Expanding the Phenotypic Spectrum of CACNA1H Mutations.

BACKGROUND: The CACNA1H gene mutations encoding the α1H subunit of Cav3.2 T-type calcium channels have been associated with generalized epilepsy. Focal or multifocal epilepsy and systemic (immunologic and gastrointestinal) involvement associated with these mutations have not been described previously. We detail the clinical characteristics of five patients with CACNA1H mutations and expand its phenotypic spectrum. METHODS: A case series of five patients with pathogenic CACNA1H mutations was evaluated. The pathogenicity of the mutations was predicted by polymorphism phenotyping (Polyphen-2) and sorting-intolerant-from-tolerant analysis. RESULTS: Mean age of seizure onset was 8.2 ± 3.7 years. Three patients had de novo mutations in the CACNA1H gene, and two patients inherited the mutation from an asymptomatic parent. The patients experienced different types of seizures including absence, focal seizures without awareness, focal seizures with secondary generalization, and myoclonic, atonic, and generalized tonic-clonic seizures. Electroencephalography showed focal, multifocal, or generalized discharges. One patient had autism and global developmental delay. Two patients had failure to thrive and selective antibody deficiency. CONCLUSIONS: CACNA1H mutations can be associated with susceptibility to develop generalized epilepsy and focal or multifocal epilepsy of varying severity. Phenotypic features involving other organ systems (immune, gastrointestinal) can occur in addition to epilepsy, developmental delay, and autism.

Myopathic mtDNA Depletion Syndrome Due to Mutation in TK2 Gene.

Whole-exome sequencing was used to identify the disease gene(s) in a Spanish girl with failure to thrive, muscle weakness, mild facial weakness, elevated creatine kinase, deficiency of mitochondrial complex III and depletion of mtDNA. With whole-exome sequencing data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The analysis of whole exome uncovered a homozygous pathogenic mutation in thymidine kinase 2 gene ( TK2; NM_004614.4:c.323 C>T, p.T108M). TK2 mutations have been identified mainly in patients with the myopathic form of mtDNA depletion syndromes. This patient presents an atypical TK2-related myopathic form of mtDNA depletion syndromes, because despite having a very low content of mtDNA (<20%), she presents a slower and less severe evolution of the disease. In conclusion, our data confirm the role of TK2 gene in mtDNA depletion syndromes and expanded the phenotypic spectrum.

Whole-exome sequencing identifies a variant of the mitochondrial MT-ND1 gene associated with epileptic encephalopathy: west syndrome evolving to Lennox-Gastaut syndrome.

We describe a West syndrome (WS) patient with unidentified etiology that evolved to Lennox-Gastaut syndrome. The mitochondrial respiratory chain of the patient showed a simple complex I deficiency in fibroblasts. Whole-exome sequencing (WES) uncovered two heterozygous mutations in NDUFV2 gene that were reassigned to a pseudogene. With the WES data, it was possible to obtain whole mitochondrial DNA sequencing and to identify a heteroplasmic variant in the MT-ND1 (MTND1) gene (m.3946G>A, p.E214K). The expression of the gene in patient fibroblasts was not affected but the protein level was significantly reduced, suggesting that protein stability was affected by this mutation. The lower protein level also affected assembly of complex I and supercomplexes (I/III2 /IV and I/III2 ), leading to complex I deficiency. While ATP levels at steady state under stress conditions were not affected, the amount of ROS produced by complex I was significantly increased.

A new mutation in the gene encoding mitochondrial seryl-tRNA synthetase as a cause of HUPRA syndrome.

BACKGROUND: HUPRA syndrome is a rare mitochondrial disease characterized by hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis. This syndrome was previously described in three patients with a homozygous mutation c.1169A > G (p.D390G) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. CASE PRESENTATION: Here we report the clinical and genetic findings in a girl and her brother. Both patients were clinically diagnosed with the HUPRA syndrome. Analysis of the pedigree identified a new homozygous mutation c.1205G > A (p.R402H) in SARS2 gene. This mutation is very rare in the population and it is located at the C-terminal globular domain of the homodimeric enzyme very close to p.D390G. CONCLUSION: Several data support that p.R402H mutation in SARS2 is a new cause of HUPRA syndrome.

