Ehlers-Danlos Syndrome (EDS)

genetic disorder that results in a defect in collagen synthesis. The severity may range from mild to life-threatening. Common symptoms include extremely flexible joints, eye lens dislocation, and bone deformities. Joints have a high tendency to dislocate.

Adrenomyeloneuropathy

A progressive degenerative disorder of the myelin sheathing of the spinal cord.

a varient of adrenoleulkodystrophy.

disorder can cause adrenal insufficiency and hypogonadism in addition to neurological symptoms

Biochemistry:

disorder of the peroxisomes, (intracellular organelles responsible for a variety of biochemical reactions) the most important being the oxidation of VLCFAs, biosynthesis of bile acids and glycoxylate detoxification.

People with adrenoleukodystrophy and adrenomyeloneuropathy do not produce fatty acylcoenzyme A (acyl-CoA) synthetase, which breaks down VLCFAs in the first step in their oxidation.

VLCFAs accumulate and form cytoplasmic inclusions, which leads to progressive dysfunction in the nervous system, adrenal glands and testes, all of which are sites of VLCFA metabolism.

Etiology:

characterized by the accumulation of very-long-chain fatty acids in plasma, the central and peripheral nervous systems, adrenal glands and testes, which leads to dysfunction of these organs and systems.

X-linked genetic disorder,  the gene is located on the long arm of the X chromosome (Xq28)

Management:

 limited and includes hormonal replacement therapy for concomitant adrenal insufficiency or hypogonadism, or both.

dietary goals:

to decrease the exogenous sources of VLCFA by instituting a low-fat diet; however, dietary modifications have not been consistently shown to prevent or slow the course of the disease.

Administration of monounsaturated fatty acids leads to competitive inhibition between saturated and unsaturated fatty acid precursors in the microsomal elongation pathway, thereby leading to a reduction in endogenous VLCFA synthesis.

Khandwala, Hasnain M, Spurek, Monika,Taylor-Gjevre,  Regina,  and Van Uum, Stan. 2004. Adrenomyeloneuropathy as a cause of primary adrenal insufficiency and spastic paraparesis. CMAJ. 171:9. Retrieved February 1, 2010 from http://www.cmaj.ca/cgi/content/full/171/9/1073

Maple syrup urine disease (branched-chain ketoaciduria)

an autosomal recessive metabolic disorder.

Etiology:

 inability of the body to properly break down branched-chain amino acids (leucine, isoleucine and valine)

due to a deficiency of the branched-chain alpha-keto acid dehydrogenase complex

resulting in accumulation of these amino acids and metabolites to toxic levels within the body

Manifestations:

• presence of sweet-smelling urine
• poor feeding
• vomiting
• dehydration
• lethargy
• hypotonuria
• seizures
• ketoacidosis
• opisthotonus
• pancreatitis
• neurological decline

Treatment:

• monitoring of blood chemistry levels
• diet low in the amino acids valine, leucine and isoleucine

Hirschsprung’s Disease (congenital aganglionic megacolon)

 

congenital condition in which a section the colon is aganglionic

there is little urge to defecate so the feces accumulate.

• genetic defect on Chr 10
• 1/5000 live births
• Sigmoid colon typically affected

 

  Mechanism:

• absence of ganglia in parts of the colon
• no peristalsis occurs in affected region
• contents accumulate
• colon becomes distended, in turn results in distended abdomen
• bowel obstruction may occur

 

Treatment:

• Surgical exision of aganglionic region

Inflammatory Bowel Disease

 

Two chronic disorders:

1.Crohn`s disease
2.Ulcerative Colitis

Etiology:

Genetic susceptibility (no gene yet identified): Intolerance of normal gut flora by the body`s immune system.
Immune response is unregulated.

1. Ulcerative Colitis

• Chronic inflammation of the colon that produces ulcers in its lining
• region of affected gut is continuous

 2. Crohn`s Disease

• A chronic form of inflammatory bowel disease that usually affects the lower small intestine (called the ileum) or the colon
• skip lesions in small and large intestine

 

Differentiating Characteristics of Crohn`s Disease and Ulcerative Colitis

Characteristics	Crohn`s Disease	Ulcerative Colitis
Type of inflammation	Granulomatous	Ulcerative and exudative:
Level of involvement	submucosa	mucosa
Area of involvement	Ileum, colon	Rectum and left colon
Extent of Involvement	skip lesions in small and large intestine	region of affected gut is continuous
Diarrhea	common	common
Rectal bleeding	rare	common
Fistuals	common	rare
Stricture	common	rare
Perianal abscesses	Common	Rare
Development of cancer	Uncommon	Relatively Common

