Akinesia

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akinesia

What is akinesia

Akinesia is a medical term for absence or reduced movements or the impairment to initiate spontaneous movements 1, is one of the cardinal symptoms of Parkinson’s disease 2. Current pathophysiological models of the Parkinson’s disease suggest that akinesia arises from dysfunctional cortico-striatal processing, induced by a functional imbalance between direct and indirect basal-ganglia pathways 3. Here, the putamen is most prominently affected by the deprivation of dopaminergic input originating from the substantia nigra 4. These findings are in line with in vivo neuroimaging studies, showing decreased activation of the putamen in Parkinson’s disease patients 5. At the cortical level, the posterior medial frontal cortex (pMFC) has been suggested to contribute to patients’ impairment in voluntary movement initiation 6. This region is considered a central interface mediating cognitive 7, motivational, and motor processes 8.

In the context of Parkinson’s disease, neuroimaging studies have indicated abnormal activity in the posterior medial frontal cortex during self-initiated movements 9, which ameliorated under dopamine replacement 9 or deep brain stimulation 10. Moreover, single cell recordings in the macaque posterior medial frontal cortex revealed specific neural responses to movement instructions 11, which were distorted after inducing akinesia by lesioning this region. Correspondingly, clinical case reports in humans also noted akinetic symptoms resulting from lesions affecting the posterior medial frontal cortex 12. Together, these findings suggest that akinesia might arise from a dysfunctional interaction between the posterior medial frontal cortex and basal ganglia, especially the putamen 13.

Of note, both of these regions’ have been described as key nodes in a larger network linked to volitional behavior 14 and self-generated movements 15. This cortical network includes lateral and medial prefrontal cortex, mid- and anterior cingulate cortex, insula as well as posterior parietal regions. Recently, an increasing number of fMRI studies have begun to investigate resting-state functional connectivity (resting-state functional connectivity) in Parkinson’s disease 16. However, most of these studies have focused on subcortical seeds, revealing that striatal seeds feature reduced resting-state functional connectivity with the sensorimotor cortex 17 and subcortical nuclei including thalamus, subthalamic nucleus, and midbrain 18. In contrast, the cortical network for movement initiation remains poorly understood with respect to resting-state functional connectivity alterations in Parkinson’s disease.

Fetal akinesia

Fetal akinesia means decreased fetal movement, which is part of the fetal akinesia deformation sequence (FADS) 19. Fetal movement is a prerequisite for normal fetal development and growth. Intrauterine movement restrictions cause a broad spectrum of disorders characterized by one or more of the following features: contractures of the major joints (arthrogryposis), pulmonary hypoplasia, facial abnormalities, hydrops fetalis, pterygia, polyhydramnios and in utero growth restriction 20. The unifying feature is a reduction or lack of fetal movement, giving rise to the term fetal akinesia deformations sequence (FADS) 21.

Fetal akinesia deformation sequence (FADS) is a clinically and genetically heterogeneous condition of which the traditionally named Pena-Shokeir syndrome type 1 is characterized by multiple joint contractures, facial abnormalities, and lung hypoplasia resulting from the decreased in utero movement of the fetuses 20. Fetal akinesia deformation sequence (FADS) is a condition characterized by decreased fetal movement (fetal akinesia) as well as intra-uterine growth restriction (IUGR), multiple joint contractures (arthrogryposis), facial anomalies, underdevelopment of the lungs (pulmonary hypoplasia) and other developmental abnormalities 20. It is generally accepted that fetal akinesia deformation sequence (FADS) is not a true diagnosis or a specific syndrome, but rather a description of a group of abnormalities resulting from fetal akinesia 22. Fetal akinesia deformation sequence (FADS) is rare: about 100 cases have been described in the literature 23. About 30% of affected fetuses are often lost as spontaneous abortions (in utero fetal demise) or stillborn; many liveborn infants survive only a short time due to complications of pulmonary hypoplasia 24.

Fetal akinesia deformation sequence (FADS) is the result of decreased fetal movement coinciding with congenital malformations related to impaired fetal movement. FADS may be caused by heterogenous defects at any point along the motor system pathway and genes encoding components critical to the neuromuscular junction and acetylcholine receptor clustering represent a major class of FADS disease genes.

