GENETIC DISORDER

INTRODUCTION:

The 20th century was a time of intense work and discovery in the field of modern genetics or
the study of human hereditary disease. The modern era of medical genetic began with the
discovery of inborn errors of metabolism. A genetic disorder is a genetic problem caused by
one or more abnormalities formed in the genome. Most disorders are quite genetic rare and
affect one person in every several thousands or millions. The earliest known genetic
condition in a hominid was in the fossil species Paranthropus robustus, with over a third of
individuals displaying Amelogenesis imperfecta.
Genetic disorders may be hereditary or non-hereditary, meaning that they are passed down
from the parents' genes. However, in some genetic disorders, defects may be caused by
new mutations, altered phenotype, or changes to the DNA. In such cases, the defect will only
be passed down if it occurs in the germline. Genetic disorders can be monogenic,
multifactoral, or chromosomal.

Congenital malformation:
Congenital anomalies are important causes of infant and childhood deaths, chronic illness and
disability. Through the resolution on birth defects of the Sitxty-third World Health Assembly
(2010), Member States agreed to promote primary prevention and improve the health of
children with congenital anomalies by:

 developing and strengthening registration and surveillance systems

 developing expertise and building capacity
 strengthening research and studies on etiology, diagnosis and prevention
 promoting international cooperation.

Congenital anomalies are also known as birth defects, congenital disorders or congenital
malformations. Congenital anomalies can be defined as structural or functional anomalies
(for example, metabolic disorders) that occur during intrauterine life and can be identified
prenatally, at birth, or sometimes may only be detected later in infancy, such as hearing
defects.In simple terms, congenital refers to the existence at or before birth.

Although approximately 50% of all congenital anomalies cannot be linked to a specific cause,
there are some known genetic, environmental and other causes or risk factors.
Genetic factors

Genes play an important role in many congenital anomalies. This might be through inherited
genes that code for an anomaly, or resulting from sudden changes in genes known as
mutations.

Consanguinity (when parents are related by blood) also increases the prevalence of rare
genetic congenital anomalies and nearly doubles the risk for neonatal and childhood death,
intellectual disability and other anomalies.

Some ethnic communities (such as Ashkenazi Jews or Finns) have a comparatively high
prevalence of rare genetic mutations such as Cystic Fibrosis and Haemophilia C.

Socioeconomic and demographic factors

Low-income may be an indirect determinant of congenital anomalies, with a higher

frequency among resource-constrained families and countries. It is estimated that about 94%
of severe congenital anomalies occur in low- and middle-income countries. An indirect
determinant, this higher risk relates to a possible lack of access to sufficient, nutritious foods
by pregnant women, an increased exposure to agents or factors such as infection and alcohol,
or poorer access to healthcare and screening. Factors often associated with lower-income may
induce or increase the incidence of abnormal prenatal development.

Maternal age is also a risk factor for abnormal intrauterine fetal development. Advanced
maternal age increases the risk of chromosomal abnormalities, including Down syndrome.

Environmental factors

Maternal exposure to certain pesticides and other chemicals, as well as certain medications,
alcohol, tobacco and radiation during pregnancy, may increase the risk of having a fetus or
neonate affected by congenital anomalies. Working or living near, or in, waste sites, smelters
or mines may also be a risk factor, particularly if the mother is exposed to other
environmental risk factors or nutritional deficiencies.
Infections

Maternal infections such as syphilis and rubella are a significant cause of congenital
anomalies in low- and middle-income countries.

Maternal nutritional status

Maternal folate insufficiency increases the risk of having a baby with a neural tube defect
while excessive vitamin A intake may affect the normal development of an embryo or fetus

Classification of Genetic Disorders:

 chromosomal abnormalities
 Unifactorial ( single, gene or Mendelian diseases)
 Multifactorial disease.

Chromosomal Abnormalities:

A chromosomal disorder, anomaly, aberration, or mutation is a missing, extra, or

irregular portion of chromosomal DNA. It can be from a typical number of chromosomes or a
structural abnormality in one or more chromosomes. Chromosome mutation was formerly
used in a strict sense to mean a change in a chromosomal segment, involving more than
one gene The term "karyotype" refers to the full set of chromosomes from an individual; this
can be compared to a "normal" karyotype for the species via genetic testing. A chromosome
anomaly may be detected or confirmed in this manner. Chromosome anomalies usually occur
when there is an error in cell division following meiosis or mitosis. There are many types of
chromosome anomalies. They can be organized into two basic groups, numerical and
structural anomalies.

