In 1968, Kennedy, an American physician, reported a sex-linked genetic disease with clinical predominance of atrophy and weakness of the proximal limb and tongue muscles. Later, this disease was called X-linked spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s Disease (KD).
[Etiology and pathogenesis].
The sex-linked inheritance pattern of KD locates its causative gene on the X chromosome. In 1991, La Spada et al. found an abnormally long CAG repeat in the first exon of the AR gene in KD patients. The number of this sequence in healthy individuals ranged from 11 to 33 times, with an average of 21 times, while the number of this sequence in KD patients ranged from 38 to 72 times, with an average of 46 times. In Japan, a neighboring country to ours, the number of CAGs ranged from 14 to 32 (21±3) times in healthy individuals, while the number of CAGs in KD patients ranged from 44 to 50 (47±3) times. Transgenic mice containing 97 CAG repeats could exhibit clinical signs and pathological features similar to those of KD, and there were gender differences. Thus, it was confirmed that the amplification of the CAG repeat sequence of AR gene was the cause of KD.
Domestic and international literature shows that, similar to other trinucleotide repeat sequence diseases, the number of CAG repeat sequences in KD patients is inversely correlated with the age of onset, i.e., the higher the number of CAG repeat sequences, the earlier the age of onset. However, there was no significant relationship between CAG repeat sequences and the rate and severity of disease progression, which was related to the duration of the patient’s disease. In addition, there was no significant genetic early presentation of KD, and the number of CAG repeat sequences did not differ significantly between the two generations.
The AR gene encodes AR, a ligand-gated target DNA transcriptional regulator, which includes amino-terminal, carboxy-terminal and central segments.
The AR is located in the cytoplasm before binding to its ligand, androgen, and forms a stable bond with the molecular companion protein. When androgens enter the cell and bind to the AR, it leads to the displacement of the AR into the nucleus and binding to the target DNA to exert transcriptional regulation. This is its normal physiological process.
Since KD patients are mostly accompanied by symptoms of hypoandrogenism, an earlier view was that mutations in the AR gene lead to hypofunction of its encoded AR. However, functional analysis of the mutated AR showed that its hormone binding capacity, displacement capacity and physiological functions were no different from those of normal receptors. Moreover, androgen treatment of KD transgenic rats did not improve the disease, but rather led to an increase in muscle weakness symptoms. Androgen therapy in KD patients has also been shown to be ineffective.
A common pathological feature of KD patients and KD transgenic rats is the presence of abnormal intranuclear inclusions in the residual motor neuron (MN). The common pathological feature of KD patients and KD transgenic rats is the presence of abnormal intranuclear inclusion bodies in the residual motor neuron. Immunohistochemical studies have shown that the main component of the inclusion bodies is the broken AR amino terminus. The inability of these inclusion bodies to degrade suggests that mutant proteins are abnormally aggregated in the nucleus, which may be the main cause of neuronal death.
The exact pathogenesis of KD is not fully understood, and several hypotheses have been proposed for the formation of intranuclear inclusion bodies and their effects on cells. It has been suggested that glutamine is the target site for the action of glutaminyl transferase, and that with increased Poly Q, the mutant AR becomes a glutamine donor with which glutaminyl transferase in the brain forms nondegradable binding proteins, thereby producing toxicity to neurons. It has also been suggested that the amplified Poly Q is toxic to neurons by forming encircling b-bonds via hydrogen ions, which then allow non-specific binding between transcription factors to form non-degradable inclusion bodies. Some animal models show a decrease in the non-phosphorylated neurofilament heavy chain (neurofilament
heavy, NF-H) is reduced, suggesting that axonal transport of cells may be impaired. In conclusion, the pathogenesis of KD may involve multiple mechanisms such as apoptosis, axonal transport, cytoprotection, and transcriptional regulation. Animal experiments have shown that androgens can lead to nuclear translocation of mutant ARs and the formation of intranuclear inclusion bodies. Regardless of the mechanism, it is achieved through the binding of androgens to mutant AR.
