Progressive Dysarthria Research Articles

Glial Fibrillary Acidic Protein (GFAP) Antibody-Associated Astrocytopathy in Systemic Sarcoidosis

Objective To report two cases of glial fibrillary acidic protein (GFAP) antibody-associated meningoencephalitis in patients with biopsy-proven systemic sarcoidosis. Background GFAP astrocytopathy is an autoimmune neurologic disease first defined in 2016. To our knowledge, no association with systemic sarcoidosis has been previously reported. Design/Methods Case Series Results Patient 1 is a 47-year-old woman with pre-existing pulmonary sarcoidosis treated with steroids and methotrexate with remission 6 years prior. She subsequently developed new-onset epilepsy, progressive ataxia and vertical diplopia. GFAP antibodies were positive in the cerebrospinal fluid (CSF) by cell-based assay (CBA). Body PET scan showed diffuse FDG avidity in her lungs, spleen, and lymph nodes, suggesting simultaneous reactivation of her systemic sarcoidosis. She was treated with steroids followed by infliximab with resolution of her symptoms. Patient 2 is a 58-year-old man with known pulmonary sarcoidosis, who was off immunosuppression at the time of his presentation but had received steroids 17 years prior. He presented with progressive apathy, memory disturbance, dysarthria, and gait instability. MRI revealed widespread T2 hyperintensities. GFAP antibodies were positive in CSF on CBA and confirmed by tissue-based immunofluorescence assay. He received steroids with initial response but relapsed after steroid discontinuation. He improved after restarting steroids and was subsequently transitioned to infliximab with sustained neurologic recovery. Conclusions Sarcoidosis is a poorly understood multi-system disorder that is presumably an immune-mediated response to yet unidentified antigen(s). It is known to co-exist with other autoimmune diseases, with autoimmune thyroiditis being most common. GFAP astrocytopathy is also poorly understood. GFAP is found intracellularly and similar to other antibody-mediated diseases against intracellular epitopes, the antibodies are believed to be a biomarker of underlying autoimmunity but not directly pathogenic. We report these cases to highlight a potential association between production of intrathecal GFAP antibodies and systemic sarcoidosis, which may provide insights into the pathogenesis of these two diseases.

Teaching Video NeuroImage: Delayed Radiation-Induced Unilateral Myokymia of the Tongue.

A 49-year-old man with undifferentiated nasopharyngeal carcinoma underwent 2 cycles of chemotherapy, followed by right-side head and neck radiation therapy. Thirteen years later, he developed progressive dysphagia and dysarthria. Neurologic examination showed atrophy associated with wave-like movements and prominent rippling in the right side of the tongue; needle electromyography revealed myokymic discharges in the right genioglossus muscle (Video 1). MRI of the head and neck confirmed isolated unilateral tongue atrophy (Figure) while laryngoscopy showed delayed initiation of swallowing and reduced laryngeal elevation.

Mutation analysis of the TATA box-binding protein (TBP) gene in Russian patients with spinocerebellar ataxia and Huntington disease-like phenotype

ObjectiveWe aimed to analyze the occurrence and clinical and genetic characteristics of spinocerebellar ataxia type 17 (SCA17) among Russian patients with progressive cerebellar ataxia or Huntington disease-like phenotype. MethodsGenetic analysis of CAG/CAA repeats in TBP gene was carried out in 217 patients, including 153 patients with progressive unspecified ataxia and 64 patients with Huntington disease-like phenotype. SCA types 1, 2, 3, 6 and 8, Friedreich's ataxia, CANVAS and Huntington disease were preliminarily excluded. ResultsSix unrelated patients with SCA17 (2.8 %) were identified (43–57 CAG/CAA repeats in TBP gene). Two patients had a positive family history. Age at the disease onset ranged from 15 to 47 years. The core clinical syndrome included progressive cerebellar ataxia, dysarthria, movement disorders, cognitive impairment, and psychiatric symptoms. One patient had epilepsy with rare generalized tonic-clonic seizures. Another patient with diffuse muscle atrophy and small expansion size (43 CAG/CAA repeats) had myopathic changes in skeletal muscles on EMG study. We also described a patient with a large expansion size of 57 CAA/CAG repeats with early onset and rapid disease progression. ConclusionSCA17 is a relatively rare cause of progressive disorders with ataxia and chorea, but it should be considered in the spectrum of differential diagnosis in such patients. Most of our SCA17 cases were sporadic which should be kept in mind when planning genetic testing in patients with spinocerebellar ataxia and chorea.