 

Martin, Glenn and Porth, Carol, Mattson. 2009. Pathophysiology Concepts of Altered Health States. 8th ed. Lippincott Williams and Wilkins. Philadelphia

Diabetes Management

 

Normal Blood Sugar

 

4-6 mmol/l

 

Hypoglycemia

 

<4mmol/L

 

• pallor

• cool, moist skin

• anxiety

• restlessness

• tingling in hands, feet tongue

• confusion

• drowsy

• nausea

 

Hyperglycemia

 

>7mmol/L

 

• drowsy

• confused

• dry skin

• nausea

• headache

• vomiting

Common Types of Insulin

 

Humulin R Toronto Short-acting	Humulin N NPH Intermediate	Glargine/LantusLong-acting
onset 30-60 min peak: 15-30min duration 30-60 min	Onset:1-2h Peak:4-12h Duration:18-24h	Onset:3-4h Peak:none Duration: 24h
administered 30 prior to the first meal of the day a second dose may be given before the evening meal or @ HS may only be given Sub Q	may be given IV or subcutaneously	Do not mix

 

Glargine/ Lantus Long-acting

Onset:3-4h Peak:none Duration: 24h

Cerebrovascular Accidents (Strokes)

Ischemic Stroke: sudden loss of function resulting from disruption of the blood supply to a part of the brain. Neurons die when they can no longer maintain aerobic respiration.

• Event usually the result of long-standing cerebrovascular disease
• early Tx results in fewer symptoms and less functional loss

5 different types

1. large thrombosis – 20%
2. small penetrating artery thrombosis – 25%
3. cardiogenic embolic stroke – 20%
4. cryptogenic 30%
5. Other – 5%

Large artery thrombosis strokes: due to atherosclerotic plaques in the large blood vessels of the brain. Thrombus formation and occlusion at the site af the atherosclerosis result in ischemia and infarction.

Small Penetrating artery thrombotic strokes: affect one or more vessels and are the most common type of ischemic stroke.

Aka lacunar strokes because of the cavity that is created once the infarcted brain tissue disintegrates.

Cardiogenic embolic strokes: are associated with cardiac dysrhythmias, usually atrial fibrillation. Emboli originate from the heart and circulate to the cerebral vasculature, most commonly the left middle cerebral artery, resulting in a stroke. Embolic strokes may be prevented by the use of anticoagulation therapy in patients with atrial fibrillation.

The 2 remaining categories of ischemic strokes are cryptogenic with no known cause and others causes such as cocaine, coagulopathies, migraine and spontaneous dissection of the carotid or vertebral arteries.

Pathophysiology:

Martin, Glenn and Porth, Carol, Mattson. 2009. Pathophysiology Concepts of Altered Health States. 8th ed. Lippincott Williams and Wilkins. Philadelphia

Congenital and Genetic abnormalities

 

Congenital abnormalities

 

1. due to developmental error during fetal development

2. almost always detected at birth

 Developmental processes are occur at a rapid rate therefore errors have devastating implications

Stem cells differentiate into their specialized cell types, move to area of organ or tissue placement then divide.

 

Errors in embryogenesis – if they occur at the particular organs critical period in development that organ will be severely development

 

Different structures devel @ different times

 

Organogensis – begins at day 15 post conception therefore this is the most vulnerable time for mutations.

 

• each organ has its own critical period within fetal development – different organs develop at different times

• The CNS has an extensive critical period therefore most congenital abnormalities will also affect the CNS

 

Tatatogens: Mutagenic agents

• drugs

• microbes

• vitamin,mineral or nutrient deficiency

 

Taratogens: – agents that affect the fetal development environment

• the maternal body

• the environment outside the maternal body

 

1. Falitamide:a taratogen causing limb reduction defects

2. Alcohol: causes Fetal alcohol Syndrome

3. Deficiency: Vitamin, mineral or nutrients eg folic acid

4. Viral infections: eg Rubella virus causing german measles

 

Fig. gestational development

 

Genetic Abnormalities

 

• Not always present at birth

• genetic code mutations

eg diabetes

 

autosomal dominant and recessive

 

Homozygous for a particular gene when identical alleles of the gene are present on both homologous chromosomes.

 

Heterozygous for a particular gene when two different alleles occupy the gene’s position on the homologous chromosomes.

 

Types of Chromosomes

1. autosomal chromosomes 22 pairs

2. sex chromosomes –1 pair, 2 chromosomes the X and Y

 

3 primary types of abnormalities

 

1. Chromosomal Abnormalities

• reflects an atypical number of chromosomes or a structural abnormality in one or more chromosomes.

