PARKINSON’S DISEASE:

PARKINSON’S DISEASE:

·         It is also known as paralysis agitans, resulting from widespread destruction of that portion of the substantia Niagra that sends dopamine secreting nerve fibers to tha caudate nucleus and putamen. Characterized by : (a) rigidity of much of the musculature of body

·          (b) involuntary tremor (even when a person is resting)

·         (c) serious difficulty in initiating movement, called akinesia.

·         Normally, the dopamine secreted in the caudate nucleus and putamen is an inhibitory transmitter. Therefore destruction of dopaminergic neurons in the subtantia nigra of the patient would allow the caudate nucleus and putamen to become overly active and possibly cause continuous output of excitatory signals to the corticospinal motor control system. These signals could overly excite many or all of the muscles of the body, thus leading to rigidity.

·         It is a progressive neurological disorder with problems of smooth and coordinated muscles movement. Dopamine is produced in substantia nigra. In Parkinson's disease, cells of substantia nigra start to die hence resulting in reduced dopamine levels. When it is dropped to 60-80% , symptoms start to appear. It usually affect the individual of 60 years or more age. It is chronic and worsen overtime. It is named after the doctor James Parkinson, who first described the disorder as “shaking palsy”.

Symptoms :

Often affect one side of body, later both. Primary symptoms related to voluntary and involuntary motor function. These include :

A.              Tremors : often occur when person is resting but not while involved in task. Trembling of fingers, hands, feets, eyes, jaws or head.

B.               Rigidity : stiffness of limbs and trunk

C.               Bradykinesia: slowness of voluntary movement. Overtime, it becomes difficult to initiate and complete the movement.

D.              Postural instability : impaired or lost reflexes make it difficult to adjust posture and to maintain balance.

E.               Parkinsonian gait : usually take small, shuffling steps and might have difficulty picking up feets.

F.               Continued damage to the brain lead to secondary symptoms. Anxiety, confusion, dementia, depression, increased sweating.

Causes:

It may have both genetic and environmental component. Dopamine acts as a messenger between two brain areas- the substantia niagra and the corpus striatum to produce smooth, controlled movements, this communication becomes ineffective and movements becomes impaired.

In most people, it is idiopathic means that it arises sporadically with no known cause. There are several genes associated with it:

·         SNCA (synuclein, alpha non A4 component of amyloid precursor)

·         PARK 2 (Parkinson's autosomal recessive, juvenile 2)

·         PARK7 (early onset7)

·         PINK1 ( PTEN- induced kinase 1)

·         LRRK2 ( leucine rich repeat kinase

 Several other chromosome regions and the genes GBA (glucosidase beta acid), SNCAIP ( synuclein, alpha interacting protein) may also be linked to PD.

Diagnosis and treatment:

Health history and neurological examination

Diagnosis is more likely if :

(a) symptoms are not due to secondary causes

(b) at least 2-3 major symptoms

 (c) symptoms are significantly improved with L-DOPA.

Therapies are available.

Levodopa which convert to dopamine in brain . Dopamine aganoists are used which initiate the action of dopamine. Less effective than levo-dopa.

Amantadine can be used along with carbidopa-levodopa. It offers short term relief for the involuntary movements.

Anticholinergic are used to block the PNS and help with rigidity.

L-DOPA : it is converted in the brain into dopamine which is then restored. The normal balance between inhibition and excitation in the caudate nucleus and putamen.

Administration of dopamine itself does not have the same effect because dopamine has a chemical structure that will not allow it to pass through the blood-brain barrier.

L-deprenyl: this drug inhibits monoamine oxidase, which is responsible for destruction of dopamine after it has been secreted. This treatment helps to slow destruction of the dopamine-secreting neurons in the substantia niagra. Therefore appropriate combinations of L-dopa therapy along with l-deprenyl therapy usually provide better treatment.

Treatment with transplanted fetal dopamine cells and by destroying part of the feedback circuitry in the basal ganglia.

PHENYLKETONURIA:

PHENYLKETONURIA:

·     Phenylketonuria is an inherited error of metabolism caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH). Loss of this enzyme results in mental retardation, organ damage, unusual posture and can, in cases of maternal PKU, severely comprise pregnancy.

·     Classical PKU is an autosomal recessive disorder, caused by mutation in both alleles of the gene for PAH, found on chromosome 12. In the body, PAH converts the amino acid phenylalanine to tyrosine, another Amino acid. Mutation in both copies of Gene for PAH means that the enzyme is inactive or less efficient, and the concentration of phenylalanine in the body can build up to toxic levels.

·     In some cases, mutations in PAH will result in a phenotypically mild form of PKU called hyperphenylalaninemia.

·     PKU is a classic ‘monogenic’ autosomal recessive disease in which mutation in the human PAH locus explain the impaired function of enzyme PAH, the attendant hyperphenylalaninemia (metabolic phenotype) and the resultant mental retardation (cognitive phenotype).

·     Tyrosine is needed to create neurotransmitter such as epinephrine, norepinephrine and dopamine.

·     Symptoms :

·     (a) seizures, tremors (shaking)

·     (b) stunted growth.

·      (c) mental retardation.

·     (d) intellectual disability

·     (e) hypopigmentation (excessively fair skin and hair)

·     (f) 'musty odor’ to the baby's sweat and urine (due to phenylacetate, a carboxylic acid produced by the oxidation of phenyl ketone).

