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Inclusion Criteria
- Progressive upper and/or lower motor neuron disease degeneration with clinical features of amyotrophy, spasticity, bulbar/pseudo-bulbar involvement - EMG/NCS consistent with MND - Positive family history of other affected family members with ALS or with FTD/ALS like phenotype or disease onset below 40 years. Individuals with severe or syndromic disease should be recruited according to standard guidance, typically as trios. Disease status of apparently unaffected participants should be determined according to standard clinical practice to detect cryptic disease. In other cases, unaffected individuals should not be recruited. Recruitment in such families should favour multiplex families over single isolated cases. These singleton recruits will not contribute to the overall singleton monitoring metrics applied to GMCs.
Exclusion Criteria
- Identified underlying cause for clinical syndrome e.g. multi-focal motor neuropathy, lymphoma
Prior Genetic Testing
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. - Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing. PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.
Genes
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice: - C9ORF72, SOD1
Closing Statement
These requirements will be kept under continual review during the main programme and may be subject to change.
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Abnormality of higher mental function
Cognitive, psychiatric or memory anomaly.
Cognitive impairment
Abnormality in the process of thought including the ability to process information.
Psychosis
A condition characterized by changes of personality and thought patterns often accompanied by hallucinations and delusional beliefs.
Neurological speech impairment
Dysarthria
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Dysphagia
Difficulty in swallowing.
Abnormality of the eye
Any abnormality of the eye, including location, spacing, and intraocular abnormalities.
Cataract
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule. Comment: Note that some ophthalmologists call any opacity in the lens a cataract, while others restrict the term to lens opacities that impair vision. We use the term to refer to the first meaning (any lens opacity).
Congenital cataract
A congenital cataract. Comment: In general, congenital cataracts are bilateral and that is the assumption with the terms in this cataract subhierarchy.
Optic atrophy
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy. Comment: The diagnosis of optic atrophy is made when the optic disc loses its normal orange-pink color. Optic atrophy is an end stage that arises from myriad causes of optic nerve damage anywhere along the path from the retina to the lateral geniculate. Some of the most common etiologies are advanced glaucoma, optic neuritis, arteritic or non-arteritic ischaemic optic neuropathy or a compressive lesion.
Abnormality of eye movement
An abnormality in voluntary or involuntary eye movements or their control.
Spasticity
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Abnormal pyramidal signs
Functional neurological abnormalities related to dysfunction of the pyramidal tract. Comment: Presence of these signs can indicate affection of the corticospinal (pyramidal) tracts.
Hyperreflexia in upper limbs
Upper limb spasticity
Skeletal muscle atrophy
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Fasciculations
Fasciculations are observed as small, local, involuntary muscle contractions (twitching) visible under the skin. Fasciculations result from increased irritability of an axon (which in turn is often a manifestation of disease of a motor neuron). This leads to sporadic discharges of all the muscle fibers controlled by the axon in isolation from other motor units. Comment: This finding can be visible clinically and can be demonstrated by electromyography (EMG).
Proximal upper limb amyotrophy
Muscular atrophy affecting proximally located muscles of the arms.
Proximal lower limb amyotrophy
Muscular atrophy affecting proximally located muscles of the legs, i.e., of the thigh.
Distal upper limb amyotrophy
Muscular atrophy of distal arm muscles.
Distal lower limb amyotrophy
Muscular atrophy of distal leg muscles. Comment: Distal lower limb muscle atrophy is commonly due to peripheral neuropathy.
Ataxia
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly). Comment: Ataxia can be differentiated into dyssynergy, asynergy, dysmetria (hypometria, hypermetria), dysdiadochokinesis, gait ataxia, truncal ataxia, limb ataxia, and dysarthria). Note: This term does not include sensory ataxia.
Gait ataxia
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
Limb ataxia
A kind of ataxia that affects movements of the extremities. Comment: Limb ataxia is generally caused by lesions of the cerebellar hemispheres and associated pathways.
Abnormality of the basal ganglia
Abnormality of the basal ganglia. Comment: The basal ganglia are a group of nuclei (striatum, pallidum substantia nigra, and the subthalamic nucleus) at the base of the forebrain that are connected to the cerebral cortex, the thalamus, and other areas. The basal ganglia subserve motor functions that are distinct from those of the pyramidal (corticospinal) tract, for which reason neurologic abnormalities caused by lesions to the basal ganglia are often referred to as extrapyramidal.
