User:Shruta.pai/sandbox
Zellweger's Syndrome[edit]
Zellweger is the most severe form of a spectrum of conditions called Zellweger spectrum. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician, a professor of pediatrics and genetics who researched this disorder. The signs and symptoms of Zellweger syndrome typically appear during the newborn period. Zellweger syndrome (ZS) is the most severe variant seen in the peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS; see this term), characterized by neuronal migration defects in the brain, dysmorphic craniofacial features, profound hypotonia, neonatal seizures, and liver dysfunction. Children with Zellweger syndrome usually do not survive beyond the first year of life. Zellweger syndrome is caused by in any one of at least 12 ; mutations in the PEX1 gene are the most common cause. It is in an manner.
The birth prevalence of PBD-ZSS is estimated to be around 1/50,000 in North America, and around 1/500,000 in Japan. The highest incidence of ZS was reported in the Saguenay-Lac St Jean region of Quebec (around 1/12,000).
Causes[edit]
PBD-ZSS is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis.Peroxisomes are structures in cells that are involved in many chemical processes needed for the body to function properly. They are vital for the proper breakdown of fatty acids and the production of certain lipids (fats) that are important to the nervous system and digestion. They are also play a role in waste disposal and help with the development and function of the brain. Mutations in the genes responsible for Zellweger syndrome cause dysfunction of peroxisomes, which leads to the signs and symptoms of the condition.
Almost 70% of individuals with a Zellweger spectrum disorder have a mutation in the PEX1 gene. The other genes associated with the Zellweger spectrum each account for a smaller percentage of cases.
Zellweger syndrome is inherited in an autosomal manner. This means that a person must have a mutation in both copies of the responsible in order to have the condition. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers do not have signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.
Signs and Symptoms[edit]
Onset is in the neonatal period, reflecting both organ malformations that occurred in utero and progressive disease due to ongoing peroxisome dysfunction. Infants present with characteristic dysmorphic craniofacial features (flattened faces, large anterior fontanel, split sutures, prominent high forehead, flattened occiput, up slanting palpebral fissures, epicanthal folds, and broad nasal bridge), profound hypotonia and seizures. Macrocephaly or microcephaly, high arched palate, micrognathia and redundant neck skin folds may be present. Skeletal abnormalities (chondrodysplasia punctata, most often in the patella and hips) and subcortical renal cysts are frequent. There is often failure to thrive, hepatomegaly, jaundice, and coagulopathy. Eye findings include cataracts, glaucoma, pigmentary retinopathy, nystagmus, corneal clouding and optic nerve atrophy. Visual changes and loss are progressive. Sensorineural hearing loss may be present. Cryptorchidism and hypospadias (male) and clitoromegaly (female) may occur. CNS function is severely affected and infants have profound psychomotor delay.
| Signs and Symptoms | Approximate number of patients (when available) |
| Cognitive impairment | Very frequent
(present in 80%-99% of cases) |
| Corneal opacity | Very frequent
(present in 80%-99% of cases) |
| Death in infancy | Very frequent
(present in 80%-99% of cases) |
| abnormality | Very frequent
(present in 80%-99% of cases) |
| Epicanthus | Very frequent
(present in 80%-99% of cases) |
| Epiphyseal stippling | Very frequent
(present in 80%-99% of cases) |
| External ear malformation | Very frequent
(present in 80%-99% of cases) |
| Failure to thrive | Very frequent
(present in 80%-99% of cases) |
| Feeding difficulties in infancy | Very frequent
(present in 80%-99% of cases) |
| Flat face | Very frequent
(present in 80%-99% of cases) |
| Hepatic failure | Very frequent
(present in 80%-99% of cases) |
| Hepatomegaly | Very frequent
(present in 80%-99% of cases) |
| High forehead | Very frequent
(present in 80%-99% of cases) |
| Jaundice | Very frequent
(present in 80%-99% of cases) |
| Profound global developmental delay | Very frequent
(present in 80%-99% of cases) |
| Respiratory insufficiency | Very frequent