Pathology]
The general pathology of KD is an extensive reduction in brainstem and spinal cord motor neurons with mild gliosis. Li et al. studied the sensory neuropathology of KD patients. found that the number of large myelinated fibers was reduced in both the central segment (L4 posterior roots, L4, T7 and C6 posterior cords) and the peripheral segment (mast nerve), while small myelinated and unmyelinated fibers were preserved, and demyelination and axonal atrophy were prevalent. Pathology of the spinal ganglia showed a decrease in the number of large cells and an increase in the number of small cells, without significant changes in the total number of nerve cells. This finding suggests that sensory nerve damage originates from neuronal alterations and that sensory system involvement is the primary manifestation of KD. muscle pathology in KD patients showed nonspecific neurogenic damage, manifested by moderate to severe atrophy of muscle fibers, with a fascicular distribution of atrophic fibers and visible histogenesis. There is increased interstitial fat in the muscle fibers without inflammatory cell infiltration.
The characteristic pathological hallmark of KD is the presence of abnormal nuclear inclusion bodies within the remaining motor neurons and some visceral cells of the brainstem and spinal cord. Immunohistochemical studies have shown that the main component of nuclear inclusion bodies is the broken mutated AR amino terminus.
Clinical presentation
Patients with KD are all male and have a positive family history, consistent with an X-linked inheritance pattern, and in a few patients, the family history may not be obvious. The age of onset is middle age, but there are some families with young onset. The clinical manifestations are divided into two aspects: neurological and endocrine system.
1. Neurological system.
Before the symptoms of muscle weakness appear, many patients have a long history of painful muscle spasms, mostly at night or after strenuous activity, most pronounced in the gastrocnemius muscle.
The earliest muscle weakness mostly appeared in the proximal part of both lower extremities, and Atsuta reported that the proximal weakness of both lower extremities accounted for 70.5% of the starting symptoms. In the 27 cases reported by Lu et al. in China, there were 20 cases with proximal onset of both lower extremities. Patients complained of difficulty in going upstairs and difficulty in getting up after squatting. The disease progressed slowly and could gradually develop to the proximal ends of both upper limbs. Patients complained of difficulty in raising both arms, difficulty in holding heavy objects, with generalized flesh jumping. Patients with longer disease duration may develop muscle atrophy of the proximal extremities. Fine movements such as writing, fastening and holding chopsticks are mostly normal, suggesting that the patient has good distal muscle strength. The duration of the disease was 6.41±3.27 years in the 27 patients counted by Lu, and the Appel scale score representing the degree of motor function impairment was 35.93±3.53 (30 to 45). Overall, the degree of motor function impairment in the patients was not severe.
On examination, the lower motor neuron signs were predominant, with a duck walk, weak proximal force in the limbs, diminished or absent tendon reflexes, and negative pathological reflexes such as Bartholin’s sign, but some patients could have upper motor neuron signs such as palmar and mandibular reflexes.
Significant tongue muscle atrophy and fibrillation may appear one to two years after the onset of the disease. The literature reports that about 10% of patients have lingual muscle atrophy as the starting symptom. Unlike motor neuron disease (MND), patients with KD have severe lingual muscle atrophy, but early ball function is well preserved. Dysarthria, choking on water, or dysphagia usually do not occur until 10 to 20 years after the onset of the disease. Since most patients eventually die from pneumonia due to aspiration, ball dysfunction, although not obvious in the early stages of the disease, is an important sign that the disease has reached an advanced stage and often heralds the terminal event.
Patients generally have no complaints of sensory abnormalities, and physical examination is mostly normal in terms of depth and superficial sensation. However, electrophysiological examination reveals significant axonal damage to the sensory nerves. Somatosensory evoked potential (SEP)
SEP (somatosensory evoked potential) mostly indicates damage to deep sensory conduction pathways.
2. Endocrine system.
Some patients show symptoms of androgen hypofunction, such as infertility, oligospermia or azoospermia, and gynecomastia.
