Oral diadochokinetic markers of X-linked dystonia-parkinsonism.

INTRODUCTION: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disorder that may result in severe speech impairment. The literature suggests that there are differences in the speech of individuals with XDP and healthy controls. This study aims to examine the motor speech characteristics of the mixed dystonia-parkinsonism phase of XDP. METHOD: We extracted acoustic features representing coordination, consistency, speed, precision, and rate from 26 individuals with XDP and 26 controls using Praat, MATLAB, and R software. Group demographics were compared using descriptive statistics. A one-way analysis of variance (ANOVA) with Tukey's post hoc test was used to test for acoustic differences between the two groups. RESULTS: The XDP group had significantly lower consistency, speed, precision, and rate than controls (p < 0.05). For coordination, the XDP group had a smaller ratio of pause duration during transitions when compared to controls. DISCUSSION: To our knowledge, this study is the first to describe the motor speech characteristics of the mixed dystonia-parkinsonism phase of XDP. The motor speech of mixed dystonia-parkinsonism XDP is similar to prior characterizations of mixed hyperkinetic-hypokinetic dysarthria with noted differences in articulatory coordination, consistency, speed, precision, and rate from healthy controls. Identifying the motor speech components of all three phenotypes of XDP (i.e., dystonia-dominant phase, parkinsonism-dominant phase, and mixed dystonia-parkinsonism phase) is needed to establish markers of speech impairment to track disease progression.

Combined Treatment of Progressive Encephalitis in an X-linked Agammaglobulinemia Patient.

Most patients with X-linked agammaglobulinemia are susceptible to infections, while some cases also suffer from inflammatory or autoimmune complications. We describe a patient with progressive encephalitis who improved after the use of immunomodulatory treatment with corticosteroids, fluoxetine, and nitazoxanide. In most of the cases the evolution of the progressive encephalitis is complicated and catastrophic. Based on our experience and the review of the literature, we propose the use of this combined treatment to control this devastating complication.

Oculomotor abnormalities indicate early executive dysfunction in prodromal X-linked dystonia-parkinsonism (XDP).

BACKGROUND: X-Linked dystonia-parkinsonism (XDP) is a movement disorder characterized by the presence of both dystonia and parkinsonism with one or the other more prominent in the initial stages and later on manifesting with more parkinsonian features towards the latter part of the disease. XDP patients show oculomotor abnormalities indicating prefrontal and striatal impairment. This study investigated oculomotor behavior in non-manifesting mutation carriers (NMC). We hypothesized that oculomotor disorders occur before the appearance of dystonic or parkinsonian signs. This could help to functionally identify brain regions already affected in the prodromal stage of the disease. METHODS: Twenty XDP patients, 13 NMC, and 28 healthy controls (HC) performed different oculomotor tasks typically affected in patients with parkinsonian signs. RESULTS: The error rate for two types of volitional saccades, i.e., anti-saccades and memory-guided saccades, was increased not only in XDP patients but also in NMC compared to HC. However, the increase in error rates of both saccade types were highly correlated in XDP patients only. Hypometria of reflexive saccades was only found in XDP patients. Initial acceleration and maintenance velocity of smooth pursuit eye movements were only impaired in XDP patients. CONCLUSIONS: Despite being asymptomatic, NMC already showed some oculomotor deficits reflecting fronto-striatal impairments, typically found in XDP patients. However, NMC did not show saccade hypometria and impaired smooth pursuit as seen in advanced Parkinson's disease and XDP, suggesting oculomotor state rather than trait signs in these mutation carriers. Neurodegeneration may commence in the striatum and prefrontal cortex, specifically the dorsolateral prefrontal cortex.

Infantile vitiligo and alopecia in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is characterized by failure to thrive, severe chronic diarrhea, neonatal type 1 diabetes or thyroiditis, and eczematous dermatitis. We report a patient with infantile onset IPEX syndrome who developed vitiligo, alopecia, and chronic diarrhea. Awaiting stem cell transplant, he had multiple episodes of sepsis and succumbed at the age of 10 months. The constellation of symptoms is important to prompt clinicians to suspect this rare syndrome as early hematopoietic stem cell transplantation is the only cure for IPEX patients.

Experimental and approved treatments for skin photosensitivity in individuals with erythropoietic protoporphyria or X-linked protoporphyria: A systematic review.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to review the clinical evidence of efficacy and safety of skin photosensitivity treatments in individuals with EPP or XLP. We systematically searched MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov. A total of 40 studies with data on 18 treatment modalities were included. Comprehensive treatment safety data were obtained from the European Medicines Agency and the United States Food and Drug Administration. The studies used different outcome measures to evaluate the sensitivity without a generally accepted method to assess treatment effect on skin photosensitivity. Of the included studies, 13 were controlled trials. Gathered, the trials showed moderate positive effect of inorganic sunscreen application and subcutaneous implant of afamelanotide and no effect of organic sunscreen application, or oral treatment with beta-carotene, cysteine, N-acetylcysteine, vitamin C, or warfarin. Studies without control groups suggested treatment effect of foundation cream, dihydroxyacetone/lawsone cream, narrow-band ultraviolet B phototherapy, erythrocyte transfusion, extracorporeal erythrocyte photodynamic therapy, or oral treatment with zinc sulphate, terfenadine, cimetidine, or canthaxanthin, but the real effect is uncertain. Assessment of treatment effect on photosensitivity in patients with EPP or XLP carries a high risk of bias since experienced photosensitivity varies with both weather conditions, exposure pattern, and pigmentation. Controlled trials of promising treatment options are important although challenging in this small patient population.