Many cases of fetal akinesia deformation sequence (FADS) result from impairment along the neuromuscular axis and from mutations in genes encoding components of the motor neurons, peripheral nervous system, neuromuscular junction and the skeletal muscle. Fetal akinesia deformation sequence (FADS) may be inherited in an autosomal recessive manner in some cases 22. Genes encoding components critical to the neuromuscular junction and acetylcholine receptor (AChR) clustering represent a major class of fetal akinesia deformation sequence (FADS) disease genes, these include RAPSN 25, DOK7 26 and MUSK 27, as well as mutations in the subunits of the muscular nicotinic acetylcholine receptor (AChR) 28. These mutations are expected to affect neuromuscular junctions 29.

Fetal akinesia deformation sequence symptoms

80%-99% of fetal akinesia deformation sequence individuals have these symptoms:

  • Absent palmar crease (absent palm lines)
  • Akinesia
  • Arthrogryposis multiplex congenita
  • Camptodactyly of finger (permanent flexion of the finger)
  • Excessive daytime somnolence

Fetal akinesia deformation sequence causes

Many underlying causes of fetal akinesia deformation sequence (FADS) have been recognized including genetic, environmental and maternal factors 20. The features of the condition are largely due to decreased fetal activity/movement 20. Failure of normal swallowing results in polyhydramnios (too much amniotic fluid), and lack of movement of the diaphragm and intercostal muscles leads to pulmonary hypoplasia (underdevelopment of the lungs). Lack of normal fetal movement also results in a short umbilical cord and multiple joint contractures 24.

Possible causes for decreased fetal movement which may contribute to the features of FADS may include 20:

  • Neurologic abnormalities such as cerebral and cerebellar dysgenesis (abnormal development); spinal tract, myelin, and end plate disturbances; and ischemia (deficient blood supply) with secondary loss of neuron function
  • Myopathic (muscle-related) abnormalities such as dystrophies and dyplasias
  • Connective tissue abnormalities including chondrodysplasias, restrictive skin, and joint limitation or laxity
  • Fetal edema for a variety of reasons (storage, metabolic, heart failure, lymphatic dysplasia, etc.)
  • Maternal illness, drugs, and antibodies (including maternal myasthenia gravis)
  • Ischemic changes during embryonic/fetal development, which may be due to developmental vascular abnormalities, trauma, hypotension, drugs, infections, and maternal illness or thrombophilia

Autosomal recessive inheritance of FADS has been implied in several published cases 22. Autosomal recessive inheritance (with parental consanguinity and/or recurrence in sibs) has been implied in about 50% of the published cases 23. The heterogeneity makes accurate recurrence risk counselling difficult. Genes in which mutations have been detected in affected individuals include the RAPSN 25, DOK7 26 and MUSK 27 genes, as well as mutations in the subunits of the muscular nicotinic acetylcholine receptor (AChR) 28. According to current literature, the recurrence risk is estimated to be 10–25% 22.

Antenatal diagnosis

Prenatal diagnosis after the birth of an index case relies on ultrasound, which may reveal polyhydramnios, ankyloses, scalp oedema, and decreased chest movements in a fetus with pulmonary hypoplasia.

Is genetic testing available for fetal akinesia deformation sequence?

There are quite a few potential underlying causes of fetal akinesia deformation sequence (FADS). Sometimes the cause is unknown, sometimes the cause is known and is not genetic, and other times although a genetic cause may be suspected, genetic testing may not be available. Currently, genetic testing is available for two genes in which mutations have reportedly caused the condition in specific cases.

What are some future pregnancy options after having a pregnancy affected with fetal akinesia deformation sequence (FADS)?

Consideration of genetic counseling is recommended for individuals who have a family history of FADS. The risk of recurrence largely depends on the underlying cause of the condition in the family, if it is known. According to current literature, the recurrence risk is estimated to be 10–25% 22.

In most cases, prenatal diagnosis for FADS relies on ultrasound during the pregnancy, which may reveal some of the characteristic features of the condition 24. It has been reported that ultrasound diagnosis of FADS is feasible from 14 weeks of gestation onwards, although it has been reported as early as 12 weeks 22. In some cases, specific features might only become evident in later ultrasounds 22.