A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family.

Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation ERCC8:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in ERCC8 as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. ERCC8 plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of ERCC8 mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.

Loss of Flocculus Purkinje Cell Firing Precision Leads to Impaired Gaze Stabilization in a Mouse Model of Spinocerebellar Ataxia Type 6 (SCA6).

Spinocerebellar Ataxia Type 6 (SCA6) is a mid-life onset neurodegenerative disease characterized by progressive ataxia, dysarthria, and eye movement impairment. This autosomal dominant disease is caused by the expansion of a CAG repeat tract in the CACNA1A gene that encodes the α1A subunit of the P/Q type voltage-gated Ca2+ channel. Mouse models of SCA6 demonstrate impaired locomotive function and reduced firing precision of cerebellar Purkinje in the anterior vermis. Here, to further assess deficits in other cerebellar-dependent behaviors, we characterized the oculomotor phenotype of a knock-in mouse model with hyper-expanded polyQ repeats (SCA684Q). We found a reduction in the efficacy of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) in SCA6 mutant mice, without a change in phase, compared to their litter-matched controls. Additionally, VOR motor learning was significantly impaired in SCA684Q mice. Given that the floccular lobe of the cerebellum plays a vital role in the generation of OKR and VOR calibration and motor learning, we investigated the firing behavior and morphology of floccular cerebellar Purkinje cells. Overall, we found a reduction in the firing precision of floccular lobe Purkinje cells but no morphological difference between SCA684Q and wild-type mice. Taken together, our findings establish that gaze stabilization and motor learning are impaired in SCA684Q mice and suggest that altered cerebellar output contributes to these deficits.

GGC Repeat Expansion of RILPL1 is Associated with Oculopharyngodistal Myopathy.

Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ptosis, dysarthria, ophthalmoplegia, and distal muscle weakness. Recent studies revealed that GGC repeat expansions in 5'-UTR of LRP12, GIPC1, and NOTCH2NLC are associated with OPDM. Despite these advances, approximately 30% of OPDM patients remain genetically undiagnosed. Herein, we aim to investigate the genetic basis for undiagnosed OPDM patients in two unrelated Chinese Han families. Parametric linkage analysis was performed. Long-read sequencing followed by repeat-primed polymerase chain reaction and amplicon length polymerase chain reaction were used to determine the genetic cause. Targeted methylation sequencing was implemented to detect epigenetic changes. The possible pathogenesis mechanism was investigated by quantitative polymerase chain reaction, immunoblotting, RNA fluorescence in situ hybridization, and immunofluorescence staining of muscle biopsy samples. The disease locus was mapped to 12q24.3. Subsequently, GGC repeat expansion in the promoter region of RILPL1 was identified in six OPDM patients from two families, findings consistent with a founder effect, designated as OPDM type4. Targeted methylation sequencing revealed hypermethylation at the RILPL1 locus in unaffected individuals with ultralong expansion. Analysis of muscle samples showed no significant differences in RILPL1 mRNA or RILPL1 protein levels between patients and controls. Public CAGE-seq data indicated that alternative transcription start sites exist upstream of the RefSeq-annotated RILPL1 transcription start site. Strand-specific RNA-seq data revealed bidirectional transcription from the RILPL1 locus. Finally, fluorescence in situ hybridization/immunofluorescence staining showed that both sense and antisense transcripts formed RNA foci, and were co-localized with hnRNPA2B1 and p62 in the intranuclear inclusions of OPDM type4 patients. Our findings implicate abnormal GGC repeat expansions in the promoter region of RILPL1 as a novel genetic cause for OPDM, and suggest a methylation mechanism and a potential RNA toxicity mechanism are involved in OPDM type4 pathogenesis. ANN NEUROL 2022;92:512-526.

Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia.

Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683). Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed. A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022;92:304-321.

Progressive cognitive impairment and familial spastic paraparesis due to PRESENILIN 1 mutation: anatomoclinical characterization.

Autosomal dominant Alzheimer's disease (ADAD) due to presenilin 1 (PSEN1) mutation can induce atypical neurological symptoms such as movement disorders and epileptic seizures in the context of early-onset progressive cognitive impairment. This study includes the anatomoclinical description of three patients of two generations of the same family with movement disorders and progressive cognitive impairment. All were evaluated by trained neurologists, underwent protocolized neuropsychological evaluation, and were assessed by structural (magnetic resonance) and functional (SPECT, PET-18FDG, or PET-18F-Florbetapir) brain imaging tests. A molecular genetic study was performed for all patients, and post-mortem confirmatory anatomopathological evaluation for one of them. The three female patients had an age of onset of symptoms of 38-51years. All developed progressive multidomain cognitive impairment, paraparesis, and dysarthria, two with ophthalmoparesis and one with untriggered epileptic seizures since early stages. Bilateral cortical fronto-parietal atrophy and global cortical hypoperfusion or posterior bilateral hypometabolism were detected. PET-18F-Florbetapir, when performed, was positive for amyloid cortical deposit. The molecular genetic study confirmed the PSEN1 mutationc.869-2 A>G. Postmortem study of one of them confirmed Alzheimer's disease anatomopathological features with classic cotton wool plaques (CWP), including coexistence of amyloid angiopathy and Lewy body co-pathology. The phenotype of ADAD due to PSEN1 mutations is very heterogeneous between and across the same family. Family history assessment should include information not only about cognitive decline, but also about movement disorders and untriggered epileptic seizures. Further studies are needed to identify genetic or epigenetic factors that determine phenotypic diversity in this disease.

789 Role of Speech Therapy (SLP) in the rehabilitation of a complicated case of glossoparesis (GP)

IntroductionGlossoparesis is defined as a neurodegenerative process resulting in progressive dysphagia and dysarthria. The deinervation of the tongue and related structures results in flaccid muscle function unilaterally and bilaterally, this process is difficult to treat and rehabilitate and prognosis is considered poor. We encountered this in a patient that had a complicated case of necrotizing fasciitis (NF) that arose from an abscessed tooth.The purpose of this case report is to summarize the overall approach to a rehabilitation plan which resulted in successful return to speech and partial swallow.MethodsThe patient was diagnosed with an abscessed tooth which resulted in Necrotizing fasciitis of the face, neck and chest. Multiple surgical interventions resulted in removal of necrotic tissue and reconstructive interventions were implemented. Initial prognosis of return of function was noted as “poor” per ENT services. Ear, Nose and Throat (ENT) specialist noted that prognosis for recovery of function is unknown but was low.Speech Therapy was also consulted and an individualized plan of care to address the deficits assessed was developed. Initial prognosis of return of functional speech / swallow was guarded. It was felt to be highly appropriate to provide the patient with therapeutic options.Speech Therapy sessions included use of Neuromuscular Electrical Stimulation, Thermal Stimulation, Tactile Stimulation, Therapeutic Massage to affected regions, Deep Pharyngeal Neuromuscular Stimulation, finger occlusion trials for speech production attempts to ready patient for use of Passy Muir Valve, Oral Motor Exercises, Laryngeal Elevation Tasks, Vocal Stretching / Relaxation tasks and oral trials of ice chips as musculature function improved.ResultsThrough the use of these multiple modalities of skilled speech therapy intervention, the patient had return of functional verbal communication prior to discharge to a skilled rehabilitation program.ConclusionsUpon initial evaluation, the true potential for return of function was questioned. It is paramount that patient be given an opportunity to succeed - to be included in the plan of care - to be provided with opportunities to return to their prior level of function or as close as possible. There is little to no research regarding return of function for patients affected by glossoparesis.