(present in 80%-99% of cases) |
| Severe muscular hypotonia | Very frequent
(present in 80%-99% of cases) |
| Skeletal dysplasia | Very frequent
(present in 80%-99% of cases) |
| Upslanted palpebral fissure | Very frequent
(present in 80%-99% of cases) |
| Very long chain fatty acid accumulation | Very frequent
(present in 80%-99% of cases) |
| Wide anterior fontanel | Very frequent
(present in 80%-99% of cases) |
| Wide nasal bridge | Very frequent
(present in 80%-99% of cases) |
| Cataract | Frequent
(present in 30%-79% of cases) |
| Chorioretinal abnormality | Frequent
(present in 30%-79% of cases) |
| Clitoral hypertrophy | Frequent
(present in 30%-79% of cases) |
| Cryptorchidism | Frequent
(present in 30%-79% of cases) |
| Flat occiput | Frequent
(present in 30%-79% of cases) |
| High palate | Frequent
(present in 30%-79% of cases) |
| Hydronephrosis | Frequent
(present in 30%-79% of cases) |
| Hypospadias | Frequent
(present in 30%-79% of cases) |
| Macrocephaly | Frequent
(present in 30%-79% of cases) |
| Malabsorption | Frequent
(present in 30%-79% of cases) |
| Microcephaly | Frequent
(present in 30%-79% of cases) |
| Micrognathia | Frequent
(present in 30%-79% of cases) |
| Multicystic kidney dysplasia | Frequent
(present in 30%-79% of cases) |
| Nystagmus | Frequent
(present in 30%-79% of cases) |
| Optic atrophy | Frequent
(present in 30%-79% of cases) |
| Polymicrogyria | Frequent
(present in 30%-79% of cases) |
| Posterior embryotoxon | Frequent
(present in 30%-79% of cases) |
| Premature birth | Frequent
(present in 30%-79% of cases) |
| Pyloric stenosis | Frequent
(present in 30%-79% of cases) |
| Seizures | Frequent
(present in 30%-79% of cases) |
| Sensorineural hearing impairment | Frequent
(present in 30%-79% of cases) |
| Underdeveloped supraorbital ridges | Frequent
(present in 30%-79% of cases) |
| Visual impairment | Frequent
(present in 30%-79% of cases) |
| Abnormality of coagulation | Occasional
(present in 5%-29% of cases) |
| Abnormality of the tongue | Occasional
(present in 5%-29% of cases) |
| Brushfield spots | Occasional
(present in 5%-29% of cases) |
| Glaucoma | Occasional
(present in 5%-29% of cases) |
| Primary adrenal insufficiency | Occasional
(present in 5%-29% of cases) |
| Thickened nuchal skin fold | Occasional
(present in 5%-29% of cases) |
| Ventricular septal defect | Occasional
(present in 5%-29% of cases) |
Diagnosis[edit]
diagnosis of a Zellweger syndrome is usually suspected when characteristic signs and symptoms are present at birth, including the distinctive facial features. Tests that measure or detect specific substances in blood or urine samples 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. Additional tests on blood and urine samples to find other substances associated with the condition may be performed. An ultrasound may be used to look for cysts on the kidneys or an enlarged liver. A genetic test to find a mutation in one of the genes associated with Zellweger spectrum disorders may also be used to confirm the diagnosis. MRI can be used to identify perisylvian polymicrogyria, and other developmental brain malformations.
The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
Treatment[edit]
There is currently no cure or effective treatment for Zellweger syndrome. Management is supportive and based on the signs and symptoms present in each person. For example, infants with feeding issues may require placement of a feeding tube to ensure proper intake of calories. Care is usually handled by a team of specialists that may include pediatrician, neurologist, surgeons, audiologists (treat hearing problems) and orthopedists (treat skeletal abnormalities). A gastrostomy tube may be needed to allow for adequate calorie intake. Foods rich in phytanic acids (i.e. cow's milk) should be restricted. Supplementation of mature bile acids, colic and chenodeoxycholic acid may help improve liver disease in infants with severe hepatopathy.
The long-term outlook (prognosis) for infants with Zellweger syndrome is very poor. Most infants do not survive past the first 6 months of life, and usually succumb to respiratory distress, gastrointestinal bleeding, or liver failure. Although no specific treatment for Zellweger syndrome currently exists, significant progress has been made in understanding the molecular and biochemical aspects of the condition, which researchers believe will lead to new research strategies and new therapies in the future.