·     (g) phenylpyruvate can be detected in urine.

·     Phenylalanine is a large neutral amino acid (LNAA). It competes for transport across blood- brain barrier via the transporter. In excess it saturate the transporter, decreasing the levels of other LNAA in brain. This hinders the development of brain.

·     Treatment:  (a) restricted diet (eliminating food rich in phe. Like eggwhite, chicken, legumes, fish, soybeans, cheese)

·     (B) oral administration of tetrahydrobiopterin.

·      (c) casein glycomacropeptide (cGMP), milk peptide naturally free of phe.

·     Detection : newborn screening.

Maple syrup urine disease

Maple syrup urine disease :

·     It is an autosomal recessive metabolic disorder affecting branched-chain amino acid.

·     It is a type of organic acidemia.

·     It is rare, and age of onset: infancy, neonatal, childhood.

·     MSUD is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex ( BCKDC), leading to a buildup of branched-chain amino acid (leucine, isoleucine, and valine) and their toxic by-products (ketoacids) in the blood and urine.

·     BCKDC consists of 4 subunits: E1a, E1b, E2, E3. Mutation in the any of four of these Genes causes MSUD: BCKDHA, BCKDHB, DBT, and DLD.

·     Mutation in any of these gene reduces or eliminate the function of the enzyme complex, preventing the normal breakdown.

·     Leucine, isoleucine and valine are present in meat, fish, soy, eggs, nuts, seeds, grains and pulses.

·     Diagnosis:

·     There are several variations of the disease:

·     Classic severe MSUD: little enzyme activity.

·     Intermediate MSUD: slightly higher EA

·     Intermittent MSUD: significant EA, doesn't affect growth.

·     Thiamine- responsive MSUD: after infancy

·     E3- deficient MSUD with lactic acidosis

·     Accumulation of these 3 amino acids and their alpha-keto acids leads to encephalopathy and progressive neurodegenerative in untreated infants.

·     The urine of these infants had an odor of maple syrup ( burnt sugar).

·     Symptoms: lethargy, weight loss, odor, alternating episodes of hypertonia (muscle rigidity) and hypotonia ( limpness), high pitched cry, delayed development, seizures, feeding problem, strong smell in ear wax, anorexia, dehydration.

·     Management:

·     DNPH may be used to test urine for ketones ( a sign of metabolic decompensation)

·     Diet control

·     Liver transplant

·     Diagnosis: newborn blood-spot screening

• Familial hypercholesterolemia:

·         Familial hypercholesterolemia:

·     It is a genetic disorder characterized by high cholesterol levels, specifically very high levels of LDL and early cardiovascular disease.

·     FH is classified as a type II familial dyslipidemia.

·     About 1 in 500 cases, people have mutation in LDLR Gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (apoB), which is the part of LDL that binds to receptor.

·     People with one abnormal copy of the LDLR gene may develop CVD prematurely at age of 30-40. Having two mutant copies cause severe CVD in childhood (rare).

·     Heterozygous FH is common and inherited in autosomal dominant pattern.

·     Signs and symptoms:

·     Yellow deposit of cholesterol rich fat may be seen in various parts such as eyelids, (xanthelasma palpebrarum), tendons of hands, elbows, knees etc.

·     Accelerated deposition of cholesterol in the walls of arteries leads to atherosclerosis, the underlying cause of CVD.

·     Development of coronary artery disease which may lead to angina pectoris or heart attacks.

·     Arteries of brain are affected, rarely leads to transient ischemic attacks or strokes.

·     Peripheral artery occlusive disease.

·     Diagnosis:

·     Lipid measurements:

·     Raised level of total cholesterol (350-550 mg/dl for heterozygous) (650-1000 mg/dl for homozygous).

·     Raised LDL

·     Normal level of HDL and triglycerides.

·     Mutation analysis : on the basis of isolated high LDL and clinical criteria, genetic testing for LDL receptor mutations and apoB mutation can be performed.

·     Differential diagnosis: FH needs to be distinguished from familial combined hyperlipidemia.

·     Genetics:  LDL receptor gene is located on short arm of chromosome 19. The plasma LDL levels are inversely related to the activity of LDLR.

·     There are 5 classes of FH due to LDLR mutations:

·     Class I : LDLR nit synthesized at all.

·     Class II : LDLR not properly transported from ER to golgi.

·     Class III : LDLR not bind LDL on cell because of defect in apolipoprotein.

·     Class IV : LDLR bound to LDL does not cluster.

·     Class V : LDLR is not recycled.

·     Pathiophysiology:

·     LDL-cholesterol normally circulates in the body and subsequently the apoB portion of LDL binds to LDLR on liver cells, triggering its uptake and digestion. This process results in the removal of LDL from circulatory system. Synthesis of cholesterol by the liver is suppressed in the HMG-CoA reductase pathway.

·     In FH, LDL receptor function is absent or reduced, resulting in high levels of LDL cholesterol in blood. In mutations of apoB, reduced binding of LDL particles cause high LDL cholesterol.

·     Treatment:

·     Statins : act by inhibiting the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA) in the liver. Thus liver produces more LDL receptors, which removes circulating LDL From blood.

·     Bile acid sequestrants (cholestryramine), nicotinic acid.

·     Ezetimibe: inhibits cholesterol absorption.

·     Liver transplant, gene therapy.

·     Lomitapide : inhibitor of microsomal triglyceride transfer protein.