[1] 6w Progressive Parkinsonism in PPP2R5D-Related Neurodevelopmental Disorder

[1] 114w PPP2R5D-related neurodevelopmental disorder (Houge-Janssens syndrome type 1) is a rare autosomal dominant condition characterized by macrocephaly, intellectual disability, and epilepsy. Progressive parkinsonism is an emerging adult phenotype that neurologists should be aware of since timely genetic diagnosis opens the door to disease-modifying therapies currently in clinical trials. We describe a 33-year-old woman with this condition who developed progressive mixed-tremor parkinsonism in early adulthood. Dopamine transporter imaging confirmed presynaptic nigrostriatal dysfunction. Whole-genome sequencing identified the recurrent de novo pathogenic missense variant PPP2R5D p.Glu198Lys. The clinical triad of macrocephaly, intellectual disability, and early-onset parkinsonism is specific for this condition and should prompt targeted genetic evaluation even in adults with a longstanding diagnosis of a neurodevelopmental disorder.

[1] 100w Neurologists in general adult practice can find themselves caught off guard when a patient with a longstanding neurodevelopmental disorder develops a progressive movement disorder in adulthood. The instinct is often to treat the two problems independently: the childhood condition on one hand, and what looks like early-onset Parkinson's disease on the other. PPP2R5D-related neurodevelopmental disorder, also known as Jordan's syndrome or Houge-Janssens syndrome type 1, is a rare condition that should shift this instinct because the parkinsonism is not coincidental: it is part of the syndrome. More importantly, a correct genetic diagnosis now opens the door to emerging disease-modifying treatments.

[2] 111w A 33-year-old woman was referred for progressive gait instability and worsening hand tremor. She had been born at term with no neonatal complications. There was no family history of neurodevelopmental or movement disorders. Her background included macrocephaly, global developmental delay, and later moderate intellectual disability, severe myopia, and childhood-onset epilepsy. She had attended special education, and no genetic evaluation had previously been performed. A brain MRI in childhood was reported as normal. Motor milestones were delayed from infancy, and independent ambulation was achieved at age 4 years, when a mild action tremor and impaired fine motor skills were first noted. Motor function did not normalize but remained relatively stable through adolescence.

[3] 41w Epilepsy consisted of a single seizure in infancy and a cluster of generalized seizures at ages 14-15, which responded to carbamazepine and later lamotrigine. At the time of her evaluation, she had been seizure-free off medication for more than a decade.

[4] 59w Motor symptoms worsened slowly through her twenties before accelerating subacutely at age 30. She developed a highamplitude mixed rest and action tremor interfering with fine motor tasks, gait freezing, frequent falls, and persistent left foot inversion-initially attributed to an orthopedic problem. By the time of referral, she needed a posterior walker or physical assistance for all walking (Figure 2).

[5] 89w Examination (Video 1) showed macrocephaly (62.5 cm, Z ~ +4.3) and dysmorphic facial features including mild hypertelorism and frontal bossing. Speech was hypophonic and dysarthric. Oculomotor examination was normal, with no supranuclear gaze palsy. There was moderate rigidity (left greater than right) and bradykinesia in all limbs, and a complex high-amplitude tremor with resting, postural, and intention components. Mild orofacial, facial, and cervical dystonia were present, along with sustained plantar flexion and inversion of the left foot during walking. Deep tendon reflexes were 2+ throughout with downgoing plantar responses.

[6] 63w Routine investigations, including complete blood counts, serum electrolytes, renal and hepatic function, thyroid function, inflammatory markers, ceruloplasmin, and 24-h urinary copper, were all normal. Brain MRI showed T2 signal shortening and increased susceptibility in the globi pallidi and putamina, and subtle callosal dysgenesis (Figure 1A-B). Dopamine transporter (DAT) imaging showed asymmetrically reduced striatal uptake in the putamina, confirming presynaptic nigrostriatal dysfunction (Figure 1C).

[7] 49w A trial of carbidopa/levodopa (25/100 mg, titrated to 1.5 tablets three times daily) produced a mild subjective improvement in bradykinesia, documented over time in Video 2, but overall functional independence was not restored. Treatment was discontinued after she developed a severe perioral erythematous rash, a rare potential side effect.

[8] 66w The distinctive combination of macrocephaly, moderate intellectual disability, childhood epilepsy, and early-onset progressive parkinsonism with DAT imaging evidence of nigrostriatal dysfunction suggested a genetic etiology, prompting enrolment in a gene discovery study (NCT05354622). Whole-genome sequencing identified a de novo heterozygous missense variant in PPP2R5D (NM_006245.4:c.592G>A, p.Glu198Lys), classified as pathogenic, establishing the diagnosis of PPP2R5D-related neurodevelopmental disorder (OMIM #616355). The clinical course is summarized in Figure 2.

[1] 104w Macrocephaly and the preceding history of developmental delays and intellectual disability without regression are the key discriminating features. This is absent from virtually every other cause of early-onset parkinsonism-including PRKN, PINK1, DJ-1, ATP13A2 (Kufor-Rakeb), beta-propeller proteinassociated neurodegeneration (BPAN), and hereditary spastic paraplegia types 11 and 15. The presence of macrocephaly alongside intellectual disability and early-onset parkinsonism should immediately prompt genetic testing for PPP2R5D. Other features that argue against other genetic causes of parkinsonism are the longstanding childhood neurodevelopmental course without evolution of additional neurological symptoms; for example, the absence of a pyramidal syndrome (against SPG11/ZFYVE26) [6] or supranuclear gaze palsy (against Kufor-Rakeb syndrome) [7].