Numerical disorders

This is called aneuploidy (an abnormal number of chromosomes), and occurs when an

individual either is missing a chromosome from a pair (monosomy) or has more than two
chromosomes of a pair (trisomy, tetrasomy, etc.)

An example of trisomy in humans is Down syndrome, which is a developmental disorder

caused by an extra copy of chromosome 21; the disorder is therefore also called trisomy 21.
Having an extra copy of this chromosome means that individuals have three copies of each of
its genes instead of two, making it difficult for cells to properly control how much protein is
made. Producing too much or too little protein can have serious consequences. Genes on
chromosome 21 that specifically contribute to the various symptoms of Down syndrome are
now being identified. The frequency of Trisomy 21 has been determined to be a function
of advanced maternal age.

An example of monosomy is Turner syndrome, where the individual is born with only one
sex chromosome, an X.

Sperm aneuploidy

Exposure of males to certain lifestyle, environmental and/or occupational hazards may

increase the risk of aneuploid spermatozoa. In particular, risk of aneuploidy is increased
by tobacco smoking, and occupational exposure to benzene insecticides and perfluorinated
compounds Increased aneuploidy is often associated with increased DNA damage in
spermatozoa.

Structural abnormalities

When the chromosome's structure is altered, this can take several forms:[11]

 Deletions: A portion of the chromosome is missing or deleted. Known disorders in

humans include Wolf-Hirschhorn syndrome, which is caused by partial deletion of the
short arm of chromosome 4; and Jacobsen syndrome, also called the terminal 11q
deletion disorder.
 Duplications: A portion of the chromosome is duplicated, resulting in extra genetic
material. Known human disorders include Charcot-Marie-Tooth disease type 1A, which
may be caused by duplication of the gene encoding peripheral myelin protein
22 (PMP22) on chromosome 17.
 Translocations: A portion of one chromosome is transferred to another chromosome.
There are two main types of translocations:
o Reciprocal translocation: Segments from two different chromosomes have
been exchanged.
o Robertsonian translocation: An entire chromosome has attached to another at
the centromere - in humans these only occur with chromosomes 13, 14, 15, 21, and
22.
 Inversions: A portion of the chromosome has broken off, turned upside down, and
reattached, therefore the genetic material is inverted.
 Insertions: A portion of one chromosome has been deleted from its normal place and
inserted into another chromosome.
 Rings: A portion of a chromosome has broken off and formed a circle or ring. This
can happen with or without loss of genetic material.
 Isochromosome: Formed by the mirror image copy of a chromosome segment
including the centromere.

Chromosome instability syndromes are a group of disorders characterized by chromosomal

instability and breakage. They often lead to an increased tendency to develop certain types of
malignancies.

Inheritance

Most chromosome abnormalities occur as an accident in the egg cell or sperm, and therefore
the anomaly is present in every cell of the body. Some anomalies, however, can happen after
conception, resulting in Mosaicism (where some cells have the anomaly and some do not).
Chromosome anomalies can be inherited from a parent or be "de novo". This is why
chromosome studies are often performed on parents when a child is found to have an
anomaly. If the parents do not possess the abnormality it was not initially inherited; however
it may be transmitted to subsequent generations.

Acquired chromosome abnormalities

Most cancers, if not all, could cause chromosome abnormalities, with either the formation of
hybrid genes and fusion proteins, deregulation of genes and overexpression of proteins, or
loss of tumor suppressor genes (see the "Mitelman Database" and the Atlas of Genetics and
Cytogenetics in Oncology and Haematology). Furthermore, certain consistent chromosomal
abnormalities can turn normal cells into a leukemic cell such as the translocation of a gene,
resulting in its inappropriate expression

DNA damage during spermatogenesis

During the mitotic and meiotic cell divisions of mammalian gametogenesis, DNA repair is

effective at removing DNA damages. However, in spermatogenesis the ability to repair DNA
damages decreases substantially in the latter part of the process as
haploid spermatids undergo major nuclear chromatin remodeling into highly
compacted sperm nuclei. As reviewed by Marchetti et al.,[17] the last few weeks of sperm
development before fertilization are highly susceptible to the accumulation of sperm DNA
damage. Such sperm DNA damage can be transmitted unrepaired into the egg where it is
subject to removal by the maternal repair machinery. However, errors in maternal DNA
repair of sperm DNA damage can result in zygotes with chromosomal structural aberrations.