Case report: Evolution of pulmonary manifestations and virological markers in critical COVID-19 infection in Bruton's agammaglobulinemia.

Despite several reports and small case series on the disease course of SARS-CoV-2 infection in patients with inborn errors of immunity (IEI), including X-linked agammaglobulinemia (XLA), this topic remains incompletely described. Here we present the case of a 38-year-old unvaccinated man with XLA, who acquired SARS-CoV-2 infection and experienced a protracted disease course with 47 days of SARS-CoV-2 positivity, critical COVID-19 with respiratory insufficiency necessitating intensive care and ventilatory support, and prompting repeated intensified treatments with remdesivir, dexamethasone, and monoclonal antibodies to eventually control infection. We describe the disease course and treatment and review the current literature on COVID-19 susceptibility and evidence for vaccine efficacy in patients with XLA.

Bone Deformities and Kidney Failure: Coincidence of PHEX-Related Hypophosphatemic Rickets and m.3243A>G Mitochondrial Disease.

X-linked hypophosphatemic rickets (XLH) and m.3243A>G mitochondrial disease share several clinical findings, including short stature, hearing impairment (HI), nephropathy, and hypertension. Here, we report on a case with the rare coincidence of these two genetic conditions. In early childhood, the patient presented with hypophosphatemia and bone deformities and was clinically diagnosed with XLH. This was genetically verified in adulthood with the identification of a de novo pathogenic deletion in phosphate-regulating endopeptidase homolog X-linked (PHEX). In addition, the patient developed HI and hypertension and when his mother was diagnosed with m.3243A>G, subsequent genetic testing confirmed the patient to carry the same variant. Over the next two decades, the patient developed progressive renal impairment however without nephrocalcinosis known to associate with XLH which could indicate an m.3243A>G-related kidney disease. Parallel with the progression of renal impairment, the patient developed hyperphosphatemia and secondary hyperparathyroidism. In conclusion, this case represents a complex clinical phenotype with the reversal of hypo- to hyperphosphatemia in XLH potentially mediated by the development of an m.3243A>G-associated nephropathy.

Meningoencephalitis in primary antibody deficiency: Our experience from northwest India.

BACKGROUND/OBJECTIVES: Patients with primary antibody deficiency (PAD) are predisposed to develop meningoencephalitis, often considered to be enteroviral. However, there is a paucity of literature on this subject, and there are no studies from developing countries. METHODS: We analyzed our cohort of children with PAD who developed meningoencephalitis. RESULTS: This complication was observed in 13/135 (10.4%) patients with PAD - 5 patients had X-linked agammaglobulinemia (XLA), 7 had common variable immunodeficiency (CVID) and 1 had suspected nuclear factor kappa B essential modulator (NEMO) defect. Mean age at onset of neurological illness was 9.3 years. Presenting features included seizures (n=8), neurodevelopmental delay (n=2), regression of milestones (n=2), and acute flaccid paralysis (n=1). Trough IgG levels were found to be low in 12/13 patients at the time of development of neurological symptoms. Herpes simplex virus (HSV), cytomegalovirus (CMV), and Streptococcus pneumoniae were isolated in 1 each. Eight (72.7%) patients had altered signal hyperintensities in gray matter and deep white matter on magnetic resonance imaging (MRI), while 4 patients showed global cerebral atrophy. All patients were treated with high-dose intravenous immunoglobulin (IVIg). Fluoxetine was given to 3 patients. Eight patients in the present series have died, 3 have recovered with varying degrees of neurological sequelae and 2 patients are showing gradual recovery. CONCLUSIONS: To conclude, meningoencephalitis is an uncommon complication in patients with PAD and is associated with high morbidity and mortality. Early diagnosis of immune deficiency and initiation of replacement immunoglobulin therapy may prevent the development of neurological complications.

Unilateral cataract and congenital stationary night blindness in a child with novel variants in TRPM1.

Unilateral cataract can cause pediatric vision impairment. Although the majority of unilateral cataracts are idiopathic in nature, genetic causes have been reported. We present the case of a 4-week-old child of nonconsanguineous parents who was affected with unilateral cataract. Whole-genome sequencing using DNA extracted from blood and the lens epithelial cells following cataract surgery revealed two presumed pathogenic variants in the TRPM1 gene, the founding member of the melanoma-related transient receptor potential (TRPM) subfamily. TRPM1 is responsible for regulating cation influx to hyperpolarized retinal ON bipolar cells, and mutations in this gene are a major cause of autosomal recessive congenital stationary night blindness (CSNB). Electroretinography revealed findings consistent with CSNB, a phenotype that was not initially suspected, and which would likely have been missed without genome sequencing. It remains unclear whether the TRPM1 variants are associated with the cataract phenotype.

