Signs and Symptoms Associated with Down Syndrome

Down syndrome is the most common autosomal trisomy identified in liveborn infants. As many as 95% of Down syndrome cases arise due to chromosomal nondisjunction during maternal meiosis (47 XX, +21) an abnormality that positively correlates with increasing maternal age. Two of the more prominent and consistent lectures of Down syndrome are mental retardation and facial dysmorphism. Almost every organ and system, however, is affected

Signs and Symptoms Associated with Down Syndrome

Trisomy 21 (Down syndrome) is characterized by mental retardation, facial dysmorphism, single palmar crease, endocardial cushion defects, and duodenal atresia. Affected individuals have an increased risk of AML-M7 and ALL in childhood and early Alzheimer disease in adulthood. 

Multiple origins of replication (DNA replication)

The process of DNA replication is similar in eukaryotes and prokaryotes. The key steps involved in DNA replication are:
1. Unwinding of double stranded DNA (dsDNA) by helicase to produce single stranded DNA (ssDNA)
2. Formation of a replication fork
3. Formation of an RNA primer by the action of the enzyme primase
4. Synthesis and concurrent proofreading of daughter DNA strands by DNA polymerases
5. Ligation of Okazaki fragments on lagging strands by ligase and removal and replacement of RNA primers with DNA by DNA polymerase I
6. Reconstitution of chromatin and ligation of daughter strands.

In E. coil, a prokaryote, the three major types of DNA polymerase are DNA polymerase I, II and III. In eukaryotes there are five major DNA polymerases: alpha, beta, gamma, delta and epsilon. Though the eukaryotic genome is much larger and more complex than the prokaryotic genome, interestingly the size of the eukaryotic genome is not the source of its complexity. Its complexity results from the presence of a large number of non-coding DNA regions between coding regions. Within genes there are introns (Non-coding regions - Think “IN” between) separating exons (Coding regions - Think “EX” pressed). Prokaryotes rarely have introns within their genes.
In contrast to prokaryotes which typically have a single origin of replication eukaryotes have multiple origins of replication? With multiple origins of replication, the genome can be copied much more quickly because multiple regions are being replicated at once. 

Patau syndrome & Edwards syndrome Manifestations

Trisomy 13 (Patau syndrome) is the third most common autosomal trisomy identified in liveborn infants, and the most severe. Affected children typically die within the first week of life, with only 5% surviving the first six months. In the majority of trisomy 13 infants cytogenetic studies demonstrate nondisjunction (47XX, +13); this chromosomal abnormality arises during maternal meiosis I and is associated with advanced maternal age.

The prominent phenotypic features of trisomy 13 are associated with an early defect in prechordal mesoderm development. As a result, the midface, eye, and forebrain are most markedly affected. The clinical manifestations of Patau syndrome include the abnormalities categorized by system below.
1. Head and neck: severe cleft lip and/or palate microphthalmia or anophthalmia, coloboma, cyclops, malformed or absent nose, deafness, scalp defects (aplasia cutis)
2. CNS: severe mental retardation microcephaly, holoprosencephaly (failure of brain to divide into hemispheres) absent olfactory nerve or bulb, neural tube defects
3. Extremities: polydactyly, rocker-bottom feet
4. Cardiac: PDA, atrial septal defect, ventricular septal defect
5. Renal: polycystic kidney disease
6. Gastrointestinal: abdominal wall defects associated with omphalocele or umbilical hernia, pyloric stenosis.

Clinical manifestations of trisomy 18 (Edwards syndrome) include
prominent occiput micrognathia,
small mouth low-set and malformed ears, and rocker-bottom feet.
Clenched hands with the index finger overriding the middle finger
and the fifth finger overriding the fourth finger are characteristic for this condition.
Meckel’s diverticulum and malrotation are common gastrointestinal abnormalities.  

