Zellweger Syndrome (ZWS) is caused by an autosomal recessive-inherited genetic mutation that manifests into severe systematic neurologic anomalies. The condition is defined by malformation of craniofacial bone structures, liver insufficiency, and the absence of biochemical peroxisomal components at the cellular level.
Bowen, et al., were the first to describe Zellweger syndrome in 1964. Later on came two proponents, Passarge and McAdams, who coined the name cerebrohepatorenal syndrome by using the triad of organs involved. ZWS is recognized today as the main prototype of the peroxisome biogenesis disorder group .
Onset of disease occurs most often in the neonatal period. During this time, organ malformations are comprised of those that developed in utero and those that subsequently develop through the disease process, as a result of the disorder of peroxisome biogenesis.
ZWS causes multiple fetal anomalies dominated by malformed craniofacial features, where the physician can inspect macrocephaly or microcephaly, a high or widened forehead, an enlarged anterior fontanel, and hypoplastic ridges in the supraorbital area, abnormally broadened nasal bridge, micrognathia, abnormal ear lobe shapes, and extra folds of nuchal skin.
The neurologic system damage is comprised of serious psychomotor degradation, profound hypotonic muscles with poor deep tendon reflexes (DTRs), seizures in neonates, and impaired auditory functioning. Other manifestations include cerebral anomalies like cortical dysplasia, pachygyria, and also neuronal heterotopia. Physiological regression and other changes that result from continuous cell death and storage will eventually be observed. In PBDs, it is apparent that dysmyelination is prominently more evident than mass demyelination.
Along with the craniofacial abnormalities mentioned above, other skeletal conditions may also exist as in the case of chondrodysplasia punctata, a deformation commonly affecting the patellar and hip bones. Renal cysts in the subcortical area may be frequently diagnosed.
Multisystem organ failure soon develops into liver insufficiency and then to hepatomegaly, causing jaundice, that later complicates into coagulopathy. Possible eye problems that may be encountered are cataract, glaucoma, cases of pigment retinopathy, reports of nystagmus, clouding in the corneal layer and optic nerve atrophy. Because of these, visual changes are progressively developed and visual loss may be imminent. ZWS may involve sensorineural hearing loss. For genital involvement, cryptorchidism and hypospadias may be evident in male, and clitoromegaly in females.
Entire Body System
Single Transverse Palmar Crease
transverse palmar crease 0000954 Subependymal cysts 0002416 Talipes equinovarus Club feet Club foot Clubfeet Clubfoot [ more ] 0001762 Ulnar deviation of the hand 0009487 Ulnar deviation of the hand or of fingers of the hand 0001193 Widely patent fontanelles [rarediseases.info.nih.gov]
Liver, Gall & Pancreas
[…] ether lipid supplementation to two children, one with classic Zellweger syndrome and 9% of control fibroblast dihydroxyacetone phosphate acyltransferase activity, and one with mild facial manifestations, wide sutures, hypotonia, developmental delay, hepatomegaly [ncbi.nlm.nih.gov]
It is characterized by severe hypotonia, failure to thrive, psychomotor retardation, liver dysfunction, and sensorineural hearing impairment. Most of the patients with this disease die before the age of 1 year. [ncbi.nlm.nih.gov]
Clinical: The clinical course is variable and may include developmental delays, vision impairment, hearing loss, liver dysfunction, episodes of hemorrhage, and intracranial bleeding. [path.upmc.edu]
The mitochondrial myopathy thereby induced allows a better understanding of general muscle hypotonia, one of the leading symptoms of this disorder. [ncbi.nlm.nih.gov]
Zellweger syndrome is typically seen in the neonatal period with features such as dysmorphic skull; muscle hypotonia; sensorineural hearing loss; visual compromise; seizures; progressive degeneration of the kidneys and the liver. [icd10data.com]
Zellweger syndrome is typically seen in the neonatal period with features such as dysmorphic skull; MUSCLE HYPOTONIA ; SENSORINEURAL HEARING LOSS ; visual compromise; SEIZURES ; progressive degeneration of the KIDNEYS and the LIVER. [hon.ch]
(hypotonia) weak sucking and swallowing reflexes high arched palate absent deep tendon reflexes seizures deafness enlarged liver (hepatomegaly) enlarged spleen gastrointestinal bleeding slow growth after birth severe mental retardation abnormal brain [encyclopedia.com]
