Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis.

Mechanotransduction, the pathway by which mechanical forces are translated to biological signals, plays important but poorly characterized roles in physiology. PIEZOs are recently identified, widely expressed, mechanically activated ion channels that are hypothesized to play a role in mechanotransduction in mammals. Here, we describe two distinct PIEZO2 mutations in patients with a subtype of Distal Arthrogryposis Type 5 characterized by generalized autosomal dominant contractures with limited eye movements, restrictive lung disease, and variable absence of cruciate knee ligaments. Electrophysiological studies reveal that the two PIEZO2 mutations affect biophysical properties related to channel inactivation: both E2727del and I802F mutations cause the PIEZO2-dependent, mechanically activated currents to recover faster from inactivation, while E2727del also causes a slowing of inactivation. Both types of changes in kinetics result in increased channel activity in response to a given mechanical stimulus, suggesting that Distal Arthrogryposis Type 5 can be caused by gain-of-function mutations in PIEZO2. We further show that overexpression of mutated PIEZO2 cDNAs does not cause constitutive activity or toxicity to cells, indicating that the observed phenotype is likely due to a mechanotransduction defect. Our studies identify a type of channelopathy and link the dysfunction of mechanically activated ion channels to developmental malformations and joint contractures.

Amyoplasia: a case report of an old woman.

PURPOSE: Little information exists about the long-term outcome of amyoplasia. In this article, a case report of a 93-year old woman is presented including both the development of the physical limitations and coping strategies. METHOD: The medical records, physical examinations and personal interviews during the last 10 years, autobiographical essays and personal photographs were included. RESULTS: Eleven surgical procedures were performed during childhood and ten during adulthood. Ambulation without aids was possible up to the age of 37 years. Thereafter, the muscular force declined gradually, first in the legs and later in the arms. Musculoskeletal pain decreased during ageing. There was an increasing demand to use technical aids. Seniority brought about several diseases, which complicated the quality of life. The woman stayed 32 years of her life in work. CONCLUSIONS: A high age can be achieved with amyoplasia although the disability increases due to a gradual deterioration of muscular force. The personal experiences of the woman suggest that her active and creative attitude towards her disability may have contributed to the quality of her life. This may encourage people with amyoplasia and their care givers. IMPLICATIONS FOR REHABILITATION: • There are no data about ageing and life-long prognosis of amyoplasia. • Severe physical limitations in amyoplasia are compatible with a long and meaningful life. • Muscular force decreases during adult life. Therefore, a potential risk of overtraining should be considered.

Problematic psychosocial adaptation and executive dysfunction in women and men with myelomeningocele.

PURPOSE: Myelomeningocele (MMC) is caused by incomplete neural tube development, affecting physical, cognitive and adaptive functioning. The aim of this study was to characterize women and men with problematic psychosocial adaptation with respect to cognitive functions and psychological symptoms. It was expected that cognitive functions, especially the executive functions, were mostly impaired. In addition, the clinical history, the neurological and the psychological functioning was investigated. METHOD: Twelve participants (six men, six women; age range 24-41 years) with MMC were recruited from TRS National Resource Centre for Rare Disorders. Inclusion criteria were (1) uncompleted upper secondary school, (2) unemployment and (3) lack of social relationships. The participants underwent a systematic clinical history, a clinical neurological examination, a neuropsychological assessment and questionnaires regarding cognitive and psychological functioning. RESULTS: All participants had major neurological deficits and most of them had hydrocephalus and Chiari-II malformation. Cognitive deficits were present in a range of domains, especially the executive functions. The neuropsychological findings showed no obvious difference between men and women. Symptoms of psychopathology were more pronounced in women. The men were less capable to structure daily living. CONCLUSIONS: The neuropsychological findings disclosed that the executive functions were most impaired. Future research should be directed towards cognitive rehabilitation.

Risk factors for pressure sores in adult patients with myelomeningocele--a questionnaire-based study.

BACKGROUND: Myelomeningocele (MMC) is a part of a complex neural tube defect and a disorder of the cerebrospinal fluid system. Pressure sores are a frequent complication for patients with MMC. Little is known about the risk factors for pressure sores in adults with MMC. The aim of this study was to investigate an association between the presence of pressure sores and other patient characteristics, in order to develop an improved strategy for the management of sores. METHODS: A structured questionnaire regarding sores, medical condition, function and living factors was designed and sent to the 193 patients with MMC registered in the year 2003 at TRS, a National Centre for Rare Disorders in Norway. RESULTS: Out of 193 total, 87 patients participated and 71 patients (82%) reported sores; 26 (30%) at the time of the interview and 45 (52%) during the last 5 years. Sores were mostly localized on toes and feet and occurred exclusively in regions with reduced or missing sensibility. A significant association was found between sores and memory deficit (p = 0.02), Arnold Chiari malformation (p = 0.02) and a record of previous sores (p = 0.004). Sores were not significantly associated with hydrocephalus, syringomyelia, nutrition, body mass index, smoking, physical activity, employment or living together with other persons. Some patients (18, 21%) reported skin inspection by others and the remainder relied on self-inspection. CONCLUSION: Patients with sensory deficit, memory problems, and Arnold Chiari malformation had a higher risk of having pressure sores. This patient group needs improved skin inspection routines and sore treatment.