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INHERITED MONOGENIC DISEASES

           

Zellweger syndrome

Zellweger syndrome is inherited in an autosomal recessive manner and is considered to be the most serious variant of peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS).

It is characterized by neuronal migration defects, dysmorphic craniofacial features, neonatal seizures and hepatic dysfunction.

The highest incidence of Zellweger syndrome has been published in the Saguenay-Lac St Jean region of Quebec with about 1 in 12,000 individuals.

It begins in the neonatal period as a result of both the organ malformation and the peroxisomal dysfunction that causes progressive deterioration. Newborns dysmorphic craniofacial features (flattened facies, large anterior fontanelle, open sutures, high and prominent forehead, flattened occiput, upward slanting palpebral fissures, epicanthal folds, broad nasal bridge, deep hypotonia and seizures). There may be macrocephaly or microcephaly, high arched palate, micrognathia and redundant folds of skin on the neck. They are frequent skeletal abnormalities (chondrodysplasia punctata) and subcortical renal cysts.

There are often stunted growth, hepatomegaly, jaundice and coagulopathy. Ocular findings include cataracts, glaucoma, retinopathy pigmentosa, nystagmus, corneal opacity and optic nerve atrophy. Visual changes and losses are progressive. There may be sensorineural hearing loss. Cryptorchidism and hypospadias and clitoromegaly may occur. CNS function is severely affected and suffer a profound psychomotor retardation.

Zellweger syndrome is suspected in the physical examination and confirmed by biochemical evaluation. The very long chain fatty acid plasma levels (VLCFA) indicate peroxisomal fatty acid metabolism defects with high plasma concentrations of C26:0 and C26:1 and high levels of C24/C22 and C26/C22. The concentrations of C16 and C18 plasmalogens in the erythrocyte membrane are reduced. Pipecolic acid levels in plasma increase. It can also be diagnosed by molecular analysis by sequencing of the 13 PEX genes.

The main differential diagnoses include Usher syndrome I and II and other disorders PBD-ZSS, individual enzyme defects in the beta-oxidation of fatty acids in peroxisomes and disorders with severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy.

Prenatal testing of VLCFA levels and plasmalogen synthesis in cultured amniocytes in chorionic villi may be performed. If the two causal alleles of the disease have been identified in the parents, a prenatal diagnosis as well as a preimplantation genetic diagnosis can be made.

Standard epileptic drugs are used to control seizures. Hepatic coagulopathy can be treated with vitamin supplements while cholestasis may require the provision of all fat-soluble vitamins. It may need feeding by gastrostomy. It should be restricted foods rich in phytanic acid. Supplements mature bile acids, cholic acid and chenodeoxycholic can help improve liver disease in infants with severe liver disease. Because patients with Zellweger syndrome cannot biosynthesized DHA, also they can be provided.

Regardless of the interventions, the prognosis is unfavorable and most babies die in the first year of life.

GENE OR REGION STUDIED


  • PEX1

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