Associations of autosomal and sex chromosomal-inherited disorders

A variety of autosomal and sex chromosomal-inherited disorders are associated with developmental cardiac and/or aortic defects or cardiac pathology. The major associations are as follows:


1. Down syndrome: endocardial cushion defects (ostium primum ,ASD, regurgitant AV valves)
2. DiGeorge syndrome: tetralogy of fallot and aortic arch anomalies
3. Friedreich’s ataxia: hypertrophic cardiomyopathy
4. Marfan syndrome: cystic medial necrosis of the aorta
5. Tuberous sclerosis: valvular obstruction due to cardiac rhabdomyomas
6. Turner’s syndrome: coarctation of the aorta. 

Mendelian Disorders List

Autosomal recessive disorders 

• Sickle cell disease
• Cystic fibrosis 
• alpha-1 antitrypsin deficiency
• 21-hydroxylase deficiency
• Wilson's disease
• Thalassemia 

Autosomal dominant disorders

• Hereditary angioedema(C1 esterase inhibitor deficiency)
• Hereditary spherocytosis
• Familial Hypercholestrolemia
• Neurofibromatosis 
• Huntington's disease
• Osteogenesis imperfecta
• Achondroplasia
• Tuberous sclerosis

X-linked recessive disorders

• Glucose-6-phosphate dehydrogenase deficiency
• Duchenne's muscular dystrophy
• Hemophilia A
• Hunter's syndrome
• Fragile X syndrome
• Lesch-Nyhan syndrome
• Testicular feminization
• Chronic granulomatous disease
• Bruton's agammaglobulinemia 

X-linked dominant disorders

• Vitamin D-resistant rickets
• Alport's syndrome

Genetic conditions (Germline genetic disease) Involved chromosomal sites

• 5q21 is the location of the APC mutation that predisposes for FAP.

• 11p13 is the site of the WT-1 tumor gene

• 13q14 is the site of the RB retinoblastoma gene.

• 17q11 is the site of the NF-1 neurofibromatosis gene,

• 22q12 is the site of the NF-2 neurofibromatosis gene.

DISEASES WITH THEIR ENZYME DEFICIENCIES

Criggler-Najjar - UDP-glucuronyl transferase
Von-Gierke’s - Glucose -6- phosphatase
Pompe’s - Acid maltase( Acid α glucosidase)
Mc Ardle’s - Muscle glycogen phosphorylase
Tarui’s disease - Muscle phosphorylase
Niemann-Pick’s - Sphingomyelinase
Farber’s - Ceramidase
Gaucher’s - β-glucosidase
Krabbe’s - β-galactosidase
Tay-Sach’s - Hexosaminidase-A
Phenylketonuria - Phenylalanine hydroxylase
Alkaptonuria - Homogentisate oxidase
Albinism - Tyrosinase
Fabry’s - α-galactosidase
Lesch-Nyhan syndrome - HGPRT
Sandhoff - Hexosaminidase-β
Xeroderma pigmentosum - DNA exinuclease
Sudden infant death syndrome - Medium chain acyl CoA dehydrogenase
Maple syrup urine - Branched chain α-ketoacid dehydrogenase
Acute Intermittent Porphyria- Uroporphyrinogen-1 synthase
Maple syrup urine disease - Alpha ketoacid decarboxylase
Hereditary fructose intolerance Aldolase b
Fructosuria - Fructokinase b
Galctosemia - Galactose-1-phosphate uridyl transferase

Important presentation about Thalassemia (Microcytic Anemia)

• Definition: hereditary underproduction of either the alpha or beta globin chains of the hemoglobin A  resulting in a  microcytic anemia.
• Beta thalassemias are due to mutations in the HBB gene on chromosome 11.
• The α thalassemias involve the genes HBA1 and HBA2 on chromosome 16.

Beta- Thalassemia

• The β-globin mutations associated with β-thalassemia fall into two categories: 
• (1) β0, in which no β-globin chains are produced; and 
• (2) β+, in which there is reduced (but detectable) β-globin synthesis
• Individuals inheriting one abnormal allele have thalassemia minor or thalassemia trait, which is asymptomatic or mildly symptomatic. 
• Most individuals inheriting any two β0 and β+ alleles have β-thalassemia major; 
• occasionally, individuals inheriting two β+ alleles have a milder disease termed β-thalassemia intermedia.

