STATE UNIVERSITY

«UZHHOROD NATIONAL UNIVERSITY»

MEDICAL FACULTY
Department of Neurology, Neurosurgery and Psychiatry

METHODOLOGICAL DEVELOPMENT
in
MEDICAL GENETICS
4th year of study

INBORN ERRORS OF METHABOLISM

Erika Patskun

Uzhhorod – 2021
Затверджено на засіданні кафедри неврології, нейрохірургії та психіатрії
(протокол № 4 від 22 грудня 2020 р.), на засіданні методичної комісії
медичного факультету (протокол № 2021-5 від 14 травня 2021 р.) та на
Вченій раді медичного факультету ДВНЗ «УжНУ» (протокол № 7 від 20
травня 2021 р.).

Автор: к.м.н., доцент Пацкун Е.Й.

Рецензенти:

Рішко М.В. – доктор медичних наук, професор, зав. кафедрою

госпітальної терапії медичного факультету ДВНЗ «УжНУ», голова
Закарпатського товариства терапевтів та кардіологів, заслужений лікар
України.
Фекета В.П. – д.б.н., к.мед.н., професор, зав. кафедри фундаментальних
медичних дисциплін медичного факультету №2 ДВНЗ «УжНУ»

© Пацкун Е.Й.
© ДВНЗ «Ужгородський національний університет», медичний факультет,
2021
 © Erika Patskun. Medical Genetics. Inborn Errors of Metabolism. Rare Diseases.

ICD 10: E 70 – E 90 / Synonyms: Hereditary Metabolic Disorders

Belong to Single Gene Disorders.
Definition. Inherited metabolic disorders are genetic conditions that result in
metabolism problems. Most people with inherited metabolic disorders have a
defective gene that results in an enzyme deficiency. There are hundreds of different
genetic metabolic disorders, and their symptoms, treatments, and prognoses vary
widely.
Most common mode of inheritance is autosomal recessive. Each inherited
metabolic disorder is quite rare in the general population. Considered all together,
inherited metabolic disorders may affect about 1 in 1,000 to 2,500 newborns.
Hundreds of inherited metabolic disorders have been identified, and new ones
continue to be discovered.
Symptoms of Inherited Metabolic Disorders
• Lethargy
• Poor appetite
• Abdominal pain
• Vomiting
• Weight loss
• Jaundice
• Failure to gain weight or grow
• Developmental delay
• Seizures
• Coma
• Abnormal odor of urine, breath, sweat or saliva
Features. The symptoms may come on suddenly or progress slowly. Symptoms may
be brought on by foods, medications, dehydration, minor illnesses, or other factors.
Symptoms appear within a few weeks after birth in many conditions. Other inherited
metabolic disorders may take years for symptoms to develop.
Diagnostics of Inherited Metabolic Disorders:
Newborn screening is a public health program designed to screen infants shortly
after birth for a list of conditions that are treatable, but not clinically evident in the
newborn period. If an inherited metabolic disorder is not detected at birth, it is often
not diagnosed until symptoms appear.
Once symptoms develop, specific blood or
DNA tests are available to diagnose most
genetic metabolic disorders.
Neonatal screening: samples drawn by
neonatal heel prick – Dry Blood Spots
(DBS).
Newborn screening identifies conditions
that can affect a child’s long-term health
or survival. Early detection, diagnosis, and
intervention can prevent death or disability
and enable children to reach their full
potential. Each year, millions of babies are routinely screened, using a few drops of

3
 © Erika Patskun. Medical Genetics. Inborn Errors of Metabolism. Rare Diseases.