[2] 59w Brain MRI is often non-diagnostic or shows only subtle changes (ventriculomegaly, callosal dysgenesis, or non-specific basal ganglia signal change). DAT imaging is a practical next step when the diagnosis is uncertain, and a positive result supports initiation of dopaminergic therapy and strengthens the case for genetic evaluation. A differential diagnosis of early-onset genetic parkinsonism is summarized in Table S1.

[3] 95w When this condition is on the differential, whole-genome or whole-exome sequencing is the most efficient diagnostic route. Standard gene panels for Parkinson's disease or movement disorders will not include PPP2R5D. Adult neurologists should be aware that testing may face insurance authorization challenges and that referral to a genetics service or specialist center experienced in rare genetic disorders may facilitate a genetic diagnosis [8]. We concur with Kim et al. that inclusion of PPP2R5D in gene panels for early-onset parkinsonism and neurodevelopmental disorders would facilitate earlier diagnosis, particularly in settings where comprehensive genomic testing is unavailable.

[1] 140w PPP2R5D encodes the B56δ regulatory subunit of protein phosphatase 2A (PP2A), a critical regulator of neuronal development and intracellular signaling. All known pathogenic variants are missense and cluster in the substrate-binding pocket of B56δ, arising almost exclusively de novo, causing autosomal dominant disease [1]. In a published cohort of 72 individuals, core features included hypotonia (75%), macrocephaly (67%), epilepsy (46%), language disorder (60%), and autism spectrum disorder (26%). Independent walking is typically achieved late, between 18 months and 9 years of age. More than 150 individuals have been reported, and p.Glu198Lys is among the most common and most severe variants in terms of cognitive outcome. The prevalence of parkinsonism among p.Glu198Lys carriers cannot yet be estimated from published cohorts, as most reported individuals are of pediatric age and have not reached the expected age of onset for this feature [1][2][3].

[1] 97w This case illustrates that adults with a history of neurodevelopmental delay who experience progressive motor symptoms warrant systematic re-evaluation for genetic etiologies rather than assumption of an idiopathic diagnosis or attribution to cerebral palsy. The combination of macrocephaly, intellectual disability, and early-onset parkinsonism is a distinctive and relatively specific clinical constellation that should prompt immediate targeted genetic evaluation for PPP2R5D. Early diagnosis enables anticipatory co-morbidity surveillance, enrollment in clinical trials, access to emerging targeted therapies, and informed family counseling. As disease-modifying treatments advance toward clinical translation, timely genetic diagnosis will be increasingly critical for optimizing long-term outcomes.

[1] 207w Movement disorder features follow a recognizable developmental arc: uncoordinated gait in childhood, hand tremors in adolescence, and early-onset parkinsonism in adulthood-a progression that clinicians may not recognize as a continuum if they encounter the patient for the first time in adulthood. Kim et al. first described levodopa-responsive parkinsonism in individuals with the recurrent p.Glu200Lys variant [4], and Hetzelt et al. documented parkinsonism with p.Glu198Lys-the same variant as our patient [5]. Compared with prior reports, our case extends the clinical characterization of the p.Glu198Lys phenotype by documenting the temporal sequence of motor symptom evolution, delineating a complex profile of mixed tremor and dystonia, and contextualizing this presentation within the emerging therapeutic landscape. Neuropathological analysis revealed focal neuronal loss and gliosis in the substantia nigra pars compacta without Lewy bodies, distinguishing this from idiopathic Parkinson's disease [4]. Our patient's DAT imaging provides in vivo confirmation of presynaptic dopaminergic degeneration and extends the imaging characterization of this phenotype. The observed clinical deterioration most likely reflects natural progression of nigrostriatal neurodegeneration rather than primary drug failure, a conclusion consistent with the neuropathological findings of Kim et al. [4]. The limited levodopa response additionally raises the possibility of concomitant postsynaptic dysfunction-an open question that warrants investigation with postsynaptic imaging in future cases.

[2] 87w Published management guidelines for this condition explicitly recommend a levodopa trial for parkinsonism [9]. Benefit can be meaningful, though as in our case a perioral rash from carbidopa is an uncommon but recognized adverse effect [10]. Alternative dopaminergic strategies (dopamine agonists, MAO-B inhibitors) are under consideration for patients who cannot tolerate levodopa. This report is limited by the absence of formal motor rating scale assessments (e.g., MDS-UPDRS) before and after levodopa initiation; prospective standardized motor evaluations should be incorporated in future cases to better characterize treatment response.

[3] 35w Deep brain stimulation is a potential option for refractory motor symptoms, but requires careful multidisciplinary evaluation including formal neuropsychological assessment: patients with pre-existing intellectual disability may carry additional risk for postoperative cognitive and behavioral complications.

[4] 75w Beyond symptomatic treatment, the diagnostic stakes have risen significantly. Young et al. demonstrated that allele-specific antisense oligonucleotides targeting the pathogenic E198K allele fully rescued neurite phenotypes in patient-derived neurons [2] representing a compelling proof-of-principle for targeted genetic therapy. In parallel, a phase 1/2 clinical trial of zatolmilast (BPN14770), a phosphodiesterase-4D inhibitor, is currently recruiting (NCT06717438). The DBSMatchMaker platform supports clinician collaboration for those considering deep brain stimulation in ultra-rare disorders, such as this one [11,12].

[5] 91w It is also worth proactively screening for associated features that are easy to overlook when parkinsonism dominates the referral. In published cohorts these include: behavioral difficulties such as anxiety, aggression, and attention deficit (present in the majority, except in those with residue 251 variants); GI dysmotility, gastro-esophageal reflux, and constipation (~24%); ophthalmologic abnormalities including strabismus and astigmatism (~45%); scoliosis and hip dysplasia; and endocrine features including precocious puberty [9]. A diagnosis also opens the door to disease registries, natural history studies, and family counseling, in addition to the emerging therapeutic trials.