Cerebrohepatorenal syndrome of Zellweger (Zellweger syndrome)

NeuroLearn NeuroHelp Metabolic @ Peroxisomal disorders, classification

Background    Gross Pathology    Histopathology & Immunohistochemistry

BACKGROUND AND CLINICAL INFORMATION: Head  

Summary: Cerebrohepatorenal syndrome of Zellweger (Zellweger syndrome) is a peroxisomal disease that is  biochemically characterized by abnormal accumulation of very long chain fatty acid, and morphologically characterized by a neuronal migration defect, typically pachymicrogyria, affecting both the cerebral hemisphere and cerebellar hemisphere. This is the first syndrome known in which malformations of the brain and other organs are associated with an inborn error of metabolism.

Spectrum: Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and Infantile Refsum’s disease constitute a disease continuum of peroxisomal disorders. Migration disorders, can be seen in both Zellweger syndrome and, less severely, in NALD. No malformation has been reported in infantile Refsum’s disease.

Background: Cerebrohepatorenal syndrome of Zellweger is the most severe form of peroxisomal disorder due to errors in peroxisomal biogenesis or defects in maintaining peroxisomal intergrity. This group constitues the generalized peroxisomal disorders and are inherited as autosomal recessive traits. There is loss of multiple peroxisomal enzyme activities often associated with morphological abnormalities of peroxisomes. Many of the disorders in this group are due to defects in importing protein(s) into the peroxisomes.

Biochemistry: The peroxisomal Beta-oxidation is impaired and lead to the accumulation of saturated very long chain (over 22 carbon) fatty acid (VLCFA). Measurment of VLCFA level is the mainstay of biochemical diagnosis. Other clinically useful markers include dihydroxyacetone phosphate acyl transferase (DHAP-AT), red blood cell plasmalogens, phytanic acid and piperocolic acid level.

• Deficient activity of dihydroxyacetone-phosphate acyl transferase (DHAPAT) in platelets.

Genetics: Autosomal recessive. There are at least 10, probably more, different human genes involved in peroxisome assembly. Mutation of peroxisomal membrane protein-1 (PXMP1) on chromosome 1p22-21 and peroxisomal assembly factor-1 (PAF1) on chromosome 8q21.1 have been identified in patients with Zellweger syndrome.

Incidence: 1 in 100,000, and may be an underestimate.

Clinical features:

• Mean age of death is 3 months. About one-quarter shows antenatal growth retardation, and virtually all show failure to thrive.

• Typical facial dysmorphism includeing high forehead, widely patent fontanelles and sutures, shallow orbital ridges, low and broad nasal bridge, epicanthus, external ear deformity, micrognathia and redundant neck skin folds.

• Neurologic features include severe hypotonia with depressed or absent tendon reflexes and poor sucking and swallowing. Generalized seizures, absence of psychgomotor development, failure to thrive and retinal degeneration. EEG is always abnormal.

• Ophthalmic features include optic atrophy, cataracts or glaucoma, and retinal pigmentary changes.

• Systemic features: hepatomegaly and liver dysfunction, polycystic kidneys, skeletal deformations, stippled calcification (most frequently in the patella) resembling those of chondrodysplasia punctata. Involvement of different organs is variable.

GROSS PATHOLOGY: Head  

Features of a migration disorder in CNS:

• Pachymicrogyria: Gross findings include pachymicrogyria which is a combination of excessively numerous gyri that are too small as well as too broad. These changes are most common in presylvian area and the adjacent frontoparietal convexity. These changes are not seen in fetal brain (probably the neurons did not complete enough migration to reveal the abnormalities). Sometimes numerous small gyri obscure the usual pattern of secondary sulcation. Abnormal deep clefts in the Sylvian region and in the parietal region have been described. Polymicrogyria is conspicious in the insula region.

• The small numerous gyri do not prepresent true classic polymicrogyria, but rather more numerous gyri with decreased amplitude.

• Neuronal heterotopia, most often in presylvian area and the adjacent frontoparietal convexity.

Dysplastic dentate and olivary nuclei are seen in the majority of patients.

Other abnormal CNS findings: These include a thin corpus callosum, decrease in the volume and amount of myelination of white matter in the cerebral hemispheres for age, increased size of the lateral and third ventricles, subependymal cysts over the caudate ncueli, small olfactory bulbs, small gliotic optic nerves, and occasionally a hypoplastic cerebral vermis.

Other organs:

• Kidney: cystic changes.

• Liver: Variable pathology. Usually a progressive fibrosis leading to a micronodular cirrhosis.

• Muscle: morphologically normal but with very low succinate dehydrogenase activity.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

Adrenal gland: Abnormal trilamina and lamellar lipid bodies are found in some cases.

Aberrant astroglial tissue under the pia, varying from a small focal wedge-shaped area of the bottom of a shallow abnormal sulcus to sheets of glial tissue that covers a gyrus or several of the small abnormal gyri.

Cortical architecture:

• Where the cortex is normal, the cortical lamination is normal. In the abnormal areas, the cortex is broken up into groups of neurons separated by acellular bands that five the cortex an overall radially striated appearance. The neurons in the radially arranged areas are that from layers II and III (by Golgi staining).

• The cortical abnormalities is not seen in fetus until after 20 weeks, probably the migration has not been completed enough to show the abnormalities. In the fetus, the cortex is narrower than normal, and there are increased numbers of cells in the intermedite zone.

• Neuronal loss is seen in older infants.

Abnormal cell clusters:

• Granuloma-like clusters of histiocytes where migral and macrophages containing a pecuiliar hyaline and very pale brown nonpolarizable material are present in both the gray and white matter.

• They are present in the basal ganglia and hypothalamus. The thalamus, brain stem, and spinal cord are almost completely spared.

• Foci of microglia and reactive astrocytes.

• Multinucleated cells (globoid cells), containing up to six peripherally placed nuclei and contain abundant finely granular eosinophilic cytoplasm, occur singly or in association with the granuloma-like clusters of histiocytes.

Cerebellum: The cerebellar cortex also shows heterotopia of Purkinje cells.

Brain stem: The only abnormality is that the inferior olivary nuclei fail to become normally convoluted.

Electron microscopy: At EM level, various inclusion bodies have been described. Macrophages containing lipid droplets and lamellae are present.

NeuroLearn NeuroHelp Metabolic For Comment: KarMing-Fung@ouhsc.edu

Background    Gross Pathology    Histopathology & Immunohistochemistry