Catching the Culprit: How Chorea May Signal an Inborn Error of Metabolism.

Background: Movement disorders, particularly chorea, are uncommon in inborn errors of metabolism, but their identification is essential for improved clinical outcomes. In this context, comprehensive descriptions of movement disorders are limited and primarily derived from single cases or small patient series, highlighting the need for increased awareness and additional research in this field. Methods: A systematic review was conducted using the MEDLINE database and GeneReviews. The search included studies on inborn errors of metabolism associated with chorea, athetosis, or ballismus. The review adhered to PRISMA guidelines. Results: The systematic review analyzed 76 studies out of 2350 records, encompassing the period from 1964 to 2022. Chorea was observed in 90.1% of the 173 patients, followed by athetosis in 5.7%. Various inborn errors of metabolism showed an association with chorea, with trace elements and metals being the most frequent. Cognitive and developmental abnormalities were common in the cohort. Frequent neurological features included seizures, dysarthria, and optic atrophy, whereas non-neurological features included, among others, facial dysmorphia and failure to thrive. Neuroimaging and biochemical testing played crucial roles in aiding diagnosis, revealing abnormal findings in 34.1% and 47.9% of patients, respectively. However, symptomatic treatment efficacy for movement disorders was limited. Discussion: This study emphasizes the complexities of chorea in inborn errors of metabolism. A systematic approach with red flags, biochemical testing, and neuroimaging is required for diagnosis. Collaboration between neurologists, geneticists, and metabolic specialists is crucial for improving early detection and individualized treatment. Utilizing genetic testing technologies and potential therapeutic avenues can aid in the improvement of patient outcomes.

Hypoxaemia and interstitial lung disease in an infant with hypothyroidism and hypotonia.

A 7-month-old-term male infant presented with cough, tachypnoea, hypoxaemia and post-tussive emesis. Clinical history was significant for respiratory failure and pulmonary hypertension in the neonatal period requiring assisted ventilation, congenital hypothyroidism, mild hypotonia, recurrent respiratory infections, hypoxaemia requiring supplemental oxygen and nasogastric tube feeds. Physical examination showed tachypnoea, coarse bilateral breath sounds and mild hypotonia. Chest radiograph revealed multifocal pulmonary opacities with coarse interstitial markings and right upper lobe atelectasis. Following antibiotic therapy for suspected aspiration pneumonia, chest CT scan was performed and showed multiple areas of pulmonary consolidation and scattered areas of bilateral ground-glass opacities. Genetic studies showed a large deletion of chromosome 14q13.1-14q21.1, encompassing the NK2 homeobox 1 (NKX2-1) gene consistent with a diagnosis of brain-thyroid-lung (BTL) syndrome. Our case highlights the importance of genetic studies to diagnose BTL syndrome in infants with hypothyroidism, hypotonia and lung disease.

Athetoid Movements as Initial Manifestation of Primary Sjögren Syndrome.

Background: Primary Sjögren syndrome (pSS) is an autoimmune disorder characterized by exocrine gland and extraglandular symptoms. We present a case report of pSS with an initial presentation of athetoid movements. Case Report: A 74-year-old female presented with a 2-month history of slow undulating movements in her trunk and thighs that eventually spread to her neck and lower extremities. She also reported dry eyes, dry mouth, as well as pain in her shoulders and thighs. Her proinflammatory markers and rheumatologic profile were positive. Her salivary gland biopsy revealed a Focus score > 2. Brain magnetic resonance imaging was normal. A diagnosis of pSS was made. The patient's symptoms improved with hydroxychloroquine, pilocarpine, gabapentin, and clonazepam. Discussion: Clinicians should consider and screen for primary autoimmune disorders as a cause of subacute athetoid movements in elderly patients. Although aggressive treatment has been recommended, treatment should be tailored to each patient's specific needs.

Heterogeneity of lung disease associated with NK2 homeobox 1 mutations.

We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.

The relationship of dystonia and choreoathetosis with activity, participation and quality of life in children and youth with dyskinetic cerebral palsy.

AIM: To relate dystonia and choreoathetosis with activity, participation and quality of life (QOL) in children and youth with dyskinetic Cerebral Palsy (CP). METHODS: Fifty-four participants with dyskinetic CP (mean age 14y6m, SD 4y2m, range 6-22y) were included. The Dyskinesia Impairment Scale (DIS) was used to evaluate dystonia and choreoathetosis. Activity, participation and quality of life (QOL) were assessed with the Gross Motor Function Measure (GMFM), the Functional Mobility Scale (FMS), the Jebsen-Taylor Hand Function Test (JTT), the ABILHAND-Kids Questionnaire (ABIL-K), the Life Habits Kids (LIFE-H) and the Quality of Life Questionnaire for children with CP (CP-QOL). Spearman's rank correlation coefficient (rs) was used to assess the relationship between the movement disorders and activity, participation and QOL measures. RESULTS: Significant negative correlations were found between dystonia and the activity scales with Spearman's rank correlation coefficient (rs) varying between -0.65 (95% CI = -0.78 to -0.46) and -0.71 (95% CI = -0,82 to -0.55). Correlations were also found with the LIFE-H (rs = -0.43; 95%CI = -0.64 to -0.17) and the CP-QOL (rs = -0.32; 95%CI = -0.56 to -0.03). As far as choreoathetosis is concerned, no or only weak relationships were found with the activity, participation and quality of life scales. INTERPRETATION: This cross-sectional study is the first to examine the relationship of dystonia and choreoathetosis in dyskinetic CP with the level of activity, participation and QOL. The results revealed dystonia has a higher impact on activity, participation and quality of life than choreoathetosis. These findings seem to suggest it is necessary to first focus on dystonia reducing intervention strategies and secondly on choreoathetosis.

