AOPEP ‐Related Dystonia with Supranuclear Vertical Gaze Palsy

The AOPEP‐related disorder (Online Mendelian Inheritance in Man: 619565), also referred to as DYT‐AOPEP, is a rare genetic disorder characterized by generalized or multifocal progressive dystonia because of biallelic loss‐of‐function variants in the AOPEP gene. Missense variants have also been reported. The disorder follows a recessive inheritance pattern and has been identified in patients from various ethnic backgrounds. ¹ In the initial cases reported by Zech et al ² seven pathogenic variants in AOPEP were found in five individuals from four European families. Further cases have since been reported. Here, we present a 31‐year‐old woman with homozygous pathogenic variants in the AOPEP gene, presenting with generalized dystonia and vertical supranuclear gaze palsy, a previously unreported feature.

Case Report

A 31‐year‐old woman of Iranian descent presented with anarthria and dystonic postures in her upper and lower limbs. She was born at term from an uncomplicated delivery. Her parents were first cousins, and she had three healthy siblings. Her symptoms began around the age of 23 with facial and oromandibular abnormal movements leading to progressive difficulty in articulation and swallowing. Four years after symptom onset, she developed a progressive dystonic posture in her left upper limb, which gradually spread to her right upper limb and both lower limbs over the next 2 years.

On our initial assessment, at the age of 31, she was anarthric, fully oriented, and displayed no evident cognitive impairments. On neurological examination, she had oromandibular dystonia with a dystonic smile.

The eye movement examination revealed slow and limited vertical saccades, a supranuclear vertical gaze palsy predominantly affecting downgaze, and slowed smooth pursuit with catch‐up saccades. There was no evidence of oculomotor apraxia and no nystagmus was observed. There was a dystonic posture in her neck, upper and lower limbs. She had brisk deep tendon reflexes and bilateral down‐going plantar reflexes (Video 1). Her brain magnetic resonance imaging (MRI) was normal, and a thorough systemic evaluation yielded normal results. Wilson disease was ruled out by normal serum ceruloplasmin and copper levels and the absence of Kayser‐Fleischer rings. Conditions such as Niemann‐Pick disease type C and Kufor‐Rakeb syndrome were excluded based on the absence of relevant mutations in genetic testing.

Video 1.

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Segment 1. First examination of the patient, at the age of 31, showing dystonic face, anarthria, dystonia of hands, severely limited vertical gaze (on asking her to look downward, there is limited and oblique movement of eyes), and leg dystonia. Segment 2. Second examination of the patient, at the age of 33, with the same findings except for complete downgaze palsy.

Whole‐exome sequencing (WES) analysis detected a homozygous variant in AOPEP: c.1201C>T (p.Arg401Trp). She had no significant improvement with medications, including levodopa, trihexyphenidyl, baclofen, and tizanidine, and her symptoms continued to worsen over time.

Twelve years after the initial evaluation, her dystonia had gradually progressed, increasingly limiting the use of her arms and further affecting her gait and balance. She was able to walk independently over short distances. Her cognition remained intact, and she had no sphincteric dysfunction or significant dysphagia (Video 2).

Video 2.

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Patient at the age of 45, demonstrating a dystonic face, procerus sign, supranuclear vertical gaze palsy, slow and limited vertical saccades, apraxia of lid opening, and progression of previously observed findings.

Discussion

We report a patient with AOPEP‐related dystonia with a vertical gaze palsy that has not been described in previous cases. Our case expands the spectrum of AOPEP‐related dystonia, highlighting phenotypic variability.

Our case carried a homozygous variant in AOPEP: c.1201C>T (p.Arg401Trp), which has been reported before in another Iranian patient by Garavaglia et al. ¹ The previously reported patient was diagnosed with generalized isolated dystonia with onset at the age of 20. He had generalized dystonia and dysarthric speech, but without any reported eye movement abnormalities. This observation may suggest a lack of direct genotype–phenotype correlation and indicate possible phenotypic variability. Tables 1 and 2 summarize the results of a systematic review of all previously reported patients with AOPEP gene variants. We identified six case reports and case series describing 15 patients from 13 distinct families with homozygous or compound heterozygous AOPEP gene variants. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ Reported patients came from different ethnic backgrounds, including seven European, three Iranian, three Chinese, one Indian, and one Turkish. Dystonia was the presenting feature in all 15 individuals. The age of onset ranged from 6 years to 37 years. Eleven patients had isolated dystonia, and four were found to have combined dystonia, nine exhibited generalized dystonia, four multifocal dystonia, one had isolated cervical dystonia, and one had segmental dystonia. None of the cases had any significant abnormality on brain imaging. Patients did not respond to levodopa (n = 7) and only experienced partial improvement with different symptomatic therapies. Responses to deep brain stimulation (DBS) in three patients were inconsistent, but some improvement was noted with pallidal DBS in all three. None of the cases identified in our literature review were documented to have ocular movement abnormalities.