80%-99% of people have these symptoms Cognitive impairment Abnormality of cognition Cognitive abnormality Cognitive defects Cognitive deficits Intellectual impairment Mental impairment [ more ] 0100543 Corneal opacity 0007957 Death in infancy Infantile [rarediseases.info.nih.gov]
A variety of eye abnormalities may occur including eyes that are spaced widely apart (hypertelorism), clouding of the lenses of the eyes (cataracts) or the clear (transparent) outer layer of the eye (corneal opacities), degeneration of the nerve that [rarediseases.org]
It is characterized by severe hypotonia, failure to thrive, psychomotor retardation, liver dysfunction, and sensorineural hearing impairment. Most of the patients with this disease die before the age of 1 year. [ncbi.nlm.nih.gov]
Furthermore, Zellweger syndrome causes hearing impairment, profound mental retardation and developmental delay. Treatment for Zellweger Syndrome The cure for Zellweger syndrome does not exist. [ic.steadyhealth.com]
Apart from it, the hearing impairment can also be observed among the sufferrer. However, the impact varies from mild impairment to total deafness. [syndromespedia.com]
impairment 0000407 Underdeveloped supraorbital ridges Flattened bony protrusion above eyes 0009891 Visual impairment Impaired vision Loss of eyesight Poor vision [ more ] 0000505 5%-29% of people have these symptoms Abnormality of coagulation Abnormal [rarediseases.info.nih.gov]
Face, Head & Neck
The literature survey did provide criteria for classic Zellweger syndrome, which include hypotonia with or without deformation of limbs, large fontanels and split sutures, prominent forehead, flattened facial profile with hypoplastic supraorbital ridges [ncbi.nlm.nih.gov]
Most infants have a peculiar craniofacial dysmorphology with frontal bossing, large fontanels, and wide set eyes. Pipecolic acid levels are low in serum and absent in the CSF. Most infants do not survive beyond 6 months of age. [disorders.eyes.arizona.edu]
Clinical Features [ edit ] Craniofacial Features Flat occiput and face Anteverted nares Epicanthal folds Brushfield spots High forehead Large fontanels Shallow orbits Ocular Features Cataracts Hypoplastic optic disk Auditory Features Abnormal helices [en.wikibooks.org]
face Circular face Round facial appearance Round facial shape [ more ] 0000311 Single transverse palmar crease 0000954 Subependymal cysts 0002416 Talipes equinovarus Club feet Club foot Clubfeet Clubfoot [ more ] 0001762 Ulnar deviation of the hand 0009487 [rarediseases.info.nih.gov]
A term male newborn was noted to have severe diffuse hypotonia, hyporeflexia, hepatosplenomegaly, and characteristic abnormal facies of Zellweger syndrome, the diagnosis of which was confirmed by identification of 2 mutations including Nt2098insT, a frameshift [ncbi.nlm.nih.gov]
Overview MeSH Major Cerebral Hemorrhage Zellweger Syndrome abstract A term male newborn was noted to have severe diffuse hypotonia, hyporeflexia, hepatosplenomegaly, and characteristic abnormal facies of Zellweger syndrome, the diagnosis of which was [vivo.med.cornell.edu]
Central nervous system function is severely affected (profound muscular hypotonia, hyporeflexia or areflexia, severe intellectual deficit). [ela-asso.com]
] 0001290 Gray matter heterotopia 0002282 High, narrow palate Narrow, high-arched roof of mouth Narrow, highly arched roof of mouth [ more ] 0002705 Hypertelorism Wide-set eyes Widely spaced eyes [ more ] 0000316 Hypoplastic olfactory lobes 0006894 Hyporeflexia [rarediseases.info.nih.gov]
For mothers with genetic predispositions and high-risk pregnancies, prenatal check up and screening for elevated VLCFA and detection of plasmalogen synthesis in the fetal blood is done by performing amniocentesis and human chorionic villi sampling. If abnormal alleles are found in the carrier parent, prenatal diagnosis can be finalized by DNA sampling. In some cases, preimplantation abnormalities can be detected early by DNA testing as well. ZWS is passed down genetically by autosomal recessive inheritance, so as a proactive measure, genetic counseling is greatly encouraged.
Magnetic resonance imaging (MRI)
MRI results in ZWS reflect neocortical dysplasia (also called pachypolymicrogyria), presence of germinolytic cysts, and shows apparent delay in myelination. These diagnostic findings are then attributed to the abnormal cortical cytoarchitecture of the cerebral tissues as a result of the defective neuron migration and transfer.
Colpocephaly may be diagnosed as there may be manifestations of hypertrophy in the lateral occipital ventricular horns, and an evident depletion of the white matter. Both of these results help to deduce the presence of disrupted synthesis of myelin.
