Objective: To report a 45-years-old Swedish man born to non-consanguineous parents affected by an adult-onset syndrome that included insidious pain at onset, hypoalbuminemia, edema, severe obesity and cerebellar ataxia. This syndrome is associated with biallelic variants in the polynucleotide kinase 3 prime phosphatase (PNKP) gene.

Background: Biallelic variants in PNKP are associated with congenital microcephaly, seizures and developmental delay (MCSZ). Later, variants in PNKPwere found to be associated with childhood-onset ataxia with oculomotor apraxia type 4 (AOA4). AOA4 is a childhood-onset disease with hyperkinetic features, and loss of ambulation during adolescence. All patients have OMA and cerebellar atrophy, intellectual disability (ID (63.6%) is common whereas hypoalbuminemia (54.5%), hypercholesterolemia and elevated alfa-fetoprotein (AFP) (45.5% each) are variable. Severe obesity and edema occur in some. A third entity associated with biallelic PNKP variants is Charcot-Marie-Tooth type 2B2 (CMT2B2).

Method: The patient provided oral and written consent for this work. A comprehensive clinical characterization was performed. Ancillary test included laboratory analyses, neurophysiology studies, neuroimaging and genetic studies.

Results: Upon evaluation the patient displayed a mild cerebellar ataxia (SARA score = 3), nystagmus conjunctival telangiectasias and edema. His current weight is 135 kg which with a BMI of 42. There were no other hyperkinetic features other than ataxia, neither was OMA. The patient has an axonal sensorimotor neuropathy, albumin levels have declined over time, the latest value was 12 g/L, (ref. 36-45 g/L): he also has hypercholesterolemia (9.3 mmol/L) and elevated AFP (22 µg/L, ref <8). Brain MRI was normal, but CNV found a sensorimotor axonal neuropathy. There was no evidence of malabsorption, nephrotic syndrome or liver disease. Initially this man was treated with furosemide but the benefit was transient. Genetic testing revealed the variants c.1029+2T>C, p? and c.1196T>C, p.(Leu399Pro), both parents carried a variant each. A sister was found to have hypoalbuminemia but was not available for further investigations.

Conclusion: This is the first time AOA4 is reported with adult-onset presentation, this incipient ataxia is mild in comparison with the classical AOA4 form. Our findings expand the spectrum of complex syndromes associated with biallelic variants in PNKP.

References: Shen J, et al. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet. 2010;42(3):245-9.
Bras J, et al. Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4. Am J Hum Genet. 2015;96(3):474-9.
Paucar M, et al. Expanding the ataxia with oculomotor apraxia type 4 phenotype. Neurol Genet. 2016 ;2(1):e49.
Poulton C, et al. Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations. Neurogenetics. 2013;14(1):43-51.
Leal A, et al. The polynucleotide kinase 3′-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. Neurogenetics. 2018;19(4):215-225. doi: 10.1007/s10048-018-0555-7.
Tzoulis C, et al. PNKP Mutations Identified by Whole-Exome Sequencing in a Norwegian Patient with Sporadic Ataxia and Edema. Cerebellum. 2017;16(1):272-275.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/adult-onset-ataxia-with-oculomotor-apraxia-type-4-with-severe-hypoalbuminemia-generalized-edema-and-obesity/