METABOLIC PROBLEMS

Metabolic problems. Metabolism is the process that converts food into energy the body can use to move, think, and
grow. Enzymes are special proteins that help with metabolism by speeding up the chemical reactions in cells. Most
metabolic problems happen when certain enzymes are missing or not working as they should.

Phenylketonuria

Phenylketonuria (PKU) is a rare genetic condition that causes an amino acid called phenylalanine to build up in the body.
Amino acids are the building blocks of protein. Phenylalanine is found in all proteins and some artificial sweeteners.

Phenylalanine hydroxylase is an enzyme your body uses to convert phenylalanine into tyrosine, which your body needs
to create neurotransmitters such as epinephrine, norepinephrine, and dopamine. PKU is caused by a defect in the gene
that helps create phenylalanine hydroxylase. When this enzyme is missing, your body can’t break down phenylalanine.
This causes a buildup of phenylalanine in your body.

Symptoms of phenylketonuria

PKU symptoms can range from mild to severe. The most severe form of this disorder is known as classic PKU. An infant
with classic PKU may appear normal for the first few months of their life. If the baby isn’t treated for PKU during this
time, they’ll start to develop the following symptoms:

 seizures
 tremors, or trembling and shaking
 stunted growth
 hyperactivity
 skin conditions such as eczema
 a musty odor of their breath, skin, or urine

Methylmalonic acidemia   

Methylmalonic acidemia is a disorder in which the body cannot break down certain proteins and fats. The result is a
buildup of a substance called methylmalonic acid in the blood. This condition is passed down through families. It is one
of several conditions called an "inborn error of metabolism."

Causes

The disease is most often diagnosed in the first year of life. It is an autosomal recessive disorder. This means the
defective gene must be passed onto the child from both parents. A newborn with this rare condition may die before it is
ever diagnosed. Methylmalonic acidemia affects boys and girls equally.

Maple syrup urine disease (MSUD)

Maple syrup urine disease (MSUD) is a life-threatening metabolic disorder.

Protein is needed by the body to function normally. Proteins are made up of 20 different types of amino acids. Proteins
must be broken down (metabolized) so they can be absorbed and used by the body. People with MSUD don’t have the
needed enzymes (either don’t have the specific enzymes at all, have the specific enzymes but they don’t work, or don’t
have enough of the specific enzyme) to break down three particular amino acids – leucine, isoleucine and valine.
Because people with MSUD can’t break down these three amino acids, these amino acids build up in the body, become
toxic to the body and cause severe health problems. Without medical management, maple syrup urine disease can lead
to a wide range of intellectual and physical disabilities and death.

Tyrosinemia

In tyrosinemia, the body doesn't have an enzyme it needs [called fumarylacetoacetate hydrolase (FAH)] to metabolize
tyrosine. Tyrosine is an amino acid that is found in most proteins. When people with tyrosinemia break down protein,
abnormal toxic break down products of tyrosine build up in their bodies. This causes progressive damage to the liver and
kidneys, but mainly the liver. This is because the liver is normally the primary place tyrosine is metabolized.

Tyrosinemia is hereditary. In families where both parents carry a mutation, there is a one in four risk that a child will
have tyrosinemia. There is now a genetic test available, so that couples at high risk of being carriers can determine their
risk of having a child with tyrosinemia. This is a very rare disease; only about one person in 100,000 has it.

Tyrosinemia Symptoms in Children

Tyrosinemia symptoms tend to fall into two categories, acute and chronic.

In the acute form of tyrosinemia, babies experience symptoms within months of birth. They may not gain weight
properly, have an enlarged liver and spleen and a swollen abdomen, which are symptoms of other liver diseases.
Jaundice is unusual. Babies with tyrosinemia also have swelling of the legs, and an increased tendency to bleed,
particularly nosebleeds. These babies may need liver transplants right away.

The chronic form of tyrosinemia presents after 6 months with a more gradual onset and less severe symptoms.
Enlargement of the liver and spleen are the main symptoms, the abdomen is distended with fluid, and these children
may have trouble gaining weight. They may vomit or have diarrhea. Liver disease develops more slowly, eventually
leading to cirrhosis.

Tyrosinemia Diagnosis

Tyrosinemia is diagnosed based on blood tests and urine tests. In both the acute and chronic forms of the disease, liver
function tests are often abnormal. Low serum albumin and clotting factors are also frequently found. Because of the
biochemical defect, the abnormal product Succinylacetone may be measured in the urine, which confirms the diagnosis.

In the United States tyrosinemia is included in the newborn screening programme, so nowadays children are usually
detected before they become unwell.

It is possible to test for tyrosinemia while the baby is still developing in the womb. Doctors can detect mutations or
measure succinylacetone in the amniotic fluid.

Tyrosinemia Treatment

The treatment for tyrosinemia is a combination of a low-protein diet and a drug called Nitisinone. Nitisinone prevents
the build up of toxic breakdown products. Meats, dairy products, and other protein rich foods such as nuts and beans
should be avoided. Good nutrition and adequate vitamin and mineral intake allow children to grow normally. Children
with tyrosinemia do require careful monitoring to ensure normal growth and because there is a risk of developing liver
cancer. Children who are treated following newborn screening do not seem to develop liver disease in childhood. For
unknown reasons some children with tyrosinemia have learning difficulties.

Liver transplantation is still the only way to correct the metabolism of tyrosine, but this is rarely necessary nowadays.
More than 90% of children respond very well to Nitisinone and diet. At present, liver transplantation is only needed
where children with the acute form do not respond to Nitisinone rapidly or where liver cancer is suspected. After
receiving a transplant, children can eat a normal diet and lead healthy, active lives.
Citrullinema

-genetic disorder in urea cycle w/c results to build up of ammonia in the blood.

Medium-chain acyl-CoA dehydrogenase (MCAD)

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an inherited disorder that prevents your body from
breaking down certain fats and converting them into energy. As a result, the level of sugar in your blood can drop
dangerously low (hypoglycemia). MCAD deficiency is present from birth and is a lifelong condition.

Left untreated, hypoglycemia caused by MCAD deficiency can lead to seizures, breathing difficulties, coma, and other
serious health problems.

