Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report.

OBJECTIVES: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive mitochondrial disorder. It manifests as a continuous clinical spectrum, from fatal infantile mitochondrial DNA depletion syndromes to adult-onset mitochondrial myopathies characterized by ophthalmoplegia-plus phenotypes with early respiratory involvement. Treatment with pyrimidine nucleosides has recently shown striking effects on survival and motor outcomes in the more severe infantile-onset clinical forms. We present the response to treatment in a patient with adult-onset TK2d. METHODS: An adult with ptosis, ophthalmoplegia, facial, neck, and proximal muscle weakness, non-invasive nocturnal mechanical ventilation, and dysphagia due to biallelic pathogenic variants in TK2 received treatment with 260 mg/kg/day of deoxycytidine (dC) and deoxythymidine (dT) under a Compassionate Use Program. Prospective motor and respiratory assessments are presented. RESULTS: After 27 months of follow-up, the North Star Ambulatory Assessment improved by 11 points, he walked 195 m more in the 6 Minute-Walking-Test, ran 10 s faster in the 100-meter time velocity test, and the Forced Vital Capacity stabilized. Growth Differentiation Factor-15 (GDF15) levels, a biomarker of respiratory chain dysfunction, normalized. The only reported side effect was dose-dependent diarrhea. DISCUSSION: Treatment with dC and dT can significantly improve motor performance and stabilize respiratory function safely in patients with adult-onset TK2d.

Adult Pompe disease: Analysis of 13 patients. / Enfermedad de Pompe del adulto: análisis de 13 pacientes.

INTRODUCTION: Pompe Disease (PD) is a lysosomal disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), primarily manifesting as a progressive myopathy with early respiratory involvement. Enzyme replacement therapy (ERT) is available since 2006. MATERIALS AND METHODS: We describe 13 patients with partial GAA deficiency, followed at Hospital 12 de Octubre, 8 of whom were receiving treatment. RESULTS: 8 patients exhibit symptoms, all with late onset. They display axial and proximal weakness predominantly in the lower limbs but maintain autonomous gait. Five patients require non-invasive mechanical ventilation due to respiratory insufficiency. All symptomatic patients receive ERT, and in 7/8 (87.5%), there is a decline in motor and pulmonary function after an average of 8.25 years of treatment (baseline and post-treatment FVC and 6MWT mean 86.6% vs 70.8% and 498 vs 430 meters, respectively). CONCLUSION: Not all patients with partial GAA deficiency experience symptoms of PD, and symptomatic patients, despite ERT with recombinant alpha-glucosidase, mostly experience a gradual decline in motor and respiratory function.

Distal hereditary motor neuronopathy as a new phenotype associated with variants in BAG3.

OBJECTIVE: To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy. METHODS: This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3. RESULTS: Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novel heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members. CONCLUSIONS: We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adult-onset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies.

Distal myopathy due to digenic inheritance of TIA1 and SQSTM1 variants in two unrelated Spanish patients.

Welander distal myopathy typically manifests in late adulthood and is caused by the founder TIA1 c.1150G>A (p.Glu384Lys) variant in families of Swedish and Finnish descent. Recently, a similar phenotype has been attributed to the digenic inheritance of TIA1 c.1070A>G (p.Asn357Ser) and SQSTM1 c.1175C>T (p.Pro392Leu) variants. We describe two unrelated Spanish patients presenting with slowly progressive gait disturbance, distal-predominant weakness, and mildly elevated creatine kinase (CK) levels since their 6th decade. Electromyography revealed abnormal spontaneous activity and a myopathic pattern. Muscle magnetic resonance imaging (MRI) showed marked fatty replacement in distal leg muscles. A muscle biopsy, performed on one patient, revealed myopathic changes with rimmed vacuoles. Both patients carried the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variants. Digenic inheritance is supported by evidence from unrelated pedigrees and a plausible biological interaction between both proteins in protein quality control processes. Recent functional studies and additional case descriptions further support this. Clinical suspicion is necessary to seek both variants.

Home calligraphic exercises as manual dexterity training in patients with Parkinson's disease: a pilot feasibility study.

