Phenotypic Clues in Infantile‐Onset Parkinsonism‐Dystonia‐2: A Treatable Neurotransmitter Disorder

Neurotransmitter disorders are a rare group of neurometabolic disorders resulting from defects in biosynthesis, transport or breakdown of neurotransmitters manifesting with overlapping clinical presentations.1 Solute Carrier Family 18 (vesicular monoamine), Member 2 (SLC18A2) encoding vesicular monoamine transporter 2 (VMAT2) protein is essential for assembly of dopamine and serotonin in the presynaptic vesicle.2 Infantile-onset Parkinsonism-Dystonia-2 caused by biallelic pathogenic variants in SLC18A2 gene was first described in a Saudi Arabian family.2 Here, we describe the phenotype and genotype of a proband manifesting with infantile-onset Parkinsonism-Dystonia-2, a rare treatable metabolic movement disorder and highlight the diagnostic clues for an underlying neurotransmitter disorder. A 10-month-old boy third born to non-consanguineous parents of Afghan origin was referred to a neurology clinic for the evaluation of developmental delay and tone abnormalities. He began experiencing episodes of twisting posturing of both upper limbs without alteration in consciousness from 5 months of age. Some episodes were accompanied by tremor in the right upper limb. The duration of these episodes was variable, typically lasting a few minutes, and they were more prominent during crying and periods of excitement. Additionally, from 7 months of age, he developed brief episodes of upward gaze deviation without loss of consciousness. These episodes occurred in isolation or in combination with twisting posture of limbs. He also exhibited salivary drooling and noisy breathing. There was no history of abnormal sweating, temperature instability, flushing, irritability, sleep disturbances, vomiting or diarrhea. He had partial head control, social smiling and babbling. Prenatal and perinatal risk factors include placenta previa, maternal group B streptococcal infection and non-reassuring fetal heart rate tracing. Mega cisterna magna was identified on fetal ultrasound. He was born full term by vaginal delivery with a birth weight of 3180 grams and there were no neonatal risk factors. Newborn screening test did not detect any abnormalities. On his neurological examination, axial hypotonia and generalized dystonia were observed. Metabolic work up was non-contributory. Brain MRI at 7 months of age revealed mild enlargement of lateral ventricles, prominent extracerebral CSF spaces, thinning of corpus callosum and mild asymmetry of hippocampus. Awake and sleep EEG recording was normal. Chromosomal microarray did not reveal any abnormalities. Trio whole genome sequencing revealed biparentally inherited homozygous novel pathogenic variant c.1441-2A>G (NM_003054.6; GRCh38/UCSC hg38) in exon 16 confirming the diagnosis of infantile-onset Parkinsonism-Dystonia-2 (OMIM #618049). Following a genetic confirmation of neurotransmitter disorder, he was referred to movement disorders clinic at 2 years of age. Neurological examination revealed an alert child with axial hypotonia, hypomimia, bradykinesia, and generalized dystonia (Video S1). Brief episodes of oculogyric crisis (OGC) were also noted. He was treated with an escalating schedule of pramipexole and a follow-up assessment after 3 months revealed cessation of OGC episodes and tremor and mild reduction in dystonia (Video S1). His drooling decreased, and his parents reported that he has become more interactive and playful. The summary of clinical phenotypes and genotypes reported in individuals with infantile-onset Parkinsonism-Dystonia-2 are summarized in Table 1 and S1.2-10 Disorders of monoamine synthesis, transport and degradation must be considered in infants manifesting with unexplained developmental delay, speech delay, epilepsy, cognitive impairment, axial hypotonia and movement disorders.11 Complex movement disorders in these individuals include dystonia with or without diurnal variation, OGC, dyskinesias, parkinsonism, tremor, ataxia and gait difficulties.11 Autonomic nervous system and gastrointestinal symptoms such as temperature instability, excessive sweating, excessive salivation, feeding and swallowing difficulties are often