Primary Central Nervous System Lymphoma with Bone and Subcutaneous Tissue Invasion

Primary central nervous system lymphoma is a rare form of extranodal non-Hodgkin lymphoma. Few cases of primary central nervous system lymphoma involving bone and subcutaneous tissue invasion have been reported. Herein, we present the case of a 45-year-old man who experienced paroxysmal throbbing pain in the occipital area for more than 1 year, followed by progressive dysarthria and dyspnea for more than 4 days. Craniotomy and tumor removal were performed. Operative findings showed a posterior occipital soft tumor whose cells had invaded the skull and subcutaneous tissue.

Respiratory dysfunction in a mouse model of spinocerebellar ataxia type 7.

ABSTRACTSpinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the ataxin-7 gene. Infantile-onset SCA7 patients display extremely large repeat expansions (>200 CAGs) and exhibit progressive ataxia, dysarthria, dysphagia and retinal degeneration. Severe hypotonia, aspiration pneumonia and respiratory failure often contribute to death in affected infants. To better understand the features of respiratory and upper airway dysfunction in SCA7, we examined breathing and putative phrenic and hypoglossal neuropathology in a knock-in mouse model of early-onset SCA7 carrying an expanded allele with 266 CAG repeats. Whole-body plethysmography was used to measure awake spontaneously breathing SCA7-266Q knock-in mice at baseline in normoxia and during a hypercapnic/hypoxic respiratory challenge at 4 and 8 weeks, before and after the onset of disease. Postmortem studies included quantification of putative phrenic and hypoglossal motor neurons and microglia, and analysis of ataxin-7 aggregation at end stage. SCA7-266Q mice had profound breathing deficits during a respiratory challenge, exhibiting reduced respiratory output and a greater percentage of time in apnea. Histologically, putative phrenic and hypoglossal motor neurons of SCA7 mice exhibited a reduction in number accompanied by increased microglial activation, indicating neurodegeneration and neuroinflammation. Furthermore, intranuclear ataxin-7 accumulation was observed in cells neighboring putative phrenic and hypoglossal motor neurons in SCA7 mice. These findings reveal the importance of phrenic and hypoglossal motor neuron pathology associated with respiratory failure and upper airway dysfunction, which are observed in infantile-onset SCA7 patients and likely contribute to their early death.

Anaplastic pilocytic astrocytoma of the cerebellum presenting with conus medullaris drop metastasis

Due to its rarity, a complete understanding of the clinical behavior, pathogenesis, and diagnostic definition of anaplastic pilocytic astrocytoma (APA) is currently lacking. The optimal clinical management and use of adjuvant therapies has yet to be defined. We present a 64 year-old-female with progressive headaches, dysarthria, and ataxia, who was found to have right cerebellar mass. A gross total resection was achieved through two staged operations. Pathology demonstrated focal areas of necrosis, tumor infiltration, and increased mitotic activity most consistent with APA. Adjuvant chemotherapy and stereotactic radiosurgery were administered. Approximately two years later, the patient presented with symptoms of cauda equina syndrome, and lumbar spine imaging demonstrated a large intradural mass at the conus medullaris with diffuse leptomeningeal enhancement. A biopsy was performed and was consistent with metastatic APA. APA may rarely progress to metastatic disease, most frequently involving the leptomeninges of the posterior fossa and cervical spine. This report represents the first case of metastases distal to the cervicomedullary junction.

