Penyakit motor neuron

Penyakit motor neuron (bahasa Inggeris: motor neuron diseases; MND) adalah sekumpulan penyakit gangguan neurologi yang memberi kesan motor neuron terpilih, sel-sel yang mengawal aktiviti-aktiviti otot dengan sendiri termasuklah bercakap, berjalan, bernafas, menelan dan pergerakan umum badan.

Terminologi
MND merujuk kepada sekumpulan  penyakit yang menjejaskan motor neuron. Di Amerika Syarikat, MND biasanya dipanggil sebagai sklerosis lateral amiotrofik (ALS), atau  Penyakit Lou Gehrig, selepas pemain besbol. Di Perancis, penyakit ini kadangkala dikenali sebagai maladie de Charcot (Penyakit Charcot), walaupun ia dirujuk sebagai terjemahan terus ALS, sclerose laterale amyotrophique (SLA). Bagi mengelakkan kekeliruan, persidangan saintifik tahunan ini ditujukan kepada kajian  MND dipanggil sebagai  Simposium ALS/MND . ALS/MND merujuk kepada subset spesifik kepada penyakit identical patologi; di sana terdapat penderitaan motor neuron yang tidak   patologi jauh daripada ALS/MND dan mempunyai kursus klinik berbeza. Contoh-contoh penyakit-penyakit lain daripada  motor neuron yang lain seharusnya tidak dikelirukan dengan  ALS/MND termasuklah atrofi otot spinobulbar, atrofi otot spina,Penyakit Charcot-Marie-Tooth, dan banyak yang lain.

Sejarah
Walaupun pakar neurologi abad ke-19 lain sebelum ini telah menghuraikan penyakit ini, pakar neurologi Perancis, Jean-Martin Charcot, mula-mula mencadangkan pengelompokan keadaan berbeza yang mempengaruhi tanduk lateral saraf tunjang pada 1869.

Pengelasan
Bentuk penyakit motor neuron termasuklah:
 Sklerosis lateral amiotropik (ALS) (juga dikenali sebagai penyakit Lou Gehrig)
 Sklerosis lateral primer (PLS)
 Sklerosis lateral progresif (PMA)
 Penyakit bulbar
 Palsi pseudobulbar - spastik
 Palsi bulbar progresif - spastik dan flasid

"Kawasan bulbar" dalam jadual di atas merujuk kepada mulut, muka dan tekak. Atrofi otot tulang belakang (SMA) dikelaskan di bawah MND oleh MeSH, tetapi tiada dalam ICD-10.

Punca 
Kira-kira 90% kes MND adalah sporadik, bermakna pesakit tidak mempunyai sejarah keluarga ALS, dan kes itu nampaknya berlaku tanpa sebab yang diketahui. Faktor genetik disyaki penting dalam menentukan kerentanan individu terhadap penyakit, dan terdapat beberapa bukti lemah yang menunjukkan bahawa permulaan boleh "dicetuskan" oleh faktor persekitaran yang belum diketahui (lihat 'Epidemiologi' di bawah).

Kira-kira 10% daripada kes adalah "MND keluarga", ditakrifkan sama ada oleh sejarah keluarga MND atau dengan ujian positif bagi mutasi genetik yang diketahui berkaitan dengan penyakit tersebut. Gen berikut diketahui dikaitkan dengan ALS: Cu/Zn superoksida dismutase , ,  (sebilangan kecil kes), senataksin () dan vesikel berkaitan protein B ().

Of these, SOD1 mutations account for some 20% of familial MND cases. The SOD1 gene codes for the enzyme superoxide dismutase, a free radical scavenger that reduces the oxidative stress of cells throughout the body. So far over 100 different mutations in the SOD1 gene have been found, all of which cause some form of ALS(ALSOD database). In North America, the most commonly occurring mutation is known as A4Vand occurs in up to 50% of SOD1 cases. In people of Scandinavian extraction there is a relatively benign mutation called D90A which is associated with a slow progression. In Japan, the H46R mutation is most common. G93A, the mutation used to generate the first animal model (and by far the most widely studied), is present only in a few families worldwide. Future research is concentrating on identifying new genetic mutations and the clinical syndrome associated with them. Familial MND may also confer a higher risk of developing cognitive changes such as frontotemporal dementia or executive dysfunction (see 'extra-motor change in MND' below).

It is thought that SOD1 mutations confer a toxic gain, rather than a loss, of function to the enzyme. SOD1 mutations may increase the propensity for the enzyme to form protein aggregates which are toxic to nerve cells.