PURPOSE: To assess the feasibility and effects on manual dexterity and the quality of life (QoL) of a 12-week home calligraphic training program in patients with Parkinson's disease (PD). METHODS: A pilot study with participants recruited from the Movement Disorders consultation at the Hospital 12 de Octubre (Madrid). The main outcome, manual dexterity, was assessed using the Purdue Pegboard Test (PPT). Secondary outcomes included clinical rating scales that contemplate aspects related to manual dexterity (DextQ-24, UPDRSII, UPDRSIII), and QoL (PDQ-39 and EuroQoL-5D). RESULTS: Thirty PD patients (57% males) with a mean age of 66.11 (9.76) years and 93% adherence rate. The PPT scores improved significantly (p < 0.0001) from T0 (start of the study) to T1 (after 24 weeks). No statistically significant change was found in DextQ-24, UPDRS-II and UPDRS-III, but a clear improvement was observed in the QoL measurement: EuroQoL-5D (p < 0.0001), PDQ-39 (p < 0.0001) and modified PDQ-39 (p = 0.022). CONCLUSIONS: This is the first study to demonstrate the feasibility and improvement in hand dexterity assessed by the PPT for patients diagnosed with PD after a 12-week home calligraphic training program. A significant improvement was noted in the QoL measurements, such as the PDQ-39, modified PDQ-39, and EuroQoL-5D.Implications for RehabilitationMost patients with Parkinson's disease suffer from impaired manual dexterity, making it difficult to perform activities of daily living such as eating, buttoning, or shaving.A 12-week home calligraphic training program could improve hand dexterity in these patients.The advantage of this home calligraphic trainingis is that it is an easy-to-perform, low-cost and no side effects.This training also improves their quality of life.

Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome.

Primary mitochondrial myopathies (PMM) are a clinically and genetically highly heterogeneous group that, in some cases, may manifest exclusively as fatigue and exercise intolerance, with minimal or no signs on examination. On these occasions, the symptoms can be confused with the much more common chronic fatigue syndrome (CFS). Nonetheless, other possibilities must be excluded for the final diagnosis of CFS, with PMM being one of the primary differential diagnoses. For this reason, many patients with CFS undergo extensive studies, including extensive genetic testing and muscle biopsies, to rule out this possibility. This study evaluated the diagnostic performance of growth differentiation factor-15 (GDF-15) as a potential biomarker to distinguish which patient with chronic fatigue has a mitochondrial disorder. We studied 34 adult patients with symptoms of fatigue and exercise intolerance with a definitive diagnosis of PMM (7), CFS (22), or other non-mitochondrial disorders (5). The results indicate that GDF-15 can accurately discriminate between patients with PMM and CFS (AUC = 0.95) and between PMM and patients with fatigue due to other non-mitochondrial disorders (AUC = 0.94). Therefore, GDF-15 emerges as a promising biomarker to select which patients with fatigue should undergo further studies to exclude mitochondrial disease.

Use of Tenecteplase in Acute Ischemic Stroke in the Time of SARS-CoV-2.

Tenecteplase (TNK) is a fibrinolytic drug that is administrated in a single bolus, recommended in eligible patients with acute ischemic stroke prior to mechanical thrombectomy. This study explores its usefulness in adverse situations, such as the SARS-CoV-2 pandemic. We conducted a retrospective study involving consecutive patients with suspected acute ischemic stroke treated either with intravenous fibrinolysis with alteplase during 2019 or with TNK (.25 mg/kg) between March 2020 and February 2021. A comparative analysis was made to compare patient treatment times and prognosis. A total of 117 patients treated with alteplase and 92 with TNK were included. No significant differences were observed in age, main vascular risk factors or previous treatments. The median National Institutes of Health Stroke Scale was 8 in the alteplase group and 10 in those treated with TNK (P = .13). Combined treatment with mechanical thrombectomy was performed in 47% in the alteplase group and 46.7% in the TNK group; Thrombolysis In Cerebral Infarction scale 2b-3 recanalization was achieved in 83% and 90.7%, respectively (P = .30). There was a decrease in onset-to-needle median time (165 min vs 140 min, P < .01) and no significant variations in door-needle median time. There was no significant difference in the incidence of symptomatic hemorrhagic transformation in mortality or functional independence at 3 months. The easier administration of TNK has improved the accessibility of fibrinolytic therapy, even in adverse circumstances, such as the COVID-19 pandemic. Its use appears to be safe and effective, even in patients who are not candidates for mechanical thrombectomy.

Cognitive Impairment Is a Common Comorbidity in Deceased COVID-19 Patients: A Hospital-Based Retrospective Cohort Study.

We analyzed the frequency of cognitive impairment (CI) in deceased COVID-19 patients at a tertiary hospital in Spain. Among the 477 adult cases who died after admission from March 1 to March 31, 2020, 281 had confirmed COVID-19. CI (21.1% dementia and 8.9% mild cognitive impairment) was a common comorbidity. Subjects with CI were older, tended to live in nursing homes, had shorter time from symptom onset to death, and were rarely admitted to the ICU, receiving palliative care more often. CI is a frequent comorbidity in deceased COVID-19 subjects and is associated with differences in care.