Peroxisomal disorders — formative SAQs

Question 1 (10 marks)

A term neonate is born with a high forehead, a large anterior fontanelle, a broad nasal bridge, and profound hypotonia. Feeding is poor, and within days the infant develops seizures that are hard to control. The liver is enlarged, the skin is mildly jaundiced, and a skeletal survey shows stippled epiphyses. ^{[1] [2]}

(a) Give a unifying diagnosis and name the mechanistic group it belongs to. (2 marks) ^[2]

(b) Outline the confirmatory investigation strategy, naming the single most useful first-line blood test and the expected biochemical signature. (4 marks) ^{[1] [2]}

(c) Describe the disease-directed therapy and the multidisciplinary supportive care this infant will need. (4 marks) ^[2]

Model answer

The unifying diagnosis is a peroxisome biogenesis disorder in the Zellweger spectrum, most likely severe neonatal Zellweger syndrome given the dysmorphism, profound hypotonia, seizures, hepatomegaly with cholestasis, and chondrodysplasia punctata. The mechanistic group is the biogenesis disorders, caused by recessive mutations in the PEX genes that prevent functional peroxisomes from assembling. ^[2]

The single most useful first-line test is the plasma very-long-chain fatty acid panel, with the C26:0 level and the C26-to-C22 ratio. In a biogenesis disorder the abnormality is global: very-long-chain fatty acids are elevated, phytanic acid and pristanic acid are elevated, and bile-acid intermediates are elevated, while red-cell plasmalogens are deficient. Molecular testing of the PEX gene panel confirms the diagnosis, defines the variant, and enables family testing and prenatal diagnosis. ^{[1] [2]}

Disease-directed therapy is cholic acid, which replaces the missing end-product of peroxisomal bile-acid synthesis and reduces the toxic intermediates. Supportive care is multidisciplinary: fat-soluble vitamin supplementation, seizure control, feeding and growth support with possible gastrostomy, management of cholestasis and liver dysfunction, hearing aids or cochlear implantation, and vision rehabilitation. The prognosis for the severe end is guarded, and early, open goals-of-care discussion with the family is part of the management. ^[2]