Understanding Genetic Disorders: From Cri-du-Chat to Fragile X Syndrome
Cri-du-Chat Syndrome (Chromosome 5p Deletion Syndrome)
What is Cri-du-Chat Syndrome?
Cri-du-chat syndrome gets its name from the infant’s distinctive cry, which is high-pitched and sounds like a cat. This rare genetic disorder occurs in approximately 1 in 216,000 births. Individuals with Cri-du-chat syndrome have 46 chromosomes but are missing a piece of chromosome number 5.
Causes
Most cases are believed to occur during the development of the egg or sperm. In a small number of cases, a parent passes a different, rearranged form of the chromosome to their child.
Symptoms
- High-pitched cry similar to a meowing kitten
- Moon-shaped face
- Malformed larynx
- Difficulty swallowing and sucking (Feeding Problem)
- Low birth weight and poor growth
- Severe cognitive, speech, and motor delays, mental retardation
- Behavioral problems such as hyperactivity, aggression, and repetitive movements
Turner Syndrome
What is Turner Syndrome?
Turner syndrome is a sex chromosomal monosomy (45, XO) that affects females. It occurs in approximately 1 in 2000-5000 live female births. Sadly, 99% of fetuses with Turner syndrome result in spontaneous termination during the first trimester.
Physical Impairments
- Short stature
- Skeletal disorders (osteoporosis which may lead to scoliosis)
- Webbed neck (due to cystic hygroma)
- Broad shoulders
- Broad chest (shield chest), widely spaced nipples
- No/Poor breast development
- Narrow hips (High waist-to-hip ratio)
Clinical Features
- Underdeveloped ovaries (streak gonads, hence this syndrome is also called ovarian dysgenesis)
- Sterile, lack expected secondary sex characteristics
- Amenorrhea (No menstruation)
- Cardiovascular problems (Coarctation of the aorta, Bicuspid aortic valve)
- Horseshoe kidney
- Thyroid problems (hypothyroidism specifically Hashimoto’s thyroiditis)
Klinefelter’s Syndrome
What is Klinefelter’s Syndrome?
Klinefelter’s syndrome (XXY Males) is a disorder occurring due to nondisjunction of the X chromosome during Meiosis. This results in an extra X chromosome. The incidence is approximately 1 in 500 live male births.
Causes
- Nondisjunction during meiosis II of the germ cell in the female, producing an XX ovum that, when fertilized with a Y-sperm, yields XXY offspring.
- Nondisjunction of the X and Y sex chromosomes during meiosis, producing a sperm with both an X and Y chromosome that, when fertilized with a normal X ovum, produces XXY offspring.
Variations
- 48, XXYY (male) syndrome: Incidence = 1 in 18,000-40,000 births
- 48, XXXY: Incidence = Extremely rare
Clinical Features
- Childhood: Weaker muscles and reduced strength.
- Puberty: Features become more prominent due to hypogonadism (less amount of testosterone produced):
- Rounded body type
- Broader hips
- Little body hair is present
- Gynecomastia (increased breast tissue)
- Microorchidism (i.e. small testicles)
Jacob’s Syndrome
What is Jacob’s Syndrome?
Jacob’s syndrome is characterized by the presence of an additional Y chromosome. It occurs in approximately 1 in 1,800 births.
Features
- Normal physically
- Normal mentally
- Increase in testosterone
- More aggressive
- Normal lifespan
Note: There are articles that claim that those with Jacob’s Syndrome are more prone to committing crimes.
Triple X Syndrome
What is Triple X Syndrome?
Triple X syndrome is characterized by the presence of an additional X chromosome. It occurs when an XX ovum fertilizes with an X-sperm. The incidence is approximately 1 in 1,000 births.
Features
- Normal physically, sometimes taller
- Normal mentally, increased risk of retardation and learning difficulties
Y-Linked Disease
What is Y-Linked Disease?
Y-linked inheritance, also known as ‘holandric inheritance,’ is the determination of a phenotypic trait by an allele (or gene) on the Y chromosome. These traits are passed from father to son with no interchromosomal genetic recombination. Y-linked diseases are very rare.
Key Points
- Deletion (missing genetic materials) in the Y-gene is a frequent genetic cause of male infertility.
- Having hairy ears was once thought to be a Y-linked trait in humans, but that hypothesis has been discredited.
X-Linked Disease
What is X-Linked Disease?
X-linked diseases are single-gene disorders that reflect the presence of defective genes on the X chromosome. They show inheritance patterns that differ from autosomal diseases. Since males have one X chromosome and one Y chromosome while females have two X chromosomes, they show different patterns of inheritance and severity of manifestation. There are both dominant and recessive X-linked diseases, and some characteristics are common to X-linked disorders in general.
Key Points
- Males are never carriers; if they have a mutated gene on the X chromosome, it will be expressed. Males are termed hemizygous.
- Females are more likely to be affected as they have a 2x increased risk of inheriting the mutated allele.
X-Linked Dominant
What is X-Linked Dominant Inheritance?
