuals affected with MMA, skin lesions resulting from yeast infections (candidosis) may be present, particularly in the mouth and facial area.

Occasionally, enlargement of the liver (hepatomegaly) is seen in MMA affected individuals.

Uncoordinated muscle movements (choreoathetosis), disordered muscle tone (dystonia), slurred speech (dysarthria), and difficulty swallowing (dysphagia), when observed in individuals affected with MMA may be signs of an acidemia-induced stroke.

Diagnosis

In newborns, a history of poor feeding, increasing lethargy, and vomiting are typical symptoms of MMA. In older infants, an episode of lethargy, often accompanied by seizures, is symptomatic. In children or adolescents, the symptoms may include muscle weakness, loss or diminishment of sensation in the legs, and/or blood clots.

Kidney (renal) disease may be observed in affected individuals with long untreated MMA.

A blood test to detect high levels of MMA is a decisive test for MMA. It may also be detected via a urine test for abnormally high levels of the chemical methylmalonate.

Prenatally, MMA may be diagnosed by measuring the activity of the apoenzyme methylmalonyl-CoA mutase in cultured cells grown from the cells obtained during an amniocentesis.

In one MMA-related case, a woman named Patricia Stallings was sentenced to life imprisonment for the presumed poisoning of her infant son with ethylene glycol, an ingredient in antifreeze. It was not until she gave birth in prison to a second son affected with MMA (and properly diagnosed) that forensic investigators discovered that the gas chromatography peak originally assigned to ethylene glycol (and used to convict Ms. Stallings) was, in fact, methylmalonic acid. All charges against Ms. Stallings were dropped and she was released from prison. This is an extreme case, but it certainly shows the importance of proper medical diagnosis of MMA.

Family history is often used to diagnose MMA when there are affected siblings or siblings that died shortly after birth for unclear reasons.

Treatment and management

Individuals affected with MMA are generally placed on low, or no, protein diets supplemented with carnitine and cobalamin (vitamin B12) and alkalinizing agents (such as bicarbonate) to neutralize the excess acid caused by MMA. Intravenous administration of glucose may be necessary during acute attacks. In individuals who do not respond to carnitine and/or cobalamin, the anti-bacterial drug, metronidazole, may be prescribed. This drug kills some of the naturally occurring bacteria in the lower digestive tract and thereby reduces the production of propionate, a precursor chemical to methylmalonic acid.

In cases of severe MMA, kidney and/or liver transplants may be called for.

Prognosis

With appropriate care and diet, MMA is a controllable disease that offers no threat of death or permanent disability in patients beyond the first year of life. However, if unchecked, MMA can lead to permanent, irreversible disabilities or conditions, or even death. Some infants affected with extremely severe genetic mutations are stillborn or die prior to an appropriate diagnosis of MMA being made.

Resources

PERIODICALS

Smith, Bill. “Not Guilty: How the System Failed Patricia Stallings.” St. Louis Post-Dispatch International Pediatrics

(October 20, 1991): 1 .

Varvogli, L, G. Repetto, S. Waisbren, H. Levy. “High cognitive outcome in an adolescent with mutmethymalonic acidemia.” American Journal of Medical Genetics (April 2000): 192-5.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. [phone] or [phone]. Fax: [phone]. http://www

.rarediseases.org .

Organic Acidemia Association. 13210 35th Ave. North, Plymouth, MN 55441. [phone]. Fax: [phone]. http://www.oaanews.org .

WEBSITES

“Entry 251000: Methylmalonicaciduria due to methylmalonic CoA mutase deficiency.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?251000 . (February 15, 2001).

“Methylmalonic acidemia.”eMedicine. http://www.emedicine

.com/ped/topic1438.htm . (February 15, 2001).