Dystonia
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Parkinsonism
Characteristic neurologic anomaly resulting form degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Myoclonus
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements. Comment: Myoclonus may be synchronous (several muscle contracting simultaneously), spreading (several muscles contracting in sequence), or asynchronous (several muscles contracting with varying and unpredictable relative timing). Myoclonus is characterized by sudden unidirectional movement due to muscle contraction (positive myoclonus) or due to sudden brief muscle relaxtion (negative myoclonus).
Sensory impairment
An abnormality of the primary sensation that is mediated by peripheral nerves (pain, temperature, touch, vibration, joint position). The word hypoesthesia (or hyesthesia) refers to a reduction in cutaneous sensation to a specific type of testing. Comment: This term does not include abnormalities of cortical sensation such as two-point discrimination, stereognosis, and graphesthesia.
Impaired vibratory sensation
A decrease in the ability to perceive vibration. Clinically, this is usually tested with a tuning fork which vibrates at 128 Hz and is applied to bony prominences such as the malleoli at the ankles or the metacarpal-phalangeal joints. There is a slow decay of vibration from the tuning fork. The degree of vibratory sense loss can be crudely estimated by counting the number of seconds that the examiner can perceive the vibration longer than the patient. Comment: Impaired vibratory sensation may suggesti involvement of the posterior column-medial lemniscus pathway, which is responsible for transmitting fine touch, vibration and conscious proprioceptive information from the body to the cerebral cortex.
Impaired tactile sensation
A reduced sense of touch (tactile sensation). This is usually tested with a wisp of cotton or a fine camel's hair brush, by asking patients to say 'now' each time they feel the stimulus.
Impaired proprioception
A loss or impairment of the sensation of the relative position of parts of the body and joint position.
Impaired temperature sensation
A reduced ability to discriminate between different temperatures. Comment: Temperature sensation can be tested by touching the skin several seconds with a water flask filled to the desired temperature. Persons with normal temperature sensation should at least be able to identify as warm a flask that is 35-36 degrees C and identify as cool a flask at 28-32 degrees C.
Impaired pain sensation
Reduced ability to perceive painful stimuli.
Abnormality of central motor conduction
Any anomaly of the conduction of motor nerve impulses in the central nervous system. Comment: Nerve conduction velocity in the central motor pathways of the brain and spinal cord can be studied by methods including transcutaneous electrical stimulation of the cortex, cervical cord, thoracic cord and conus medullaris and determination of motor latencies to various muscles. This measure is thought to represent conduction in large diameter fibres in the corticospinal tracts.
Motor axonal neuropathy
Progressive impairment of function of motor axons with muscle weakness, atrophy, and cramps. The deficits are length-dependent, meaning that muscles innervated by the longest nerves are affected first, so that for instance the arms are affected at a later age than the onset of deficits involving the lower leg. Comment: Distal motor neuropathy is a bundled term that should not be used if more detailed information about the phenotype is available.
Demyelinating motor neuropathy
Demyelination of peripheral motor nerves. Comment: Demyelinating motor neuropathy demonstrates slow motor nerve conduction velocities with reduced amplitudes of motor nerve conduction and prolonged distal latencies.
Distal peripheral sensory neuropathy
Peripheral sensory neuropathy affecting primarily distal sensation.
Sensory axonal neuropathy
An axonal neuropathy of peripheral sensory nerves.
Demyelinating sensory neuropathy
Demyelination of peripheral sensory nerves.
Mixed demyelinating and axonal polyneuropathy
Hypoplasia of the corpus callosum
Underdevelopment of the corpus callosum. Comment: The corpus callosum appears thin in midline views of the brain in neuroradiological images.
Focal white matter lesions
Cerebral atrophy
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum. Comment: Atrophy may be progressive over time.
Cerebellar atrophy
Atrophy (wasting) of the cerebellum. Comment: Cerebellar atrophy can be diagnosed if the cerebellum is small with shrunken folia and large cerebellar fissures or if it has been shown to undergo progressive volume loss.
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- Spastic Paraplegia Assessment
- General Imaging Diagnostics
General imaging diagnostics report to capture reports that aren't included in the specific subclasses. Inherits all the elements in the abstract Imaging Diagnostics class and the abstract Investigation Class.
- General Non-imaging Diagnostics