Melphalan is a bifunctional alkylating agent frequently used in chemotherapy. Meiotic inter-

strand DNA damages caused by melphalan can escape paternal repair and cause
chromosomal aberrations in the zygote by maternal misrepair. Thus both pre- and post-
fertilization DNA repair appear to be important in avoiding chromosome abnormalities and
assuring the genome integrity of the conceptus.

Unifactorial diseases:

A genetic disorder is a genetic problem caused by one or more abnormalities formed in the
genome. Most genetic disorders are quite rare and affect one person in every several
thousands or million. The earliest known genetic condition in a hominid was in the fossil
species Paranthropus robustus, with over a third of individuals displaying Amelogenesis
imperfecta.

Genetic disorders may be hereditary or non-hereditary, meaning that they are passed down
from the parents' genes. However, in some genetic disorders, defects may be caused by
new mutations, altered phenotype, or changes to the DNA. In such cases, the defect will only
be passed down if it occurs in the germline. Genetic disorders can be monogenic,
multifactoral, or chromosomal.

Some types of recessive gene disorders confer an advantage in certain environments when

only one copy of the gene is present.

Single-gene

A single-gene (or monogenic) disorder is the result of a single mutated gene. Over 6000

human diseases are caused by single-gene defects.Single-gene disorders can be passed on to
subsequent generations in several ways. Genomic imprinting and uniparental disomy,
however, may affect inheritance patterns. The divisions between recessive and
dominant types are not "hard and fast", although the divisions between autosomal and X-
linked types are (since the latter types are distinguished purely based on the chromosomal
location of the gene). For example, achondroplasia is typically considered as a dominant
disorder, but children with two genes for achondroplasia have a severe skeletal disorder of
which achondroplasics could be viewed as carriers. Sickle-cell anemia is also considered as a
recessive condition, but heterozygous carriers have increased resistance to malaria in early
childhood, which could be described as a related dominant condition. When a couple where
one partner or both are sufferers or carriers of a single-gene disorder wish to have a child,
they can do so through in vitro fertilization, which enables preimplantation genetic diagnosis
to occur to check whether the embryo has the genetic disorder.

Most congenital metabolic disorders known as inborn errors of metabolism result from

single-gene defects.

Autosomal dominant

Only one mutated copy of the gene will be necessary for a person to be affected by an
autosomal dominant disorder. Each affected person usually has one affected parent.[12] The
chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions
sometimes have reduced penetrance, which means although only one mutated copy is needed,
not all individuals who inherit that mutation go on to develop the disease. Examples of this
type of disorder are Huntington's disease neurofibromatosis type 1, neurofibromatosis type
2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, hereditary multiple
exostoses (a highly penetrant autosomal dominant disorder), Tuberous sclerosis, Von
Willebrand disease, and acute intermittent porphyria. Birth defects are also called congenital
anomalies.

Autosomal recessive

Two copies of the gene must be mutated for a person to be affected by an autosomal
recessive disorder. An affected person usually has unaffected parents who each carry a single
copy of the mutated gene and are referred to as genetic carriers. Each parent with a defective
gene normally do not have symptoms.  Two unaffected people who each carry one copy of
the mutated gene have a 25% risk with each pregnancy of having a child affected by the
disorder. Examples of this type of disorder are Albinism, Medium-chain acyl-CoA
dehydrogenase deficiency, cystic fibrosis, sickle-cell disease, Tay–Sachs disease, Niemann-
Pick disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such
as wet versus dry earwax, are also determined in an autosomal recessive fashion
X-linked dominant

X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a
few disorders have this inheritance pattern, with a prime example being X-linked
hypophosphatemic rickets. Males and females are both affected in these disorders, with males
typically being more severely affected than females. Some X-linked dominant conditions,
such as Rett syndrome, incontinentia pigmenti type 2, and Aicardi syndrome, are usually fatal
in males either in utero or shortly after birth, and are therefore predominantly seen in
females. Exceptions to this finding are extremely rare cases in which boys with Klinefelter
syndrome (47,XXY) also inherit an X-linked dominant condition and exhibit symptoms more
similar to those of a female in terms of disease severity. The chance of passing on an X-
linked dominant disorder differs between men and women. The sons of a man with an X-
linked dominant disorder will all be unaffected (since they receive their father's Y
chromosome), and his daughters will all inherit the condition. A woman with an X-linked
dominant disorder has a 50% chance of having an affected fetus with each pregnancy,
although in cases such as incontinentia pigmenti, only female offspring are generally viable.