TABLE 1.

Genetic findings of all previously reported patients with AOPEP gene variants

Family no.; proband no. (reported by) Ref.	AOPEP variant(s)	Variant zygosity	Protein variant	Consanguinity	Family history	Geographic origin (ethnicity)
Family 1; proband 1 (Zech et al.) 2	c.1477C>T	Homozygous	p.Arg493*	Not reported	Negative	Italy (European)
Family 2; proband 2 (Zech et al.) 2	c.763C>T; c.777G>A	Compound heterozygous	p.Arg255*; p.Trp259*	Not reported	Negative	Australia (European)
Family 3; proband 3 (Zech et al.) 2	c.696_697delAG; c.2041‐1G>A	Compound heterozygous	p.Ala234Serfs*5; p.Val681_Lys705del; p.Pro660_Lys705del	Not reported	Negative	Germany (European)
Family 4; proband 4–1 (Zech et al.) 2	c.1215delT; c.1744delA	Compound heterozygous	p.Val406Cysfs*14; p.Met582Cysfs*6	Not reported	Positive (two affected sisters)	France (European)
Family 4; proband 4–2 (Zech et al.) 2	c.1215delT; c.1744delA	Compound heterozygous	p.Val406Cysfs*14; p.Met582Cysfs*6	Not reported	Positive (two affected sisters)	France (European)
Family 5; proband 5 (Fevga et al.) 3	c.333_402dup	Homozygous	p.Gly135*	Yes	Negative	India (Indian)
Family 6; proband 6 (Menden et al.) 5	c.122G>A; 696_697del	Compound heterozygous	p.Gly41Glu; Ala234Serfs*5	Not reported	Negative	Unknown (European)
Family 7; proband 7 (Menden et al.) 5	c.618C>G; 920 T>C	Compound heterozygous	p.Tyr206Ter; Leu307Ser	Not reported	Negative	Unknown (European)
Family 8; proband 8–1 (Garavaglia et al.) 1	c.1917‐1G>A	Homozygous	p.?	Yes	Positive (two affected cousins)	Iran (Iranian)
Family 8; proband 8–2 (Garavaglia et al.) 1	c.1917‐1G>A	Homozygous	p.?	Yes	Positive (two affected cousins)	Iran (Iranian)
Family 9; proband 9 (Garavaglia et al.) 1	c.1909G>T a	Homozygous	p.Glu637*	Unknown	Negative	China (Chinese)
Family 10; proband 10 (Garavaglia et al.) 1	c.1201C>T	Homozygous	p.Arg401Trp	Yes	Negative	Iran (Iranian)
Family 11; proband 11 (Lin et al.) 4	c.870delinsCA	Heterozygous	p.M291Nfs*68	Yes	Negative	China (Chinese)
Family 12; proband 12 (Lin et al.) 4	c.C635A; c.G646A	Compound heterozygous	p.A212D; p.G216R	Not reported	Negative	China (Chinese)
Family 13; proband 13 (Minnerop et al.) 6	c.703C>T	Homozygous	p.Gln235*	Yes	Negative	Unknown (Turkish)

^a A heterozygous mosaic likely pathogenic CHD8 variant, c.3725G>A (p.Arg1242Gln), was also detected.

TABLE 2.