De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis.

BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder that manifests recurrent attacks of hemiplegia, oculogyric, and choreoathetotic involuntary movements. De novo mutations in ATP1A3 cause three types of neurological diseases: AHC; rapid-onset dystonia-Parkinsonism (RDP); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndromes. It remains to be determined whether or not a rare mutation in ATP1A3 may cause atypical phenotypes. CASE PRESENTATION: A 7-year-old boy presented with recurrent symptoms of generalized paralysis since 1 year and 5 months of age. Hypotonia, dystonia, and choreoathetosis persisted with exacerbation under febrile conditions, but no cerebellar ataxia had ever evolved in 6 years. Whole-exome sequencing (WES) was performed to determine his genetic background, and mutations were validated by the Sanger method. Crude protein extracts were prepared from the cultured cells, and expression of the wild-type or mutant ATP1A3 proteins were analyzed by Western blotting. WES identified a de novo pathogenic mutation in ATP1A3 (c.2266C > T:p.R756C) for this patient. A literature overview of two reported cases with p.R756C and p.R756H mutations showed both overlapping and distinct phenotypes when compared with those of the present case. The expression of the mutant form (R756C) of ATP1A3 did not differ markedly from that of the wild-type and D801N proteins. CONCLUSIONS: This study confirmed that p.R756C mutation of ATP1A3 cause atypical forms of AHC-associated disorders. The wide spectra of neurological phenotypes in AHC are linked to as-yet-unknown deficits in the functions of mutant ATP1A3.

Hyperglycemia induced hemichoreoathetosis, an uncommon presenting symptom of diabetes mellitus.

Chorea is brief, quasi-purposeful, irregular muscle contractions, not repetitive or rhythmic, but flows from one muscle to the next and athetosis is slow, writhing, continuous, worm-like movements of distal extremities (chiefly the fingers) which show bizarre positioning without posturing. Metabolic causes have been documented earlier, note worthy of that being Diabetes. Choreoathetosis has been reported earlier in diabetes mostly in an elderly female, diagnosed most often by Brain MRI. We report a case of hemichoreoathetosis in a male diabetic, whose involuntary movement completely resolved with glycemic control and diagnosis was easily confirmed with just a Brain CT.

The Dyskinesia Impairment Scale: a new instrument to measure dystonia and choreoathetosis in dyskinetic cerebral palsy.

AIM: The aim of this study was to examine the reliability and validity of the Dyskinesia Impairment Scale (DIS). The DIS consists of two subscales: dystonia and choreoathetosis. It measures both phenomena in dyskinetic cerebral palsy (CP). METHOD: Twenty-five participants with dyskinetic CP (17 males; eight females; age range 5­22y; mean age 13y 6mo; SD 5y 4mo), recruited from special schools for children with motor disorders, were included. Exclusion criteria were changes in muscle relaxant medication within the previous 3 months, orthopaedic or neurosurgical interventions within the previous year, and spinal fusion. Interrater reliability was verified by two independent raters. For interrater reliability, intraclass correlation coefficients were assessed. Standard error of measurement, the minimal detectable difference, and Cronbach's alpha for internal consistency were determined. For concurrent validity of the DIS dystonia subscale, the Barry­Albright Dystonia Scale was administered. RESULTS: The intraclass correlation coefficient for the total DIS score and the two subscales ranged between 0.91 and 0.98 for interrater reliability. The reliability of the choreoathetosis subscale was found to be higher than that of the dystonia subscale. The standard error of the measurement and minimal detectable difference values were adequate. Cronbach's alpha values ranged from 0.89 to 0.93. Pearson's correlation between the dystonia subscale and Barry­Albright Dystonia Scale was 0.84 (p<0.001). INTERPRETATION: Good to excellent reliability and validity were found for the DIS. The DIS may be promising for increasing insights into the natural history of dyskinetic CP and evaluating interventions. Future research on the responsiveness of the DIS is warranted.

A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability.