In the U.S., all states test for MCAD deficiency at birth as part of newborn screening. If MCAD deficiency is diagnosed and
treated early, the disorder can be well managed through diet and lifestyle.

Symptoms

Signs and symptoms of MCAD deficiency typically first appear in babies and young children. In rare cases, the disorder is
not diagnosed until adulthood.

Signs and symptoms can vary among people with MCAD deficiency, but they typically include:

 Vomiting
 Lack of energy
 Low blood sugar (hypoglycemia)

Hypoglycemia can be triggered by:

 Going too long without eating or by fasting

 Not eating enough complex carbohydrates
 Viral infections and other illnesses
 Recurrent fever
 Vomiting
 Diarrhea
 Increased exercise
 Vaccinations
 Significant stress

Sometimes episodes of hypoglycemia can occur with no symptoms in between these episodes.

When to see a doctor

In the U.S., all newborn screening programs now test for MCAD deficiency. If you notice signs and symptoms
of MCAD deficiency or if you have concerns about your child's health, contact your doctor. After the initial evaluation,
you may be referred to a doctor trained in evaluating and treating MCAD deficiency and other health care team
members such as a dietitian.

Causes

When you don't have enough of the MCAD enzyme in your body, certain fats called medium-chain fatty acids can't be
broken down and converted to energy. This results in hypoglycemia and low energy. Also, fatty acids can build up in
body tissues and cause damage to the liver and brain.
MCAD deficiency is inherited from both parents. Though both parents are carriers — each one has an abnormal gene —
they typically don't have symptoms of the condition. The affected child inherits two copies of the abnormal gene — one
from each parent.

If you inherit only one affected gene, you won't develop MCAD deficiency, but you are a carrier and can pass the
abnormal gene to your children. But they wouldn't develop the condition unless they also inherited an affected gene
from their other parent.

Complications

If the hypoglycemia caused by MCAD deficiency is left untreated, it can lead to:

 Seizures
 Breathing problems
 Liver problems
 Brain damage
 Coma
 Sudden death

HORMONE PROBLEMS
Hormones are chemical messengers made by glands. Hormone problems happen when glands make too much or not
enough hormones.

Congenital hypothyroidism

Congenital hypothyroidism, previously known as cretinism, is a severe deficiency of thyroid hormone in newborns. It
causes impaired neurological function, stunted growth, and physical deformities. The condition may occur because of a
problem with the baby’s thyroid gland, or a lack of iodine in the mother’s body during pregnancy.

A baby’s body needs iodine to make thyroid hormones. These hormones are essential for healthy growth, brain, and
nervous system development.

Between 1 in 2,000 and 1 in 4,000 Trusted Source babies are born with congenital hypothyroidism.

The introduction of iodized salt in the early 20th century made congenital hypothyroidism very rare in the United States
and the rest of the Western world. However, severe iodine deficiency is still common in developing nations.

Congenital hypothyroidism vs. myxedema

Myxedema is a term used to describe a severely underactive thyroid gland in an adult. Congenital hypothyroidism
refers to a thyroid deficiency in an infant.

Myxedema can also be used to describe skin changes caused by low thyroid hormone levels.

Symptoms

Signs of cretinism or congenital hypothyroidism in a newborn include:

 lack of weight gain

 stunted growth
 fatigue, lethargy
 poor feeding
 thickened facial features
  abnormal bone growth
 mental retardation
 very little crying
 excessive sleep
 constipation
 yellowing of the skin and whites of the eyes (jaundice)
 floppiness, low muscle tone
 hoarse voice
 unusually large tongue
 swelling near the navel (umbilical hernia)
 cool, dry skin
 pale skin
 swelling of the skin (myxedema)
 swelling in the neck from an enlarged thyroid gland (goiter)

Causes

Congenital hypothyroidism in newborns can be caused by:

 a missing, poorly formed, or abnormally small thyroid gland

 a genetic defect that affects thyroid hormone production
 too little iodine in the mother’s diet during pregnancy
 radioactive iodine or antithyroid treatment for thyroid cancer during pregnancy
 use of medicines that disrupt thyroid hormone production — such as antithyroid drugs, sulfonamides, or lithium
— during pregnancy

Iodine deficiency is no longer considered a health risk in the United States due to the introduction of iodized salt.
However, it’s still the most common preventable cause Trusted Source of impaired neurological function in the world.

Because our bodies don’t make iodine, we need to get it from food. Iodine gets into food through soil. In some parts of
the world, the soil is lacking in iodine.

Congenital adrenal hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders that affect the adrenal glands, a pair of
walnut-sized organs above the kidneys. The adrenal glands produce important hormones, including:

 Cortisol, which regulates the body's response to illness or stress

 Mineralocorticoids, such as aldosterone, which regulate sodium and potassium levels
 Androgens, such as testosterone, which are male sex hormones

In people who have CAH, a genetic problem results in a lack of one of the enzymes needed to make these hormones.

Although there is no cure, with proper treatment, most people who have congenital adrenal hyperplasia can lead
normal lives.

There are two major types of congenital adrenal hyperplasia:

 Classic CAH. This form is rarer and is usually detected in infancy. Approximately two-thirds of people who have
classic CAH have what's known as the salt-losing form, while one-third have what's referred to as the simple-
virilizing form.
  Nonclassic CAH. This form is milder and more common, and may not become evident until childhood or early
adulthood.

Symptoms

Signs and symptoms of CAH vary, depending on which gene is defective and the level of enzyme deficiency.

Classic CAH

Female infants who have classic CAH may have a condition known as ambiguous genitalia, in which the clitoris is
enlarged or the genitals look more like those of a male child. Male infants who have classic CAH have normal appearing
genitals. Both male and female infants can be seriously affected by a lack of cortisol, aldosterone or both. This is known
as an adrenal crisis, and it can be life-threatening.

The salt-losing form and simple-virilizing form of classic CAH cause children's bodies to produce an insufficient amount of
cortisol. These children can have problems maintaining normal blood pressure, normal blood sugar and energy levels,
and are more vulnerable to stress. An excess of the male sex hormones can result in short height and early puberty for
both boys and girls.

