Objective: To illustrate the symptoms, signs, and videotaped examination of a rare genetic disorder.

Background: POU4F1 encodes a transcription factor involved in nervous system development. [1] Homozygous knockout mice (Pouf1-/-) have decreased neuronal populations in the inferior olivary nuclei, red nuclei, trigeminal ganglia, and superior colliculus, and die shortly after birth. [1,2] Heterozygous, loss of function variants in POU4F1 cause a novel syndrome now termed Ataxia, intention tremor, and hypotonia syndrome, childhood onset (MIM 619352). Only 4 cases have been reported at present. [1]

Method: To further report on the phenotype of POU4F1-related ataxia in the oldest known case.

Results:

The patient is a 24-year-old female with a heterozygous POU4F1 pathogenic variant (c.271_281 del;p.Thr91HisfsTer254) and history of hypotonia, ataxia, and intention tremor since infancy. She has motor delay, speech apraxia, and mild intellectual delay. In childhood, she had paroxysmal tonic upgaze and esotropia requiring surgical correction. She had transient T2 hyperintensity of the inferior olivary nuclei, and has had progressive global cerebellar atrophy. In her 20s, she has experienced progression of her cerebellar syndrome, with trouble walking, interruptions in speech, and mild dysphagia. Most recently, she has developed dyspnea on exertion and chronic cough, and has been diagnosed with asthma. It is unclear at this time whether these respiratory symptoms are related to this genetic mutation.

Her examination demonstrates mild kyphosis and scoliosis. There is slight hypotelorism, and epicanthal folds are present. Extraocular motor testing demonstrates saccadic intrusions with pursuit, slight horizontal end-gaze nystagmus, and hypermetric saccades. She has scanning, mildly dysfluent dysarthria. Motor testing reveals diffuse hypotonia. There is relatively symmetric dysmetria and dysdiadochokinesia in all extremities, and intention tremor less than 2 cm in amplitude. Stance is wide-based and gait is moderately ataxic.

Conclusion: We present a case of POU4F1-related ataxia in a 24-year-old woman and provide video illustrating her phenotype. This case contributes to the small body of literature on this condition. This case is an important addition as she represents the oldest patient with this mutation reported to date, thereby offering insight into the evolution of phenotype over time.

References: [1] Webb BD, Evans A, Naidich TP, et al. Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor. Hum Mutat. 2021 Jun;42(6):685-693.

[2] Xiang M, Gan L, Zhou L, Klein WH, Nathans J. Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling. Proc Natl Acad Sci USA. 1996;93(21):11950–11955.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/pou4f1-related-ataxia-phenotyping-of-a-rare-genetic-ataxia/