blood from the newborn’s heel, for certain genetic, endocrine, and metabolic
disorders, and are also tested for hearing loss and critical congenital heart defects
(CCHDs) prior to discharge from a hospital or birthing center.
Selective screening
• If newborn screening for some disorder doesn’t exist we can conduct selective
screening in cases of symptoms which were indicated before;
• Urinalysis - screening of inborn errors of metabolism of amino acid and organic acid
disorders;
• Chromatographic techniques;
• Tandem mass spectrometry.
Treatment / general principles
• Reduce or eliminate intake of any food or drug that can't be metabolized properly;
• Replace the enzyme or other chemical that is missing or inactive, to restore
metabolism to as close to normal as possible;
• Remove toxic products of metabolism that accumulate due to the metabolic disorder.
Treatment may include
• Special diets that eliminate certain nutrients;
• Taking enzyme replacements, or other supplements that support metabolism;
• Treating the blood with chemicals to detoxify dangerous metabolic by-products.
AMINOACIDOPATHIES
Rare inherited disorders of amino acid metabolism. Abnormality in either activity of
specific enzyme, in metabolic pathway or in the membrane specific transport system
for amino acid. These defects lead to accumulation of amino acid itself, its precursor
or a by-product. Excessive accumulation in blood leads to physical symptoms of the
disease or Aminoacidopathies: any of a group of inborn errors of metabolism which
results in the buildup in the body of one or more amino acids in the blood and/or
urine. The range and severity of symptoms is hugely variable
Symptoms
• Increased level of amino acid in blood
• Increased level of amino acid in urine
• Bleeding problems
• Clotting problems
• Impaired mental function
• Developmental problems
• Mental retardation
• Neurological symptoms
• Impaired organ function
• Enlarged organs
• Organ failure
Phenilketonuria (PKU) / MIM 261600
AR type of inheritance
This is a classic example of metabolic disorder
Epidemiology. The occurrence of PKU varies among ethnic groups and geographic
regions worldwide. In the world occurs in 1 in 10,000 to 15,000 newborns. In Europe
1 in 10,000 carriers 1 in 50 – 70.

4
 © Erika Patskun. Medical Genetics. Inborn Errors of Metabolism. Rare Diseases.

Genetics. Mutations in the PAH gene cause phenylketonuria. Gene is located on

12q22-24. More than 400 mutations have been described in PAH gene. The most
common is R408W (57%). Phenylalanine hydroxylase (PAH) deficiency results in
intolerance to the dietary intake of the essential amino acid phenylalanine. Babies
with PKU are missing an enzyme called phenylalanine hydroxylase, which is needed
to break down an essential amino acid called phenylalanine. The substance is found
in foods that contain protein. Without the enzyme, levels of phenylalanine and two
closely-related substances build up in the body. These substances are harmful to the
central nervous system and cause brain damage.
Symptoms
• Phenylalanine plays a role in the body's production of melanin, the pigment
responsible for skin and hair color. Therefore, infants with the condition often have
lighter skin, hair, and eyes than brothers or sisters without the disease
• Delayed mental and social skills
• Head size significantly below normal
• Hyperactivity
• Jerking movements of the arms or legs
• Intellectual disability
• Seizures
• Skin rashes
• Tremors
• Unusual positioning of hands
• Mousy odor urine
Clinical course of the disease. Most individuals with phenylketonuria (PKU) appear
normal at birth. If newborn screening fails, progressive developmental delay is the
most common presentation. Other findings in untreated children in later infancy and
childhood may include vomiting, mousy odor, eczema, seizures, self-mutilation, and
severe behavioral disorders.
Treatment. PKU is a treatable
disease. Treatment involves a
diet that is extremely low in
phenylalanine, particularly
when the child is growing. The
diet must be strictly followed.
This requires close supervision
by a registered dietitian or
doctor, and cooperation of the
parent and child. Those who
continue the diet into
adulthood have better physical
and mental health. “Diet for
life” has become the standard
recommended by most
experts. This is especially

5
 © Erika Patskun. Medical Genetics. Inborn Errors of Metabolism. Rare Diseases.