Signs and symptoms of classic CAH in children and adults include:

 Appearance of pubic hair at a very early age

 Rapid growth during childhood, but shorter than average final height

Nonclassic CAH

Often there are no symptoms of nonclassic CAH when a baby is born. The condition is not identified on routine infant
blood screening and usually becomes evident in late childhood or early adulthood. Cortisol may be the only hormone
that's deficient.

Teenage and adult females who have nonclassic CAH may have normal appearing genitals at birth, but later in life, they
may experience:

 Irregular or absent menstrual periods

 Masculine characteristics such as facial hair, excessive body hair and a deepening voice
 Severe acne

In both females and males, signs of nonclassic CAH may also include:

 Early appearance of pubic hair

 Rapid growth during childhood, an advanced bone age and shorter predicted final height

When to see a doctor

Classic CAH is usually detected at birth through required newborn screening or when female babies have ambiguous
genitalia. CAH may also be identified when male or female babies show signs of severe illness due to low levels of
cortisol, aldosterone or both.

In children who have nonclassic CAH, signs and symptoms of early puberty may appear. If you have concerns about your
child's growth or development, make an appointment with your child's doctor.

If you are pregnant and may be at risk of CAH because of your own medical history or your ethnicity, ask your doctor
about genetic counseling.

Causes
Autosomal recessive inheritance
The most common cause of CAH is the lack of the enzyme known as 21-hydroxylase. CAH may sometimes be called 21-
hydroxylase deficiency. There are other much rarer enzyme deficiencies that also cause CAH.

Children who have the condition have two parents who either have CAH themselves or who are both carriers of the
genetic mutation that causes the condition. This is known as the autosomal recessive inheritance pattern.

Risk factors

Factors that increase the risk of having CAH include:

 Parents who both have CAH or are both carriers of the genetic defect for the disorder
 Certain ethnic heritages, such as Ashkenazi Jew, but also Hispanic, Italian, Yugoslav and Yupik Inuit

Complications

People who have classic CAH are at risk of adrenal crisis because they have very low levels of cortisol in the blood. This
can cause diarrhea, vomiting, dehydration, low blood sugar levels and shock. Adrenal crisis is a life-threatening medical
emergency that requires immediate treatment. Aldosterone also may be low, which leads to dehydration and low
sodium and high potassium levels. The nonclassic form of CAH doesn't cause adrenal crisis.

Males and females who have either classic or nonclassic CAH may also experience fertility problems.

Prevention

There is no known way to prevent congenital adrenal hyperplasia. If you're thinking of starting a family and you're at risk
of having a child with CAH, your doctor may recommend that you see a genetic counselor.

HORMONE PROBLEMS
Sickle Cell Disease

Sickle cell disease is a group of inherited red blood cell disorders that affects hemoglobin, the protein that carries oxygen
through the body. Normally, red blood cells are disc shaped and flexible to move easily through the blood vessels. If you
have sickle cell disease, your red blood cells are crescent or “sickle” shaped. These cells do not bend and move easily
and can block blood flow to the rest of your body.
The blocked blood flow through the body can lead to serious problems, including stroke, eye problems, infections and
episodes of pain, called pain crises. Having sickle cell disease also raises your risk for severe illness from COVID-19.

Sickle cell disease is a lifelong illness. A blood and bone marrow transplant are currently the only cure for sickle cell
disease, but there are effective treatments that can reduce symptoms and prolong life.

Your healthcare team will work with you on a treatment plan to reduce your symptoms and manage the condition.

Hemoglobin SC disease

Hemoglobin SC disease, is a type of sickle cell disease, which means it affects the shape of the red blood cells. Red
blood cells contain a protein called hemoglobin, which is responsible for carrying blood throughout the body. People
with hemoglobin SC disease have red blood cells that are differently shaped and therefore do not carry oxygen as
effectively. Symptoms of hemoglobin SC disease include anemia and episodes of fatigue and extreme pain (vaso-
occlusive crisis). The severity of the symptoms can vary from person to person.

Hemoglobin SC disease is caused by mutations in the gene that tells our bodies how to make hemoglobin. These
mutations cause changes in the shape of the red blood cells. People affected by hemoglobin SC disease need to be
especially careful to avoid infection and should be checked regularly by doctors to make sure all of the organs in the
body are functioning properly. In times when the anemia becomes severe, a person affected by hemoglobin SC disease
may require a blood transfusion. A bone marrow transplant may also be recommended depending on the severity of the
symptoms.

Beta thalassemia

Beta thalassemia is a blood disorder that reduces the production of hemoglobin. Hemoglobin is the iron-containing
protein in red blood cells that carries oxygen to cells throughout the body.

In people with beta thalassemia, low levels of hemoglobin lead to a lack of oxygen in many parts of the body. Affected
individuals also have a shortage of red blood cells (anemia), which can cause pale skin, weakness, fatigue, and more
serious complications. People with beta thalassemia are at an increased risk of developing abnormal blood clots.

Beta thalassemia is classified into two types depending on the severity of symptoms: thalassemia major (also known as
Cooley's anemia) and thalassemia intermedia. Of the two types, thalassemia major is more severe.

The signs and symptoms of thalassemia major appear within the first 2 years of life. Children develop life-threatening
anemia. They do not gain weight and grow at the expected rate (failure to thrive) and may develop yellowing of the skin
and whites of the eyes (jaundice). Affected individuals may have an enlarged spleen, liver, and heart, and their bones
may be misshapen. Some adolescents with thalassemia major experience delayed puberty. Many people with
thalassemia major have such severe symptoms that they need frequent blood transfusions to replenish their red blood
cell supply. Over time, an influx of iron-containing hemoglobin from chronic blood transfusions can lead to a buildup of
iron in the body, resulting in liver, heart, and hormone problems.

Thalassemia intermedia is milder than thalassemia major. The signs and symptoms of thalassemia intermedia appear in
early childhood or later in life. Affected individuals have mild to moderate anemia and may also have slow growth and
bone abnormalities.

Causes

Mutations in the HBB gene cause beta thalassemia. The HBB gene provides instructions for making a protein called beta-
globin. Beta-globin is a component (subunit) of hemoglobin. Hemoglobin consists of four protein subunits, typically two
subunits of beta-globin and two subunits of another protein called alpha-globin.
Some mutations in the HBB gene prevent the production of any beta-globin. The absence of beta-globin is referred to as
beta-zero (β0) thalassemia. Other HBB gene mutations allow some beta-globin to be produced but in reduced amounts.
A reduced amount of beta-globin is called beta-plus (β+) thalassemia. Having either β0 or β+ thalassemia does not
necessarily predict disease severity, however; people with both types have been diagnosed with thalassemia major and
thalassemia intermedia.