X-linked recessive

X-linked recessive conditions are also caused by mutations in genes on the X chromosome.
Males are more frequently affected than females, and the chance of passing on the disorder
differs between men and women. The sons of a man with an X-linked recessive disorder will
not be affected, and his daughters will carry one copy of the mutated gene. A woman who is a
carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are
affected and a 50% chance of having daughters who carry one copy of the mutated gene and
are therefore carriers. X-linked recessive conditions include the serious diseases hemophilia
A, Duchenne muscular dystrophy, and Lesch-Nyhan syndrome, as well as common and less
serious conditions such as male pattern baldness and red-green color blindness. X-linked
recessive conditions can sometimes manifest in females due to skewed X-
inactivation or monosomy X (Turner syndrome).

Y-linked

Y-linked disorders are caused by mutations on the Y chromosome. These conditions may
only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same
sex. More simply, this means that Y-linked disorders in humans can only be passed from men
to their sons; females can never be affected because they do not possess Y-allosomes.

Y-linked disorders are exceedingly rare but the most well-known examples typically cause
infertility. Reproduction in such conditions is only possible through the circumvention of
infertility by medical intervention.

Mitochondrial

This type of inheritance, also known as maternal inheritance, applies to genes encoded
by mitochondrial DNA. Because only egg cells contribute mitochondria to the developing
embryo, only mothers can pass on mitochondrial DNA conditions to their children. An
example of this type of disorder is Leber's hereditary optic neuropathy. It is important to
stress that the vast majority of mitochondrial disease (particularly when symptoms develop in
early life) is actually caused by an underlying nuclear gene defect, and most often follows
autosomal recessive inheritance.

Multifactorial disorder

Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely
associated with the effects of multiple genes in combination with lifestyles and environmental
factors. Multifactorial disorders include heart disease and diabetes. Although complex
disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This
makes it difficult to determine a person’s risk of inheriting or passing on these disorders.
Complex disorders are also difficult to study and treat, because the specific factors that cause
most of these disorders have not yet been identified. Studies which aim to identify the cause
of complex disorders can use several methodological approaches to determine genotype-
phenotype associations. One method, the genotype-first approach, starts by identifying
genetic variants within patients and then determining the associated clinical manifestations.
This is opposed to the more traditional phenotype-first approach, and may identify causal
factors that have previously been obscured by clinical heterogeneity, penetrance, and
expressivity.

On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit
simple patterns as with Mendelian diseases. But this does not mean that the genes cannot
eventually be located and studied. There is also a strong environmental component to many
of them (e.g., blood pressure).
 asthma
 autoimmune diseases such as multiple sclerosis
 cancers
 ciliopathies
 cleft palate
 diabetes
 heart disease
 hypertension
 inflammatory bowel disease
 intellectual disability
 mood disorder
 obesity
 refractive error
 infertility

Chromosomal disorder
Chromosomes in Down syndrome, the most common human condition due to
aneuploidy.
A chromosomal disorder is a missing, extra, or irregular portional of chromosomal DNA. It
can be from an atypical number of chromosome or a structural abnormality in one or more
chromosome. An example of these disorder is Trisomy 21 (Down syndrome), in which there
is an extra copy of chromosome 21.

Diagnosis
Due to the wide range of genetic disorders that are known, diagnosis is widely varied and
dependent of the disorder. Most genetic disorders are diagnosed at birth or during early
childhood however some, such as Huntington's disease, can escape detection until the patient
is well into adulthood.
The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in
depth family history, it is possible to anticipate possible disorders in children which direct
medical professionals to specific tests depending on the disorder and allow parents the chance
to prepare for potential lifestyle changes, anticipate the possibility of stillbirth, or
contemplate termination. Prenatal diagnosis can detect the presence of characteristic
abnormalities in fetal development through ultrasound, or detect the presence of characteristic
substances via invasive procedures which involve inserting probes or needles into the uterus
such as in amniocentesis
Prognosis
Not all genetic disorders directly result in death; however, there are no known cures for
genetic disorders. Many genetic disorders affect stages of development, such as Down
syndrome, while others result in purely physical symptoms such as muscular dystrophy.
Other disorders, such as Huntington's disease, show no signs until adulthood. During the
active time of a genetic disorder, patients mostly rely on maintaining or slowing the
degradation of quality of life and maintain patient autonomy. This includes physical
therapy, pain management, and may include a selection of alternative medicine programs.