Clinical characteristics of all previously reported patients with AOPEP gene variants

Family no.; proband no. (reported by) Ref.	Age at exam (y)	Age at onset (y)	Sex	Eye movement abnormality	Dystonia syndrome	Other movement disorders	Other neurological features	Brain MRI findings	Medications and response to treatment
Family 1; proband 1 (Zech et al.) 2	13	9	M	Not reported	Childhood‐onset generalized isolated dystonia	No	No	Normal	Levodopa (no response); anticholinergics (no response)
Family 2; proband 2 (Zech et al.) 2	61	12	F	Not reported	Childhood‐onset multifocal isolated dystonia	No	No	Normal	Anticholinergics (partial response); tetrabenazine (partial response); botulinum toxin (no response)
Family 3; proband 3 (Zech et al.) 2	58	36	M	Not reported	Multifocal isolated dystonia with onset in early adulthood	No	No	Normal	Levodopa (no response); anticholinergics (no response); botulinum toxin (no response)
Family 4; proband 4–1 (Zech et al.) 2	61	22	F	Not reported	Generalized combined dystonia with onset in early adulthood	Parkinsonism	No	Normal	Pallidal DBS (partial response); levodopa (partial response)
Family 4; proband 4–2 (Zech et al.) 2	52	24	F	Not reported	Generalized combined dystonia with onset in early adulthood	Parkinsonism	Depression	Normal	Levodopa (no response); botulinum toxin (no response); baclofen (partial response)
Family 5; proband 5 (Fevga et al.) 3	31	20	M	Not reported	Generalized isolated dystonia with onset in adolescence	No	No	Normal	Unknown
Family 6; proband 6 (Menden et al.) 5	38	20	M	Not reported	Multifocal isolated dystonia with onset in adolescence	No	No	Minor ventricular asymmetry	Levodopa (no response); propranolol (no response); trihexyphenidyl (partial response)
Family 7; proband 7 (Menden et al.) 5	37	24	M	Not reported	Multifocal isolated dystonia with onset in early adulthood	No	Mild cognitive deficit	Non‐specific white matter hyperintensities	Levodopa (no response); botulinum toxin (no response); trihexyphenidyl (partial response); pallidal DBS (marked improvement)
Family 8; proband 8–1 (Garavaglia et al.) 1	25	18	M	Not reported	Generalized isolated dystonia with onset in adolescence	No	No	Normal	Anticholinergics
Family 8; proband 8–2 (Garavaglia et al.) 1	20	13	M	Not reported	Generalized isolated dystonia with onset in adolescence	No	No	Normal	Unknown
Family 9; proband 9 (Garavaglia et al.) 1	34	6	M	Not reported	Childhood‐onset generalized combined dystonia	Parkinsonism	Intellectual disability; behavioral problems macrocephaly a	Normal	Levodopa (no response); left thalamic DBS (unsuccessful); bilateral GPi‐DBS (improvement); anticholinergics; botulinum toxin
Family 10; proband 10 (Garavaglia et al.) 1	31	20	M	Not reported	Generalized isolated dystonia with onset in adolescence	No	No	Normal	Unknown
Family 11; proband 11 (Lin et al.) 4	47	37	M	Not reported	Focal isolated dystonia with onset in early adulthood	No	No	Normal	Botulinum toxin (improvement)
Family 12; proband 12 (Lin et al.) 4	20	Unknown	F	Not reported	Childhood‐onset combined segmental dystonia	Myoclonus	No	Normal	Unknown
Family 13; proband 13 (Minnerop et al.) 6	–	29	M	Not reported	Generalized isolated dystonia with onset in early adulthood	No	No	Normal	Levodopa (no response); trihexyphenidyl (no response); botulinum toxin (improvement)

^a Certain symptoms may be attributable to the detected likely pathogenic CHD8 variant.

Abbreviations: MRI, magnetic resonance imaging; M, male; F, female; DBS, Deep brain stimulation; GPi, Globus pallidus internus.

To conclude, AOPEP‐related dystonia is an autosomal‐recessive condition characterized by a distinct clinical presentation and progression pattern. Unfortunately, the majority of reported cases, including our case, demonstrated an unfavorable response to standard treatments and exhibited a progressive and disabling disease course. Although treatment options like DBS show promise, further research is needed to optimize management strategies. Future patients should be examined carefully for associated oculomotor abnormalities to determine whether a vertical gaze palsy is more common than previously appreciated.

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Patients gave informed consent before inclusion in this report. The authors confirm that the approval of an institutional review board was not required for this work.

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for Previous 12 Months: The authors declare that there are no disclosures to report.

Authors Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

S.K.: 1A, 1B, 3A

A.S.: 1B, 3B

A.S.N.: 2B, 3B

M.S.: 3B

M.Z.: 3B

J.W.: 3B

A.E.L.:3B

M.R.: 1A, 1B, 2B, 3B

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.