A lack of beta-globin leads to a reduced amount of functional hemoglobin. Without sufficient hemoglobin, red blood
cells do not develop normally, causing a shortage of mature red blood cells. The low number of mature red blood cells
leads to anemia and other associated health problems in people with beta thalassemia.

OTHER PROBLEMS
Galactosemia

Galactosemia is a rare, hereditary disorder of carbohydrate metabolism that affects the body’s ability to convert
galactose (a sugar contained in milk, including human mother’s milk) to glucose (a different type of sugar). The disorder
is caused by a deficiency of an enzyme galactose-1-phosphate uridylyl transferase (GALT) which is vital to this process.
Early diagnosis and treatment with a lactose-restricted (dairy-free) diet is absolutely essential to avoid profound
intellectual disability, liver failure and death in the newborn period. Galactosemia is inherited as an autosomal recessive
genetic condition. Classic galactosemia and clinical variant galactosemia can both result in life-threatening health
problems unless treatment is started shortly after birth. A biochemical variant form of galactosemia termed Duarte is
not thought to cause clinical disease due to lactose consumption.

Signs & Symptoms

An infant with galactosemia appears normal at birth, but within a few days or weeks loses his or her appetite (anorexia)
and starts vomiting excessively. Yellowing of the skin, mucous membranes, and whites of the eyes (jaundice),
enlargement of the liver (hepatomegaly), appearance of amino acids and protein in the urine, growth failure, and,
ultimately, accumulation of fluid in the abdominal cavity (ascites) with abdominal swelling (edema) may also occur.
Diarrhea, irritability, lethargy and a bacterial infection may also be early signs of galactosemia. In time, wasting of body
tissues, marked weakness, and extreme weight loss occur unless lactose is removed from the diet.

Children with galactosemia who have not received early treatment may show arrested physical and mental development
and are particularly susceptible to cataracts in infancy or childhood. In severe cases, overwhelming infection in the
newborn period can cause life-threatening complications, but mild cases present few signs and no serious
impairment(s).

In order to avoid the consequences of galactosemia, which may include liver failure and kidney dysfunction, brain
damage and/or cataracts, infants must be treated promptly by removing lactose from the diet. Children treated with this
special diet usually show satisfactory general health and growth. They can make reasonable, though often not optimal,
intellectual progress. Speech and learning difficulties and some behavioral problems are still likely to occur. Ovarian
impairment is almost always seen in girls with classic galactosemia and is associated with an increase in the blood level
of the gonadotropin hormone, follicle-stimulating hormone (FSH); males with galactosemia do not usually exhibit
abnormalities in gonadal function.

The above-mentioned complications associated with classic galactosemia and clinical variant galactosemia have not
occurred in individuals with Duarte variant galactosemia, which is the best example of the biochemical variant
galactosemia subdivision. However, in a minority of subjects, developmental delay and/or a speech abnormality has
occurred but it is unclear whether this is related to accumulation of galactose and its metabolites. Individuals with
Duarte variant galactosemia do not need to maintain a special diet.
Causes

Galactosemia occurs due to disruptions or changes (mutations) in the GALT gene resulting in deficiency of the GALT
enzyme. This leads to abnormal accumulation of galactose-related chemicals in various organs of the body causes the
signs and symptoms and physical findings of galactosemia.

The galactose-1-phosphate uridyl transferase (GALT) enzyme is needed for the breakdown of the milk sugar, galactose.
Deficiency of this enzyme results in the accumulation of toxic products: galactose-1-phosphate (a derivative of
galactose), and galactitol (an alcohol derivative of galactose). Galactitol accumulates in the lens of the eye where it
causes lens swelling and protein precipitation and, subsequently, cataracts. Accumulation of galactose-1-phosphate is
thought to cause the other signs and symptoms of disease.

Galactosemia is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a
non-working gene from each parent. If an individual receives one working gene and one non-working gene for the
disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents
to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a
child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from
both parents is 25%. The risk is the same for males and females.

Biotinidase deficiency

Biotinidase deficiency is an inherited disorder in which the body is unable to recycle the vitamin biotin. If this condition
is not recognized and treated, its signs and symptoms typically appear within the first few months of life, although it can
also become apparent later in childhood.

Profound biotinidase deficiency, the more severe form of the condition, can cause seizures, weak muscle tone
(hypotonia), breathing problems, hearing and vision loss, problems with movement and balance (ataxia), skin rashes,
hair loss (alopecia), and a fungal infection called candidiasis. Affected children also have delayed development. Lifelong
treatment can prevent these complications from occurring or improve them if they have already developed.

Partial biotinidase deficiency is a milder form of this condition. Without treatment, affected children may experience
hypotonia, skin rashes, and hair loss, but these problems may appear only during illness, infection, or other times of
stress.

Causes

Mutations in the BTD gene cause biotinidase deficiency. The BTD gene provides instructions for making an enzyme called
biotinidase. This enzyme recycles biotin, a B vitamin found in foods such as liver, egg yolks, and milk. Biotinidase
removes biotin that is bound to proteins in food, leaving the vitamin in its free (unbound) state. Free biotin is needed by
enzymes called biotin-dependent carboxylases to break down fats, proteins, and carbohydrates. Because several of
these enzymes are impaired in biotinidase deficiency, the condition is considered a form of multiple carboxylase
deficiency.

Mutations in the BTD gene reduce or eliminate the activity of biotinidase. Profound biotinidase deficiency results when
the activity of biotinidase is reduced to less than 10 percent of normal. Partial biotinidase deficiency occurs when
biotinidase activity is reduced to between 10 percent and 30 percent of normal. Without enough of this enzyme, biotin
cannot be recycled. The resulting shortage of free biotin impairs the activity of biotin-dependent carboxylases, leading to
a buildup of potentially toxic compounds in the body. If the condition is not treated promptly, this buildup damages
various cells and tissues, causing the signs and symptoms described above.