Paul A. Johnson

acidemia Methylmalonic

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Methylmalonicaciduria due to methylmalonic CoA mutase deficiency

I Methylmalonicaciduria due to methylmalonic CoA mutase deficiency

Definition

Methylmalonicaciduria results from an autosomal recessive inherited genetic defect in methylmalonic CoA mutase (MCM), an enzyme required for the proper metabolism of some protein components, cholesterol, and fatty acids. As a result of a deficiency in MCM, methylmalonic acid accumulates in the bloodstream and urine, causing a severe metabolic disorder that may lead to death. Treatment consists chiefly of diet modification and the administration of several medications that may counteract this process.

Description

Proteins are important building blocks of the body, serving many different functions. They provide the structure of muscles, tissues, and organs, and regulate many functions of the human body. Proteins are made from amino acids obtained through the digestion of proteins (found in meats, dairy products, and other foods in the diet). Excess protein that is not required by the body can be broken down into its individual amino acid components. These amino acids can then be converted into glucose or directly enter metabolic pathways that supply the body with energy.

Each of the approximately 20 amino acids that are used to make human proteins are metabolized by specific biochemical reactions. Several of these amino acids (isoleucine, valine, threonine, methionine), as well as cholesterol and some fatty acids, share a common biochemical reaction in the pathway to conversion to usable energy. Each of these substances is converted to methylmalonic acid (also known as methylmalonic CoA), an intermediate product on the pathway leading to the production of usable energy.

In the next step of this biochemical pathway, methylmalonic acid is converted to succinic acid (also called succinyl CoA) by the enzyme, methylmalonic CoA mutase (MCM). In order for MCM to function properly, it also requires a vitamin B12-derivative called adenosylcobalamin (when an enzyme requires another substance in order to perform its job, the helping substance is known as a coenzyme or cofactor).

When there is a defect or deficiency of MCM, methylmalonic acid cannot be converted into succinic acid and methylmalonic acid accumulates in high levels in the bloodstream (methylmalonicacidemia) and in the

urine (methylmalonicaciduria). A deficiency in the cofactor, adenosylcobalamin, renders the MCM enzyme unable to perform its job, and will cause a similar effect. Abnormally high amounts of methylmalonic acid in the bloodstream causes a serious and dangerous metabolic condition that may lead to death.

The condition of methylmalonicacidemia was first described by V. G. Oberholzer in 1967 in infants critically sick with accumulations of methylmalonic acid in their blood and urine. An interesting historical note in respect to this disorder relates to the story of a woman named Patricia Stallings. In 1989, Ms. Stallings brought her son, Ryan, to the emergency room in St. Louis because he was very ill, and Ryan was noted to have high levels of acid in his bloodstream. Poisoning with ethylene glycol (antifreeze) also produces high levels of acid in the bloodstream. When Ryan later died, Ms. Stallings was sentenced to life in prison in January 1991, for the crime of murder by poisoning. However, while in prison the woman gave birth to a second son, who was diagnosed with the condition, methylmalonicacidemia. After discovering this diagnosis, scientists examined frozen samples of the first son’s blood and determined that he, too, had methylmalonicacidemia which was responsible for his death. All charges against Ms. Stallings were dropped, and she was released from prison in September 1991. This is a dramatic illustration of the critical importance of proper diagnosis of complicated and rare genetic disorders.

Genetic profile

MCM deficiency is a genetic condition and can be inherited or passed on in a family. The genetic defect for the disorder is inherited as an autosomal recessive trait, meaning that two abnormal genes are needed to display the disease. A person who carries one abnormal gene does not display the disease and is called a carrier. A carrier has a 50% chance of transmitting the gene to their children, who must inherit one disease gene from each parent to display the disease.

At least two forms of MCM deficiency have been identified. The disease genes are called, mut0, in which there is no detectable enzyme activity, and mut-, in which there is some, but greatly reduced, enzyme activity present. The gene for MCM is located on chromosome 6 (locus 6p21), and about 30 different mutations in the gene have been reported. Other mutations in pathways that produce the cofactor, adenosylcobalamin, exist and produce a condition similar to MCM deficiency.

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