Patofisiologi
Skeletal muscles are innervated by a group of neurones (lower motor neurones) located in the ventral horns of the spinal cord which project out the ventral roots to the muscle cells. These nerve cells are themselves innervated by thecorticospinal tract or upper motor neurones that project from the motor cortex of the brain. On macroscopic pathology, there is a degeneration of the ventral horns of the spinal cord, as well as atrophy of the ventral roots. In the brain, atrophy may be present in the frontal and temporal lobes. On microscopic examination, neurones may showspongiosis, the presence of astrocytes, and a number of inclusions including characteristic "skein-like" inclusions, Bunina bodies, and vacuolisation. Bunina bodies were first described in 1962; they are markers of neuronal degeneration.

The availability of mouse models has led to extensive research into the causes of SOD1-mutant linked familialALS. The most commonly used mouse model is G93A,although many others have since been generated. At the gross physiological level, the mouse models faithfully recapitulate the features of human ALS (motorneuron death, muscle atrophy, respiratory failure).

Although there is tiada consensus as to the exact mechanism by which mutated SOD1 causes the disease (in either mice or patients), studies based largely on mouse models suggest a role for excitotoxicity and more controversially, oxidative stress, presumably secondary to mitochondrial dysfunction. Death by apoptosis has also been suggested.

Punca dan simpton
Symptoms usually present themselves between the ages of 50-70, and include progressive weakness, muscle wasting, and musclefasciculations, spasticity or stiffness in the arms and legs, and overactive tendon reflexes. Patients may present with symptoms as diverse as a dragging foot, unilateral muscle wasting in the hands, or slurred speech. 

Neurological examination presents specific signs associated with upper and lower motor neurone degeneration. Signs of upper motor neurone damage include spasticity, brisk reflexes and the Babinski sign. Signs of lower motor neurone damage include weakness and muscle atrophy. 

Note that every muscle group in the body requires both upper and lower motor neurones to function. The signs described above can occur in any muscle group, including the arms, legs, torso, and bulbar region. 

The symptoms described above may resemble a number of other rare diseases, known as "MND Mimic Disorders". These include, but are not limited to, multifocal motor neuropathy, Kennedy's disease, hereditary spastic paraplegia, spinal muscular atrophy and monomelic amyotrophy. A small subset of familial MND cases occur in children, such as "juvenile ALS", Madras syndrome, and individuals who have inherited the ALS2 gene. However, these are not typically referred to as MND, but by their specific names.

Diagnosis
The diagnosis of MND is a clinical one, established by a neurologist on the basis of history and neurological examination. There is tiada diagnostic test for MND. Investigations such as blood tests, electromyography (EMG), magnetic resonance imaging  (MRI), and sometimes genetic testing are useful to rule out other disorders that may mimic MND. However, the diagnosis of MND remains a clinical one. Having excluded other diseases, a relatively rapid progression of symptoms is a strong diagnostic factor. Although an individual's progression may sometimes "plateau", it will not improve. 

A set of diagnostic criteria called the El Escorial criteria have been defined by the World Federation of Neurologists for use in research, particularly as inclusion/exclusion criteria for clinical trials. Owing to a lack of clinical diagnostic criteria, some neurologists use the El Escorial criteria during the diagnostic process, although strictly speaking this is functionality creep, and some have questioned the appropriateness of the criteria in a clinical setting.
 
It is possible that Transcranial magnetic stimulation can be used to diagnose MND.

Rawatan
Currently there is tiada cure for ALS.  The only drug that affects the course of the disease is riluzole. The drug functions by blocking the effects of the neurotransmitter glutamate, and is thought to extend the lifespan of an ALS patient by only a few months.

The lack of effective medications to slow the progression of ALS does not mean that patients with ALS cannot be medically cared for. Instead, treatment of patients with ALS focuses on the relief of symptoms associated with the disease. This involves a variety of health professionals including neurologists, speech-language pathologists, physical therapists,occupational therapists, dieticians, respiratory therapists, social workers, palliative care specialists, specialist nurses and psychologists.

Prognosis
Most cases of MND progress quite quickly, with noticeable decline occurring over the course of months. Although symptoms may present in one region, they will typically spread. If restricted to one side of the body they are more likely to progress to the same region on the other side of the body before progressing to a new region. After several years, most patients require help to carry out activities of daily living such as self care, feeding, and transportation. 

MND is typically fatal within 2–5 years. Around 50% die within 14 months of diagnosis. The remaining 50% will not necessarily die within the next 14 months as the distribution is significantly skewed. As a rough estimate, 1 in 5 patients survive for 5 years, and 1 in 10 patients survive 10 years. Professor Stephen Hawking is a well-known example of a person with MND, and has lived for nearly 50 years with the disease. The television film Hawking starring Benedict Cumberbatch was made in 2004 about him and this disease.