Prodromal X-Linked Dystonia-Parkinsonism is Characterized by a Subclinical Motor Phenotype.

BACKGROUND: Early diagnosis in patients with neurodegenerative disorders is crucial to initiate disease-modifying therapies at a time point where progressive neurodegeneration can still be modified. OBJECTIVES: The objective of this study was to determine whether motor or non-motor signs of the disease occur as indicators of a prodromal phase of X-linked dystonia-parkinsonism (XDP), a highly-penetrant monogenic movement disorder with striking basal ganglia pathology. METHODS: In addition to a comprehensive clinical assessment, sensor-based balance and gait analyses were performed in non-manifesting mutation carriers (NMCs), healthy controls (HCs), and patients with XDP. Gradient-boosted trees (GBT) methodology was utilized to classify groups of interest. RESULTS: There were no clinically overt disease manifestations in the NMCs. Balance analysis, however, revealed a classification accuracy of 90% for the comparison of NMC versus HC. For the gait analysis, the best-performing GBT-based model showed a balanced accuracy of 95% (NMC vs. HC; walking at maximum speed). Using a separate analysis of genetic modifiers, several gait parameters correlated strongly with the estimated age at disease onset in the NMC group. CONCLUSIONS: Our study unraveled balance and gait abnormalities in NMCs that preceded the onset of XDP. These findings demonstrate prodromal motor changes among NMCs who will develop XDP with a very high likelihood in the future. Gait abnormalities had a predictive value for the estimated age at onset highlighting the impact of genetic modifiers in personalized treatment in monogenic neurodegenerative disorders. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Retrospective study of 98 patients with X-linked agammaglobulinemia complicated with arthritis.

OBJECTIVE: We preformed this retrospective study of clinical manifestation, imaging feature, and mutations to describe joint involvement in X-linked agammaglobulinemia (XLA) patients, aimed to provide recommendation for physicians. METHODS: A total number of 98 XLA patients who have been diagnosed between January 2000 and February 2020 were enrolled and grouped based on whether they developed arthritis and analyzed for the clinical, imaging, and gene mutation data using the t test or the Mann-Whitney test. RESULTS: Forty-five out of 98 patients (45.9%) had joint involvement, 40.8% had symptom prior to the diagnosis of XLA, and 54.1% had no articular symptom. Patients with joint involvement had a higher median diagnostic age of XLA and initial IgG level than patients without it, while their intravenous immunoglobulin was lower (p < 0.05). Knee, hip, and ankle were the most frequent joint, and oligoarthritis (≦ 4 joints) was more common than polyarthritis (88.9% vs 11.1%). Red and tenderness were the most frequent clinical symptoms (80%) with 24.4% reporting limited activity and 8.9% reporting deformity. Imaging data collected from 32 patients indicated that joint effusion (53.3%), synovitis (15.5%), and swollen soft tissue (15.5%) were the most common feature. Seventeen patients were treated by antibiotics plus intravenous immunoglobulin (IVIG) with an effective rate of 70.6%, and 28 patients only received IVIG with an effective rate of 67.9%. In comparison to patients without arthritis who have higher frequency nonsense and frameshift mutation, patients with arthritis had a higher incidence of missense mutation (p < 0.05). CONCLUSION: High prevalence of arthritis among X-linked agammaglobulinemia patients and subsequent progression through IVIG replacement therapy highlight the importance of timely diagnosis and better management of these patients. Our finding indicated a potential correlation between genotype and phenotype, and further research on the mechanism of arthritis in XLA patients could increase physicians' awareness and improve patients' prognosis. Key Points • This study described the feature of arthritis in XLA patients and indicated a potential correlation between this complication and genotype.

Sleep and daytime behavior in individuals with Christianson Syndrome.

BACKGROUND: The objectives of this study were to: 1) characterize the sleep behaviors and symptoms of individuals with Christianson Syndrome (CS) by means of validated questionnaires; and 2) determine their associations with daytime emotional and behavioral symptoms in this population. METHODS: Participants included 16 boys genetically diagnosed with CS, between 2.5 and 40 years of age (M = 14.5 ± 8.08). Parents completed questionnaires regarding the sleep, daytime behavior, and health of their child. RESULTS: Of the participants, 31% did not obtain the recommended amount of sleep for their age, 43% experienced a prolonged sleep latency, and 88% had a clinical or sub-clinical score for at least one subscale of the Sleep Disturbance Scale for Children (SDSC). Specific problems detected included insomnia, sleep-wake transition disorders, periodic limb movements in sleep, and sleep related breathing disorders. About half of the participants manifested emotional and behavioral problems at clinical levels. Higher levels of sleep disturbances were associated with higher levels of behavioral and emotional daytime symptoms. CONCLUSIONS: Sleep problems are common in individuals with CS and are associated with daytime behavioral and emotional symptoms.