Objective: To report a case of Perrault syndrome with unusually severe cerebellar, cognitive, gastrointestinal, and psychiatric features, with “likely pathogenic” HSD17B4 variant and CNBP mutation.

Background: Perrault syndrome is an autosomal recessive disorder defined by sensorineural hearing loss, ovarian dysfunction in females, with neurologic features of ataxia, peripheral neuropathy, and cognitive impairment.1,2 HSD17B4 mutations account for 7% of cases and cause juvenile D-bifunctional protein deficiency.

Method: 22-year-old man with normal early development presented with progressive cognitive decline and imbalance since age 10 and hearing loss requiring cochlear implant since age 4. He reported progressive imbalance, bilateral hand tremor, limb incoordination, dizziness, distal numbness, mixed anxiety-depression, and recurrent esophagitis. Examination showed scanning speech, dysarthria, horizontal and torsional nystagmus, severe limb and gait ataxia, severe intention tremor, titubation, dysmetria, dysdiadochokinesia, and mild proximal leg weakness. Family history notable for blindness in two paternal aunts.

Results: Metabolic evaluation including chemistries, serum lactate, ceruloplasmin, plasma amino acids, urine organic acids, acylcarnitine profile, arylsulfatase activity, CSF neurotransmitters, and autoimmune panels were unremarkable, except elevated creatine kinase. Chromosomal microarray was normal. Brain and spine MRI, MR spectroscopy, EEG, and EMG were normal. Neuropsychological testing at age 20 revealed major neurocognitive disorder. Genome sequencing showed a pathogenic CNBP repeat expansion and two HSD17B4 variants, one “likely pathogenic” and one of uncertain significance.

Conclusion: This Perrault-spectrum phenotype has distinctive features, including early and progressive cognitive decline, marked cerebellar ataxia, recurrent esophagitis, and mood symptoms, with normal metabolic studies and normal neuroimaging. Co-occurrence of these features with CNBP mutation raises possibility of digenic inheritance or genetic modifier effect. We propose that HSD17B4 variant impairs peroxisomal β-oxidation and cerebellar integrity and interacts with CNBP mutation-mediated RNA toxicity to produce additive stress on cerebellar pathways here. Systematic sequencing and repeat expansion analysis may uncover similar dual hits, refine variant interpretation, and clarify digenic mechanisms in hereditary ataxia.

References: References

1. Pierce, S. B., Walsh, T., Chisholm, K. M., Lee, M. K., Thornton, A. M., Fiumara, A., Opitz, J. M., Levy-Lahad, E., Klevit, R. E., & King, M. C. (2010). Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. American journal of human genetics, 87(2), 282–288. https://doi.org/10.1016/j.ajhg.2010.07.007

2. Özkan Kart, P., Sahin, Y., Yildiz, N., Cebi, A. H., Esenulku, G., & Cansu, A. (2024). A Homozygous Missense Variant in HSD17B4 Identified in Two Different Families. Molecular syndromology, 15(2), 143–148. https://doi.org/10.1159/000534785

3. Faridi, R., Rea, A., Fenollar-Ferrer, C., O’Keefe, R. T., Gu, S., Munir, Z., Khan, A. A., Riazuddin, S., Hoa, M., Naz, S., Newman, W. G., & Friedman, T. B. (2022). New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder. Human genetics, 141(3-4), 805–819. https://doi.org/10.1007/s00439-021-02319-7

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MDS Abstracts - https://www.mdsabstracts.org/abstract/perrault-syndrome-in-a-young-adult-with-co-existing-hsd17b4-variant-and-cnbp-mutation/