Clinical and Neuroimaging Features of Peroxisomal Disorders

A 1-day-old term infant with prenatal polyhydramnios presented with hypotonia, minimal movement, nystagmus, dysmorphisms, and drug-resistant epilepsy. Serum studies showed elevated ammonia, liver enzymes, and hyperbilirubinemia requiring phototherapy and intravenous immunoglobulin. Neuroimaging showed subependymal germinolytic pseudocysts and extensive polymicrogyria of perisylvian regions, frontal, and parietal lobes ([Fig. 1]). Very long chain fatty acids were elevated. Trio exome sequencing revealed novel variants in HSD17B4 (NM_000414.4:c.1768–1G > A and c.936_937delTA, in trans) causative of D-bifunctional protein deficiency (OMIM no.: 261515), a multisystem single enzyme defect peroxisomal disorder with dysmorphism, liver dysfunction, neuronal migration defects, epileptic encephalopathy, and death <2 years[1] [2] ([Tables 1] and [2]).

Table 1 Common clinical and laboratory findings of individuals with peroxisomal biogenesis and single protein disorders

Dysmorphisms	Brain abnormalities	Neurological findings	Other system involvement	Laboratory findings
High forehead	Perisylvian polymicrogyria	Psychomotor retardation	Failure to thrive	↑VLCFA
Enlarged fontanelle	Frontoparietal pachygyria	Severe hypotonia	Liver disease	↑PH/PR
Broad nasal bridge	Generalized atrophy	Sensorineural hearing loss	Renal cysts	↑D/THCA
Epicanthus	Delayed myelination	Visual impairment	Skeletal abnormalities	↑LFTs (ammonia, GGT)
Anteverted nares	Subependymal germinolytic cysts	Nystagmus	Congenital heart defects
High arched palate		Progressive leukoencephalopathy	Cataracts
Micrognathia		Drug-resistant epilepsy	Adrenal insufficiency

Abbreviations: D/THCA, di/trihydroxycholestanoic acid; GGT, gamma-glutamyl transferase; LFTs, liver function tests; PH, phytanic acid; PR, pristanic acid; VLCFA, very long-chain fatty acids.

Table 2 Genetic etiologies of peroxisomal biogenesis and single enzyme defects

Disease classification	Gene symbol	Disorder (MIM no.)
Peroxisomal biogenesis disorders	PEX1	Peroxisome biogenesis disorder 1A (214100) Peroxisome biogenesis disorder 1B (601539)
	PEX2	Peroxisome biogenesis disorder 5A (614866) Peroxisome biogenesis disorder 5B (614867)
	PEX3	Peroxisome biogenesis disorder 10A 614882) Peroxisome biogenesis disorder 10B (617370)
	PEX5	Peroxisome biogenesis disorder 2A (214110) Peroxisome biogenesis disorder 2B (202370)
	PEX6	Peroxisome biogenesis disorder 4A (614862) Peroxisome biogenesis disorder 4B (614863)
	PEX7	Peroxisome biogenesis disorder 9B (614879)
	PEX10	Peroxisome biogenesis disorder 6A (614870) Peroxisome biogenesis disorder 6B (614871)
	PEX11B	Peroxisome biogenesis disorder 14B (614920)
	PEX12	Peroxisome biogenesis disorder 3A (614859) Peroxisome biogenesis disorder 3B (266510)
	PEX13	Peroxisome biogenesis disorder 11A (614883) Peroxisome biogenesis disorder 11B (614885)
	PEX14	Peroxisome biogenesis disorder 13A (614887)
	PEX16	Peroxisome biogenesis disorder 8A (614876) Peroxisome biogenesis disorder 8B (614877)
	PEX19	Peroxisome biogenesis disorder 12A (614886)
	PEX26	Peroxisome biogenesis disorder 7A (614872) Peroxisome biogenesis disorder 7B (614873)
Single enzyme peroxisomal disorders	ACOX1	Peroxisomal acyl-CoA oxidase deficiency acyl-CoA oxidase deficiency (264470)
	HSD17B4	D-bifunctional protein deficiency (261515)

Fig. 1 Ultrasonography and magnetic resonance imaging (MRI) of an infant with peroxisomal disorder. (A) Coronal ultrasonography, white arrows-subependymal germinolytic pseudocysts. (B) Coronal MRI T2 showing bilateral subependymal germinolytic pseudocysts. (C) Axial T2 image showing extensive bilateral polymicrogyria involving the Sylvian and parietal regions (dashed arrows).

Peroxisomal disorders, subdivided into peroxisomal biogenesis (structural peroxisomal assembly) and single enzyme defects ([Table 2]) constitute a large disease group with overlapping phenotypic characteristics and affect 1 in 50,000 births ([Table 1]).[3] To date, 14 peroxisome biogenesis factors (PEX genes) have been linked to 23 peroxisome biogenesis disorders with highly variable clinical spectrum, from severe early infantile onset to later-onset neurodegenerative features. Two single enzyme peroxisomal disorders due to ACOX1 and HSD17B4 have been described.[4] No cure exists and treatment is supportive.[5] Given significant morbidity and mortality, early diagnosis is imperative for family counseling, including preimplantation genetic testing to minimize recurrence risk.

Publication History

Received: 09 May 2021

Accepted: 30 May 2021

Article published online:
23 July 2021

• References

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