Alpha-Thalassemias

• alpha- thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns.The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal . The severity of the alpha- thalassemias is correlated with the number of affected alpha-globin genes.  
•  alpha0 thalassaemias, where there is lots of gama4 but no alpha-globins at all (referred to as Hb Barts), often result in still birth.

• The most severe form of alpha thalassemia major causes stillbirth.
• Other symptoms can include:
• Bone deformities in the face
• Fatigue
• Growth failure
• Shortness of breath
• splenomegaly

Diagnostic features of beta-thalassaemia

Dx

• A physical exam may reveal a swollen (enlarged) spleen.
• Blood test:
• Red blood cells will appear small and abnormally shaped when looked at under a microscope.
• A complete blood count (CBC) reveals anemia.
• A test called hemoglobin electrophoresis shows the presence of an abnormal form of hemoglobin

Rx

• Treatment for thalassemia major often involves regular blood transfusions and folate supplements.
• If you receive blood transfusions, you should not take iron supplements. Doing so can cause a high amount of iron to build up in the body, which can be harmful.
• Persons who receive significant numbers of blood transfusions need a treatment called chelation therapy to remove excess iron from the body.
• Bone marrow transplant may help treat the disease in some patients, especially children.
• Hydrops fetalis: none available 
• Haemoglobin H: no specific therapy required; avoid iron therapy; folic acid if necessary 

TREATMENT OF BETA-THALASSAEMIA MAJOR

Cystic fibrosis

Most common lethal genetic disorder

   

Defect: mutation of the chloride channel protein, cystic fibrosis trans-membrane conductance regulator (CFTR)

Genetics

  

i. CFTR gene is located on chromosome 7

ii. Most common mutation is a deletion in amino acid position 508 (AF508)

Pathogenesis: 

• defective chloride channel protein leads to abnormally thick viscous mucous, which obstructs the ducts of exocrine organs

Distribution of disease

i. Lungs

• Recurrent pulmonary infections with P. aeruginosa and S. aureus . 
• Chronic bronchitis
• Bronchiectasis

ii. Pancreas

•  Plugging of pancreatic ducts results in atrophy and fibrosis
•  Pancreatic insufficiency
•  Fat malabsorption 
•  Malodorous steatorrhea
•  Deficiency of fat-soluble vitamins

iii. Male reproductive system

• Obstruction of the vas deferens and epididymis
• May lead to male infertility

 iv. Liver:

•  plugging of the biliary canaliculi may result in biliary cirrhosis

v. GI tract:

• small intestinal obstruction (meconium ileus)

Diagnosis

i. Sweat test (elevated NaCl)
ii. DNA probes

Treatment

• Chest Physiotherapy
• Antibiotics
• Mucolytics : N-acetylcysteine
• Gene therapy

Prognosis
i. Mean survival: 30 years
ii. Most common cause of death is pulmonary infections

Genetic diseases

MUTATIONS

Mutations involving nucleotides

Point mutation

Silent

Misesnse

Nonsense

Frame shift mutation – deletions and insertions

Trinucleotide repeat sequence

Mendelian disorders

Autosomal dominant diseases

Nervous

Huntington disease

Neurofibromatosis

Myotonic dystrophy

Tuberous sclerosis

Urinary

Polycystic kidney disease

Gastrointestinal

Familial polyposis coli

Hematopoietic

Hereditary spherocytosis

von Willebrand disease

Skeletal

Marfan syndrome

Ehlers-Danlos syndrome (some variants)

Osteogenesis imperfecta

Achondroplasia

Metabolic

Familial hypercholesterolemia

Acute intermittent porphyria

Autosomal Recessive Disorders

Metabolic

Cystic fibrosis

Phenylketonuria

Galactosemia

Homocystinuria

Lysosomal storage diseases

a1 -Antitrypsin deficienc

Wilson disease

Hemochromatosis

Glycogen storage diseases

Hematopoietic

Sickle cell anemia

Thalassemias

Endocrine

Congenital adrenal hyperplasia

Skeletal

Ehlers-Danlos syndrome (some variants)

