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]

Question 2 (10 marks)

A previously well seven-year-old boy becomes withdrawn and irritable, his school performance falls, and he begins to misread and to ask for the television to be louder. A brain MRI shows symmetric, confluent, gadolinium-enhancing demyelination in the occipito-parietal white matter with a Loes score of 6. A morning cortisol is low. [3] [4]

(a) Give the diagnosis, the gene, and the inheritance. (2 marks) [3]

(b) Explain why the imaging and the cortisol findings are both expected, naming the accumulated substrate. (3 marks) [3] [4]

(c) Outline the time-critical management, naming the disease-modifying therapy and the constraint on its window. (5 marks) [3] [4]

Model answer

The diagnosis is childhood cerebral X-linked adrenoleukodystrophy, caused by a defect in the ABCD1 gene, which is X-linked recessive. [3]

The ABCD1 gene encodes the peroxisomal membrane transporter that imports very-long-chain fatty acids, so its defect lets very-long-chain fatty acids accumulate. In the brain white matter they trigger an inflammatory cascade that strips myelin from the occipito-parietal regions outward, producing the symmetric, gadolinium-enhancing demyelination on the MRI. In the adrenal cortex they injure the zona fasciculata and reticularis, producing primary adrenal insufficiency and the low morning cortisol. The inflammation, not the storage alone, drives the rapid clinical decline. [3] [4]

Management is time-critical because untreated cerebral disease progresses to a vegetative state and death within two to five years. Haemopoietic stem cell transplant is the established disease-modifying therapy and is effective when given inside the early Loes-score window — typically a score between four and nine with gadolinium enhancement and a still-functioning child — because donor-derived microglia supply a functional transporter and calm the inflammatory cascade. A Loes score of 6 with a still-ambulant boy is inside that window, so the metabolic and transplant services are contacted the same day. Adrenal insufficiency is treated in parallel with oral hydrocortisone and a stress-day plan, because transplant does not rescue the adrenal cortex. The family is counselled about the X-linked inheritance and the need for cascade carrier testing of at-risk female relatives. [3] [4]