The prevalence of endocrine abnormalities such as diabetes mellitus is higher in KD patients than in the normal population. Patients usually have disorders of lipid metabolism, especially elevated triglycerides. Elevated blood uric acid is also common, but there are usually no obvious symptoms of gout. Thyroxine levels are usually normal.
Female carriers tend to have no obvious muscle atrophy or weakness. However, very mild clinical or subclinical manifestations such as mild lingual muscle atrophy, EMG abnormalities, and elevated muscle enzymes have been reported in female carriers. Usually, these symptoms are extremely mild to the point of being unnoticeable. Patients also do not seek medical attention for these symptoms.
As with other CAG repetitive sequence disorders, the number of CAG sequences in a patient is inversely proportional to the time of onset of myasthenia gravis symptoms. That is, the higher the number of CAG sequences, the earlier the onset. However, there was no significant correlation between the number of CAG sequences and the degree of motor function impairment, which was related to the duration of the disease, i.e., the longer the onset, the more severe the motor function impairment.
Patients progress slowly. Atsuta et al.’s statistics of 227 KD patients showed that the time from onset to the need for support was 5 years, the time to the onset of dysarthria was 6 years, and the time to the onset of dysphagia was 10 years, with a total disease duration of about 20 to 30 years, and finally death from respiratory failure or aspiration pneumonia caused by bulbar palsy. The average age of KD patients at death is 10-15 years lower than that of the general population.
Laboratory tests]
Serum creatine kinase (CK) levels were significantly increased, and some patients had increased levels of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), suggesting varying degrees of muscle fiber destruction. the increased levels of CK did not correlate significantly with the number of CAG repeat sequences.
Some patients had increased serum triglyceride (TG) and uric acid (UA) levels, and abnormal glucose tolerance test or 2-hour postprandial glucose. Thyroxine levels were normal in all.
The androgen levels were not low in almost all patients, and even the testosterone level was maintained at a high level, even in the elderly, which indicates that the symptoms of hypoandrogenism in KD patients are not related to the level of androgens in their bodies. The reason for their higher testosterone levels in the body may be due to the compensatory mechanism after the abnormal AR function.
The EMG showed non-specific neurogenic damage, with fibrillation potentials and positive sharp waves visible in the resting state, significantly higher MUAP wave amplitude and prolonged time frame during small force contractions, and simple phase or simple mixed phase during large force contractions. Unlike motor neuron disease (ALS), although the EMG of KD patients also showed neurogenic changes, the magnitude of MUAP wave amplitude increase and time limit prolongation were significantly higher than that of ALS patients, suggesting that the anterior horn damage in KD patients is a relatively chronic process. The motor nerve conduction velocity is mostly normal, but the sensory nerve SNAP amplitude may be reduced, and the sensory nerve conduction velocity (SCV) may be slowed in some patients. There are reports of abnormal motor evoked potentials (MEP) in patients with KD, suggesting damage to the pyramidal tract. In addition, abnormalities in the trigeminal cervical reflex (TCR) are also seen.
Muscle MRI suggests muscle atrophy in the proximal limb, and the atrophied muscle may be replaced by adipose tissue. Foreign literature shows that muscle MRI in KD patients presents muscle atrophy and fatty degeneration selectively, which is different from the generalized muscle atrophy in ALS patients. Muscle MRI can effectively determine the extent and degree of muscle atrophy in KD patients.
Muscle biopsy suggests non-specific neurogenic damage. Moderate-to-severe atrophy of muscle fibers with a small fascicular distribution is seen with NADH staining. GRM, ORO, and PAS staining are free of abnormal material accumulation, and Dys staining is positive, usually without inflammatory cell infiltration. Biopsy of the peroneal nerve suggested a decrease in large myelinated fibers, demyelination of a few fibers, and degeneration of Schwann cells. The presence of intracellular specific nuclear inclusion bodies in the scrotal skin biopsy of KD patients has been reported in the literature.
[Diagnosis].