A novel SACS p.Pro4154GlnfsTer20 mutation in a family with autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Loss-of-function mutations in the sacsin (SACS) gene lead to autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), impairing the function of sacsin. Genotype-phenotype correlations are still unclear for the different mutations reported in ARSACS. Here, we present a Turkish ARSACS family in whom the novel homozygous frameshift mutation in SACS c.12461delC (p.Pro4154GlnfsTer20) was detected by next-generation sequencing (NGS). The index patient was admitted with progressive spastic ataxia and dysarthria. Since no common mutation in autosomal recessive (AR) cerebellar ataxias, whole gene sequencing provide an advantage to detect novel mutations and may be more effective for clinical diagnosis.

Effect of boost articulation therapy (BArT) on intelligibility in adults with dysarthria.

BackgroundThe articulatory accuracy of patients with dysarthria is one of the most affected speech dimensions with a high impact on speech intelligibility. Behavioural treatments of articulation can either involve direct or indirect approaches. The latter have been thoroughly investigated and are generally appreciated for their almost immediate effects on articulation and intelligibility. The number of studies on (short‐term) direct articulation therapy is limited.AimsTo investigate the effects of short‐term, boost articulation therapy (BArT) on speech intelligibility in patients with chronic or progressive dysarthria and the effect of severity of dysarthria on the outcome.Methods & ProceduresThe study consists of a two‐group pre‐/post‐test design to assess speech intelligibility at phoneme and sentence level and during spontaneous speech, automatic speech and reading a phonetically balanced text. A total of 17 subjects with mild to severe dysarthria participated in the study and were randomly assigned to either a patient‐tailored, intensive articulatory drill programme or an intensive minimal pair training. Both training programmes were based on the principles of motor learning. Each training programme consisted of five sessions of 45 min completed within one week.Outcomes & ResultsFollowing treatment, a statistically significant increase of mean group intelligibility was shown at phoneme and sentence level, and in automatic sequences. This was supported by an acoustic analysis that revealed a reduction in formant centralization ratio. Within specific groups of severity, large and moderate positive effect sizes with Cohen's d were demonstrated.Conclusions & ImplicationsBArT successfully improves speech intelligibility in patients with chronic or progressive dysarthria at different levels of the impairment. What this paper addsWhat is already known on the subject Behavioural treatment of articulation in patients with dysarthria mainly involves indirect strategies, which have shown positive effects on speech intelligibility. However, there is limited evidence on the short‐term effects of direct articulation therapy at the segmental level of speech. This study investigates the effectiveness of BArT on speech intelligibility in patients with chronic or progressive dysarthria at all severity levels. What this paper adds to existing knowledge The intensive and direct articulatory therapy programmes developed and applied in this study intend to reduce the impairment instead of compensating it. This approach results in a significant improvement of speech intelligibility at different dysarthria severity levels in a short period of time while contributing to exploit and develop all available residual motor skills in persons with dysarthria. What are the potential or actual clinical implications of this work? The improvements in intelligibility demonstrate the effectiveness of a BArT at the segmental level of speech. This makes it to be considered a suitable approach in the treatment of patients with chronic or progressive dysarthria.

