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Thursday, 22 November 2007

Treament of genetic diseases in the real world 9: familial hypokalemic periodic paralysis

What is hypokalemic periodic paralysis?
Hypokalemic periodic paralysis is a condition that causes episodes of extreme muscle weakness typically beginning in childhood or adolescence. Most often, these episodes involve a temporary inability to move muscles in the arms and legs. Attacks cause severe weakness or paralysis that usually lasts from hours to days. Some people may have episodes almost every day, while others experience them weekly, monthly, or only rarely. Attacks can occur without warning or can be triggered by factors such as rest after exercise, a viral illness, or certain medications. Often, a large, carbohydrate-rich meal or vigorous exercise in the evening can trigger an attack upon waking the following morning. Although affected individuals usually regain their muscle strength between attacks, repeated episodes can lead to persistent muscle weakness later in life.
People with hypokalemic periodic paralysis have reduced levels of potassium in their blood (hypokalemia) during episodes of muscle weakness. Researchers are investigating how low potassium levels may be related to the muscle abnormalities in this condition.
How common is hypokalemic periodic paralysis?
Although its exact prevalence is unknown, hypokalemic periodic paralysis is estimated to affect 1 in 100,000 people. Men tend to experience symptoms of this condition more often than women.

Diagnosis/testing. The diagnosis of HOKPP is based on a history of episodes of flaccid paralysis; low serum concentration of potassium (<0.9 to 3.0 mmol/L) during attacks; the absence of myotonia clinically and on electromyography (EMG) (with the exception of one family with heat-induced myotonia and cold-induced HOKPP); and a family history consistent with autosomal dominant inheritance. Molecular genetic testing identifies disease-causing mutations in CACNA1S or SCN4A in 80% of individuals meeting clinical diagnostic criteria. Of all individuals with HOKPP, about 55-70% have mutations in CACNA1S and about 8-10% in SCN4A. Such testing is clinically available.

Management. Treatment of a paralytic crisis by administration of potassium by mouth or IV aims to normalize the serum concentration of potassium and to shorten the paralytic episode. ECG and blood potassium concentration must be monitored during treatment. Surveillance depends on the affected individual's symptoms and response to preventive treatment. Neurologic examination should focus on muscle strength in the legs to detect permanent weakness associated with myopathy. A number of factors can trigger paralytic attacks: unusually strenuous effort, excess of carbohydrate-rich meals, sweets, and alcohol should be avoided; oral or intravenous corticosteroids should be used with care; glucose infusion should be replaced by another type of infusion.
Potassium in doses of 0.2 to 0.4 mmol/kg is administered orally every 15 to 30 minutes over one to three hours.
If the individual is unable to swallow or does not tolerate potassium by mouth, potassium may be administered intravenously. In that case, it must be diluted in 5% mannitol rather than in glucose or sodium chloride, which trigger crises in individuals with HOKPP. The concentration of potassium administered intravenously must not exceed 40 mmol/L and the flow must not exceed 20 mmol/hour or 200-250 mmol/day; administration must be stopped when the serum potassium concentration is normalized, even if weakness persists.
Because the hypokalemia and subsequent changes in potassium

Genetic counseling. HOKPP is inherited in an autosomal dominant manner. Most individuals diagnosed with HOKPP have an affected parent. The proportion of cases caused by a de novo gene mutation is unknown. Offspring of a proband have a 50% risk of inheriting the mutation. Penetrance is about 90% in males and may be as low as 50% in females depending on the causative mutation. Prenatal testing is possible if the disease-causing mutation has been identified in the proband; however, requests for prenatal testing for conditions such as HOKPP that do not affect intellect and have some treatment available are not common.




POTASSIUM

Treatment of genetic diseases in tha real world 8: Hemochromatosis

Disease characteristics. HFE-associated hereditary hemochromatosis (HFE-HHC) is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa, resulting in excessive storage of iron particularly in the liver, skin, pancreas, heart, joints, and testes. Abdominal pain, weakness, lethargy, and weight loss are early symptoms. Without therapy, males may develop symptoms between age 40 and 60 years and females after menopause. Hepatic fibrosis or cirrhosis may occur in untreated individuals after age 40 years. Other findings in untreated individuals may include progressive increase in skin pigmentation, diabetes mellitus, congestive heart failure and/or arrhythmias, arthritis, and hypogonadism.--> -->This description applies to individuals with clinical expression of HFE-HHC. A large, but yet as undefined, fraction of homozygotes for HFE-HHC do not develop clinical symptoms (i.e., penetrance is low).

Diagnosis/testing. The diagnosis of HFE-HHC in individuals with clinical symptoms consistent with HFE-HHC and/or biochemical evidence of iron overload is typically based on the results of the screening tests transferrin-iron saturation and serum ferritin concentration, and of confirmatory tests such as molecular genetic testing for the p.C282Y and p.H63D mutations in the HFE gene and/or histologic assessment of hepatic iron stores on liver biopsy. A threshold transferrin-iron saturation of 45% may be more sensitive for detecting HFE-HHC than the higher values used in the past. Although serum ferritin concentration may increase progressively over time in untreated individuals with HFE-HHC, it is not specific for HFE-HHC and cannot be used alone for identification of individuals with HFE-HHC. About 87% of individuals of European origin with HFE-HHC are either homozygotes for the p.C282Y mutation or compound heterozygotes for the p.C282Y and p.H63D mutations.

