enzyme origin

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ENZYME ORIGIN: METABOLIC DISORDERS

Michael Lesch and William Nyhan provided the first detailed clinical description of LESCH-NYHANdisease in 1964.The enzymatic defect associated with Lesch-Nyhan disease, deficiency of the enzymehypoxanthine-guanine phosphoribosyl transferase (HPRT), was discovered by Seegmiller andcolleagues in 1967. The gene encoding the human enzyme was cloned and sequenced by Friedmann

and colleagues in 1985.

Lesch-Nyhandisease is a genetic disorder associated with 3 major clinical elements: overproduction

of uric acid, neurologic disability, and behavioral problems.[2] The overproduction of uric acid isassociated withhyperuricemia.If left untreated, it can produce nephrolithiasis with renal failure, goutyarthritis, and solid subcutaneous deposits known as tophi. The neurologic disability is dominated bydystonia but may include choreoathetosis, ballismus, spasticity, or hyperreflexia.

The behavioral problems include intellectual disability (mental retardation) and aggressive andimpulsive behaviors. Patients with the classic disease also develop persistent and severe self-injuriousbehavior.

Etiology

Lesch-Nyhan disease and its variants are caused by mutations in the HPRTgene on the Xchromosome.The mutations are heterogeneous, with more than 600 different ones documented,including single base substitutions, deletions, insertions, or substitutions

Mutations in the HPRT1gene cause Lesch-Nyhan syndrome. The HPRT1gene provides instructions formaking an enzyme called hypoxanthine phosphoribosyltransferase 1. This enzyme is responsible forrecycling purines, a type of building block of DNA and its chemical cousin RNA. Recycling purinesensures that cells have a plentiful supply of building blocks for the production of DNA and RNA.

HPRT1gene mutations that cause Lesch-Nyhan syndrome result in a severe shortage (deficiency) orcomplete absence of hypoxanthine phosphoribosyltransferase 1. When this enzyme is lacking, purinesare broken down but not recycled, producing abnormally high levels of uric acid. For unknownreasons, a deficiency of hypoxanthine phosphoribosyltransferase 1 is associated with low levels of achemical messenger in the brain called dopamine. Dopamine transmits messages that help the braincontrol physical movement and emotional behavior, and its shortage may play a role in the movementproblems and other features of this disorder. However, it is unclear how a shortage of hypoxanthinephosphoribosyltransferase 1 causes the neurological and behavioral problems characteristic of Lesch-Nyhan syndrome.

Some people with HPRT1gene mutations produce some functional enzyme. These individuals are saidto have Lesch-Nyhan variant. The signs and symptoms of Lesch-Nyhan variant are often milder thanthose of Lesch-Nyhan syndrome and do not include self-injury.

Symptoms

The first symptom of Lesch-Nyhan syndrome may be orange-colored crystal-like deposits in thediaper. This may occur in children as young as three months. These deposits are caused by increaseduric acid in the urine. Other symptoms include:

Irritability Nervous system impairment:

4 to 6 monthslack of muscle tone and inability to lift the head 6 monthsunusual arching of the back 9 monthsinability to crawl or stand 12 monthsinability to walk 12+ monthsspasms of the limbs and facial muscles

Blood in the urine Pain and swelling of joints Difficulty swallowing Behavioral problems and self injuryoccurs in all cases

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Self-Injury

Self-mutilating behavior is the hallmark of this disease. Children begin to bite their fingers, lips, andthe insides of their mouths as early as two years old.

As children grow, self-injury becomes increasingly compulsive and severe. Eventually, mechanicalphysical restraints will be necessary to prevent head and leg banging, nose gouging, loss of fingers

and lips from biting, and loss of vision from eye rubbing, among others. In addition to self-injury,older children and teens will become physically and verbally aggressive.

The cause of these behaviors is not entirely understood. However, some experts believe it is related to

abnormalities in brain chemicals called neurotransmitters. It should be stressed that the child does notwant to hurt himself or others, but is incapable of preventing these behaviors. People with Lesch-Nyhan syndrome have been described as doing the opposite of what they really want.

Treatment

There is no treatment to cure Lesch-Nyhan. However, good hydration and certain medications mayhelp to alleviate some of its symptoms. For example:

Medications

The following medications may be used:

Allopurinolto control excessive levels of uric acid in the body Diazepam, haloperidol, or phenobarbitalto help reduce problem behaviors Baclofento reduce muscle spasms

Behavioral problems may also be managed with a combination of behavioral modification techniquesand medication.