CADASIL in a patient with bilateral internal carotid artery agenesis

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a well-recognised cause of stroke in the young. Bilateral internal carotid artery (ICA) agenesis is a rare congenital malformation, with few previous reported cases in the literature. CADASIL is not reported to be associated with ICA agenesis. We report the case of a 41 year old man who presented with recurrent orthostatic symptoms associated with increasingly frequent falls. Initial investigation with CT angiography revealed absent bilateral ICAs with an ectatic vertebrobasilar arterial tree supplying the intracranial circulation. Skull base CT revealed simultaneous absence of ICAs and bilateral carotid canals, confirming agenesis of bilateral ICAs. MRI of the brain revealed extensive areas of confluent high T2 signal intensity in the subcortical and periventricular zones of both hemispheres. The patient subsequently developed episodic and progressive headache, dysarthria, ataxia, cognitive impairment and personality changes. Radiological progression of cerebral subcortical and periventricular abnormalities was demonstrated with established lacunar infarcts and generalised atrophic changes. Genetic testing confirmed the diagnosis of CADASIL with the presence of a heterozygous c.994C > T (p.Arg332Cys) mutation in exon 6 of the NOTCH 3 gene.We report the first case of coexistent bilateral ICA agenesis and CADASIL. This case highlights the need to consider CADASIL in patients with cerebral subcortical and periventricular imaging abnormalities, even with coexistent large vessel pathology.

A case of unusual cerebellar ataxia

Case: Pt is a 76 year old male with a four year history of progressive gait imbalance and dysarthria. Symptoms started at age 72. He had fallen multiple times since onset of symptoms with one of his falls resulting in radial fracture. He also endorsed incoordination of upper extremities, frequently dropping objects, difficulty picking up small objects, and frequent spilling when eating and drinking. At initial presentation he was wheelchair bound due to balance difficulties.

Detection of Articulatory Deficits in Parkinson's Disease: Can Systematic Manipulations of Phonetic Complexity Help?

Purpose This study sought to determine the feasibility of using phonetic complexity manipulations as a way to systematically assess articulatory deficits in talkers with progressive dysarthria due to Parkinson's disease (PD). Method Articulatory kinematics were recorded using three-dimensional electromagnetic articulography from 15 talkers with PD (58-84 years old) and 15 healthy controls (55-80 years old) while they produced target words embedded in a carrier phrase. Majority of the talkers with PD exhibited a relatively mild dysarthria. For stimuli selection, phonetic complexity was calculated for a variety of words using the framework proposed by Kent (1992), and six words representative of low, medium, and high phonetic complexity were selected as targets. Jaw, posterior tongue, and anterior tongue kinematic measures that were used to test for phonetic complexity effects included movement speed, cumulative path distance, movement range, movement duration, and spatiotemporal variability. Results Significantly smaller movements and slower movement speeds were evident in talkers with PD, predominantly for words with high phonetic complexity. The effect sizes of between-groups differences were larger for several jaw kinematic measures than those of the tongue. Discussion and Conclusion Findings suggest that systematic manipulations of phonetic complexity can support the detection of articulatory deficits in talkers with PD. Phonetic complexity should therefore be leveraged for the assessment of articulatory performance in talkers with progressive dysarthria. Future work will be directed toward linking speech kinematic and auditory-perceptual measures to determine the clinical significance of the current findings.

Editors' note: Pearls & Oy-sters: Challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: Clinical and imaging findings.