encountered. Disorders of monoamine metabolism also exhibit behavioral, psychiatric and sleep problems of varying severity. Infantile-onset Parkinsonism-Dystonia-1 caused by biallelic variants in SLC6A3 and Infantile-onset Parkinsonism-Dystonia-2 caused by biallelic variants in SLC18A2 are transportopathies manifesting with complex movement disorders. SLC18A2-associated transportopathy results in constellation of clinical symptoms and signs related to dopamine and serotonin deficiency. Our patient had global developmental delay (GDD), truncal hypotonia, dystonia, OGC, and parkinsonism. GDD (100%), truncal hypotonia (95%), dystonia (92%), OGC (87%), parkinsonism (64%) and autonomic symptoms/feeding problems (>50%) have been reported.9 Though neuroimaging seems normal in most cases, findings including white matter signal changes, thinning of corpus callosum, cortical atrophy, signal changes in brainstem, and widening of subarachnoid spaces are reported in less than one-third of cases.2, 7, 9, 10 Our patient also had cortical atrophy, thinning of corpus callosum and enlargement of lateral ventricles. Low plasma serotonin level may serve as a biochemical marker and diagnosis is confirmed by identification of biallelic variants in SLC18A2 gene. However, plasma serotonin level was not estimated in our patient. Unlike other neurotransmitter disorders that respond to levodopa, individuals with aromatic amino acid decarboxylase (AADC) deficiency, SLC6A3 and SLC18A2 gene defects show worsening on treatment with levodopa which can be explained by their pathophysiological and biochemical attributes (Fig. S1). Though our patient had a mild reduction in dystonia and control of OGC episodes after short-term treatment with pramipexole, a variable treatment response to dopamine agonist has been reported previously.9 To conclude, infantile-onset Parkinsonism-Dystonia-2 must be considered in individuals presenting with developmental delay, OGC, dystonia, parkinsonism, autonomic disturbances, sleep and behavioral symptoms with a non-diagnostic newborn screening test and worsening of symptoms after treatment with levodopa. We recommend considering an early genetic evaluation in infants with complex movement disorders. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. S.Y.: 1A, 1B, 1C, 3A. H.S.A.: 1A, 1B, 1C, 3A. L.V.: 1A, 3B. M.E.: 1A, 3B. A.M.: 1A, 3B. S.R.C.: 1A, 3B. D.C.: 1A, 3B. P.K.: 1A, 3B. L.A.: 1A, 3B. E.T.: 1A, 3B. C.G.: 1A, 1B, 3B. Figure S1 was created by the authors using BioRender.com and has been carefully reviewed for accuracy. Ethical compliance statement: Name of the institutional review board or ethics committee that approved the study: Research Ethics Board approval was not obtained for this case report. Funding sources and conflict of interest: “No specific funding was received for this work.” “The authors declare that there are no conflicts of interest relevant to this work.” Financial disclosures for the previous 12 months: CG received consulting fees from Medtronic Inc and Ipsen, participated as an advisor at the advisory board meetings Medtronic Inc. Author disclosures are available in the Supporting Information. Written consent for publication was obtained from the parent. 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. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1. Biochemical pathway of neurotransmitter synthesis, transport and breakdown (Created using Biorender.com). Administration of levodopa is not appropriate in most cases of L-AADC deficiency as this enzyme is needed for the conversion of dopa to dopamine; similarly, levodopa administration Tremorin individuals with SLC6A3 and SLC18A2 gene defects causes worsening of symptoms because of defects in dopamine transport and vesicular packaging of dopamine respectively. Table S1. Genotype of individuals with infantile-onset Parkinsonism-dystonia-2. Video S1. Pre-Treatment video shows generalized dystonia with axial hypotonia; post-treatment video (three months after treatment with pramipexole) shows a mild reduction in dystonia and improvement in hand functions were observed. Axial hypotonia still persists. Data S1. COI_disclosure. 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