Management. Evaluations at initial diagnosis: liver biopsy in individuals with serum ferritin concentration greater than 1000 ng/mL to determine if cirrhosis is present. Treatment of manifestations: There is no general agreement that phlebotomy (removal of blood) treatment is indicated in the presence of biochemically defined abnormalities (i.e., elevated transferrin-iron saturation and elevated serum ferritin concentration) and the absence of characteristic clinical endpoints (i.e., diabetes mellitus, cirrhosis, and liver carcinoma). Since the long-term clinical course appears benign in the majority of those who have abnormal laboratory tests only, phlebotomy may be deferred; biannual follow-up testing for increasingly abnormal serum ferritin concentration and transferrin-iron saturation levels is recommended. In the presence of characteristic clinical endpoints, treatment by phlebotomy is indicated to maintain serum ferritin concentration at 50 ng/mL or lower. If affected individuals are identified before hepatic cirrhosis develops and if total body iron depletion is successfully accomplished by therapeutic phlebotomy, life expectancy approaches normal.

Genetic counseling. HFE-HHC is inherited in an autosomal recessive manner. Usually the genetic risk to sibs of a proband of having HFE-HHC is 25%. However, the high carrier frequency for a mutant HFE allele in the general population of European origin (11% of the population, or 1/9 persons) means that on occasion one parent has two abnormal HFE alleles, usually in the absence of clinical findings. In such instances, the risk to each sib of a proband of being homozygous for HFE-HHC is 50%. Offspring of an individual with HFE-HHC inherit one mutant HFE allele from the affected parent. Because the chance that the other parent is a carrier for a mutant HFE allele is 1/9, the risk to the offspring of having HFE-HHC is about 5%. Although prenatal testing would be technically feasible when both parents carry identified HFE mutations, such requests would be highly unusual because HFE-HHC is an adult-onset, treatable disease and the homozygous p.C282Y mutation has low clinical penetrance.


THERAPEUTIC PHLEBOTOMY

Treament of genetic diseases in a real world 7: Wilson disease

See clinical synopsis in this link: wilson disease
Wilson disease can be treated effectively with metal chelating agent:
d-penicillamine (Cuprimine) especially in mild or asymptomatic cases, but patients with neurological symptoms way be worsen in the early period after treatment, and trientine(Syprine )is recommended for acute neurological alterations. Long term side effects of d-penicillamine is nephrotic syndrome, skin disruption and immune and bone marrow suppression. Zinc suphate is used in asymptomatic case or in maintenance phase after d-penicillamine treatment.


Agents/Circumstances to Avoid
Foods very high in copper (liver, brain, chocolate, mushrooms, shellfish, nuts), especially at the beginning of treatment

Treatment of genetic diseases in a real world 6: Maturity Onset of Diabetes in the young (MODY)

WHAT IS MATURITY-ONSET DIABETES OF THE YOUNG (MODY)?
Maturity-Onset Diabetes of the Young or MODY affects 1-2% of people with diabetes, although it often goes unrecognised.
The 3 main features of MODY are:
Diabetes often develops before the age of 25
Diabetes runs in families from one generation to the next
Diabetes may be treated by diet or tablets and does not always need insulin treatment
WHY DOES MODY RUN IN FAMILIES?
MODY runs in families because of a change in a single gene which is passed on by affected parents to their children. We call this Autosomal Dominant Inheritance. All children of an affected parent with MODY have a 50% chance of inheriting the affected gene and developing MODY themselves.
WHY IS IT IMPORTANT TO RECOGNISE IT?
There are different types of MODY. By finding out which type of MODY a person has the most appropriate treatment for them can be determined.
Knowing the type of MODY a person has also means we can advise them about how their diabetes will progress in the future.
As it runs in families, it is important to advise other family members of their risk of inheriting it.
WHAT DIFFERENT TYPES OF MODY HAVE BEEN IDENTIFIED?
MODY is caused by a change in a single gene. 6 genes have been identified that account for 87% of UK MODY:
HNF1-a

Treatment for patients with HNF1-a
Patients with HNF-1a MODY are extremely sensitive to the blood sugar lowering effects of a group of drugs called sulphonylureas (SU). This is an example of pharmacogenetics in diabetes – a persons genes influencing response to treatment. SUs include drugs like Gliclazide, Glipizide, Glibenclamide, Tolbutamide. SUs work to stimulate the pancreas to produce insulin. Preliminary findings are that SU sensitivity in HNF-1a MODY is due to two factors: Firstly, an increased pancreatic response to SUs, and secondly an increased sensitivity to insulin compared with Type 2 diabetes.
Glucokinase
HNF1-b (including Renal Cysts and Diabetes (RCAD)

HNF4-a
IPF1

Neuro D1
Changes in these different genes lead to different types of MODY. There are still more genes to identify as 13% of MODY is not yet accounted for.
http://www.projects.ex.ac.uk/diabetesgenes/mody/ATHtalk.PPT