Peroxisomal disorders — branching viva

Branch 1 — The dysmorphic neonate

The unifying diagnosis is a peroxisome biogenesis disorder in the Zellweger spectrum. The combination of dysmorphism (high forehead, large fontanelle, broad nasal bridge), profound hypotonia, seizures, hepatomegaly with cholestasis, and chondrodysplasia punctata is characteristic, and the severity points to the Zellweger syndrome end of the continuum. The mechanistic group is the biogenesis disorders, caused by recessive PEX gene defects that prevent functional peroxisomes from forming. [1] [2]

The confirmatory investigation is the plasma very-long-chain fatty acid panel, which is abnormal across the whole Zellweger spectrum. The biochemical signature is global: elevated very-long-chain fatty acids, elevated phytanic and pristanic acid, elevated bile-acid intermediates, and deficient red-cell plasmalogens. Molecular testing of the PEX gene panel confirms the diagnosis and enables family testing and prenatal diagnosis. [1] [2]

The disease-directed therapy is cholic acid, which replaces the missing bile-acid end-product and reduces the toxic intermediates. Beyond cholic acid the management is supportive and multidisciplinary: fat-soluble vitamins, seizure control, feeding and growth support, hearing and vision rehabilitation. The prognosis for the severe end is guarded, and early goals-of-care discussion with the family is essential. [2]

Branch 2 — The failing boy

The diagnosis is childhood cerebral X-linked adrenoleukodystrophy. A previously well boy aged four to ten with behavioural change, declining school performance, and vision or hearing loss, whose MRI shows symmetric, confluent, gadolinium-enhancing demyelination in the occipito-parietal white matter, has the classic cerebral phenotype. The gene is ABCD1, inherited X-linked recessive. [3]

The accumulated substrate is the very-long-chain fatty acid, which the defective peroxisomal transporter cannot import for beta-oxidation. In the brain white matter it triggers an inflammatory cascade that strips myelin; in the adrenal cortex it produces primary adrenal insufficiency, so a morning cortisol must be checked and hydrocortisone started. The plasma very-long-chain fatty acid level is elevated, and ABCD1 sequencing confirms the diagnosis. [3]

The disease-modifying therapy is haemopoietic stem cell transplant, effective when given inside the early Loes-score window — a score between four and nine with gadolinium enhancement and a still-functioning child. Donor-derived microglia supply a functional transporter and calm the inflammation, but transplant given after the demyelination is advanced does not help. This is a transplant emergency, not an outpatient referral, and the metabolic and transplant services are mobilised the same day. [3]

Branch 3 — The adult with retinitis pigmentosa and anosmia

The diagnosis is adult Refsum disease, an autosomal recessive defect in phytanic acid alpha-oxidation (the PHYH gene). The combination of retinitis pigmentosa, anosmia, progressive sensorineural deafness, ataxia, and polyneuropathy is characteristic, and anosmia is one of the earliest and most under-recognised clues. The phytanic acid level is elevated, and molecular testing confirms the diagnosis. [1]

The management is a phytanic-acid-restricted diet — avoiding ruminant fat and dairy and foods high in chlorophyll-bound phytol — which can halt progression and reverse some of the neuropathy. Acute overload that threatens the heart or the vision is treated with plasmapheresis or lipid apheresis. Lifelong surveillance for cardiomyopathy and arrhythmia is part of the care. [1]