Severe affectations in later stages of ZWS are diagnosed with the appearance of cortical tissue atrophy.
For peroxisomal biogenesis disorders like ZWS, EEG more likely reflects the presence of multifocal spikes when undergoing preliminary stages in the disease process.
Neuropathologies in PBDs may be classified into 3 divisions:
- Problems in neuronal migration and differentiation
- Abnormal myelination
- Evidence of post developmental neuron degeneration
[…] hypoplastic olfactory lobes Extremities Single palmar creases Joint contractures Stippled epiphyses Camptodactyly Cardiovascular Features Cardiac septal defects PDA Other Features Hepatomegaly Postnatal growth deficiency and low birth weight Poor suck Albuminuria [en.wikibooks.org]
Hole in heart wall separating two lower heart chambers 0001629 Percent of people who have these symptoms is not available through HPO Abnormal electroretinogram 0000512 Abnormality of the helix 0011039 Adrenal hypoplasia Small adrenal glands 0000835 Albuminuria [rarediseases.info.nih.gov]
No absolute cure has been found for ZWS; however, symptoms may be relieved by pharmacologic treatment, as in using anti-epileptic drugs for patients that experience episodes of seizures. Coagulopathy in patients with liver dysfunction can be resolved with supplements of vitamin K, while cholestasis may need ideal amounts of fat soluble vitamins. The patient may be fed through a nasogastric tube or in other cases, a gastrostomy tube to ensure adequate calorie intake. It is highly suggested to restrict intake of phytanic acid-rich foods. For immunocompromised infants with severe stage hepatopathy, provision of supplementary mature bile acids, cholic acids and chenodeoxycholic acid are essential to improve liver function. Since ZWS patients are incapable of synthesizing docosahexaenoic acid (DHA) naturally, supplements of DHA may also be required. Palliative care, supportive counseling, and providing group assistance for the relatives of the patient are highly encouraged.
A promising mode of treatment under study is to maintain the normal proportions of docosahexaenoic acid in the blood. DHA concentration would be expected in low levels for cerebral, retinal, as well as other tissues affected, and thus precipitates into delays in neuron transfer. According to the study, 20 individuals with PBD-ZSS that were inducted using DHA ethyl ester showed beneficial effects . Improvements then resulted to normalized DHA levels and sufficient liver function, recovery from hypotonia and a decrease in visual disturbances in about 50% of the patients. Evidences of enhanced myelination were observed in nine of the subjects, as confirmed by MRI scans. Prospective results were shown greatly in two of the subjects who had begun with the induction of treatment before six months of age.
One more potentially effective approach is the pharmacologic induction of agents to facilitate the process of peroxisome biogenesis and proliferation. In one research study, treatment with sodium 4-phenylbutyrate improved the presence of peroxisome bodies in cultures of fibroblastic tissues from individuals with PBDs. It was also deducted that there was enhanced transcription of ALD-associated chromosomes and the gene of interest, PEX11alpha . This pharmacologic approach lowered VLCFA concentration as a result, and instead elevated VLCFA beta-oxidation and concentrations of plasmologen bodies in NALD, as well as in IRD fibroblast tissues, although not particularly in ZWS.
Several studies have helped clinicians predict that prognosis for Zellweger syndrome (ZWS) is poor, with a high percentage of infants dying before reaching one year of age as a result of respiratory complications related to immature lung capacity, infection and unmanageable epilepsy attacks. This is the reason why most interventions are primarily focused on palliative care after confirmed diagnosis.
PBD-ZSS is a result of chromosomal mutations in one of the 13 PEX genes that function to encode peroxins. Mutations such as this essentially lead to abnormalities in the generating new peroxisomes.
All of the peroxisome biogenesis disorders, including ZS, NALD, and IRD, are passed down to generations by autosomal recessive inheritance. All of these PBDs are effects of chromosomal mutations that may occur in any of 11 different genes that are commonly affected . A great number of infants with PBDs have chromosomal mutations in PEX1 or PEX6, where the genes involved encode enzymes known as ATPases that play a part in the transfer of proteins from the cellular cytosol to the peroxisomes .
One study showed a child with ZWS as an offspring from uniparental disomy, as an effect of maternal isodisomy particularly in chromosome 1 .
The total morbidity rate for all peroxisomal disorders combined is 1:20,000. ZWS has the highest occurrence to manifest during the neonatal period compared to other peroxisomal disorders, with an incidence of approximately 1 in between 50,000 to 100,000 infants.
