Zellweger spectrum disorders

Peroxisomes are sac-like compartments in cells that contain enzymes for breaking down many substances, including very long-chain fatty acids and certain toxic compounds. They also help make lipids used in digestion and in the nervous system. Peroxins are the proteins that build the peroxisome membrane and bring enzymes inside. When one of the PEX genes that make peroxins is altered, peroxisomes cannot form normally and the enzymes cannot do their work.

PEX1 is the commonest cause, accounting for nearly 70 per cent of affected individuals. In the severe end of the spectrum functional peroxisomes are absent, while in intermediate and mild forms some peroxisomes still form.

The severe form, once called Zellweger syndrome, shows at birth with weak muscle tone, feeding problems, hearing and vision loss and seizures. Reduced myelin leads to loss of white matter. There can be life-threatening liver, heart and kidney problems, an enlarged liver or spleen, skeletal differences including a large gap between the skull bones, and characteristic spots on bone X-rays. Distinctive facial features include a flattened face, broad nose bridge, high forehead and widely spaced eyes. Eye problems include cataracts and involuntary eye movements. Metabolic Support UK notes that children at the severe end do not tend to survive into adulthood.

People with intermediate or mild disease have variable features that progress more slowly and usually appear in late infancy or early childhood. They often have low muscle tone, visual problems, hearing loss, liver dysfunction, developmental delay and some degree of intellectual disability. Most people with the intermediate form survive into childhood and those with the mild form may reach adulthood. In rare cases people at the mildest end have only developmental delay in childhood and then hearing or vision problems beginning in adulthood.

• Zellweger syndrome: most severe, symptoms from birth.

• Neonatal adrenoleukodystrophy: intermediate severity.

• Infantile Refsum disease: the least severe of the three older labels.

Metabolic Support UK adds that children may develop kidney stones and low bone mineral density, which affects bone strength. Low cortisol from the adrenal glands commonly accompanies the condition, and blood clotting deficiencies can occur, which is why vitamin K may be prescribed. Seizures need anti-seizure medicines and feeding difficulties may require a feeding tube after discussion with the paediatric team.

Diagnosis begins with clinical assessment, family history and the pattern of symptoms. Blood and urine tests check very long-chain fatty acid levels, which are typically high in peroxisomal disorders and give an important clue. Ultrasound can look for kidney cysts. Individuals at the severe end are usually diagnosed early in the newborn period, and genetic testing of the PEX genes confirms the diagnosis and identifies the gene for the family.

Because peroxisomal disorders share features with other early-life conditions, a newborn who is floppy, feeds poorly and has seizures and eye or hearing problems is usually referred quickly to a specialist metabolic or genetics service.

Metabolic Support UK states that there is currently no available treatment that cures or reverses ZSD and that care is aimed at managing symptoms as they appear. Past approaches included treating low cortisol, giving vitamin K for clotting problems and anti-seizure medicines, and some children have benefited from docosahexaenoic acid (DHA).

Care is shared by a multi-disciplinary team: audiologists for hearing, ophthalmologists for vision, gastroenterology and hepatology for liver problems, renal services for stones and cysts, and physiotherapy and speech therapy. A palliative care team can support families of babies with severe disease alongside active care, with attention to comfort and to what matters to the family.

ZSD is autosomal recessive. If both parents carry a faulty copy there is a one in four chance of an affected child in each pregnancy and a one in two chance of a carrier child. A genetic counsellor can explain inheritance and offer testing for relatives and for future pregnancies, including testing in pregnancy where the family variants are known.

Alex, The Leukodystrophy Charity, provides support for those affected by a genetic leukodystrophy and information is also available through Metabolic Support UK.

Call 999 for seizures that do not stop, breathing difficulty or collapse. Seek same-day advice for bleeding or easy bruising, vomiting with drowsiness, or fever in a child with a feeding tube.