S-adenosylmethionineA single 2006 report suggests that administration of s-adenosylmethionine, a food supplement, may reduce self-mutilating behaviors in adults withthis syndrome. This supplement, which is available in health food stores, is naturallysynthesized by the human body and important for many bodily processes. Talk to your doctor

before taking any supplements.

With treatment, the average life expectancy is early- to mid-20s. There may be an increased risk ofsudden death due to respiratory causes. However, many patients live longer with good medical andpsychological care.

Diagnosis

The doctor will ask about symptoms, behavior traits, and medical history. A physical exam will bedone. Your bodily fluids may be tested. This can be done with blood tests.

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ZELLWEGER SYNDROMEis the most severe form of a spectrum of conditions calledZellwegerspectrum disorders.The signs and symptoms of Zellweger syndrome typically appear during thenewborn period and may include poor muscle tone (hypotonia), poor feeding, seizures, hearing loss,vision loss, distinctive facial features, and skeletal abnormalities.

Affected children also develop life-threatening problems in other organs and tissues, such as the liver,heart, and kidneys Children with Zellweger syndrome usually do not survive beyond the first year of

life. Zellweger syndrome is caused bymutations in any one of at least 12genes; mutations inthePEX1gene are the most common cause. It is inherited in anautosomal recessive manner. There isno cure for Zellweger syndrome; treatment is generally symptomatic and supportive.

Zellweger spectrum disorders are also known as peroxisome biogenesis disorders (PBDs) - a group ofdisorders characterized by the failure of the body to produce peroxisomes that function properly.Peroxisomes are very small, membrane-bound structures within the gel-like fluid (cytoplasm) of cellsthat play a vital role in numerous biochemical processes in the body. PBDs are subdivided into thethree Zellweger spectrum disorders and rhizomelicchondrodysplasia punctata.

Etiology

Zellweger syndrome is one of a group of four related diseases called peroxisome biogenesis disorders(PBD). The diseases are caused by defects in any one of 13 genes, termed PEXgenes, required for

the normal formation and function of peroxisomes.

The PBDs are divided into two groups: Zellweger spectrum disorders and Rhizomelic

Chondrodysplasia Punctua spectrum. The Zellweger spectrum is comprised of three disorders thathave considerable overlap of features.

These include Zellweger syndrome (ZS, the most severe form), neonatal adrenoleukodystrophy(NALD), and Infantile Refsum disease (IRD, the least severe form).

Symptoms

The signs and symptoms of Zellweger syndrome typically become apparent within the first few hoursor days of life. Affected newborns often have poor muscle tone (hypotonia); seizures; feedingdifficulties; liver cysts with liver dysfunction; vision loss; hearing loss; and distinctive

facial characteristics including a flattened face, broad nasal bridge, high forehead, upslantingpalpebralfissures,epicanthal folds and other features.[1][2][3]Some individuals have an abnormally small orlarge head size (microcephaly or macrocephaly); protruding tongue; neck skinfolds;cataracts;glaucoma;nystagmus;and/or other findings.

Many affected infants have skeletal abnormalities, which may include a large space between the bonesof the skull and bone spots known as chondrodysplasia punctata that can be seen with an X-ray.

The function of the central nervous system is typically severely affected.[3]Children with Zellwegersyndrome also develop life-threatening problems in other organs and tissues, such as the liver, heart,and kidneys

Treatments

There is no cure for Zellweger syndrome, nor is there a standard course of treatment. Since themetabolic and neurological abnormalities that cause the symptoms of Zellweger syndrome are causedduring fetal development, treatments to correct these abnormalities after birth are limited. Mosttreatments are symptomatic and supportive.

Diagnosis

A diagnosis of a Zellweger syndrome is typically first suspected due to the characteristic signs andsymptoms present at birth, including the distinctive facial features. Tests that measure or detect

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specific substances in blood or urine samples (biochemical assays) can confirm a diagnosis ofZellweger syndrome.

For example, detection of elevated levels of very long chain fatty acids (VLCFA) in the blood is the

most commonly used screening test and is indicative of Zellweger spectrum disorders. Additional testson blood and urine samples to detect other substances associated with the condition may beperformed. An ultrasound may be used to detect cysts on the kidneys or an enlarged liver.

A genetic test to detect a mutation in one of the genes associated with Zellweger spectrum disordersmay also be used to confirm the diagnosis.