• Trisomy 21 – Downs Syndrome

 

1. Single gene (monogenic) Chromosomal Abnormalities

2a. autosomal recessive

• 25% chance of the individual being affected

• 50% of individuals will be carriers for the gene

• 25% of individuals will be unaffected

• Cystic Fibrosis

 

2b. autosomal dominant

• 25% of individuals will be carriers for the gene

• 50% chance of inheritance

• 25% will be lethals (noncompatoible with life)

• Dwarfism

 

2c.X-linked recessive

• the mutated affected gene is linked to the X chromosome

• hemophilia

 

1. Complex trait (polygenic and environmental) Chromosomal Abnormalities

• type 2 diabetes

• more than one gene is affected

• lifestyle (enviro factors)

 

 

1. Chromosomal abnormalities

Numeric abnormalities:

 

• Aneuploidy – extra or missing Chromosome

• Trisomy – additional Chromosome to the pair eg trisomy 21

• Monosomy – only one chromosome, one missing from the pair (lethal)

• named for the Chromosome # involved

• Karyotype is the characteristic chromosome complement of a eukaryote species

   

1. Trisomy 21

2. Turners Syndrome

• female XO (1 in 3000 live births)

1. Klinfelters syndrome

• male XXY (1 in 500)

• fig 7-11

 

Structural defects:

1. Chromosomal deletion: The loss of a segment of the genetic material from a chromosome.

 

1. Chromosomal Inversion: a chromosome rearrangement in which a segment of a chromosome is reversed end to end.

2. Chromosome translocation: is a chromosome abnormalitycaused by rearrangement of parts between nonhomologous chromosomes.

Martin, Glenn and Porth, Carol, Mattson. 2009. Pathophysiology Concepts of Altered Health States. 8th ed. Lippincott Williams and Wilkins. Philadelphia

Osteogenesis Imperfecta or Brittle Bone Disease, or “Lobstein syndrome”

 

Osteogenesis Imperfecta, OA or Brittle Bone disease

 

Etiology

 

• Osteogenesis Imperfecta is subdivided into 6 clinical types

• genetic mutation collagen compromising bone formation and development

• autosomal dominant pattern of inheritance

• mutation in Type 1 collagen gene, however, type 4 has no detectable mutation

• Causes bone fragility and low bone mass

• results in moderate to severe increase in fragility of long bones and vertebral bodies

• Elevated collagen type I N-telopeptide levels in urine (indicative of increased osseous hyperplasia due to fracture healing)

                   Clinical Presentation

                          Presentation/Fractures Pathologic Minimal Trauma

                         Note: May be suspect child abuse (prior to diagnosis)

 

                     Type 1

• symptoms are mild

• normal of near normal height

• blue sclera (visible sign in the eye, indicative of collagen dysfunction)

                            Type 2

• typically lethal in the perinatal period

                           Type 3

• progressive deforming osteogenesis imperfecta

• the most severe form in children surviving the neonatal period

• characteristic phenotype

• extreme short stature

• severe spinal, thoracic and extremity deformities

• blue sclera

                           Type 4

• patients presenting with moderate to severe symptoms of osteogenesis imperfecta yet who do not fit into the above descriptions

                          Type 5

• present with moderate to severe symptoms of osteogenesis imperfecta

• have no detectable genetic mutation

                         Type 6

• present with moderate to severe symptoms

• have mineralization defect and present with accumulation of osteoid

• note: osteoid is the organic matrix of protein and polysaccharides, secreted by osteoblasts, that becomes bone after it mineralizes

                             Tx

• Symptoms and Pain management

• Continued care for chronic condition

 

                            Sources:

1. Bishop, Nicholas, J, Fassier, Francois, Glorieux, Delphine, F, Glorieux, Franis, H, Lalic, Ljiljana, Plotkin, Horacio, Rauch, Frank, Roughley, Peter, Travers, Rose and Ward, Leanne. 2000Type V Osteogenesis Imperfecta: A new form of brittle bone disease. Journal of Bone and Mineral Research. 15:1650-1658.

2. Bishop, Nicholas, J, Fassier, Francois, Glorieux, Delphine, F, Glorieux, Franis, H, Lalic, Ljiljana, Plotkin, Horacio, Rauch, Frank, Roughley, Peter, Travers, Rose and Ward, Leanne. 2000Type V Osteogenesis Imperfecta: A new form of brittle bone disease. Journal of Bone and Mineral Research. 15:1650-1658.