important before conception and throughout pregnancy. Phenylalanine occurs in

significant amounts in milk, eggs, and other common foods.
Prognosis. The outcome is expected to be very good if the diet is closely followed,
starting shortly after the child's birth. If treatment is delayed or the condition remains
untreated, brain damage will occur. School functioning may be mildly impaired. If
proteins containing phenylalanine are not avoided, PKU can lead to intellectual
disability by the end of the first year of life.
Hyperphenylalaninemia / positive result of newborn screening test
• The baby needs to have a new blood test to check for PKU
• If new test shows positive result we diagnose PKU and prescribe treatment
Treatment – diet without/low phenylalanine
Newborns – breastfeeding + formula without phenylalanine
Later products with low Phe level
Control
Control the level of phenylalanine in blood
• Weekly during the first year of life
• Twice a month from 1 to 12 years
• Monthly after 12 y
• Biweekly for pregnant women with PKU
Maternal PKU. Maternal PKU is the term used when a woman with PKU is
pregnant (her genotype is autosomal recessive homozygote), child’s father does not
have such recessive mutation. According to II Mendel’s Law all their children will be
carries (аа х АА = Аа) – without PKU. Poor diet control, high Phe diet, or lack of
formula may cause in fetus:
• Heart problems 15%
• Small head size (microcephaly) 75%
• Low birth weight 50%
• Mental retardation 90%
• Slow development
• Language deficit
When planning to become pregnant, or already pregnant, the woman must
maintain strict metabolic control both before and throughout her pregnancy to
protect her baby.
Rare Diseases / Orphan Diseases
Rare diseases are diseases which affect a small number of people compared to
the general population and specific issues are raised in relation to their rarity. In
Europe, a disease is considered to be rare when it affects 1 person per 2000. (A
disease can be rare in one region, but common in another. This is the case of
thalassemia, an anemia of genetic origin, which is rare in Northern Europe, but it is
frequent in the Mediterranean region. 'Periodic disease' is rare in France, but common
in Armenia. There are also many common diseases whose variants are rare).
There are thousands of rare diseases. To date, six to seven thousand rare diseases
have been discovered and new diseases are regularly described in medical literature.
While nearly all genetic diseases are rare diseases, not all rare diseases are genetic
diseases. There are also very rare forms of infectious diseases, auto-immune diseases

6
© Erika Patskun. Medical Genetics. Inborn Errors of Metabolism. Rare Diseases.

and rare cancers. To date, the cause remains unknown for many rare diseases.
Rare diseases are serious, often chronic and progressive, diseases. For many
rare diseases, signs may be observed at birth or in childhood, however, over 50% of
rare diseases appear during adulthood.
The field of rare diseases suffers from a deficit of medical and scientific
knowledge. For a long time, doctors, researchers and policy makers were unaware of
rare diseases and until very recently there was no real research or public health policy
concerning issues related to the field. There is no cure for most rare diseases, but the
appropriate treatment and medical care can improve the quality of life of those
affected and extend their life expectancy. Impressive

progress has already been made for certain diseases, which shows that we must not
give up the fight, but on the contrary, continue and step up efforts in the fields of
research and social solidarity.
SOME Rare Metabolic Diseases: examples
Lisosomal Storage Diseases Treatment: ENZYME REPLACEMENT
THERAPY
Gaucher’s Disease / E 75.2/ MIM
230800, 230900, 231000
is a genetic disease in which fatty
substances (sphingolipids) accumulate in
cells and certain organs. The disorder is
characterized by bruising, fatigue,
anemia, low blood platelets, and
enlargement of the liver and spleen. It is
caused by a hereditary deficiency of the
enzyme glucocerebrosidase
Epidemiology. Gaucher disease occurs
in 1 in 50,000 to 100,000 people in the
general population. Types are shown on
the table:
Type 1 is the most common form of the
disorder; Type 1affects 1 in 500 to
1,000 people of Ashkenazi Jewish
heritage (eastern and central European)
Treatment. For those with type-I and
most type-III, enzyme replacement
treatment with intravenous recombinant
glucocerebrosidase can decrease liver
and spleen size, reduce skeletal
abnormalities, and reverse other
manifestations.This treatment costs
about US$200,000 annually for a single
person and should be continued for life
Treatment

7
© Erika Patskun. Medical Genetics. Inborn Errors of Metabolism. Rare Diseases.

Patients receive ERT via intravenous (IV) infusion about every 2 weeks, either at an
infusion center or at home. The FDA has approved treatments for Gaucher Disease
including: Cerezyme® (imiglucerase); VPRIV® (velaglucerase alfa); Elelyso®
(taliglucerase alfa)

Pompe disease / Type II glycogen storage disease (GSD2) (МІМ 232300)