Based on the family history of sex-linked; male patient with middle-aged onset; slowly progressive muscle weakness and atrophy mainly in the lingual muscles and proximal extremities; predominantly lower motor neuron signs on examination; increased serum CK and electromyography suggesting neurogenic damage, the possibility of this disease should be thought of. If the number of CAG repeats is >40, the diagnosis of KD can be confirmed.
Differential diagnosis
1. amyotrophic lateral sclerosis (ALS): According to the diagnostic criteria of ALS, the necessary condition for the diagnosis of ALS is to have evidence of both upper and lower motor neuron damage. In contrast, patients with KD usually have no or mild upper motor neuron signs, which is an important basis for differentiating between the two. In addition, there is no family history of ALS, muscle weakness and atrophy are usually in the distal limbs, the disease progresses faster, and symptoms such as dysarthria and choking on water appear earlier are also important aspects for differentiation. Clinically, it is not difficult to distinguish KD from ALS, but the literature reports that about 2% of KD patients are misdiagnosed as ALS. Therefore, for those patients with clinically atypical ALS, it is important to think of the possibility of KD, and the final differentiation must rely on genetic testing.
2. Spinal muscular atrophy (SMA): SMA is an autosomal genetic disease and can be classified into 4 types depending on the mode of inheritance, causative genes and age of onset. Types I-III are infantile or juvenile onset; type IV is adult onset. The main symptoms of type IV are slowly progressive weakness and atrophy of the proximal extremities and, in later stages, medullary paralysis. The ultimate differentiation relies on genetic testing.
3, myotonic dystrophy: some specific types of myotonic dystrophy can be adult onset, clinical weakness of the proximal limb is predominant, and serum CK levels are increased. However, myotonic dystrophy often does not have obvious tongue muscle atrophy and muscle fibrillation, its electrophysiology and muscle biopsy often suggest myogenic damage, can be distinguished.
Treatment】
General treatment includes exercise and rehabilitation of limb function.
Currently, there is a lack of effective specific therapeutic drugs for KD. According to the pathogenesis of KD, several possible treatment pathways have been proposed. In the pathogenesis of KD, nuclear inclusion bodies may have an important role as a cause of degenerative death of neuronal cells. In contrast, cellular and animal experiments have shown that androgens, the ligands of AR, accelerate nuclear translocation of mutant AR and that nuclear accumulation of mutant AR is ligand (androgen)-dependent. Myasthenia gravis symptoms in male transgenic rats after castration or pharmacological depot treatment can be dramatically improved and their lifespan prolonged, while the symptoms worsen after testosterone administration, and testosterone can also cause myasthenia gravis and weakness in otherwise asymptomatic female transgenic rats, suggesting a key role of androgens in the pathogenesis of KD. Clinical trials on the administration of pharmacological depot treatment (leuprolide) to KD patients are now in phase III.
Curcumin is a natural phenolic food pigment extracted from turmeric, a plant of the ginger family. In recent years, it has been found to have anti-inflammatory and antioxidant pharmacological effects with low toxicity.In 2007, a study by Yang et al. showed that curcumin significantly improved clinical symptoms, reduced muscle atrophy, and caused a reduction in nuclear inclusion bodies in KD transgenic rats. Moreover, curcumin does not affect serum androgen levels, so it theoretically does not cause significant interference with patients’ lives. Due to its precise efficacy and low toxic side effects demonstrated in animal studies, curcumin is expected to be used clinically, but human study results are still lacking.
In recent years, research on the therapeutic effects of molecular companion proteins on KD has also been a hot topic. Until the mutant AR binds to androgens and is displaced to the nucleus, the AR forms a stable binding to molecular chaperone proteins. Molecular chaperone proteins are usually heat shock proteins (HSP). Basic studies have shown that overexpression of certain molecular chaperone proteins such as HSP70 or HSP105a can improve clinical signs or pathological damage in KD transgenic rats. However, more systematic clinical studies are needed for the application of these drugs in the clinic.