Depleción del ácido desoxirribonucleico mitocondrial y mutaciones de POLG en un paciente con neuropatía sensorial atáxica, disartria y oftalmoplejía / Mitochondrial DNA depletion and polg mutations in a patient with sensory ataxia, dysarthria and ophthalmoplegia

Fundamento y objetivo: Un amplio espectro de enfermedades mitocondriales está producido por mutaciones de POLG y se caracterizan por una alteración en la integridad del genoma mitocondrial. La oftalmoplejía progresiva externa suele ser el marcador clínico en los casos de deleciones múltiples, pero no lo es en aquellas enfermedades que cursan con depleción del ácido desoxirribonucleico mitocondrial (ADNmt). En este trabajo presentamos un paciente con la tríada clínica que define el síndrome de neuropatía sensorial atáxica, disartria y oftalmoplejía, las mutaciones del gen POLG y la presencia inusual de una marcada disminución en el contenido del ADNmt en el músculo esquelético.Paciente y método: El paciente presentó un cuadro clínico caracterizado por neuropatía sensorial atáxica, disartria y oftalmoplejía. El diagnóstico se realizó mediante estudios histológicos y análisis molecular del ADNmt y del gen POLG. Resultados: La biopsia del nervio sural detectó una pérdida intensa de las fibras nerviosas mielinizadas gruesas. El estudio molecular reveló mutaciones en el gen POLG, así como deleciones múltiples y una marcada depleción del genoma mitocondrial. Conclusiones: Los pacientes con síndromes atáxicos de origen mitocondrial presentan fenotipos mitocondriales moleculares diferentes, por lo que se aconseja la búsqueda de mutaciones del gen POLG en todos ellos, independientemente de la anomalía que presenten en el genoma mitocondrial (AU)

Background and objetive: A broad spectrum of clinical disorders is produced by mutations in the DNA polymerase gamma mitochondrial (POLG) gene which are associated with altered mitochondrial DNA (mtDNA) integrity. The majority of disorders characterized by multiple mtDNA deletions present with progressive external ophthalmoplegia, though this feature is not usually found in syndromes caused by mtDNA depletion. We report on a patient having the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoplegia (SANDO), POLG mutations and reduced muscle mtDNA content. Patient and methods: The patient presented with sensory ataxic neuropathy, dysarthria and ophthalmoplegia. Diagnosis was established by using histological and genetic procedures (nerve biopsy, mtDNA molecular analysis in skeletal muscle and mutation screening in the POLG gene). Results: Sural nerve biopsy showed marked loss of large myelinated fibers. Skeletal muscle analysis revealed multiple mtDNA deletions, a marked decrease in mtDNA copy number and pathogenic mutations in the POLG gene. Conclusions: POLG mutations must be considered in all patients with the cardinal findings of the SANDO phenotype, without taking into account the type of abnormalities encountered in the mitochondrial genome (AU)

An analysis of falls experienced by older adult patients diagnosed with cancer

PURPOSE/OBJECTIVES: To examine themes associated with falls specific to older adult patients diagnosed with cancer. DESIGN: Prospective, exploratory, qualitative study. SETTING: A senior adult oncology program at a cancer and research center in the southeastern United States. SAMPLE: Men and women aged 70 years and older with any cancer diagnosis who had experienced a fall within three months. METHODS: Patients were telephoned after research consent to participate in an interview about their falls. Frequencies were conducted on the biographic data. Themes were identified and grouped according to topic. MAIN RESEARCH VARIABLES: Eastern Cooperative Oncology Group performance status, cancer site, cancer treatment modality, location of fall, and fear of falls. FINDINGS: Mean age was 76.2 years. Most falls occurred at home (75%). The themes of physical problems, general weakness, and walking were found to be the most common motivations for falls. Themes associated with self-imposed activities as a result of falls included "being more careful" and "using an assistive device." CONCLUSIONS: Perceptions of physical problems, general weakness, and difficulty walking should be included in an oncology nursing fall-risk assessment. Exploration of perceptions concerning activities that have potentially caused a past fall and self-imposed activities also should be included. IMPLICATIONS FOR NURSING: Beyond the boundaries of a fall-risk assessment, conducting a subjective interview to identify the individualities of falls and fall risk is vital to constructing a realistic plan of care.

Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency.

Mutations in BCS1L, an assembly factor that facilitates the insertion of the catalytic Rieske Iron-Sulfur subunit into respiratory chain complex III, result in a wide variety of clinical phenotypes that range from the relatively mild Björnstad syndrome to the severe GRACILE syndrome. To better understand the pathophysiological consequences of such mutations, we studied fibroblasts from six complex III-deficient patients harboring mutations in the BCS1L gene. Cells from patients with the most severe clinical phenotypes exhibited slow growth rates in glucose medium, variable combined enzyme deficiencies, and assembly defects of respiratory chain complexes I, III, and IV, increased H(2)O(2) levels, unbalanced expression of the cellular antioxidant defenses, and apoptotic cell death. In addition, all patients showed cytosolic accumulation of the BCS1L protein, suggestive of an impaired mitochondrial import, assembly or stability defects of the BCS1L complex, fragmentation of the mitochondrial networks, and decreased MFN2 protein levels. The observed structural alterations were independent of the respiratory chain function and ROS production. Our results provide new insights into the role of pathogenic BCS1L mutations in mitochondrial function and dynamics.

