Novel RAB39B variant associated intellectual disability and levodopa-responsive young-onset parkinsonism.

We report a 37-year-old Caucasian male with history of developmental delay, childhood onset Intellectual Disability (ID) and attention deficit hyperactivity disorder (ADHD) who presented at the age of 34 with tremor-dominant parkinsonism. Next Generation Sequencing (NGS) revealed pathogenic hemizygous sequence variant, c.200G > T, in the RAB39B gene. This report expands the number of described individuals with young onset PD associated with RAB39B mutation.

Expanding the genotype-phenotype landscape of PDE10A-associated movement disorders.

BACKGROUND: Phosphodiesterase 10A (PDE10A) controls body movements by regulating cyclic adenosine monophosphate signaling in the basal ganglia. Two classes of PDE10A variants are reported with distinctive genotype-phenotype correlation. The autosomal recessive mutations in the GAF-A and catalytic domains are associated with compromised membrane localization, and manifest with infantile onset chorea, developmental, and cognition delay with normal brain MRI. Conversely, autosomal dominant mutations in the GAF-B domain cause protein aggregates which results in childhood onset chorea in the context of normal cognition and development, with striatal lesions. METHODS: Phenotypic characteristics of affected individuals with PDE10A mutations belonging to a single family were recorded. In addition, Sanger sequencing and in silico analysis were used to identify the mutations. Homozygosity mapping was applied together with whole exome sequencing. RESULTS: Four individuals from a consanguineous family affected with PDE10A mutations were observed for up to 40 years. Although these individuals displayed a clinical phenotype attributed to the recessive GAF-A mutations, they revealed a bi-allelic GAF-B mutation (c.883G > A:p. D295 N; p.Asp295Asn) that was segregated with all affected individuals. In addition to chorea, we observed peculiar foot deformities and pronounced social phobia, with normal brain MRI. In silico structural analysis suggested that the GAF-B mutation blocked allosteric PDE10A activation. The resulting lack of PDE10A activity likely phenocopies GAF-A mutations, and this is achieved through a distinct mechanism. CONCLUSIONS: Collectively, our findings demonstrate the association of recessive and dominant phenotypes of known variants, and further expands the genotype-phenotype landscape of PDE10A-associated movement disorders.

Tremor in Parkinson's Disease: From Pathophysiology to Advanced Therapies.

Background: Tremor is one of the most prevalent symptoms in Parkinson's Disease (PD). The progression and management of tremor in PD can be challenging, as response to dopaminergic agents might be relatively poor, particularly in patients with tremor-dominant PD compared to the akinetic/rigid subtype. In this review, we aim to highlight recent advances in the underlying pathogenesis and treatment modalities for tremor in PD. Methods: A structured literature search through Embase was conducted using the terms "Parkinson's Disease" AND "tremor" OR "etiology" OR "management" OR "drug resistance" OR "therapy" OR "rehabilitation" OR "surgery." After initial screening, eligible articles were selected with a focus on published literature in the last 10 years. Discussion: The underlying pathophysiology of tremor in PD remains complex and incompletely understood. Neurodegeneration of dopaminergic neurons in the retrorubral area, in addition to high-power neural oscillations in the cerebello-thalamo-cortical circuit and the basal ganglia, play a major role. Levodopa is the first-line therapeutic option for all motor symptoms, including tremor. The addition of dopamine agonists or anticholinergics can lead to further tremor reduction. Botulinum toxin injection is an effective alternative for patients with pharmacological-resistant tremor who are not seeking advanced therapies. Deep brain stimulation is the most well-established advanced therapy owing to its long-term efficacy, reversibility, and effectiveness in other motor symptoms and fluctuations. Magnetic resonance-guided focused ultrasound is a promising modality, which has the advantage of being incisionless. Cortical and peripheral electrical stimulation are non-invasive innovatory techniques that have demonstrated good efficacy in suppressing intractable tremor.

Multimodal Evoked Potential Profiles in Woodhouse-Sakati Syndrome.

PURPOSE: Woodhouse-Sakati syndrome is a rare autosomal recessive syndrome caused by homozygous mutations in the DCAF17 gene, characterized by marked neurologic and endocrine manifestations in the setting of brain iron accumulation and white matter lesions on neuroimaging. Here, we report electrophysiologic profiles in Woodhouse-Sakati syndrome and their possible value in understanding disease pathophysiology and phenotypic variability. METHODS: Thirteen genetically confirmed Woodhouse-Sakati syndrome patients were evaluated via different evoked potential (EP) modalities, including brainstem auditory EPs, pattern reversal visual EPs, and somatosensory EPs to tibial and/or median nerves. RESULTS: All EP modalities showed variable abnormalities. Pattern reversal visual EPs were recorded in all patients, with nine patients exhibiting abnormal results. From those, seven patients showed prolonged P100 latencies after stimulation of right and left eyes for each in turn. Two patients showed P100 latency abnormality after single eye stimulation recorded from midoccipital electrode. Median somatosensory EPs were recorded in 10 patients, with 6 patients having a prolonged cortical N19 response. Tibial somatosensory EP was performed for 11 patients, and 8 patients showed abnormal results where P37 cortical response was absent or prolonged, whereas peripheral potentials at the popliteal fossa were normal. Brainstem auditory EPs were abnormal only in two patients, with prolonged wave III and V latencies. Five patients with hearing impairment presented with normal brainstem auditory EP results. CONCLUSIONS: Multiple EP abnormalities are observed in Woodhouse-Sakati syndrome patients, mainly in pattern reversal visual EPs and somatosensory EPs. These findings indicate potential myelin dysfunction that has a role in the underlying pathophysiology, disease course, and phenotypic variability.

Patterns of neurological manifestations in Woodhouse-Sakati Syndrome.

BACKGROUND: Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disease with characteristic neuro-endocrine manifestations. WSS encompasses heterogeneous phenotypes and disease course. OBJECTIVE: We aimed to characterize neurological involvement of the disease through subgrouping of core neurological manifestations. METHODS: A single-institution retrospective analysis of patients with clinically and genetically confirmed diagnosis of WSS. RESULTS: A total of 38 individuals belonging to 17 families were identified to have WSS. The mean age at enrollment was 30.1 years (range 16-53 years). Neurological involvement was noted in 31 patients (81.5%). Dystonia was the most common neurological manifestation (67%), followed by intellectual disability (45%) and sensorineural hearing loss (30%). Based on the Neurological Impairment Scale (NIS), the disease was recognized to have two distinct patterns. A disabling, rapidly progressive pattern (NIS of 3-4; Type 1) was noted in eighteen patients (12 males, 6 females; 47.4%) with severe disability that occurs within a mean duration of 7.4 ±â€¯3.6 years. Type 2 WSS was identified in twenty patients (8 males, 12 females; 52.6%), and showed either absent or mild neurological involvement with preserved activities of daily living (NIS of 0-1). The mean age of onset for neurological manifestations was earlier in type 1 (12.6 ±â€¯4.5 years) compared to type 2 (18.1 ±â€¯4.3 years). Type 1 WSS has a significantly higher rate of intellectual disability (p= <0.001). CONCLUSIONS: In this pleiotropic syndrome, we identified two distinct phenotypes with variable prognosis. A high Interfamilial and intrafamilial phenotypic variability despite having a similar gene mutation suggests a possible role of genetic or environmental modifying factor.