Zellweger syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Zellweger syndrome
ICD-10 Q87.8
ICD-9 277.86, 759.8
OMIM 214100
DiseasesDB 14248
MeSH D015211

Overview

Zellweger syndrome is one of a group of four related diseases called peroxisome biogenesis disorders (PBD), which are part of a larger group of diseases known as the leukodystrophies. These are inherited conditions that damage the white matter of the brain and also affect how the body metabolizes particular substances in the blood and organ tissues. Zellweger syndrome is the most severe of the PBDs. Infantile Refsum disease (IRD) is the mildest, and neonatal adrenoleukodystrophy and rhizomelic chondrodysplasia have similar but less severe symptoms. The PBDs are caused by defects in genes that are active in brain development and the formation of myelin, the whitish substance found in the cerebral cortex area of the brain. After birth, defects in the same genes reduce or eliminate the presence of peroxisomes – cell structures that break down toxic substances in the cells of the liver, kidneys, and brain. As a result, in Zellweger syndrome, high levels of iron and copper build up in blood and tissue and cause the characteristic symptoms of the disease. These symptoms include an enlarged liver; facial deformities such as a high forehead, underdeveloped eyebrow ridges, and deformed ear lobes; and neurological abnormalities, such as mental retardation and seizures. Infants with Zellweger syndrome also lack muscle tone, sometimes to the point of being unable to move, and may not be able to suck or swallow. Some babies will be born with glaucoma, retinal degeneration, and impaired hearing. Jaundice and gastrointestinal bleeding may also occur.

Historical Perspective

Named after Hans Zellweger, a former professor of Pediatrics and Genetics at the University of Iowa who did research into the disease.[1]

Classification

The disorder is one of three peroxisome biogenesis disorders which are also known as the Zellweger spectrum. The other two diseases are neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD)[2]

Very long chain fatty acids are generally found in the central nervous system (brain and spinal cord) and the peroxisomes of these cells can not import the necessary degrative proteins for B-oxidation to occur.

Zellweger syndrome is one of a group of genetic disorders called peroxisomal diseases that affect brain development and the growth of the myelin sheath, the fatty covering—which acts as an insulator—on nerve fibers in the brain.

Pathophysiology

Causes

It is characterized by an individual's inability to beta-oxidize very-long chain fatty acids in the peroxisomes of the cell, due to a genetic disorder in one of the several genes involved with peroxisome biogenesis.

Several peroxins are associated with Zellweger syndrome, including 1, 2, 3, 5, 6, 12, 14, and 26.[3]

Differentiating Zellweger syndrome from Other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, complications, and Prognosis

There is no cure for Zellweger syndrome, nor is there a standard course of treatment. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive. The prognosis for individuals with Zellweger syndrome is poor. Death usually occurs by 6 months of age, and may be caused by respiratory distress, gastrointestinal bleeding, or liver failure.

Diagnosis

Diagnostic Criteria

History and Symptoms

Physical Examination

The most common features of Zellweger syndrome include an enlarged liver, high levels of iron and copper in the blood stream, and vision disturbances. Some affected infants may show prenatal growth failure. Symptoms at birth may include a lack of muscle tone, an inability to move and glaucoma. Other symptoms may include unusual facial characteristics, mental retardation, seizures, and an inability to suck and/or swallow. Jaundice and gastrointestinal bleeding may also occur.

Laboratory Findings

Imaging Findings

Other Diagnostic Studies

Differential diagnosis

Zellweger syndrome must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases Type of motor abnormality Clinical findings Laboratory findings and diagnostic tests Radiographic findings
Spasticity Hypotonia Ataxia Dystonia
Leigh syndrome - - + +
Niemann-Pick disease type C - - + +
  • Abnormal liver function tests
  • Fibroblast cell culture with filipin staining
Infantile Refsum disease - + + - Elevated plasma VLCFA levels --
Adrenoleukodystrophy + - - -
  • Elevated plasma VLCFA levels
  • Molecular genetic testing for mutations in the ABCD1 gene
--
Zellweger syndrome - + - - --
Pyruvate dehydrogenase deficiency + + + -
  • Elevated lactate and pyruvate levels in blood and CSF
  • Abnormal PDH enzymatic activity in cultured fibroblasts
--
Arginase deficiency + - - - --
Holocarboxylase synthetase deficiency - + - - Elevated levels of:
  • Beta-hydroxyisovalerate
  • Beta-methylcrotonylglycine
  • Beta-hydroxypropionate
  • Methylcitrate
  • Tiglylglycine
--
Glutaric aciduria type 1 - - - + Elevated levels of:
Ataxia telangiectasia - - + - --
Pontocerebellar hypoplasias - + - - Genetic testing for PCH gene mutations
Metachromatic leukodystrophy - + + -
  • Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts
--
Pelizaeus-Merzbacher + - + -
Angelman syndrome - - + -
  • Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations
--
Rett syndrome + - - +
  • Occurs almost exclusively in females
  • Normal development during first six months followed by regression and loss of milestones
  • Loss of speech capability
  • Stereotypic hand movements
  • Seizures
  • Autistic features
  • Clinical diagnosis
  • Genetic testing for MECP2 mutations
--
Lesch-Nyhan syndrome + - - + --
Miller-Dieker lissencephaly + + - -
  • Cytogenetic testing for 17p13.3 microdeletion
--
Dopa-responsive dystonia + - - +
  • Onset in early childhood
  • Symptoms worsen with fatigue and exercise
  • Positive response to a trial of levodopa
--

Treatment

Medical Therapy

Surgery

Prevention

External links

References

  1. synd/1670 at Who Named It
  2. http://www.genetests.org/query?dz=pbd
  3. "OMIM - ZELLWEGER SYNDROME; ZS". Retrieved 2007-07-11.

de:Zellweger-Syndrom fi:Zellwegerin oireyhtymä



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