Pompe disease is a rare (estimated at 1 in every 40,000 births), inherited and often
fatal disorder that disables the heart and skeletal muscles. It is caused by mutations in
a gene that makes an enzyme called acid alpha-glucosidase (GAA). Normally, the
body uses GAA to break down glycogen, a stored form of sugar used for energy. The
enzyme performs its function in intracellular compartments called lysosomes. In
Pompe disease, mutations in the GAA gene reduce or completely eliminate this
essential enzyme. Excessive amounts of lysosomal glycogen accumulate everywhere
in the body, but the cells of the heart and skeletal muscles are the most seriously
affected.
Early onset (or the infantile form) is the result of complete or near complete
deficiency of GAA. Symptoms begin in the first months of life, with feeding
problems, poor weight gain, muscle weakness, floppiness, and head lag. Respiratory
difficulties are often complicated by lung infections. The heart is grossly enlarged.
Many infants with Pompe disease also have enlarged tongues. Most babies die from
cardiac or respiratory complications before their first birthday. Infants typically have
extreme muscle weakness and a “floppy” appearance. X-rays usually reveal a greatly
enlarged heart. Other symptoms include breathing difficulties, trouble feeding, and a
failure to meet developmental milestones such as rolling over and sitting up.
Late onset (or juvenile/adult) Pompe disease is the result of a partial deficiency of
GAA. The onset can be as early as the first decade of childhood or as late as the sixth
decade of adulthood. The primary symptom is muscle weakness progressing to
respiratory weakness and death from respiratory failure after a course lasting several
years. The heart is usually not involved. A diagnosis of Pompe disease can be
confirmed by screening for the common genetic mutations or measuring the level of
GAA enzyme activity in a blood sample.
Children and adults tend to have greater variety in their symptoms, often including
weakness of the leg and hip muscles, leading to difficulties with mobility, as well as
breathing difficulties. Older patients rarely have the heart problems typical in infants.
Treatment. Individuals with Pompe disease are best treated by a team of specialists
(such as cardiologist, neurologist, and respiratory therapist) knowledgeable about the
disease, who can offer supportive and symptomatic care. The discovery of the GAA
gene has led to rapid progress in understanding the biological mechanisms and
properties of the GAA enzyme. As a result, an enzyme replacement therapy has been
developed that has shown, in clinical trials with infantile-onset patients, to decrease
heart size, maintain normal heart function, improve muscle function, tone, and
strength, and reduce glycogen accumulation. A drug called alglucosidase alfa
(Myozyme©), has received FDA approval for the treatment of infants and children
with Pompe disease. Another algluosidase alfa drug, Lumizyme©, has been
approved for late-onset (non-infantile) Pompe disease.

8
 © Erika Patskun. Medical Genetics. Inborn Errors of Metabolism. Rare Diseases.

What is the prognosis? Without enzyme replacement therapy, the hearts of babies
with infantile onset Pompe disease progressively thicken and enlarge. These babies
die before the age of one year from either cardiorespiratory failure or respiratory
infection. For individuals with late onset Pompe disease, the prognosis is dependent
upon the age of onset. In general, the later the age of onset, the slower the
progression of the disease. Ultimately, the prognosis is dependent upon the extent of
respiratory muscle involvement.
Mucopolysacharidoses / MPS / E 76
The MPSs are a group of inherited disorders
that result from the deficiency of 1 or more of
the lysosome enzymes required for
glycosaminoglycan (GAG) catabolism.
GAGs, which are a major constituent of
connective tissues, are long-chain complex
carbohydrates that are usually linked to
proteins to form proteoglycans and include
chondroitin 4-sulfate, chondroitin 6-sulfate,
heparan sulfate, dermatan sulfate, keratan
sulfate, and hyaluronic acid.
Because GAGs are primarily found in
connective tissue, the sites of pathology
primarily include the skeleton, heart valves,
and other areas with connective tissue
stroma.
MPS / Common symptoms
• CNS disease / mental retardation
• Coarse facial features
• Cardiovascular disease
• Musculoskeletal disease / short stature, deformity
• Ophthalmologic disease
• Pulmonary disease
• Deafness
• Hepatosplenomegaly
• Carpal tunnel syndrome - compression of the
median
nerve as it travels through the wrist at the carpal tunnel. The main symptoms are pain,
numbness and tingling in the thumb, index finger, middle finger and the thumb side
of the ring fingers
MPS І / Hurler syndrome/AR. Symptoms most often appear between ages 3 and 8.
Infants with severe Hurler syndrome appear normal at birth. Facial symptoms may
become more noticeable during the first 2 years of life. Frequency 1 per 100,000.
Death frequently occurring by the age of 10 years.
Features: short broad hands, limited joint mobility , including interphalangeal joints
Treatment. Enzyme replacement therapies are currently in use - laronidase
(Aldurazyme).

9
 © Erika Patskun. Medical Genetics. Inborn Errors of Metabolism. Rare Diseases.