Alkaptonuria

Nervous

Neurogenic muscular atrophies

Friedreich ataxia

Spinal muscular atrophy

X-Linked Recessive Disorders

Musculoskeletal

Duchenne muscular dystrophy

Blood

Hemophilia A and B

Chronic granulomatous disease

Glucose-6-phosphate dehydrogenase deficiency

Immune Agammaglobulinemia

Wiskott-Aldrich syndrome

Metabolic

Diabetes insipidus

Lesch-Nyhan syndrome

Nervous

Fragile-X syndrome

Biochemical and Molecular Basis of Some Mendelian Disorders

Enzyme Phenylalanine hydroxylase mutation: reduced amount of enzyme causing Phenylketonuria

Hexosaminidase mutation with stop codon:

reduced amount causing Tay-Sachs disease

Adenosine deaminase mutation causing Severe combined immunodeficiency

a1 –Antitrypsin mutations: impaired secretion from liver to serum, causing emphysema and liver cirrhosis

Low-density lipoprotein receptor mutations: Familial hypercholesterolemia

Vitamin D receptor mutations: Vitamin D-resistant rickets

Hemoglobin gene Deletions: reduced amount causing Thalassemia

Hb Point mutations: abnormal structure causing Sickle cell anemia

Cystic fibrosis transmembrane conductance regulator( CFTR) mutation causingCystic fibrosis

Collagen gene mutations cause reduced amount causing Osteogenesis imperfecta; Ehlers-Danlos syndromes, etc

Fibrillin mutation causing Marfan syndrome

Dystrophin Deletion with reduced synthesis:

Duchenne/Becker muscular dystrophy

Spectrin, ankyrin of RBC mutation: Hereditary spherocytosis

Factor VIII Deletions, insertion or nonsense mutations: reduced synthesis or abnormal factor VIII causing Hemophilia A

Rb protein Deletions causing Hereditary retinoblastoma

Neurofibromin gene mutation causing Neurofibromatosis type 1

Schematic diagram illustrating the pathogenesis of lysosomal storage diseases. In the example shown, a complex substrate is normally degraded by a series of lysosomal enzymes (A, B, and C) into soluble end products. If there is a deficiency or malfunction of one of the enzymes (e.g., B), catabolism is incomplete and insoluble intermediates accumulate in the lysosomes.

Some storage disesases

Lysosomal storage diseases

Gaucher’s disease

Niemann Pick Disease

Gangliosidosis

Sphingolipidosis

Tay Sachs disease

Sandhoff’s disease

Fabry’s disease

Glycogen storage diseases

Von Gierke’s disease

McArdle’s disease

Pompe’s disease

Pathways of glycogen metabolism. Asterisks mark the enzyme deficiencies associated with glycogen storage diseases

What is Down Syndrome?

What is Down Syndrome?

Down syndrome (DS), also called Trisomy 21, is a condition in which extra genetic material causes delays in the way a child develops, both mentally and physically. It affects about 1 in every 800 babies.

The physical features and medical problems associated with Down syndrome can vary widely from child to child. While some kids with DS need a lot of medical attention, others lead healthy lives.

Though Down syndrome can't be prevented, it can be detected before a child is born. The health problems that can go along with DS can be treated, and there are many resources within communities to help kids and their families who are living with the condition.

What Causes It?

Normally, at the time of conception a baby inherits genetic information from its parents in the form of 46 chromosomes: 23 from the mother and 23 from the father. In most cases of Down syndrome, a child gets an extra chromosome 21 — for a total of 47 chromosomes instead of 46. It's this extra genetic material that causes the physical features and developmental delays associated with DS.

Although no one knows for sure why DS occurs and there's no way to prevent the chromosomal error that causes it, scientists do know that women age 35 and older have a significantly higher risk of having a child with the condition. At age 30, for example, a woman has about a 1 in 900 chance of conceiving a child with DS. Those odds increase to about 1 in 350 by age 35. By 40 the risk rises to about 1 in 100.