Lincoln university college

[CLINICAL PHYSIOLOGY]

Mitochondrial myopathies
These are group of neuromuscular diseases caused by damage to the mitochondria. Nerve cells in the brain and muscles require a great deal of energy, and thus appear to be particularly damaged when mitochondrial dysfunction occurs.

Common mitochondrial myopathies include

1. Kearns-Sayre syndrome 2. Myoclonusepilepsy with ragged-red fibers 3. Mitochondrial encephalomyopathy with lactic acidosis 4. Stroke-like episodes

Symptoms
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Muscle weakness or exercise intolerance Heart failure or rhythm disturbances Dementia Movement disorders Stroke-like episodes Deafness Blindness Droopy eyelids Limited mobility of the eyes Vomiting Seizures

Path physiology
Mitochondrial disorders may be caused by mutations, acquired or inherited, in mitochondrial DNA (mtDNA) or in nuclear genes that code for mitochondrial components. Nuclear DNA has two copies per cell (except for sperm and egg cells), one copy being inherited from the father and the other from the mother. Mitochondrial DNA, however, is strictly inherited from the mother and each mitochondrial organelle typically contains multiple mtDNA copies .During cell division the mitochondrial DNA copies segregate randomly between the two new mitochondria, and then those new mitochondria make more copies. If only a few of the mtDNA copies inherited from the mother are defective, mitochondrial division may cause most of the defective copies to end up in just one of the new mitochondria. Mitochondrial disease may become clinically apparent once the number of affected mitochondria reaches a certain level; this phenomenon is called "threshold expression". Most mitochondrial function and biogenesis is controlled by nuclear DNA. Human mitochondrial DNA encodes only 13 proteins of the respiratory chain, while most of the estimated 1,500 proteins and components targeted to mitochondria are nuclear-encoded. Defects in nuclear-encoded mitochondrial genes are associated with hundreds of clinical disease phenotypes including anemia, dementia,hypertension, lymphoma, retinopathy, seizures, and neurodevelopmental disorders. DR SAMIA AMIN 1

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[CLINICAL PHYSIOLOGY]

Nuclear and chromosomal disorder

Numerical disorders Aneuploidy an abnormal number of chromosomes), occurs when an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy, tetrasomy, etc.) Down syndrome, also known as Trisomy 21 (an individual with Down syndrome has three copies of chromosome 21, rather than two). Turner Syndrome is an example of a monosomy where the individual is born with only one sex chromosome, an X.

Structural disorders
When the chromosome's structure is altered, this can take several forms:

1. 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. 2. 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. 3. Translocations: A portion of one chromosome is transferred to another chromosome. There are two main types of translocations: 4. Reciprocal translocation: Segments from two different chromosomes have been exchanged. 5. 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. 6. Inversions: A portion of the chromosome has broken off, turned upside down and reattached, therefore the genetic material is inverted. 7. Insertions: A portion of one chromosome has been deleted from its normal place and inserted into another chromosome.

Lysosomal storage disease

These are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomalfunction. Lysosomal storage diseases result when the lysosome a specific organelle in the body's cells malfunctions.

Path physiology
Lysosomal storage disorders are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins (sugar containing proteins) or socalled mucopolysaccharides. Individually, LSDs occur with incidences of less than 1:100,000

DR SAMIA AMIN

Lincoln university college

[CLINICAL PHYSIOLOGY]

The lysosomal is commonly referred to as the cells recycling center because it processes unwanted material into substances that the cell can utilize. Lysosomes break down this unwanted matter via enzymes, highly specialized proteins essential for survival. Lysosomal disorders are triggered when a particular enzyme exists in too small an amount or is missing altogether. When this happens, substances accumulate in the cell. In other words, when the lysosome doesnt function normally, excess products destined for breakdown and recycling are stored in the cell. Like other genetic diseases, individuals inherit lysosomal storage diseases from their parents. Although each disorder results from different gene mutations that translate into a deficiency in enzyme activity, they all share a common biochemical characteristic all lysosomal disorders originate from an abnormal accumulation of substances inside the lysosome. Lysosomal storage diseases affect mostly children and they often die at a young and unpredictable age, many within a few months or years of birth. Many other children die of this disease following years of suffering from various symptoms of their particular disorder.

Symptoms
1. 2. 3. 4. 5. 6. 7. 8. 9. Developmental delay Movement disorders Seizures Dementia Deafness Blindness Enlarged livers (hepatomegaly) and enlarged spleens (splenomegaly) Pulmonary and cardiac problems Bones that grow abnormally.

Phospholipidosis
It is a lysosomal storage disorder characterized by the excess accumulation of phospholipids in tissues. Many cationic amphiphilic drugs, including anti-depressants, antianginal, antimalarial, and cholesterol-lowering agents, are reported to cause drug-induced phospholipidosis (DIPL)

Path physiology
The mechanisms of DIPL involve trapping or selective uptake of DIPL drugs within the lysosome and acidic vesicles of affected cells. Drug trapping is followed by a gradual accumulation of drugphospholipid complexes within the internal lysosomal membranes. The increase in undigested materials results in the abnormal accumulation of multi-lamellar bodies (myeloid bodies) in tissues. The traditional method to evaluate DIPL is visual confirmation of myeloid bodies in tissues by electron microscopy. Electron microscopy has limited utility to monitor DIPL in humans because of the invasive nature of acquiring patient tissue biopsy samples. A qualified biomarker of DIPL in the blood or urine is needed to provide a more routine, non-invasive, and cost effective means to monitor DIPL. DR SAMIA AMIN 3

Lincoln university college

[CLINICAL PHYSIOLOGY]

Golgi complex disorder

Inclusion-cell (I-cell) disease, also referred to as mucolipidosis II (ML II), results from a defective phosphotransferase (an enzyme of the Golgi apparatus). This enzyme transfers phosphate to mannose residues on specific proteins, and serves as a marker for them to be targeted to lysosomes within the cell. Without this marker, the proteins are instead excreted outside the cell -- the default pathway for proteins moving through the Golgi apparatus. Lysosomes cannot function without these proteins, which function as catabolic enzymes for the normal breakdown of substances throughout the body. As a result, a buildup of these substances occurs within lysosomes because they cannot be degraded, resulting in the characteristic "I cells," or "inclusion cells." These cells can be identified under the microscope. In addition, the defective lysosomal enzymes normally found only within lysosomes are instead found in high concentrations in the blood.

Cell membrane disorder

Duchenne muscular dystrophy (DMD) The disorder is caused by a mutation in the dystrophin gene, located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue that provides structural stability to the dystroglycan complex (DGC) of the cell membrane. While both sexes can carry the mutation, females rarely exhibit signs of the disease. Symptoms usually appear in male children before age 5 and may be visible in early infancy. Progressive proximal muscle weakness of the legs and pelvis associated with a loss of muscle mass is observed first. Eventually this weakness spreads to the arms, neck, and other areas. Early signs may include pseudo hypertrophy (enlargement of calf and deltoid muscles), low endurance, and difficulties in standing unaided or inability to ascend staircases. As the condition progresses, muscle tissue experiences wasting and is eventually replaced by fat and fibrotic tissue (fibrosis). By age 10, braces may be required to aid in walking but most patients are wheelchair dependent by age 12. Later symptoms may include abnormal bone development that lead to skeletal deformities, including curvature of the spine. Due to progressive deterioration of muscle, loss of movement occurs, eventually leading to paralysis. Intellectual impairment may or may not be present but if present, does not progressively worse as the child ages. The average life expectancy for patients afflicted with DMD is around 25, but this varies from individual to individual.

DR SAMIA AMIN