X-linked dominant disorders are expressed in females when only a single copy of the mutated gene is present. Very few diseases have been identified as X-linked dominant, including:
- Alport syndrome
- Nephrogenic Diabetes Insipidus
- Hypophosphatemic rickets or vitamin D resistant rickets (leading to low serum phosphorus & skeletal abnormalities)
Key Points
- Never passed from father to son.
- Affected males produce only affected females. (An affected male only has one X chromosome to pass on to his daughters.)
- Affected females produce 50% normal and 50% affected offspring. (Heterozygous)
- Males are usually more severely affected than females. Some X-linked traits may even be lethal.
Alport Syndrome
What is Alport Syndrome?
Alport syndrome is an inherited, heterogeneous disorder involving the basement membranes of the kidney, frequently affecting the cochlea and eyes.
Clinical Manifestations
- Renal: Hematuria, Proteinuria, Hypertension with edema and nephrotic syndrome at a later stage.
- Hearing: Sensorineural deafness (90% are deaf by the age of 40 years)
- Ocular: Dot-and-fleck retinopathy, Leiomyomatosis, Diffuse leiomyomatosis
Nephrogenic Diabetes Insipidus
What is Nephrogenic Diabetes Insipidus?
Nephrogenic diabetes insipidus occurs when the kidneys cannot concentrate urine normally, resulting in the excretion of large amounts of dilute urine. This happens because the kidney tubules do not respond to Antidiuretic Hormone (ADH). It is a very rare disorder.
Symptoms
- Intense or uncontrollable thirst and craving ice water
- Producing large amounts of urine (usually more than 3 liters, and up to 15 liters per day)
- Easily dehydrated
Hypophosphatemic Rickets
What is Hypophosphatemic Rickets?
Hypophosphatemic rickets is a form of rickets characterized by low serum phosphate levels and resistance to treatment with ultraviolet radiation or vitamin D ingestion. The incidence is approximately 1 in 20,000 newborns.
Symptoms
- Short stature
- Disproportionate stature, resulting from deformity and growth retardation of the lower extremities
- Bow legged and deformities associated with bones
- Bone pain and joint pain
X-Linked Recessive
What is X-Linked Recessive Inheritance?
X-linked recessive inheritance is a hereditary pattern in which a recessive gene on the X chromosome results in the manifestation of characteristics in males and carrier status (usually) in females.
Key Points
- Males are more likely affected as they only need one copy of the mutant allele to express the phenotype.
- Females must have two copies of the mutant allele in order for the mutant phenotype to develop.
- Females with one copy of the mutant allele are only carriers.
Disorders
- Color blindness
- Duchenne Muscular Dystrophy
- Hemophilia
Color Blindness
What is Color Blindness?
Color blindness, also known as color vision deficiency (CVD), is a condition where individuals have trouble seeing red, green, blue, or a mix of these colors. It is rare for a person to see no color at all.
Causes
The three types of cone cells in the eye each sense either red, green, or blue light, and are most concentrated in the macula. Individuals with color blindness do not have these cone cells.
Duchenne Muscular Dystrophy
What is Duchenne Muscular Dystrophy?
Duchenne muscular dystrophy is a form of muscular dystrophy (muscle weakness and loss of muscle tissues) that worsens quickly. It is caused by a defective gene for dystrophin, a type of protein in muscles. The incidence is approximately 1 in 3,600 male infants.
Signs and Symptoms
Symptoms usually appear before age 6 and may appear as early as infancy. They include:
- Fatigue
- Learning difficulties (IQ can be below 75)
- Intellectual disability
- Muscle weakness that:
- Begins in the legs and pelvis, less severe in the arms, neck, and other areas of the body
- Quickly gets worse
- Problems with motor skills (running, hopping, jumping)
- Frequent falls
- Trouble getting up from a lying position or climbing stairs
Hemophilia
What is Hemophilia?
Hemophilia is a bleeding disorder in which the blood fails to clot normally. It is caused by a lack of blood clotting factor VIII (antihemophilic globulin, AHG) or IX (Christmas Factor). The incidence is approximately 1 in 1,500 newborn males.
Types
- Hemophilia A: Lack of clotting factor VIII (75% of cases)
- Hemophilia B: “Christmas Disease” is a defect in clotting factor IX
Symptoms
- Bleeding from even minor cuts
Treatment
Transfusions of fresh whole blood or plasma or clotting factor are used to control bleeding.
Fragile X Syndrome
What is Fragile X Syndrome?
Fragile X syndrome, also known as Martin-Bell syndrome or Marker X syndrome, is a genetic condition involving changes in the long arm of the X chromosome. It is characterized by mental retardation.
Inheritance
The inheritance pattern of Fragile X syndrome is complex. Some consider this syndrome as X-linked dominant, some consider it as X-linked recessive, while others claim it does not fall under either category.
Causes
The fragile area on the X chromosome tends to repeat bits of the genetic code. The more repeats, the more likely there is to be a problem.
Symptoms
- Family history of fragile X syndrome, especially a male relative
- Mental retardation
- Large testicles (macro-orchidism)
- Large size
- Tendency to avoid eye contact
- Hyperactive behavior
- Large forehead