Treatment

The treatment of genetic disorders is an ongoing battle with over 1800 gene therapy clinical
trials having been completed, are ongoing, or have been approved worldwideDespite this,
most treatment options revolve around treating the symptoms of the disorders in an attempt to
improve patient quality of life.Gene therapy refers to a form of treatment where a healthy
gene is introduced to a patient. This should alleviate the defect caused by a faulty gene or
slow the progression of disease. A major obstacle has been the delivery of genes to the
appropriate cell, tissue, and organ affected by the disorder.

REFERENCE:

1. Rudolph C, Rudolph A, Lister GE, et al., eds.  Rudolph’s Pediatrics,

22nd edn. New York, NY: McGraw-Hill Professional, 2011.
2. American Academy of Pediatrics, Committee on Children with
Disabilities, 2001. Role of the pediatrician in family-centered early
intervention services. Pediatrics 2011;107(5):1155-7.
3. Centers for Disease Control and Prevention. Developmental disabilities
increasing in US: www.cdc.gov/features/dsdev_disabilities.
4. WHO 19 February 2018 www.who.int/news-room/fact-
sheets/detail/rubella
5. Le Doaré K, Bland R, Newell ML. Neurodevelopment in children born
to HIV-infected mothers by infection treatment status. Pediatrics
2012;130(5):e1326-44.
6. Swanson EC, Schleiss MR. Congenital cytomegalovirus infection:
New prospects for prevention and therapy. Pediatr Clin N Am
2013;60(2):335-49.
7. Torgerson PR, Mastroiacovo P. The global burden of congenital
toxoplasmosis: A systematic review. Bull World Health Organ
2013;91(7):501-8.
8. WHO 16 July 2018 www.who.int/news-room/fact-
sheets/detail/immunization-coverage
9. WHO 3 August 2016 www.who.int/news-room/fact-
sheets/detail/sexually-transmitted-infections-(stis)
10. WHO Guideline on Syphilis screening and treatment for pregnant
women, 2017 ISBN:  978-92-4-155009-3
11. WHO WHO/Global Health Observatory/map gallery syphilis(WHO
2018) Percentage of antenatal care attendees positive for
syphilis www.gamapserver.who.int
12. Robinson, Joan L., Zika virus: What does a physician caring for
children in Canada need to know?  Canadian Pediatric Society,
Infectious Diseases Committee. Paediatr Child Health (2017) 22 (1): 
48-51
13. https://wwwnc.cdc.gov/travel/files/zika-areas-of-risk-pdf
14. WHO 20 July 2018 www.who.int/news-room/fact-sheets/detail/zika-
virus
15. Lanpeer, Bruce P., The impact of Toxins on the Developing Brain.
Annual Review of Public Health, Volume 36:  211-23- 2015
16. Abel EL, Sokol RJ. Incidence of fetal alcohol syndrome and economic
impact of FAS-related anomalies. Drug Alcohol Depend
1987;19(1):1951-70.
17. Liu Y, McDermott S, Lawson A, et al. The relationship between
mental retardation and developmental delays in children and the levels
of arsenic, mercury and lead in soil samples taken near their mother’s
residence during pregnancy. Int J Hyg Environ Health 2010;13(2):116-
123.
18. WHO 9 February 2018 www.who.int/news-room/fact-
sheets/detail/lead-poisoning and health
19. Eskenazi B, Marks AR, Bradman A, et al. In utero exposure to
dichlorodiphenyltrichloroethane (DDT) and
dichlorodiphenyldichloroethylene (DDE) and neurodevelopment
among young Mexican American children. Pediatrics
2006;118(1):233-41.
 20. WHO September 7, 2016 www.who.int/news-room/fact-
sheets/detail/congenital-anomalies
21. WHO, UNICEF, ICCIDD.  Assessment of iodine deficiency disorders
and monitoring their elimination: A guide for programmer managers,
3rd edn. Geneva: WHO,
2008: www.who.int/nutrition/publications/micronutrients/iodine_defici
ency/9789241595827/en/
22. Bath SC, Steer C, Golding J, et al. Effect of inadequate iodine intake
status in UK pregnant women on cognitive outcomes in their children:
Results from the Avon longitudinal study of parents and children
(ALSPAC). Lancet 2013;382(9889):331-7.
23. WHO. Feto-maternal nutrition and low birth
weight: www.who.int/nutrition/topics/feto_maternal/en/
Dagnew AF, Cunnington MC, Dube Q, et al. Variation in reported group B streptococcal
disease incidence in developing countries. Clin Infect