Kennedy's Disease and other Motor Neuron Diseases.
P.K. Ghatak, M.D.
In 1966 Dr. William R. Kennedy reported a case from Minnesota of a 54 old man with progressive weakness of limb muscles and facial muscles. Working an an assumption that it was an inherited disease, he studied all the members of the entire family for evidence of similar cases. He concluded that it was inherited as an X-linked disease, a new type of spinal bulbar muscular atrophy. Subsequently, other investigators found abnormal sex hormone levels, gynecomastia, low sperm count, testicular atrophy, diabetes mellitus and some sensory impairments in these patients. This disease in known as Kennedy's disease.
Motor neuron disease(MND).
In 1933 Russell Brain of the UK coined the term motor neuron disease for a group of neurodegenerative diseases. Until then, these diseases were known by their neuroanatomical pathophysiological basis. MND is the third most common degenerative disease of the nervous system, after Alzheimer disease and Parkinson's disease.
The incidence of MND is 2 to 3 per 100,000 per year in the USA; 0.8 in the Far East, 1 to 2 in South Asia and 3 to 4 in Europe per 100,000 respectively.
Motor Neuron Disease (MND) includes - Amyotrophic Lateral Sclerosis, Progressive Bulbar Palsy, Primary Lateral Sclerosis, Spinal Muscular Atrophy, Post-polio Syndrome and Kennedy's Disease. However, many others consider all MNDs are variations of ALS; still others include Pseudobulbar palsy, Facial Skeletal Atrophy, Spinobulbar Atrophy and Hereditary Spastic Paralysis as distinct additional entities of MND.
The motor neuron cells of the cerebral cortex are called Upper motor Neurons (UMN). These cells make synaptic connections with motor neurons of the cranial nerves and the anterior horn cells of the spinal cord. UMNs do not directly carry impulses to muscle fibers. The motor neurons of the cranial nerves and the anterior horn cells of the spinal cord are called Lower Motor Neurons (LMN). They are the final common path of all motor actions – voluntary actions and involuntary reflex actions.
The common characteristic of Motor neuron disease is the progressive loss of either UMN or LMN or both UMN and LMN. The motor cranial nerves are 3rd,4th, 6th, 9th, 11th and 12th. The following cranial nerves are mainly sensory but also carry motor fibers – 5th, 7th and 10th.
Amyotrophic Lateral Sclerosis (ALS).
In ALS, both UMN and LMN are affected. In the USA, ALS is better known as Lou Gehrig's disease, named after a famous baseball player who developed ASL in 1939. The disease usually manifests in midlife as muscular twitching and stiffness, then progressively develops muscle weakness of limbs, larynx, throat and the rest of the body. There are wide variations of the site of origin of weakness, spread and rate of progression of the disease. In some cases, muscle weakness starts and stays limited to limbs and in others in muscles of swallowing and breathing. However, in most cases, ALS involves both groups of muscles and the disease progresses rapidly. The death is usually in 3 to 4 years from respiratory failure. [ amyotrophy = atrophy ]
Progressive Bulbar Palsy.
The muscles supplied by motor neurons of cranial nerves slowly degenerate, it is a LMN disease. Health and survival of these muscles are vital for longevity, once symptoms related to muscle weakness begin the prognosis becomes poor. In some patients, a full picture of ALS develops.
Primary Lateral Sclerosis (PLS).
In PLS, only UMNs are involved. The symptoms of PLS start between 40 and 60 years of age. The initial symptoms are muscle stiffness and unsteady balance. Weakness of skeletal muscles develops, but life is not cut short in many PLS patients, while others are not.
Spinal Muscular Atrophy (SMA).
The incidence of SMA is less than ALS. It mainly affects the LMN. Limb and facial muscles become weak and atrophic, and spinal curvature develops. Four different types of SMA are known,
Type 1 is also known as Werdnig- Hoffman disease. The disease begins at 6 months of age, muscle tone is poor and reflexes are slow and feeble. Milestone of development lags behind. Ultimately, the child develops difficulty in breathing and death is from respiratory failure.
Type 2. It is a milder form of SMA. The symptoms start at 6 to 12 months of age. The child shows difficulty in standing by himself and walking. But does not develop respiratory muscle weakness.
Type 3. It is also called Kugelburg-Welander disease. The symptoms start between 3 and 10 years of age, mainly in the form of joint and spinal column deformities due to short muscles and tendons.
Type 4. The symptoms appear at around the age of 30 years. The muscles of the arms and legs are weak and later become atrophic.
Post-polio syndrome.
Poliomyelitis virus affects the anterior horn cells of the spinal cord. Those cells survive the initial onslaught and recover, however, are susceptible to viral infection and affected by a variety of illnesses including surgery and general anesthesia. The most offending organism is is E-B virus. Patients develop flaccid paralysis of limbs or difficulty in swallowing, nasal intonation of speech and breathing difficulties. Recovery is the general rule with gamma globulin therapy and other measures to preserve and recover muscle functions.
Cause of MND.
Most cases occur sporadically and are not inherited. Only about 5 to 10 % of cases are due to inherited mutations of a gene or multiple genes. As of today, many genetic mutations are mentioned but here only those mutations that are proven to be the cause, will be presented.
Kennedey's Disease.
The proximal arm of chromosome X carries the DXYS gene which encodes CAG (cytosine, Adenine and Guanine) nucleotides. Mutation of the DXYS gene results in an expansion of repeat of CAG from the normal 30 to 40 - 60 times. Overcrowding, which results from so many repeats, interferes with the functioning of the gene that encodes proteins for androgen receptors. Deficiency of androgen hormone results in testicular atrophy, oligospermia, and hypogonadism.
ALS.
In ALS, the mutation is present in the SOD1(superoxide dismutase 1) gene and to a lesser extent in the SOD2 gene. Mutation of these two genes results in the accumulation of superoxide dismutase and other radicals. Accumulated radicals sicken and kill neurons. The chromosome 9 open reading frame 72 (C9orf72) encodes a protein that ferries nerve impulses across the synapses and to the muscle end plates. When muscles lose nerve connection, they undergo atrophy and degeneration. The speed of progression of ALS depends on the degree of mutation of these genes and is responsible for the wide variation of the clinical features of ALS.
The mode of inheritance is usually autosomal recessive, but autosomal dominant and X-link recessive modes are also seen.
Spinal Muscular Atrophy (SMA).
Motor neurons require a special protein, Survival Motor Neuron (SMN) protein. The SMA1 gene encodes SMA protein and the SMA2 gene also encodes SMA protein to a much lesser extent. SMA1 gene mutation varies greatly and some patients carry multiple copies of the mutated gene. The more mutated genes one carries, the disease manifests early and the clinical picture gets worse. A normal SMA 2 gene can have a beneficial influence but if also mutated then the outlook becomes dismal. The clinical types of SMA are due to this variation in the number of mutated SMA1 and SMA2 genes and their ratio.
***************************************************
