Neurodevelopmental Gene‐Related Dystonia‐Parkinsonism with Onset in Adults: A Case with <scp><i>NAA15</i></scp> Variant

Abstract

Genomic sequencing and animal-model studies have begun to define a strong neurodevelopmental basis of dystonia.1 In addition, neurodevelopmental defects are also thought to represent factors contributing to the manifestation of Parkinson's disease (PD) and parkinsonian syndromes.2-4 Knowledge about single-gene disorders presenting with neurodevelopmental dystonia and/or parkinsonism is still limited, hindering individualized patient care and comprehensive mechanistic understanding. We have enrolled a male proband demonstrating adult-onset generalized dystonia combined with akinetic-rigid symptoms in our research program aiming to unravel the etiologies of dystonic syndromes.1 The proband's movement-disorder features started at the age of 46 years, without prior medication intake. He developed dystonic posturing of the lower extremities left>right, and subsequently also posturing of both arms and the trunk with intermittent lateroflexion/camptocormia. These symptoms were followed by manifestation of postural instability, swallowing difficulties, and muscle stiffness. Over time, dystonia became less prominent, whereas slowness of movements and gait dysfunction worsened. Examination at the age of 52 years revealed constant dystonia affecting predominantly the left arm associated with marked parkinsonism (Video S1). During childhood, the proband had experienced gross-motor and speech delays but he had never visited special pediatric services. He showed mild coarse facial features (Video S1) but no evidence of significant cognitive impairment (Montreal Cognitive Assessment [MoCA] score 27/30), autism, or cardiac abnormalities, consistent with the heterogeneous nature of NAA15-related disease.5 There was no family history of neurological disorders. Evaluations including blood biochemistry, metabolic screenings, and genetic testing for spinocerebellar ataxias (SCA 1,2,3,6) and LRRK2-associated PD yielded unremarkable results. Chromosomal microarray analysis was unrevealing. Brain imaging could not be performed because the patient did not tolerate the procedure due to abnormal postures. A trial of L-dopa/carbidopa produced improvement with decreased tone, although no sustained response was seen. By trio whole-exome sequencing,1 the proband was found to carry a de novo pathogenic nonsense variant in NAA15: NM_057175.5:c.382C>T, p.Arg128*. The same variant has previously been identified in two unrelated patients (one published6 and one from our in-house pediatric cohorts) with classic neurodevelopmental-disease features but no movement disorder. No alternative genetic causes were observed upon in-depth analysis of the exome data (including ExomeDepth-based copy number variation [CNV] assessment), especially no potentially pathogenic variants in established dystonia/parkinsonism-related genes. NAA15 encodes N-alpha-acetyltransferase-15, an essential component of the N-terminal-acetyltransferase-complex-A mediating the attachment of acetyl-groups to the N-termini of various substrate proteins.5 N-terminal acetylation has significant impact on protein properties such as folding, complex formation, and activity, and dysfunction of this process has been associated with both neurodevelopmental and neurodegenerative pathological effects including alterations in the stability of α-synuclein.7 NAA15-related disease has been characterized as an infantile-/childhood-onset disorder that presents with variable combinations of milestone delay, intellectual impairment, and dysmorphia.5 To date, abnormal (limb dystonic) movements have been reported in only a single affected child.5 Our case study expands the phenotype of NAA15-related disease and serves to enhance awareness of the natural history of this syndrome which can involve adult-onset movement-disorder presentations. Moreover, the findings add NAA15 to the growing list of genes whose variants can underlie both typical pediatric neurodevelopmental conditions and phenotypes with parkinsonism/dystonia-parkinsonism later in life.3, 4 Notable, yet only recently emerging examples of this group of neurodevelopmental genes include NR4A2, PLXNA1, PPP2R5D, WARS2, and YY1, which are associated in certain adult cases with dopa-responsive dystonia-parkinsonism, atypical parkinsonian syndromes with dystonia, and parkinsonism resembling PD (Table 1). Further elucidation of this novel class of genetically determined entities is important to gain broader insights into pathogenesis and stratify patients according to etiological subtype and treatment response. We encourage additional collaborative research to improve identification of the spectrum and outcomes of neurodevelopmental gene-linked dystonia-parkinsonism, with the eventual goal of designing more efficient therapies. We thank the patient and his family for their generous participation and permission to publish this case. Open Access funding enabled and organized by Projekt DEAL. Data available on request from the authors. I. Straka: acquisition of data, clinical examination, analysis and interpretation of data, revision of manuscript for critical intellectual content J. Švantnerová: study design and concept, acquisition of data, clinical examination, analysis and interpretation of data, revision of manuscript for critical intellectual content M. Minár: acquisition of data, revision of manuscript for critical intellectual content S. Stanková: acquisition of data, clinical examination, revision of manuscript for critical intellectual content M. Zech: study design and concept, study supervision, analysis and interpretation of data, wrote original manuscript Disclosures (for the preceding 12 months): Nothing to report. Data available on request from the authors. Video S1: Our patient at the age of 52 years presenting with dystonia affecting predominantly the left arm and parkinsonism. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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