MPS ІІ / Hunter syndrome / XR. The symptoms are generally not apparent at birth,
but usually start to become noticeable after the first year of life. Often, the first
symptoms of Hunter syndrome may include abdominal hernias, ear infections, runny
noses, and colds.
Treatment. An enzyme replacement treatment – idursulfatase.
MPS ІІІ / Sanfilippo syndrome/AR. Symptoms often appear after the first year of
life. A decline in learning ability typically occurs between ages 2 and 6. The child
may have normal growth during the first few years, but final height is below average.
Delayed development is followed by deteriorating mental status. Features: behavioral
problems; coarse facial features; diarrhea; full lips; synophrys; sleep difficulties; stiff
joints that may not extend fully; walking problems
MPS IV / Morquio syndrome/AR. Is estimated to occur in 1 of every 200,000
births. Symptoms usually start between ages 1 and 3. Abnormal development of
bones, including the spine; bell-shaped chest with ribs flared out at the bottom; coarse
facial features; hypermobile joints; knock-knees; large head (macrocephaly); short
stature with a particularly short trunk; widely spaced teeth.
MPS VI / Maroteaux-Lamy syndrome/AR. Phenotype like MPS I with normal
intelligence.
Fabry Disease / МІМ 301500
Synonyme: Anderson–Fabry disease.
Fabry disease is an X-linked lysosomal disorder that leads to excessive deposition of
neutral glycosphingolipids in the vascular endothelium of several organs and in
epithelial and smooth muscle cells. Progressive endothelial accumulation of
glycosphingolipids accounts for the associated clinical abnormalities of skin, eye,
kidney, heart, brain, and peripheral nervous system.
The prevalence has been estimated to be 1 per 40,000 people.
The National Society of Genetic Counselors recommends testing for any patient with
a family history of Fabry disease or corneal verticillata ("whorls") on slit lamp
exam. In the absence of these factors, it is recommended to test patients who have
any of the following two features:
1. Decreased sweating (anhidrosis or hypohidrosis)
2. Reddish-purple skin rash in
the bathing trunk area
(angiokeratomas)
3. Personal and/or family
history of kidney failure
4. Personal or family history
of "burning" or "hot"
pain in the hands and feet,
particularly during fevers
(acroparesthesias)
5. Personal or family history
of exercise, heat, or cold
intolerance
6. Patients with sporadic or

10
 © Erika Patskun. Medical Genetics. Inborn Errors of Metabolism. Rare Diseases.
non-autosomal dominant (no male-
to-male) transmission of

unexplained cardiac hypertrophy

If the family history suggests a
diagnosis of Fabry disease, genetic
testing and counseling should be
offered to all family members,
regardless of their sex.
Treatment: Enzyme replacement therapy.

References
1. Jones Kenneth Lyons. Smith's Recognizable Patterns of Human Malformation. 5th
edition, 1997, W.B. Saubders Company, 861 pages. ISBN: 0-7216-6115-7.
2. Josef Warkany. Congenital Malformations: Notes and Comments. 1971, Year Book
Medical Publishers. INC. 1309 pages. ISBN: 0-8151-9098-0.
3. OMIM: Online Mendelian Inheritance in Man. An Online Catalog of Human Genes
and Genetic Disorders https://www.omim.org/
4. Clinical Eye Openers http://ceo.medword.net/
5. I.B.I.S. – Вроджені вади розвитку: Міжнародна інформаційна система»
http://ukr.ibis-birthdefects.org/
6. Orphanet. The portal for rare diseases and orphan drugs
https://www.orpha.net/consor/cgi-bin/index.php
7. Richard M. Pauli. Achondroplasia: a comprehensive clinical review. Orphanet
Journal of Rare Diseases volume 14, Article number: 1 (2019)
8. MedlinePlus https://medlineplus.gov/
9. NIH. National Institutes of Health https://www.nih.gov/
10.Medscape Pathology & Lab Medicine https://www.medscape.com/pathology
11.GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1116/
12.Neurofibromatosis Program https://www.uab.edu/medicine/nfprogram/
13.The National Health Service (NHS) https://www.nhs.uk/
14.NORD. National Organization for Rare Disorders https://rarediseases.org/about/
15.UDN. Undiagnosed Diseases Network https://undiagnosed.hms.harvard.edu/

11
 Авторська верстка

Підписано до друку 31.05.2021. Формат 60х84/8.

Умов. друк. арк. 0,7. Гарнітура Times New Roman.
Зам. № 2998. Наклад 100 прим.

Надруковано з готового оригінал-макету:

ТОВ «РІК-У», 88000, м. Ужгород, вул. Гагаріна, 36
Свідоцтво суб’єкта видавничої справи ДК №5040 від 21.01.2016 р.