[Mitochondrial DNA depletion and POLG mutations in a patient with sensory ataxia, dysarthria and ophthalmoplegia]. / Depleción del ácido desoxirribonucleico mitocondrial y mutaciones de POLG en un paciente con neuropatía sensorial atáxica, disartria y oftalmoplejía.

BACKGROUND AND OBJECTIVE: A broad spectrum of clinical disorders is produced by mutations in the DNA polymerase gamma mitochondrial (POLG) gene which are associated with altered mitochondrial DNA (mtDNA) integrity. The majority of disorders characterized by multiple mtDNA deletions present with progressive external ophthalmoplegia, though this feature is not usually found in syndromes caused by mtDNA depletion. We report on a patient having the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoplegia (SANDO), POLG mutations and reduced muscle mtDNA content. PATIENT AND METHODS: The patient presented with sensory ataxic neuropathy, dysarthria and ophthalmoplegia. Diagnosis was established by using histological and genetic procedures (nerve biopsy, mtDNA molecular analysis in skeletal muscle and mutation screening in the POLG gene). RESULTS: Sural nerve biopsy showed marked loss of large myelinated fibers. Skeletal muscle analysis revealed multiple mtDNA deletions, a marked decrease in mtDNA copy number and pathogenic mutations in the POLG gene. CONCLUSIONS: POLG mutations must be considered in all patients with the cardinal findings of the SANDO phenotype, without taking into account the type of abnormalities encountered in the mitochondrial genome.

Marked mitochondrial DNA depletion associated with a novel SUCLG1 gene mutation resulting in lethal neonatal acidosis, multi-organ failure, and interrupted aortic arch.

The aim of this study was to identify the causative genetic lesion in two apparently unrelated newborns having lethal lactic acidosis, multi-organ failure and congenital malformations including interrupted aortic arch, who exhibited mild methylmalonic aciduria, combined mitochondrial respiratory chain deficiency, and marked muscle mitochondrial DNA depletion. A novel mutation in the SUCLG1 gene was identified. Phenotype severity in Succinate-CoA ligase dysfunction appears to be more correlated to the muscle mtDNA content than to the tissue distribution of the heterodimer subunits. Prominent impairment of mitochondrial respiratory chain may result in deep ravages in developmental tissues leading to multiple organ failure and malformations.

Depression symptoms in cancer caregivers.

Patients with cancer are living longer as the disease has become a more chronic condition. Family and friends assume the role of caregiver as more cancer care shifts to the home. The value of informal caregivers and the support they provide to patients will continue to increase. However, caregiving has physical and psychological consequences, including depression. The purpose of this article is to increase awareness of the problem of caregiver depression because of its impact on health deterioration and early death in caregivers. This article discusses caregiving, depression, factors that may contribute to caregiver depression, and implications for oncology nurses. A case study, examples of instruments that can be used to identify caregivers exhibiting depressive symptoms, caregiver resources, and mental health resources are provided.

Coenzyme Q10 deficiency associated with a mitochondrial DNA depletion syndrome: a case report.

OBJECTIVES: To report on a case with a mitochondrial DNA (mtDNA) depletion syndrome. DESIGN AND METHODS: Laboratory studies were done in muscle biopsy and fibroblasts to evaluate coenzyme Q(10) (CoQ(10)) status and quantify mitochondrial DNA. RESULTS: Decreased CoQ(10) values and a 78% of mtDNA depletion were detected in muscle. Mutational studies failed to reveal any pathogenic mutation in nuclear genes related with mtDNA maintenance. CONCLUSIONS: mtDNA depletion syndrome was associated with CoQ(10) deficiency in our patient.

Physical performance evaluation of older cancer patients: a preliminary study.

UNLABELLED: Performance status measures can provide clinical incite into understanding patients who are at risk for falls. PURPOSE: This preliminary, prospective study is to determine the sensitivity and specificity of the Timed Up & Go instrument and the Simmonds Performance Test Battery in older cancer patients with falls as the outcome measure. METHODS: The Timed Up & Go instrument, fall assessment and the Simmonds Performance Test Battery were administered. RESULTS: Age range was 68-83 years. Participants (n=20) who reported Falls Within a Year were 65% (n=13), 79% (n=15) reported Falls Within Three Months, and 60% (n=12) reported Falls Since Cancer Diagnosis. The questions of Falls Within One Year and Falls Within Three Months had equal area under the curve at .85. CONCLUSION: The sensitivity and specificity of the fall assessment questions of Falls Within One Year and Falls Within Three Months were found to be equal when using the Timed Up & Go as an outcome measure. The Timed Up & Go instrument was found to have more robust sensitivity and specificity levels as compared to the Simmonds performance status battery.

OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.

Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA 'plus' phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability.

Mild ocular myopathy associated with a novel mutation in mitochondrial twinkle helicase.

Autosomal dominant PEO is associated with mutations in a number of nuclear genes affecting the intergenomic communication with mitochondrial DNA. We report a Spanish family showing a mild phenotype characterized by autosomal dominant ocular myopathy and morphological signs of mitochondrial dysfunction, that harboured a novel c.1071G>C (p.R357P) mutation in the hot-spot linker region of the twinkle protein.

Immunophenotype characteristics of peripheral blood mononuclear leukocytes of chronic idiopathic urticaria patients.

The pathogenesis of chronic idiopathic urticaria (CIU) is not completely understood although autoimmunity has been proposed. The aim of the study was to assess the expression of different leukocyte antigens, by flow cytometry, assaying total blood of 29 patients with CIU and of 20 sex and age matched controls. Moreover, we assessed soluble CD154 a marker of immune cell activation, predominantly memory T cells. When patients were divided depending an their response to the autologous serum skin test (ASST), three different groups were encountered: group 1 (n=11): with negative ASST-, group 2 (n=11): positive ASST (ASST+) with normal lymphocyte counts and group 3 (n=7): ASST+ with low lymphocyte counts (< 1500 cells/mm3). A significant increase in CD19+ percentage and not in the absolute count (P < 0.05) was observed in group 1 as compared to controls and to the other groups. In contrast, CD30+, CD45RO+ and CD4+/CD45RO+ percentages and biologically active soluble CD154 levels were significantly higher (P < 0.05) in group 3 as compared to group 1 or to controls. In ASST positive groups, CD45RO+ and CD4+/CD45RO+ positiveness correlates with wheal diameter. In conclusion, memory cells may play a role in these different types of patients and in understanding CIU pathogenesis.

Immunophenotype characteristics of peripheral blood mononuclear leukocytes of chronic idiopathic urticaria patients

La patogénesis de la urticaria crónica idiopática (CIU) no se conoce completamente; sin embargo, la autoinmunidad juega un papel importante en un subgrupo de pacientes. El objetivo de este estudio fue la determinación de antígenos leucocitarios en sangre total, utilizando citometría de flujo, de 29 pacientes con CIU y 20 controles de similar edad y sexo. Adicionalmente, se determinó el CD154 soluble como marcador de activación de células inmunes, predominantemente linfocitos T de memoria. Se describieron 3 grupos de pacientes de acuerdo al resultado de la prueba de suero antólogo (ASST): grupo 1: negativo (n = 11), grupo 2: prueba positiva y contaje linfocitario normal (n = 11) y grupo 3 prueba positiva y contaje linfocitario bajo (< 1500 células/mm3) (n = 7). En el grupo 1, se observó un aumento significativo (P < 0,05) en el porcentaje de células CD19+ aunque no en su número absoluto cuando se comparó con los controles y los pacientes con ASST +. En contrapartida, el porcentaje de células positivas para CD30, CD45RO y CD4/CD45RO y los niveles de CD154 soluble biológicamente activo fueron significativamente mayores (P < 0,05) en el grupo 3, en comparación con los controles y el grupo 1. Además, en los grupos con ASST positiva, los porcentajes de células CD45RO+ y CD4/CD45RO+ se correlacionan con el tamaño del habón a la ASST. En conclusión, las células de memoria pudieran jugar un papel importante en la patogénesis de la CIU.

Hypodense eosinophils: characterization of surface molecule expression.

Distinct eosinophil populations have been characterized on the basis of discontinuous Percoll density gradients. In peripheral blood, normal individuals show a low number of normodense and hypodense eosinophils, contrasting with the high amount of hypodense cells in patients who have allergies. To characterize these two eosinophil populations, we analyzed membrane expression of several antigens and cytokine receptors in normodense and hypodense eosinophils from patients who have allergies and controls. Hypodense eosinophils expressed higher levels of CD122, CD69, and CD4 in both patients with allergies and control individuals when compared to normodense eosinophils. The expression of CD125, CD124, CD25, CD132, and CD23 were similar in both cell types.