Cystic fibrosis (CF)

Cystic fibrosis (CF) is an inherited disorder that causes severe damage to the lungs, digestive system and other organs in
the body.

Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin
and slippery. But in people with CF, a defective gene causes the secretions to become sticky and thick. Instead of acting
as lubricants, the secretions plug up tubes, ducts and passageways, especially in the lungs and pancreas.

Although cystic fibrosis is progressive and requires daily care, people with CF are usually able to attend school and work.
They often have a better quality of life than people with CF had in previous decades. Improvements in screening and
treatments mean that people with CF now may live into their mid- to late 30s or 40s, and some are living into their 50s.

Symptoms

In the U.S., because of newborn screening, cystic fibrosis can be diagnosed within the first month of life, before
symptoms develop. But people born before newborn screening became available may not be diagnosed until the signs
and symptoms of CF show up.

Cystic fibrosis signs and symptoms vary, depending on the severity of the disease. Even in the same person, symptoms
may worsen or improve as time passes. Some people may not experience symptoms until their teenage years or
adulthood. People who are not diagnosed until adulthood usually have milder disease and are more likely to have
atypical symptoms, such as recurring bouts of an inflamed pancreas (pancreatitis), infertility and recurring pneumonia.

People with cystic fibrosis have a higher than normal level of salt in their sweat. Parents often can taste the salt when
they kiss their children. Most of the other signs and symptoms of CF affect the respiratory system and digestive system.

Respiratory signs and symptoms

The thick and sticky mucus associated with cystic fibrosis clogs the tubes that carry air in and out of your lungs. This can
cause signs and symptoms such as:

 A persistent cough that produces thick mucus (sputum)

 Wheezing
 Exercise intolerance
 Repeated lung infections
 Inflamed nasal passages or a stuffy nose
 Recurrent sinusitis

Digestive signs and symptoms

The thick mucus can also block tubes that carry digestive enzymes from your pancreas to your small intestine. Without
these digestive enzymes, your intestines aren't able to completely absorb the nutrients in the food you eat. The result is
often:

 Foul-smelling, greasy stools

 Poor weight gain and growth
 Intestinal blockage, particularly in newborns (meconium ileus)
 Chronic or severe constipation, which may include frequent straining while trying to pass stool, eventually
causing part of the rectum to protrude outside the anus (rectal prolapse)

When to see a doctor

If you or your child has symptoms of cystic fibrosis — or if someone in your family has CF — talk with your doctor about
testing for the disease. Consult a physician who is knowledgeable about CF.
Cystic fibrosis requires consistent, regular follow-up with your doctor, at least every three months. Contact you doctor if
you experience new or worsening symptoms, such as more mucus than usual or a change in the mucus color, lack of
energy, weight loss, or severe constipation.

Seek immediate medical care if you're coughing up blood, have chest pain or difficulty breathing, or have severe
stomach pain and distention.

Causes

In cystic fibrosis, a defect (mutation) in a gene — the cystic fibrosis transmembrane conductance regulator (CFTR) gene
— changes a protein that regulates the movement of salt in and out of cells. The result is thick, sticky mucus in the
respiratory, digestive and reproductive systems, as well as increased salt in sweat.

Many different defects can occur in the gene. The type of gene mutation is associated with the severity of the condition.

Children need to inherit one copy of the gene from each parent in order to have the disease. If children inherit only one
copy, they won't develop cystic fibrosis. However, they will be carriers and could pass the gene to their own children.

Risk factors

Because cystic fibrosis is an inherited disorder, it runs in families, so family history is a risk factor. Although CF occurs in
all races, it's most common in white people of Northern European ancestry.

Complications

Complications of cystic fibrosis can affect the respiratory, digestive and reproductive systems, as well as other organs.

Respiratory system complications

 Damaged airways (bronchiectasis). Cystic fibrosis is one of the leading causes of bronchiectasis, a chronic lung
condition with abnormal widening and scarring of the airways (bronchial tubes). This makes it harder to move
air in and out of the lungs and clear mucus from the bronchial tubes.
 Chronic infections. Thick mucus in the lungs and sinuses provides an ideal breeding ground for bacteria and
fungi. People with cystic fibrosis may often have sinus infections, bronchitis or pneumonia. Infection with
bacteria that is resistant to antibiotics and difficult to treat is common.
 Growths in the nose (nasal polyps). Because the lining inside the nose is inflamed and swollen, it can develop
soft, fleshy growths (polyps).
 Coughing up blood (hemoptysis). Bronchiectasis can occur next to blood vessels in the lungs. The combination
of airway damage and infection can result in coughing up blood. Often this is only a small amount of blood, but it
can also be life-threatening.
 Pneumothorax. In this condition, air leaks into the space that separates the lungs from the chest wall, and part
or all of a lung collapses. This is more common in adults with cystic fibrosis. Pneumothorax can cause sudden
chest pain and breathlessness. People often feel a bubbling sensation in the chest.
 Respiratory failure. Over time, cystic fibrosis can damage lung tissue so badly that it no longer works. Lung
function usually worsens gradually, and it eventually can become life-threatening. Respiratory failure is the most
common cause of death.
 Acute exacerbations. People with cystic fibrosis may experience worsening of their respiratory symptoms, such
as coughing with more mucus and shortness of breath. This is called an acute exacerbation and requires
treatment with antibiotics. Sometimes treatment can be provided at home, but hospitalization may be needed.
Decreased energy and weight loss also are common during exacerbations.

Severe combined immunodeficiency (SCID)

Severe combined immunodeficiency (SCID) is a group of rare disorders caused by mutations in different genes involved
in the development and function of infection-fighting immune cells. Infants with SCID appear healthy at birth but are
highly susceptible to severe infections.

Severe combined immunodeficiency (SCID) is an inherited primary immunodeficiency disease (PIDD) that typically
presents in infancy results in profound immune deficiency condition resulting in a weak immune system that is unable to
fight off even mild infections. 

As a rule, children with SCID should not receive the standard childhood vaccinations. Because the B cells of children with
SCID do not function properly, their bodies can't produce the normal antibodies that fight off viruses. Since many
vaccines are actually live viruses, they pose too high a risk of infection to be safe for a child with a drastically weakened
immune system.