Mortality normally results when control of the diaphragm is impaired and the ability to breathe is lost. One exception isPrimary Lateral Sclerosis (PLS), which may last for upwards of 25 years. Given the typical age of onset, this effectively leaves most PLS patients with a normal life span. PLS can progress to ALS, decades later.

Komplikasi

Kesan emosi

Around a third of all MND patients experience labile affect, also known as emotional lability, pseudobulbar affect, or pathological laughter and crying. Patients with pseudobulbar palsy are particularly likely to be affected, as are patients with PLS.

Kesan terhadap kognisi dan deria
Cognitive change occurs in between 33–50% of patients. A small proportion exhibit a form offrontotemporal dementia characterised by behavioural abnormalities such as disinhibition, apathy, and personality changes. A small proportion of patients may also suffer from an aphasia, which causes difficulty in naming specific objects. A larger proportion (up to 50%) suffer from a milder version of cognitive change which primarily affects what is known as executive function. Briefly, this is the ability of an individual to initiate, inhibit, sustain, and switch attention and is involved in the organisation of complex tasks down to smaller components. Often patients with such changes find themselves unable to do the family finances or drive a car. Depressionis surprisingly rare in MND (around 5–20%) relative to the frequency with which it is found in other, less severe, neurological disorders e.g. ~50% in multiple sclerosis and Parkinson's disease, ~20% in Epilepsy.  Depression does not necessarily increase as the symptoms progress, and in fact many patients report being happy with their quality of life despite profound disability.  This may reflect the use of coping strategies such as reevaluating what is important in life.

Although traditionally thought only to affect the motor system, sensory abnormalities are not necessarily absent, with some patients finding altered sensation to touch and heat, found in around 10% of patients. Patients with a predominantly upper motor neurone syndrome, and particularly PLS, often report an enhanced startle reflex to loud noises.

Neuroimaging and neuropathology has demonstrated extra-motor changes in the frontal lobes including the inferior frontal gyrus, superior frontal gyrus, anterior cingulate cortex, and superior temporal gyrus. The degree of pathology in these areas has been directly related to the degree of cognitive change experienced by the patient, if any. Patients with MND and dementia have been shown to exhibit marked frontotemporal lobe atrophy as revealed by MRI or SPECT neuroimaging.

Epidemiologi
The incidence of MND is approximately 1–5 out of 100,000 people. Men have a slightly higher incidence rate than women. Approximately 5,600 cases are diagnosed in the U.S. every year. By far the greatest risk factor is age, with symptoms typically presenting between the ages of 50-70. Cases under the age of 50 years are called "young onset MND", whilst incidence rates appear to tail off after the age of 85. 

There are three "hot spots" of MND in the world. One is in the Kii peninsula of Japan, one amongst a tribal population inPapua New Guinea. Chamorro inhabitants from the island of Guam in the Pacific Ocean have an increased risk of developing a form of MND known as Guamanian ALS-PD-dementia complex or "lytico bodig", although the incidence rate has declined over the last 50 years and the average age of onset has increased.Putative theories involve neurotoxins in the traditional diet including cycad nut flour and bats that have eaten cycad nuts.

Etimologi
Terminology around the motor neurone diseases can be confusing; in the UK "motor neurone disease" refers to both ALS specifically (the most common form of disease) and to the broader spectrum of motor neurone diseases including progressive muscular atrophy, primary lateral sclerosis, and progressive bulbar palsy. In the United States the most common terms used are ALS (both specifically for ALS and as a blanket term) or "Lou Gehrig's disease".

Amyotrophic comes from the Greek language: A- means "no", myo refers to "muscle", and trophic means "nourishment"; amyotrophic therefore means "no muscle nourishment," which describes the characteristicatrophication of the sufferer's disused muscle tissue. Lateral identifies the areas in a person's spinal cord where portions of the nerve cells that are affected are located. As this area degenerates it leads to scarring or hardening ("sclerosis") in the region.

Lihata juga 
 :Category:People with motor neurone disease
 :Category:Deaths from motor neurone disease
 Kennedy's disease
 Monomelic amyotrophy
 Primary lateral sclerosis
 Progressive muscular atrophy
 Riluzole

Rujukan

Pautan luar 
 MND Association
 MND Scotland
 
 MND Association of Australia
 Motor Neuron Disease Association of South Africa
 ALS Association (US-based)
 ALS Society of Canada
 Project A.L.S
 ALSOD Database of all known SOD1 mutations
 ALS Therapy Development Foundation

Disability
 
Systemic atrophies primarily affecting the central nervous system
Rare diseases
nl:Amyotrofische laterale sclerose