In the article “Pearls & Oy-sters: Challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: Clinical and imaging findings,” Kang et al. presented the case of a 49-year-old man with progressive ataxia, dysarthria, and cognitive impairment who was found to have a heterozygous mutation in the prion protein (PRNP) gene, suspected to be de novo, resulting in a diagnosis of Gerstmann-Sträussler-Scheinker disease (GSS). In the accompanying discussion, they also presented a review of the clinical manifestations, diagnostic test results, and presence of family history of GSS in 86 patients (including theirs). In response, Dr. Paucar notes that the polymorphic PRNP codon 129M has disease-modifying effect on GSS and that real-time quaking-induced conversion (RT-QuIC) can be helpful in patients with suspected prion disease, especially with ambiguous family history, and that a discussion of transmissibility of GSS-associated PRNP mutations would have been helpful. Responding to these comments, Park et al. report the results of PRNP codon 129M polymorphisms in their review and that they found the methionine/valine heterozygote to have slightly earlier disease onset. They note that they could not evaluate the role of RT-QuIC but report that 87.7% of the patients with the P102L mutation (found in their patient) had a positive family history, whereas 8 other single-case mutations had a negative family history. In the article “Pearls & Oy-sters: Challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: Clinical and imaging findings,” Kang et al. presented the case of a 49-year-old man with progressive ataxia, dysarthria, and cognitive impairment who was found to have a heterozygous mutation in the prion protein (PRNP) gene, suspected to be de novo, resulting in a diagnosis of Gerstmann-Sträussler-Scheinker disease (GSS). In the accompanying discussion, they also presented a review of the clinical manifestations, diagnostic test results, and presence of family history of GSS in 86 patients (including theirs). In response, Dr. Paucar notes that the polymorphic PRNP codon 129M has disease-modifying effect on GSS and that real-time quaking-induced conversion (RT-QuIC) can be helpful in patients with suspected prion disease, especially with ambiguous family history, and that a discussion of transmissibility of GSS-associated PRNP mutations would have been helpful. Responding to these comments, Park et al. report the results of PRNP codon 129M polymorphisms in their review and that they found the methionine/valine heterozygote to have slightly earlier disease onset. They note that they could not evaluate the role of RT-QuIC but report that 87.7% of the patients with the P102L mutation (found in their patient) had a positive family history, whereas 8 other single-case mutations had a negative family history.

A clinical report of the massive CAG repeat expansion in spinocerebellar ataxia type 2: Severe onset in a Mexican child and review previous cases.

The spinocerebellar ataxia type 2 is a neurodegenerative disease with autosomal dominant inheritance; clinically characterized by progressive cerebellar ataxia, slow ocular saccades, nystagmus, ophthalmoplegia, dysarthria, dysphagia, cognitive deterioration, mild dementia, peripheral neuropathy. Infantile onset is a rare presentation that only has been reported in four instances in the literature. In the present work a boy aged 5 years 7 months was studied due to horizontal gaze-evoked nystagmus, without saccades, ataxic gait, dysarthria, dysphagia, dysmetria, generalized spasticity mainly pelvic, bilateral Babinsky. The mother aged 27 years-old presented progressive cerebellar ataxia, dysarthria, dysmetria, dysdiadochokinesis, limb ataxia and olivopontocerebellar atrophy. The molecular analysis was made by identifying the expansion repeats in tandem by long PCR to analyze the repeats in the ATXN2 gene. We found an extreme CAG expansion repeats of ~884 repeats in the child. We describe a Mexican child affected by SCA2 with an infantile onset, associated with a high number of CAG repeats previously no reported and anticipation phenomenon.

Yolŋu with Machado–Joseph disease: Exploring communication strengths and needs

Purpose: Yolŋu are Aboriginal Australians from northeast Arnhem Land in the Northern Territory (NT). Machado–Joseph disease (MJD) prevalence in the NT Aboriginal population is the highest in the world. Yolŋu living with progressive dysarthria associated with MJD could benefit from augmentative and alternative communication (AAC). However, there are no aided AAC systems in Yolŋu languages. This research aimed to explore the views of Yolŋu with MJD about communication, speech-language pathology (SLP) services and AAC.Method: A collaborative, culturally responsive research design was informed by Indigenist Research methodology and Constructivist Grounded Theory. Yolŋu with MJD (n = 10) and their interested family members (n = 4) participated in interviews and created visual representations of their social networks. Data were analysed through an oral interpretive process with Yolŋu researchers.Result: A Yolŋu metaphor, Goŋdhu “Building understanding by hand”, emerged as a culturally meaningful way to represent the core understandings required for speech-language pathologists (SLPs) to work effectively with Yolŋu with MJD. Elements of this metaphor include seeking to understand the complex lived experiences of Yolŋu with MJD, and working with families to explore the potential benefits of SLP services and AAC.Conclusion: Yolŋu with MJD and their families want to work collaboratively with SLPs to develop bilingual AAC systems and culturally responsive SLP services that build on strengths of Yolŋu culture and kinship to improve communication opportunities and participation.