Because the underlying cause of FADS in many cases is unknown, and/or genetic testing is not always available or informative, ensuring an unaffected pregnancy is often not possible. Preimplantation genetic diagnosis (PGD) for a genetic condition is an option when a specific genetic cause for the condition has been identified and genetic testing is available. If a particular case of FADS is known to be due to a specific genetic abnormality (FADS may be associated with a variety of conditions) and the above conditions are met, preimplantation genetic diagnosis for the condition associated with FADS may be possible. A genetics professional can help determine if this is an option on a case-by-case basis.

Likewise, if a genetic cause for FADS has been identified and the causative mutations in a family are known, prenatal diagnosis during the pregnancy via chorionic villus sampling (CVS) or amniocentesis may also be possible.

Individuals seeking information about their specific preconception and prenatal options should speak with a genetics professional.

Akinesia and bradykinesia

Bradykinesia is a medical term for slowness of movement, which is one of the common symptoms along with muscle rigidity, tremor and changes in balance (postural Instability) in Parkinson’s disease. Bradykinesia is considered the most common and bothersome of Parkinson’s disease symptoms. Initially bradykinesia presents as a general slowness of voluntary movements and is seen in combination with hypokinesia (reduced magnitude of movement). This is often noticeable as reduced or lack of one sided arm swing. Bradykinesia may lead to abnormal movements or a complete lack of voluntary movement (akinesia) .

Akinesia and dyskinesia

Dyskinesia is a medical term for involuntary movement including athetosis and chorea.

Tardive dyskinesia is a serious side effect that may occur with certain medications used to treat mental illness. Tardive means delayed and dyskinesia means abnormal movement. Symptoms of tardive dyskinesia include uncontrollable movements of the face and body such as:

  • Facial grimacing (commonly involving lower facial muscles)
  • Finger movement (piano playing movements)
  • Rocking or thrusting of the pelvis (duck-like gait)
  • Jaw swinging
  • Repetitive chewing
  • Rapid eye blinking
  • Tongue thrusting
  • Restlessness

Tardive dyskinesia may appear as repetitive, jerking movements that occur in the face, neck, and tongue. The symptoms of tardive dyskinesia can be very troubling for patients and family members. The muscle movements are outside of the patient’s control.

Long-term use of medications called antipsychotics can cause tardive dyskinesia. Some medications used for nausea can also cause tardive dyskinesia. The symptoms of tardive dyskinesia might continue even when the medication is stopped. About one in four patients who receive long-term treatment with an antipsychotic will experience tardive dyskinesia.

Anyone taking an antipsychotic may develop tardive dyskinesia, but certain factors increase the risk such as:

  • being elderly
  • being female
  • having diabetes
  • having other mental illnesses

It is important to remember that tardive dyskinesia usually happens after taking antipsychotics for a long time. Some patients may have tardive dyskinesia after 3 months, but many develop tardive dyskinesia after several years of treatment. tardive dyskinesia is unlikely to occur if an antipsychotic is only taken for a few weeks.

Once tardive dyskinesia develops, some effects may be permanent or take a long time to go away. However, many patients require long term use of antipsychotic medication to treat ongoing mental illness. If tardive dyskinesia develops, the first step is to notify your doctor so the medication can be safely adjusted, stopped or switched. The doctor may choose to switch the patient to a different antipsychotic that may lessen tardive dyskinesia. Many available treatments for tardive dyskinesia offer some benefit to patients, but response to treatment depends on the patient.

A dopamine-depleting medicine, tetrabenazine is most effective treatment for tardive dyskinesia. Your doctor can tell you more about these.

If tardive dyskinesia is very severe, a procedure called deep brain stimulation (DBS) may be tried. Deep brain stimulation uses a device called a neurostimulator to deliver electrical signals to the areas of the brain that control movement.

New medications have been developed for tardive dyskinesia, but may be too expensive for many patients. In addition to these approved medications, other alternative agents have shown mild benefit in treating tardive dyskinesia such as gingko biloba and vitamin E.

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