Other ways to avoid potential infections include basic precautions such as:

 keep your child away from crowds, dirty places or anyone who is ill or seems to be "coming down with
something"
 follow a strict hand washing regimen for your child, your family and any visitors
 use protective face masks at the recommendation of your child's doctor
 give your child antibiotics, antifungal or antiviral medications at the direction of your child's doctor
 Nearly every child with SCID is treated with a stem cell transplant, also known as a bone marrow transplant. This
is the only available treatment option that has a chance of providing a permanent cure. The bone marrow cells
or stem cells are administered through an IV, similar to a blood transfusion.
 Stem cells are a versatile type of cell found in bone marrow. These cells have a unique and powerful ability: they
can develop into several different types of specialized cells.

Pompe disease
Pompe disease is a genetic disorder in which complex sugar called glycogen builds up in the body’s cells. The disease
results from the deficiency of an enzyme called acid alfa glucosidase (GAA), which breaks downs complex sugars in the
body. This buildup occurs in organs and tissues, especially in muscles, causing them to break down.

Mutations in the GAA gene, which helps break down glycogen, cause this disorder.

There are three types of Pompe disease:

 Classic infantile-onset appears within a few months of birth.

 Non-classic infantile-onset appears at about 1 year of age.
 Late-onset appears later in a child’s life, or even into the teen years or adulthood.

Who gets Pompe disease?

Since this is a genetic condition, the people who get this disease inherit it from a parent. It is common, however, that
neither parent shows any symptoms. The disease is rare. In the United States, only 1 person in 40,000 is affected by
Pompe disease. It can affect both males and females of all ethnic groups.

SYMPTOMS AND CAUSES

Symptoms can be a bit different, depending on when the disease makes itself present. In infants, symptoms include the
following:

Classic type:
  Weak muscles
 Poor muscle tone
 Enlarged liver
 Failure to gain weight and grow at the expected rate (failure to thrive)
 Trouble breathing
 Feeding problems
 Infections in the respiratory system
 Problems with hearing

Non-classic type:

 Motor skills delayed (such as rolling over and sitting)

 Muscles get steadily weaker
 Abnormally large heart
 Breathing problems
 Late-onset type, which includes adult-onset:
 The legs and the trunk get steadily weaker.
 Breathing problems
 Enlarged heart
 Increasing difficulty in walking
 Muscle pain over a large area
 Loss of the ability to exercise
 Falling often
 Frequent lung infections
 Shortness of breath when the person pushes himself or herself
 Headaches in the morning
 Becoming tired during the day
 Losing weight
 Cannot swallow as easily as before
 Irregular heart beat
 Increased difficulty hearing
 Higher levels of creatine kinase (CK) , an enzyme that helps the body’s functions work and provides energy to
cells

DIAGNOSIS AND TESTS

A blood sample is taken and enzymes in the blood are studied and counted. Also, there are tests such as sleep studies,
breathing tests to measure lung capacity, and electromyography (a test that measures how well the muscles work).

A blood sample is taken and enzymes in the blood are studied and counted. Confirmation is made via DNA testing. Other
tests include:

 Taking of a complete patient and family history

 Breathing tests to measure lung capacity (pulmonary function tests)
 Electromyography (a test that measures how well the muscles work) and MRIs
 Heart studies, including X-rays, electrocardiogram and echocardiogram
 Sleep studies
 A prenatal diagnosis may be done for pregnant women at risk.

MANAGEMENT AND TREATMENT

Enzyme replacement therapy (ERT) is an approved treatment for all Pompe patients. A drug called alglucosidase alfa is
given intravenously (through the patient’s vein). It is a genetically engineered enzyme that acts like the naturally
occurring acid alfa glucosidase enzyme.

Specialist teams (heart doctors, respiratory therapists, neurologists, etc.) can treat symptoms and offer supportive care
for those with Pompe disease. Ask your doctors about details for each specific case.

COMPLICATIONS

Without treatment, infants with Pompe disease will die. Many of the people with Pompe disease have respiratory
(breathing) problems, heart problems, and almost all are plagued with muscle weakness. Most people will have to use
oxygen and wheelchairs at some point.

PREVENTION

As this is a genetic disease it cannot currently be prevented. Supportive treatment and care are available.

OUTLOOK / PROGNOSIS

Patients with either type of infantile-onset Pompe disease may have their lives prolonged with early detection and
treatment. However, both of these types of Pompe disease often are fatal. Patients with classic infantile-onset type
rarely live past 1 year of age. Patients with non-classic infantile–onset type may live to early childhood. Children with
late-onset types of Pompe disease can live longer as the disease progresses more slowly.

Mucopolysaccharidosis type I (MPS I)

Mucopolysaccharidosis type I (MPS I) is a condition that affects many parts of the body. It is a progressively debilitating
disorder; however, the rate of progression varies among affected individuals. MPS I is caused by mutations in the gene.
These mutations lead to reduced levels or the complete lack of the IDUA enzyme. Without the proper amount of this
enzyme, large sugar molecules called glycosaminoglycans (GAGs) accumulate within cells called lysosomes. This causes
the lysosomes to increase in size, causing many different organs and tissues of the body to become enlarged. This leads
to the medical problems seen in the condition.

MPS I was once divided into three separate syndromes: Hurler syndrome, Hurler-Scheie syndrome, and Scheie
syndrome, listed from most to least severe. Because no biochemical differences have been identified and the clinical
findings overlap, the condition is now divided into two subtypes, severe MPS I and attenuated MPS I.  People with severe
MPS I typically have an earlier onset of symptoms, a decline in intellectual function, and a shorter lifespan. Although
there is no cure for MPS I, bone marrow transplant and enzyme replacement therapy are treatment options that may
help manage the symptoms of this condition. Mucopolysaccharidosis type I (MPS I) is a condition that affects many parts
of the body. It is a progressively debilitating disorder; however, the rate of progression varies among affected
individuals. MPS I is caused by mutations in the IDUA gene. These mutations lead to reduced levels or the complete lack
of the IDUA enzyme. Without the proper amount of this enzyme, large sugar molecules called glycosaminoglycans
(GAGs) accumulate within cells called lysosomes. This causes the lysosomes to increase in size, causing many
different organs and tissues of the body to become enlarged. This leads to the medical problems seen in the condition. 

