Neuro-Imaging in Zellweger Syndrome

A preterm (36 weeks) newborn male child presented with complaints of GTCS on day 2 of life, generalised hypotonia with absent DTRs, respiratory distress and mild facial dysmorphic features.

MRI brain revealed large germinolytic in both the lateral ventricles along the caudo-thalamic groove. It appeared multiseptated on the left side.

Subtle polymicrogyria was seen in bilateral perisylvian region.

Moderate dilatation of the lateral and ventricles was seen.

A cephalhematoma measuring approx. 4x3x1 cm was also noted in right high parietal region.

In addition, an erect radiograph of bilateral lower limbs with knee joints was also acquired which showed stippled calcification within both knee joints.

Background 

Zellweger syndrome (also known as Cerebrohepatorenal syndrome) is an autosomal recessive genetic disorder, that affects peroxisomes within cells.

It is the most severe form of the PBDs (peroxisomal biogenesis disorders) which also includes neonatal adrenoleukodystrophy, infantile refsum disease, and rhizomelic chondrodysplasia [2]. The clinical features are apparent at birth and results in death within the first year of life.

Pathophysiology and Clinical Features

Peroxisomes are primarily responsible for fatty acid metabolism and are involved in beta-oxidation of very-long-chain fatty acids (VLCFA), alpha oxidation of branched-chain fatty acids, catabolism of amino acids, biosynthesis of bile acids, steroid hormones, gluconeogenesis and plasmalogen formation which are important constituents of the cell membrane and myelin [2].

Zellweger syndrome is thus characterized by increased accumulation of VLCFA, increased fatty acids in plasma, fibroblasts, and amniocytes. Major abnormalities are present in the kidney (cortical cysts), liver (fibrotic), and brain (demyelination, centrosylvian polymicrogyria) - hence the name cerebrohepatorenal syndrome. Manifestations include severe craniofacial abnormalities, hypotonia, severe neurodevelopmental delay, sensorineural hearing loss, ocular abnormalities, and enamel abnormalities.

Depending on the age of presentation, ZS patients are divided into three groups [2]:

• Neonatal-infantile presentation

Present with facial dysmorphism, hypotonia, reduced spontaneous movements, poor cry, ocular abnormalities like glaucoma, cataracts, and retinopathy. They frequently have difficulty feeding, and seizures can be early onset during neonatal life.

• Childhood presentation

Developmental delay, failure to thrive, eye and hearing abnormalities including varying levels of hepatic dysfunction, adrenal insufficiency, and renal calcium oxalate stones.

• Adolescent - adult presentation

Developmental delay and neuroregression, cerebellar ataxia, peripheral neuropathy, adrenal insufficiency, leukodystrophy.

Imaging Features

ZS is often suspected on physical examination and confirmed with biochemical evaluation and sequence analysis of the PEX genes.

MRI findings include developmental brain malformations like pachygyria, polymicrogyria (especially in the perisylvian region), periventricular neuronal heterotopia and poor myelination [1]. Marked colpocephaly, lissencephaly, subependymal cysts and mild hydrocephalus have been observed in few cases.  

Scimitar-shaped calcifications in patella [3] and triradiate acetabular cartilage have been described as typical of the Zellweger syndrome.

Another radiologic finding is cortical cystic disease in the kidneys. Bell-shaped thorax [3] is seen in affected children which may be related to the flaccidity.

Outcome

The prognosis for infants with Zellweger syndrome is poor. Most infants do not survive past the first 6 months and usually succumb to respiratory distress, gastrointestinal bleeding, or liver failure.

With no curative treatment available, management options are limited to supportive care to improve quality of life. Modalities like docosahexaenoic acid, Lorenzo's oil, cholic acid and citrate have been used [2]; but with little evidence regarding their efficacy.

Take-Home Message / Teaching Points

Clinical features like hypotonia with facial dysmorphic features and peculiar MRI findings including pachygyria [1] and germinolytic cysts should strongly raise the suspicion of Zellweger syndrome. It can be followed up by biochemical tests and genetic testing for confirmation of diagnosis.