Zellweger syndrome: what is it, symptoms, treatment, prognosis

What is Zellweger Syndrome?

Zellweger's Syndrome - a rare congenital disease characterized by a reduction or absence of functional peroxisomes in human cells. It is one of a family of disorders called Zellweger spectrum disorders, which are leukodystrophies. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician and professor of pediatrics and genetics at the University of Iowa who studied the disease.

Signs and symptoms

Zellweger's syndrome is one of three peroxisome biogenesis disorders that belong to the spectrum of Zellweger peroxisome biogenesis disorders. The other two diseases are neonatal adrenoleukodystrophy and infantile Refsum disease (IDB). Although all of these diseases have a similar molecular basis for their occurrence, Zellweger syndrome is the most severe of the three disorders.

Zellweger's syndrome is associated with impaired neuronal migration, positioning, and brain development. In addition, in patients with Zelweger syndrome, there may be a decrease in the content of myelin in the central nervous system (CNS), especially cerebral, which is called hypomyelination. Myelin is critical for the normal functioning of the central nervous system and in this regard serves as the isolation of nerve fibers in the brain. Patients may also show post-developmental sensorineuronal degeneration, which results in progressive hearing and vision loss.

Zellweger syndrome can also affect the function of many other organ systems. Patients may show craniofacial abnormalities (eg, high forehead, hypoplastic supraorbital ridges, epicantal folds, midface hypoplasia, and large fontanelle), hepatomegaly (liver enlargement), punctate chondrodysplasia (punctate calcification of cartilage in certain areas of the body), eye abnormalities, and kidney cysts. Newborns may have profound hypotension (low muscle tone), epilepsy, apnea and the inability to eat.

Cause

Zellweger's syndrome is an autosomal recessive disorder caused by mutations in genes that code for peroxins, proteins required for the normal assembly of peroxisomes. Most often, patients have mutations in their genes PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19 or PEX26. In almost all cases, patients have mutations that inactivate or significantly reduce the activity of both the maternal and paternal copies of one of these aforementioned genes PEX.

As a result of dysfunction of peroxisomes, human tissues and cells can accumulate acyl-CoA dehydrogenase of very long-chain fatty acids (from the English. Very long chain acyl-CoA dehydrogenase, abbr. VLCAD) and branched chain fatty acids (BCFA), which are usually degraded in peroxisomes. The accumulation of these lipids can disrupt the normal function of many organ systems, as discussed above. In addition, these people may have insufficient levels of plasmalogens, essential phospholipids that are especially important for brain and lung function.

Epidemiology

The prevalence at birth of peroxisome biogenesis disorder is estimated at about 1 / 50,000 in North America and about 1 / 500,000 in Japan. The highest incidence of Zelweger syndrome was reported in the Saguenay-Lac-Saint-Jean area of ​​Quebec (about 1 / 12,000).

Diagnostics

In addition to genetic analyzes, including gene sequencing PEX, biochemical analyzes have proven to be highly effective in the diagnosis of Zellweger syndrome and other peroxisomal disorders. Typically, patients with Zelweger syndrome have elevated levels of very long chain fatty acids in their blood plasma. Primarily cultured dermal fibroblasts obtained from patients show an increased content of a very long chain of fatty acids, disruption of beta-oxidation with very long chain fatty acids, alpha-oxidation of phytanic acid, alpha-oxidation of pristanic acid and biosynthesis of plasmogenic substances.

Standard treatments

There is no cure or standard treatment for the syndrome. Since the metabolic and neurological disorders that cause the symptoms of Zelweger syndrome are occur during intrauterine development of the fetus, methods of correcting these disorders after birth limited. Most treatments are symptomatic and supportive.

Malabsorption caused by a lack of bile acid has led to the proposal of an elemental formula that is low in fat and <3% of calories derived from long chain triglycerides. However, it has not been shown that the reduced Acyl-CoA dehydrogenase of very long chain fatty acids (VLCAD) reduce blood levels of VLCAD, probably because humans can endogenously produce most VLCAD. Plasma VLCAD levels decrease when very long-chain fatty acid acyl-CoA dehydrogenase is decreased in dietary combined with the addition of Lorenzo oil (a 4: 1 mixture of glycerol trioleate and glycerol trierucate) in X-linked patients adrenoleukodystrophy. Because docosahexaenoic acid (DHA) synthesis is impaired, DHA supplementation has been recommended, but a placebo-controlled study has not shown clinical efficacy since then. Due to the impaired synthesis of bile acids, it is recommended to take fat-soluble supplements of vitamins A, D, E and K.

Forecast

The prognosis for infants with the syndrome is poor. There is currently no known cure for Zellweger's syndrome. Most babies do not live until the first 6 months and usually die from respiratory failure, gastrointestinal bleeding, or liver failure. Beware of infections to prevent complications such as pneumonia and respiratory distress syndrome.