MPS I was once divided into three separate syndromes: Hurler syndrome, Hurler-Scheie syndrome, and Scheie
syndrome, listed from most to least severe. Because no biochemical differences have been identified and the clinical
findings overlap, the condition is now divided into two subtypes, severe MPS I and attenuated MPS I. People with severe
MPS I typically have an earlier onset of symptoms, a decline in intellectual function, and a shorter lifespan. Although
there is no cure for MPS I, bone marrow transplant and enzyme replacement therapy are treatment options that may
help manage the symptoms of this condition.
SYMPTOMS

The signs and symptoms of mucopolysaccharidosis type I (MPS I) are not present at birth, but they begin to appear
during childhood. People with severe MPS I develop the features of this condition earlier than those with attenuated
MPS I. The following list includes the most common signs and symptoms of MPS I:

 Enlarged head, lips, cheeks, tongue, and nose

 Enlarged vocal cords, resulting in a deep voice
 Frequent upper respiratory infections
 Sleep apnea
 Hydrocephalus
 Hepatosplenomegaly (enlarged liver and spleen)
 Umbilical hernia
 Inguinal hernia
 Hearing loss
 Recurrent ear infections 
 Corneal clouding
 Carpal tunnel syndrome
 Narrowing of the spinal canal (spinal stenosis)
 Heart valve abnormalities, which can lead to heart failure
 Short stature
 Joint deformities (contractures)
 Dysostosis multiplex (generalized thickening of most long bones, particularly the ribs)
 Developmental delays and regression 

Cause

Mutations in the IDUA gene cause mucopolysaccharidosis type I (MPS I). The IDUA gene provides instructions for
producing an enzyme (alpha-L-iduronidase) that is involved in the breakdown of large
sugar molecules called glycosaminoglycans (GAGs). Mutations in the IDUA gene reduce or completely eliminate the
function of alpha-L-iduronidase. This leads to the accumulation of GAGs within cells, specifically inside the lysosomes.
Lysosomes are compartments in the cell that digest and recycle different types of molecules. Conditions that cause
molecules to build up inside the lysosomes, including MPS I, are called lysosomal storage disorders. The accumulation of
GAGs increases the size of the lysosomes, which is why many tissues and organs are enlarged in this disorder.[1][3]

Inheritance

Mucopolysaccharidosis type I (MPS I) is inherited in an autosomal recessive manner.[1] This means that to be affected, a

person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated
copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically
do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have
children, each child has a:

 25% (1 in 4) chance to be affected

 50% (1 in 2) chance to be an unaffected carrier like each parent
 25% chance to be unaffected and not be a carrier

If you are concerned about your risks to be a carrier of MPS I, we would recommend you consult with a genetics
specialist, such as a geneticist or a genetic counselor. See our page on how to find a genetics clinic to identify a local
genetics specialist.  

Diagnosis
Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a
person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The
following resources provide information relating to diagnosis and testing for this condition. If you have questions about
getting a diagnosis, you should contact a healthcare professional.

Newborn Screening

Baby's First Test is the nation's newborn screening education center for families and providers. This site provides
information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for
newborn screening information.

Treatment

Management of mucopolysaccharidosis type I (MPS I) requires a multidisciplinary team given the wide range
of symptoms. This team may include: primary care; cardiology; pulmonology; gastroenterology; neurology; ear, nose,
and throat specialists; audiology; ophthalmology; orthopedics; physical therapy; dental; and developmental specialists.

The two main treatment options for MPS I include hematopoietic stem cell transplant (HSCT) and enzyme replacement
therapy (ERT). Both of these treatments work by replacing the missing IDUA enzyme (alpha-L-iduronidase).

HSCT is considered standard of care for individuals with severe MPS I; however, its success is dependent on timing of
treatment. It is typically recommended that HSCT occur early in the disease process, prior to two years of age. Studies
have shown that when successful, HSCT can improve facial, auditory, and cardiac manifestations. The effect on
intellectual development is unclear with some studies suggesting an improvement, while others report a slowing of
cognitive decline.
 
A drug called laronidase or Aldurazyme is the enzyme replacement therapy for MPS I. Treatment with laronidase can
improve problems with breathing, growth, the bones, joints and heart. However, this treatment is not expected to treat
problems with mental development because laronidase cannot cross the blood-brain barrier.

X-linked adrenoleukodystrophy (ALD)

X-linked adrenoleukodystrophy (X-ALD) is a genetic disease that affects the nervous system and the adrenal

glands (small glands located on top of each kidney). People with this disease often have progressive loss of the fatty
covering (myelin) that surrounds the nerves in the brain and spinal cord. They may also have a shortage of
certain hormones that is caused by damage to the outer layer of the adrenal glands (adrenal cortex). This is
called adrenocortical insufficiency, or Addison disease. There are three forms of X-ALD: a childhood cerebral form,
an adrenomyeloneuropathy (AMN) type, and an adrenal-insufficiency-only-type. The disease primarily affects males.

X-ALD is caused by a variation (mutation) in the ABCD1 gene and it is inherited in an X-linked. manner. Diagnosis of the
disease is based on testing the levels of a molecule called very long-chain fatty acids (VLCFA). The diagnosis can be
confirmed with genetic testing. There is still no cure for X-ALD, but taking special oils such as Lorenzo’s oil can lower the
blood levels of VLCFA. Bone marrow transplantation may be an option for boys who have evidence of brain involvement
on MRI, but do not yet have obvious symptoms of the disease with a normal neurological exam. Adrenocortical
insufficiency is treated with corticosteroids.

Spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) is a genetic (inherited) neuromuscular disease that causes muscles to become weak and
waste away. People with SMA lose a specific type of nerve cell in the spinal cord (called motor neurons) that control
muscle movement. Without these motor neurons, muscles don’t receive nerve signals that make muscles move. The
word atrophy is a medical term that means smaller. With SMA, certain muscles become smaller and weaker due to lack
of use.

Who might get spinal muscular atrophy?

A person with SMA inherits two copies of a missing or faulty (mutated) survival motor neuron 1 (SMN1) gene. One faulty
gene comes from the mother and the other comes from the father. An adult can have a single copy of the defective gene
that causes SMA and not know it.

