New Progressive Generalized Dystonia Phenotype in a Patient with NBEA ‐Related Neurodevelopmental Disease

Dystonia is a hyperkinetic movement disorder characterized by extensive clinical and genetic heterogeneity. Recent studies have underscored the emerging role of neurodevelopmental genes in the pathogenesis of dystonia. ¹ De novo variants in NBEA, encoding a neuron‐specific protein neurobeachin, cause a neurodevelopmental disorder (NDD) with developmental delay (DD), intellectual disability (ID), autistic features, and early generalized epilepsy. ² We report an adult patient with a de novo pathogenic variant in NBEA, presenting with early‐onset, slowly progressive generalized dystonia, and highlight this gene as a novel cause of complex dystonia.

Case Report

The patient is a 38‐year‐old woman born at term to healthy unrelated parents, with unremarkable family history. At birth, she was cyanotic with an Apgar score of 8. Transient adaptation problems were observed, including poor feeding, irritability, and muscle stiffness but she was discharged home in good general condition. She started sitting with support at the age of 9 months, walking independently at 3.5 years, and speaking simple sentences by the age of four. Since attempting to stand and walk the patient presented postural instability with a tendency to fall backwards, as well as cervical and right limb dystonia and slurred speech. She was initially diagnosed with dyskinetic cerebral palsy. She attended primary school with individual tuition and secondary school with inclusive learning. Her manual dexterity has been severely affected since childhood with predominant dystonia in the right limb.

She has been hospitalized several times in the psychiatric ward due to organic affective disorder with emotional lability, apathy, disinhibition, perseverative thoughts, compulsive shopping, aggression and occasional delusions since the age of 25. Psychiatric medications included haloperidol, levomepromazine, tiapride, clonazepam, alprazolam, and chlorprothixene. Worsening of dystonia was not observed at that time. Psychological assessment with the Wechsler Adult Intelligence Scale (WAIS‐R (PL)) performed at the age of 34 indicated borderline intellectual functioning/mild intellectual disability (verbal IQ 69).

The patient was referred to a neurology clinic at the age of 37 due to exacerbation of involuntary movements, gait disorder with falls, and fatigue for about a year. She denied any provoking factors and has been on stable pharmacologic treatment with biperiden, duloxetine, trazodone, lamotrigine, amantadine, and hydroxyzine for the last 3 years before the visit. On neurological examination her gait was disturbed with dystonic bending of the torso backwards and to the right, equinovarus feet, and extended and elevated hips, more pronounced on the right. Dystonic movements of upper limbs (Fig. 1), orofacial dystonia with involuntary tongue movements, and dysarthric speech were observed. Muscle strength was normal, and there were no signs of pyramidal or cerebellar tract damage (Video 1). The Unified Dystonia Rating Scale (UDRS) score was 80.5 points, and The Global Dystonia Severity Rating Scale (GDS) score was 86 points in total. Levodopa challenge was performed with levodopa+benserazide (100 mg + 25 mg) tid with no change in neurological state.

Figure 1.

Description: Dystonic hand posture while attempting Finger Dexterity Test, especially on the right.

VIDEO 1.

Description: Segment 1: gait; Segment 2: Romberg test; Segment 3: Hand movements; Segment 4: Orofacial dystonia, dysarthria; Segment 5: Hand dystonia, finger to nose test; Segment 6: Heel to knee test; Segment 7: Standing up.

Basic laboratory investigations and magnetic resonance brain imaging showed no abnormalities. Importantly, the patient has never experienced epileptic seizures, and electroencephalography showed no epileptiform activity.

Neuropsychological assessment revealed global cognitive deterioration with predominant executive dysfunction, marked impulsivity and relatively well preserved verbal episodic memory (Supplementary Table S1). Despite poor global intellectual function as assessed with Raven's Progressive Matrices Test 2, she scored slightly above (126) the cut‐off score for dementia (123) on Mattis Dementia Rating Scale—2. ³

Trio exome sequencing identified a novel de novo heterozygous frameshift variant in NBEA: NM_015678.4: c.6564dup, (p.Phe2189Leufs*13). According to the American College of Medical Genetics and Genomics criteria, the variant was classified as pathogenic (PVS1, PS2, PM2). ⁴ NBEA is a mutation‐constrained gene intolerant of heterozygous loss‐of‐function variants (constraint metric pLI of 1 in gnomAD version 4.1.0). In line with this observation, a diverse set of NBEA heterozygous loss‐of‐function alleles including nonsense and frameshift alterations have previously been documented as disease‐causing in individuals with neurodevelopmental syndromes. ²

Discussion

According to the current classification of dystonia, the patient's phenotype corresponds to hereditary, infantile‐onset, progressive, and persistent generalized dystonia with associated features of DD and ID. ⁵ This case represents an example of a dyskinetic CP mimic. Neurobeachin was shown to be implicated in endosomal trafficking processes that are crucial for synaptic function, like other previously described products of dystonia‐associated genes. ⁶ , ⁷ In a cohort of 24 cases with NBEA variants, all patients had NDD, most (15/24) had epilepsy and eight presented abnormal movements, but only three were diagnosed with dystonia. ² Miura et al described two members of a Japanese family with an adolescent‐onset paroxysmal kinesigenic dyskinesia (PKD), carrying a novel missense NBEA variant, suggesting an association of NBEA with PKD. ⁸ Also, Hull et al reported a boy with a de novo missense variant in NBEA and PKD responsive to oxcarbazepine. ⁹ Of note, our patient did not develop epilepsy or paroxysmal movement disorder. ² , ⁸ , ⁹ This finding further highlights the significant overlap among epilepsy, dystonia, and PKD phenotypes linked to neurodevelopmental genes. ¹⁰ In conclusion, our report broadens the clinical and molecular spectrum of NBEA‐related neurodevelopmental disorder to include complex dystonia phenotype with prominent neuropsychiatric symptoms.

Author 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.

M.S.: 1A, 1B, 1C, 3A, 3B.

M.K.: 1A, 1B, 1C, 3A, 3B.

E.S.: 1B, 1C, 3B.

M.M.B.: 3B.

M.Z.: 1A, 1C, 3B.

Disclosures

Ethical Compliance Statement: This study was approved by the Technical University of Munich. Written informed consent for publishing genetic and clinical data, including videos was obtained from the patient. 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.

Funding sources and Conflicts of Interest: This work was supported by funding from the EJP RD (EJP RD Joint Transnational Call 2022) and the German Federal Ministry of Education and Research (BMBF, Bonn, Germany), awarded to the project PreDYT (PREdictive biomarkers in DYsTonia, 01GM2302). This research was also supported by a “Schlüsselprojekt” grant from the Else Kröner‐Fresenius‐Stiftung (2022_EKSE.185). In addition, this study (MZ) has received funding from the Federal Ministry of Education and Research (BMBF) and the Free State of Bavaria under the Excellence Strategy of the Federal Government and the Länder, as well as by the Technical University of Munich‐Institute for Advanced Study. MZ receives research support from the German Research Foundation (DFG 458949627; ZE 1213/2–1). The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: MS received honoraria for lectures from Abbvie, Merz and Ipsen. MK received honoraria for lectures and consultancy fees from Angelini Pharma and Swixx Biopharma. ES received honoraria from Cogstate. MMB received consultant and speaker honoraria from Sanofi, Roche, Novartis, UCB, and Biogen. MMB is a PI in clinical trials for Roche, Scholar Rock, Takeda, Biohaven.

Supporting information

TABLE S1. Neuropsychological assessment results at the age of 38.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.