ENZYME ORIGIN: METABOLIC DISORDERS

Michael Lesch and William Nyhan provided the first detailed clinical description of LESCH-NYHAN disease in 1964. The enzymatic defect associated with Lesch-Nyhan disease, deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), was discovered by Seegmiller and colleagues in 1967. The gene encoding the human enzyme was cloned and sequenced by Friedmann and colleagues in 1985. Lesch-Nyhan disease 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 is associated with hyperuricemia. If left untreated, it can produce nephrolithiasis with renal failure, gouty arthritis, and solid subcutaneous deposits known as tophi. The neurologic disability is dominated by dystonia but may include choreoathetosis, ballismus, spasticity, or hyperreflexia. The behavioral problems include intellectual disability (mental retardation) and aggressive and impulsive behaviors. Patients with the classic disease also develop persistent and severe self-injurious behavior. Etiology Lesch-Nyhan disease and its variants are caused by mutations in the HPRT gene on the X chromosome.The mutations are heterogeneous, with more than 600 different ones documented, including single base substitutions, deletions, insertions, or substitutions Mutations in the HPRT1 gene cause Lesch-Nyhan syndrome. The HPRT1 gene provides instructions for making an enzyme called hypoxanthine phosphoribosyltransferase 1. This enzyme is responsible for recycling purines, a type of building block of DNA and its chemical cousin RNA. Recycling purines ensures that cells have a plentiful supply of building blocks for the production of DNA and RNA. HPRT1 gene mutations that cause Lesch-Nyhan syndrome result in a severe shortage (deficiency) or complete absence of hypoxanthine phosphoribosyltransferase 1. When this enzyme is lacking, purines are broken down but not recycled, producing abnormally high levels of uric acid. For unknown reasons, a deficiency of hypoxanthine phosphoribosyltransferase 1 is associated with low levels of a chemical messenger in the brain called dopamine. Dopamine transmits messages that help the brain control physical movement and emotional behavior, and its shortage may play a role in the movement problems and other features of this disorder. However, it is unclear how a shortage of hypoxanthine phosphoribosyltransferase 1 causes the neurological and behavioral problems characteristic of LeschNyhan syndrome. Some people with HPRT1 gene mutations produce some functional enzyme. These individuals are said to have Lesch-Nyhan variant. The signs and symptoms of Lesch-Nyhan variant are often milder than those 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 the diaper. This may occur in children as young as three months. These deposits are caused by increased uric 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, and the insides of their mouths as early as two years old. As children grow, self-injury becomes increasingly compulsive and severe. Eventually, mechanical physical 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 not want to hurt himself or others, but is incapable of preventing these behaviors. People with LeschNyhan 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 may help 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 techniques and medication. S-adenosylmethionineA single 2006 report suggests that administration of sadenosylmethionine, a food supplement, may reduce self-mutilating behaviors in adults with this syndrome. This supplement, which is available in health food stores, is naturally synthesized 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 of sudden death due to respiratory causes. However, many patients live longer with good medical and psychological care. Diagnosis The doctor will ask about symptoms, behavior traits, and medical history. A physical exam will be done. Your bodily fluids may be tested. This can be done with blood tests.

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ZELLWEGER SYNDROME is the most severe form of a spectrum of conditions called Zellweger spectrum disorders. The signs and symptoms of Zellweger syndrome typically appear during the newborn 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 by mutations in any one of at least 12 genes; mutations in the PEX1 gene are the most common cause. It is inherited in an autosomal recessive manner. There is no cure for Zellweger syndrome; treatment is generally symptomatic and supportive. Zellweger spectrum disorders are also known as peroxisome biogenesis disorders (PBDs) - a group of disorders 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 cells that play a vital role in numerous biochemical processes in the body. PBDs are subdivided into the three Zellweger spectrum disorders and rhizomelic chondrodysplasia 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 PEX genes, 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 that have 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 hours or days of life. Affected newborns often have poor muscle tone (hypotonia); seizures; feeding difficulties; liver cysts with liver dysfunction; vision loss; hearing loss; and distinctive facial characteristics including a flattened face, broad nasal bridge, high forehead, upslanting palpebral fissures, epicanthal folds and other features.[1][2][3] Some individuals have an abnormally small or large head size (microcephaly or macrocephaly); protruding tongue; neck skin folds; cataracts; glaucoma; nystagmus; and/or other findings. Many affected infants have skeletal abnormalities, which may include a large space between the bones of 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 Zellweger syndrome 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 the metabolic and neurological abnormalities that cause the symptoms of Zellweger syndrome are caused during fetal development, treatments to correct these abnormalities after birth are limited. Most treatments are symptomatic and supportive. Diagnosis A diagnosis of a Zellweger syndrome is typically first suspected due to the characteristic signs and symptoms 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 of Zellweger 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 tests on blood and urine samples to detect other substances associated with the condition may be performed. 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 disorders may also be used to confirm the diagnosis.