ZWS is considered the most serious type of peroxisomal disorder and it is highly probable to result in death even before infant reaches one year of age.
ZWS is predominantly the outcome of abnormal peroxisomal metabolism and is found to be the most severe of all disorders concerning peroxisome components . One feature of these peroxisomal disorders is the elevation of very long chain fatty acids (VLCFA), mostly evidenced by with a chain of 26 carbon atoms. Other defining characteristics include a disproportionately high ratio of C26 compared to C22 fatty acid components in the blood plasma, as well as the presence of fibroblasts and amniocytes in the blood . The accumulation of VLCFA in the neuronal membranes later manifests into signs of neurologic affectation . VLCFA aggregation also causes changes in the structure and function of erythrocyte membranes and impairs the ability of adrenal cells to act in response to adeno-corticotropic hormone (ACTH)  and has also been shown to impair the chemical composition that contributes to model membrane stability .
On the other hand, VLCFA show normal levels in some of the PBDs. Normal fatty acid levels are also seen in Refsum disease, where one contributing factor is the proliferation of phytanic acid in blood.
The etiology of peroxisomal disorders can be related to any one or more of these underlying neuropathologies:
- Defects in neuron migration (in ZSDs and DBP deficient disorders)
- Abnormal composition of the myelin bodies in the cerebral and peripheral areas
- Neuronal degeneration (but not absolutely applicable to all PBDs)
Pathophysiology is assumed to begin with the proliferation of accumulated VLCFA in the neuronal membranes that lead to dysfunction, atrophy, and apoptosis or death of the weak neuronal cells . Studies were done to comprehend the pathophysiology of ZWS in animal models and it was shown that the defect in neuron migration is related to the insufficient receptor mechanism for N-methyl-D-aspartate .
The difference in the severity of each of the disorders, with regards to neuron transfer and membrane differentiation varies according to the specific PBD type . In these conditions the physiological migration of all types of neurons are disrupted, but can be most observed in neurons that travel the outer layers of the cortex.
The manifestations can more likely be observed in ZWS and other conditions that resemble ZWS. An example of a disorder with resemblance to ZWS is DBP deficiency, which is defined by a unique composition of centrosylvian pachygyria-polymicrogyria that greatly contributes to seizures and retardation of mental function .
Neurologic involvement, malformations, and failure to maintain cerebral white matter and peripheral myelin membranes are usually found in PBD patients. In PBD, the damage of central lesions is presently well identified but the extent of peripheral nerve affectation has not been discovered yet, except for its role in Refsum disease. Refsum disease is mostly defined by hyperactive demyelination that develops into a neuropathy often described as an onion bulb.
The resulting degeneration of central white matter layers consist of myelin mesh that can either be inflammatory in nature   or may be noninflammatory. As can be expected, there is also a decrease in myelin volume and staining . The myelin staining can still occur even without the use of reactive astrocytosis. It is always important to consider that the type of neuron degeneration varies according to the disorder.
Inflammation and demyelination generally occurs in NALD, causing the bilateral and symmetric thinning of the myelin sheath in the cerebral as well as in the cerebellar layers of white matter . The parietal and occipital areas are initially affected along with the asymmetric growth of the lesions as they approach the frontal and/or temporal lobes. It is more likely that the arcuate fibers will be left undamaged, except in severe or chronic conditions. Axonal loss may occur at times, but myelin loss is definitely more pronounced. Brainstem lesions may sometimes be involved, with the pons manifesting more affectation. The spinal cord would more likely be unaffected as well, except when it involves the degeneration of bilateral corticospinal tract structures.
Genetic descent among all relatives of ZWS patients are highly probable to be a carrier of the PEX chromosome mutation. As long as no genetic study has been done, the status of autosomal recessive inheritance in the clan and the reproductive probability cannot be plotted out. If one relative of any ZWS patient is found to be a carrier, the partner may undergo further biomolecular testing to identify their chances of achieving successful birth without the disorder.
Zellweger syndrome (ZWS) is a severely damaging type of peroxisome biogenesis disorder (PBD). The Zellweger syndrome spectrum (PBD-ZSS) includes Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) and is marked by neuronal migration defects, malformation in craniofacial bone structures, profound hypotonic muscles, seizures in neonates, and liver insufficiency.