About six million Americans (1 in 50) carry the mutated SMN1 gene. These carriers have one healthy SMN1 gene and
one missing or defective SMN1 gene. Carriers don’t develop SMA. There's a 1 in 4 chance that two carriers will have a
child with SMA.

There are four primary types of SMA:

Type 1 (severe): About 60% of people with SMA have type 1 , also called Werdnig-Hoffman disease. Symptoms appear at
birth or within an infant’s first six months of life. Infants with type 1 SMA have difficulty swallowing and sucking. They
don’t meet typical milestones like holding up their heads or sitting. As muscles continue to weaken, children become
more prone to respiratory infections and collapsed lungs (pneumothorax). Most children with type 1 SMA die before
their second birthday.

Type 2 (intermediate): Symptoms of type 2 SMA (also called Dubowitz disease) appear when a child is between six
months and 18 months old. This type tends to affect the lower limbs. Children with type 2 SMA may be able to sit up but
can’t walk. Most children with type 2 SMA live into adulthood.

Type 3 (mild): Symptoms of type 3 SMA (also called Kugelbert-Welander or juvenile-onset SMA) appear after a child’s
first 18 months of life. Some people with type 3 don’t have signs of disease until early adulthood. Type 3 symptoms
include mild muscle weakness, difficulty walking and frequent respiratory infections. Over time, symptoms can affect the
ability to walk or stand. Type 3 SMA doesn’t significantly shorten life expectancy.

Type 4 (adult): The rare adult form of SMA doesn’t typically appear until the mid-30s. Muscle weakness symptoms
progress slowly, so most people with type 4 remain mobile and live full lives.

CAUSE

People with SMA are either missing part of the SMN1 gene or have a changed (mutated) gene. A healthy SMN1 gene
produces SMN protein. Motor neurons need this protein to survive and function properly.

People with SMA don’t make enough SMN protein, and so the motor neurons shrink and die. As a result, the brain can’t
control voluntary movements, especially motion in the head, neck, arms and legs.

People also have SMN2 genes that produce a small amount of SMN protein. A person may have up to eight copies of an
SMN2 gene. Having multiple copies of the SMN2 gene typically leads to less severe SMA symptoms because the extra
genes make up for the missing SMN1 protein. Rarely, non-SMN gene mutations (non-chromosome 5) cause SMA.

SYMPTOMS

SMA symptoms vary depending on the type. In general, people with SMA experience a progressive loss of muscle
control, movement and strength. Muscle loss gets worse with age. The disease tends to severely affect the muscles
closest to the torso and neck. Some people with SMA never walk, sit or stand. Others gradually lose their ability to do
these actions.

DIAGNOSIS
Some SMA symptoms resemble those resulting from neuromuscular disorders like muscular dystrophy. To find the cause
of symptoms, your healthcare provider will perform a physical exam and get a medical history. Your physician may also
order one or more of these tests to diagnose SMA:

Blood test: An enzyme and protein blood test can check for high levels of creatine kinase. Deteriorating muscles release
this enzyme into the bloodstream.

Genetic test: This blood test identifies problems with the SMN1 gene. As a diagnostic tool, a genetic test is 95% effective
at finding the altered SMN1 gene. Some states test for SMA as part of routine newborn screenings.

Nerve conduction test: An electromyogram (EMG) measures the electrical activity of nerves muscles and nerves.

Muscle biopsy: Rarely, a physician may perform a muscle biopsy. This procedure involves removing a small amount of
muscle tissue and sending it to a lab for examination. A biopsy can show atrophy, or loss of muscle.

Can spinal muscular atrophy be diagnosed during pregnancy?

If you’re pregnant and have a family history of SMA, prenatal tests can determine if your unborn baby has the disease.
These tests slightly increase the risk of miscarriage or pregnancy loss. Prenatal tests for SMA include:

Amniocentesis: During amniocentesis, your obstetrician inserts a thin needle into your belly to draw out a small amount
of fluid from the amniotic sac. A lab specialist (pathologist) checks the fluid for SMA. This test takes place after the 14th
week of pregnancy.

Chorionic villus sampling (CVS): Your obstetrician removes a small tissue sample from the placenta through the mother’s
cervix or stomach. A pathologist checks the sample for SMA. CVS can take place as early as the 10th week of pregnancy.

TREATMENT

There isn’t a cure for SMA. Treatments depend upon the type of SMA and symptoms. Many people with SMA benefit
from physical and occupational therapy and assistive devices, such as orthopaedic braces, crutches, walkers and
wheelchairs.

These treatments may also help:

Disease-modifying therapy: These drugs stimulate production of SMN protein. Nusinersen (Spinraza®) is for children
ages 2 to 12. Your provider injects the drug into the space around the spinal canal. A different medication, risdaplam
(Evrysdi®), helps adults and children older than two months. People take risdaplam daily by mouth (orally).

Gene replacement therapy: Children younger than two may benefit from a one-time intravenous (IV) infusion of a drug
called onasemnogene abeparvovec-xioi (Zolgensma®). This therapy replaces a missing or faulty SMN1 gene with a
functioning gene.

What are the complications of spinal muscular atrophy?

Over time, people with SMA experience progressive muscle weakness and loss of muscle control. Potential
complications include:

Bone fractures, hip dislocation and scoliosis (curvature of the spine).

Malnutrition and dehydration due to problems eating and swallowing that may require a feeding tube.

Pneumonia and respiratory infections.

Weak lungs and breathing problems that may require breathing support (ventilation).

PREVENTION
SMA is an inherited disease. If you or your partner carries the mutated gene that causes SMA, a genetic counselor can
explain the chances of your child having SMA or being a carrier.

You may be able to take steps before pregnancy to lower the risk of passing on SMA. A process called preimplantation
genetic diagnosis (PGD) identifies embryos that don’t have the mutated gene. Your doctor implants healthy embryos
during in vitro fertilization (IVF). PGD ensures your child will have two healthy SMN1 genes and not get SMA.

Newborn screening is important because it aids in the early detection of several genetic, endocrine, and metabolic
diseases that can have a negative impact on a baby's health. This allows babies to begin treatment as soon as possible
before the disease becomes serious or so that early interventions can be made.  This test may be utilized to address the
underlying problems that, if left untreated, can result in a severe health problem in the future.