Hydroxysteroid (17beta) dehydrogenase 10 (HSD10) is a mitochondrial multifunctional enzyme encoded by the HSD17B10 gene. Missense mutations in this gene result in HSD10 deficiency, whereas a silent mutation results in mental retardation, X-linked, syndromic 10 (MRXS10). Here we report a novel missense mutation found in the HSD17B10 gene, namely c.194T>C transition (rs104886492), brought about by the loss of two forked methyl groups of valine 65 in the HSD10 active site. The affected boy, who possesses mutant HSD10 (p.V65A), has a neurological syndrome with metabolic derangements, choreoathetosis, refractory epilepsy and learning disability. He has no history of acute decompensation or metabolic acidosis whereas his urine organic acid profile, showing elevated levels of 2-methyl-3-hydroxybutyrate and tiglylglycine, is characteristic of HSD10 deficiency. His HSD10 activity was much lower than the normal control level, with normal ß-ketothiolase activity. The c.194T>C mutation in HSD17B10 can be identified by the restriction fragment polymorphism analysis, thereby facilitating the screening of this novel mutation in individuals with intellectual disability of unknown etiology and their family members much easier. The patient's mother is an asymptomatic carrier, and has a mixed ancestry (Hawaiian, Japanese and Chinese). This demonstrates that HSD10 deficiency patients are not confined to a particular ethnicity although previously reported cases were either Spanish or German descendants.

Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study.

BACKGROUND: Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. METHODS: We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke-Fahn-Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. FINDINGS: The mean Burke-Fahn-Marsden dystonia rating scale movement score improved from 44.2 (SD 21.1) before surgery to 34.7 (21.9) at 1 year post-operatively (p=0.009; mean improvement 24.4 [21.1]%, 95% CI 11.6-37.1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus [GPe]). INTERPRETATION: Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. FUNDING: National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.

Severe long-standing dysimmune sensory neuronopathy responsive to etanercept.

Sensory neuronopathy in association with connective tissue disease is a disabling disorder for which there is no well-established therapy. Various immunosuppressive agents, plasmapheresis, and intravenous immunoglobulin have shown only anecdotal or modest beneficial effects. Tumor necrosis factor alpha is a proinflammatory cytokine that mediates TH1-cell inflammatory responses and is a plausible contributor to dorsal root ganglion injury in sensory neuronopathy. We describe a patient with severe painful and ataxic sensory neuronopathy in association with systemic lupus erythematosus, who showed marked and sustained improvement on etanercept, a tumor necrosis factor alpha inhibitor, despite a chronic and progressive course that was refractory to several immunomodulatory interventions. We review the therapeutic potential of tumor necrosis factor alpha blockade in immune-mediated neuropathies and the reported neurologic complications from its use, most notably central and peripheral demyelination.

Occlusal characteristics in cerebral palsy patients.

PURPOSE: The purpose of this study was to evaluate the occlusal characteristics of 104 randomly selected, noninstitutionalized patients with a medical diagnosis of cerebral palsy (CP). METHODS: Patients were grouped according to the CP motor disorder and clinical patterns. Occlusal characteristics were collected by one examiner. Nonparametric statistical tests, including Fisher's exact test (P) and chi-square test were used. RESULTS: The results showed that Class II molars were statistically higher (P<.05) for spastic patients. Anterior open bite and an increased overjet were significant (P<.01) in spastic patients with clinical patterns of quadriplegia, double-hemiplegia, and diplegia. Double hemiplegia patients presented a higher incidence of open bite (64%) with an edge-to-edge overjet (45%). A deep overbite was presented in athetoid (50%) and ataxic (67%) patients. A high incidence of tooth wear was observed in the athetoid group (54%). CONCLUSION: Spastic patients presented a high incidence of open bite and Class II malocclusion. A low level of malocclusion was observed in the ataxic group compared to the other groups studied. Further studies would be useful to determine if neurological injuries can be the cause of changes of the craniofacial growth and development patterns resulting in malocclusion in cerebral palsy patients.

Bilateral stimulation of the globus pallidus internus to treat choreathetosis in Huntington's disease: technical case report.

OBJECTIVE AND IMPORTANCE: Huntington's disease (HD) produces debilitating motor abnormalities that are poorly responsive to medical therapy. Deep brain stimulation (DBS) may offer a treatment option for afflicted patients, but its role in the management of HD remains unclear. In the present case, DBS leads were implanted bilaterally into the posteroventral globus pallidus internus (GPi) to control disabling and medically intractable choreathetosis in a severely affected HD patient. The surgical procedure, intraoperative electrophysiological findings, and 12-month postoperative course, with patient video, are presented. CLINICAL PRESENTATION: This 41-year-old man with genetically confirmed HD developed motor symptoms at age 28. He had completed multiple medical trials without alleviation of his progressive and debilitating choreathetosis. Extensive clinical assessment, including neuropsychological testing, was performed to determine surgical candidacy. INTERVENTION: DBS leads were bilaterally implanted, under stereotactic guidance, into the posteroventral GPi. Disease progression and symptom control were assessed at regular postoperative intervals. Bilateral pallidal stimulation produced a dramatic reduction in choreathetoid movements and improvement in overall motor functioning. The patient also exhibited normalization of body weight, mood, and energy level, as well as improved performance of activities of daily living. These effects were sustained at 1 year after surgery. CONCLUSION: The clinical benefits of DBS observed in this HD patient were comparable to those reported in other hyperkinetic disorders and demonstrate that pallidal stimulation can provide long-term alleviation of HD-associated choreathetosis.