ZWS, also widely known in the medical field as cerebro-hepato-renal syndrome, can be defined as a rare metabolic anomaly that can affect multiple body systems. As this name suggests, it can disrupt three functional systems of the body which are:
Zellweger syndrome (ZWS), also called cerebro-hepato-renal syndrome in some cases, is a metabolic anomaly that can inflict damage in multiple systems. ZWS proves to be most fatal among all of the peroxisomal biogenesis disorders (PBDs) which are characterized by defects in neuronal migration, impaired brain development, malformed craniofacial bone structures, liver dysfunction, and the absence of peroxisomal components at the biochemical cellular level.
The physical symptoms found in ZWS patients are dysmorphic craniofacial structures such as an abnormally high and wide forehead, hypertelorism, extra epicanthal skin folds, flattened supraorbital ridges, broadened nasal bridge, and enlarged fontanels. Mostly, the ZWS patient exhibits neurological abnormalities that are manifested by hypotonic muscles, showing an elicit decrease in sucking ability, poor deep tendon reflexes, episodes of seizures, and nystagmus. Liver and skeletal problems, such as the calcification of the patellae may also be observed. A large percentage of ZWS patients fail to survive and leads to death before reaching the first year of age.
The most common pathological anomalies found in ZWS are cholestasis, liver fibrosis, and the presence of cysts in the kidneys. This disease inflicts damage due to the absence of essential liver peroxisome bodies resulting to a severe decrease in liver function. The brain shows neuronal migration defects in neuron function, inconsistency in white matter, and stored lipid components.
Currently, no form of medical intervention has been found effective to treat ZWS. Palliative care, appropriate counseling, and providing support systems for the family members are encouraged.
- Gootjes J, Mooijer PA, Dekker C, et al. Biochemical markers predicting survival in peroxisome biogenesis disorders. Neurology 2002; 59:1746.
- Geisbrecht BV, Collins CS, Reuber BE, Gould SJ. Disruption of a PEX1-PEX6 interaction is the most common cause of the neurologic disorders Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. Proc Natl Acad Sci U S A 1998; 95:8630.
- Turner CL, Bunyan DJ, Thomas NS, et al. Zellweger syndrome resulting from maternal isodisomy of chromosome 1. Am J Med Genet A 2007; 143A:2172.
- Ter rahe BS, Majoie CB, Akkerman EM et-al. Peroxisomal biogenesis disorder: comparison of conventional MR imaging with diffusion-weighted and diffusion-tensor imaging findings. AJNR Am J Neuroradiol. 25 (6): 1022-7.
- Moser AB, Kreiter N, Bezman L, et al. Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999; 45:100.
- Powers JM, Moser HW. Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis. Brain Pathol 1998; 8:101.
- Knazek RA, Rizzo WB, Schulman JD, Dave JR. Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy. J Clin Invest 1983; 72:245.
- Ho JK, Moser H, Kishimoto Y, Hamilton JA. Interactions of a very long chain fatty acid with model membranes and serum albumin. Implications for the pathogenesis of adrenoleukodystrophy. J Clin Invest 1995; 96:1455.
- Gressens P, Baes M, Leroux P, et al. Neuronal migration disorder in Zellweger mice is secondary to glutamate receptor dysfunction. Ann Neurol 2000; 48:336.
- Powers JM. Normal and defective neuronal membranes: structure and function: neuronal lesions in peroxisomal disorders. J Mol Neurosci 2001; 16:285.
- Volpe JJ, Adams RD. Cerebro-hepato-renal syndrome of Zellweger: an inherited disorder of neuronal migration. Acta Neuropathol 1972; 20:175.
- Griffin DE, Moser HW, Mendoza Q, et al. Identification of the inflammatory cells in the central nervous system of patients with adrenoleukodystrophy. Ann Neurol 1985; 18:660.
- Powers JM, Liu Y, Moser AB, Moser HW. The inflammatory myelinopathy of adreno-leukodystrophy: cells, effector molecules, and pathogenetic implications. J Neuropathol Exp Neurol 1992; 51:630.
- Powers JM. Adreno-leukodystrophy (adreno-testiculo-leukomyelo-neuropathic-complex). Clin Neuropathol 1985; 4:181.
- Bowen P, Lee CS, Zellweger H, Lindenberg R. A Familial Syndrome of Multiple Congenital Defects. Bull Johns Hopkins Hosp. 1964 Jun. 114:402-14.
- Martinez M. Restoring the DHA levels in the brains of Zellweger patients. J Mol Neurosci 2001; 16:309.
- Wei H, Kemp S, McGuinness MC, et al. Pharmacological induction of peroxisomes in peroxisome biogenesis disorders. Ann Neurol 2000; 47:286.