Juvenile amyotrophic lateral sclerosis
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《美国医学杂志》
Department of Pediatrics, University College of Medical Sciences, Guru Tegh Bahadur Hospital, Delhi, India
Abstract
Juvenile amytrophic lateral sclerosis (JALS) is a type of motor neuron disease presenting before 25 years of age. It is characterized by a combination of upper and lower motor signs. It may be familial or sporadic. We are reporting a sporadic case of JALS with onset of symptoms at 4 years of age. Diagnostic criteria and a brief review of literature are presented.
Keywords: Juvenile amyotrophic lateral sclerosis; Early onset
Juvenile amyotrophic lateral sclerosis (JALS) is a form of chronic motor neuron disease with gradual weakness of voluntary muscles resulting from the destruction of neural cells. It is characterized by a combination of upper and lower motor neuron signs. The term JALS has been used for patients with onset of disease before 25 years of age. They usually have a prolonged survival.[1] It may be sporadic or familial. This paper presents a sporadic case of JALS with the onset of symptoms at 4 years of age.
Case Report
A 10-year-old male child presented with progressive weakness of all four limbs since the age of 4. He had difficulty in combing hair, putting on clothes and climbing stairs, suggesting a proximal muscle weakness. The child used to fall while walking and the frequency of falls was gradually increasing. He did not experience any difficulty in swallowing and speech. Bowel and bladder functions were normal. There was no family history of similar illness. He was the first born of a non-consanguineous marriage. Birth was uneventful. On examination, the child was underweight; but height for age was normal. Examination revealed normal intelligence and memory. He had difficulty in getting up from sitting position (Grower's sign positive). Upper and lower limb muscles were wasted bilaterally, more so in proximal muscles, deltoid and glutei. Fasciculations were seen on tongue and upper limbs in the region of deltoid muscle. Tone in the neck extensors was decreased; tone was decreased in the lower limbs as well. There was tightening of tendoachilles, and dorsiflexion of ankle was limited. Tendon reflexes were brisk in all four limbs. Plantar was extensor. Abdominal reflexes were present. Gag reflex was present. There were fine tremors of hands which increased on activity. There were no cerebellar signs or sensory involvement. Evaluation of other organ systems was normal.
Total creatine kinase was 564 U/L. Thyroid function tests were within normal limits. Nerve conduction studies revealed normal motor conduction parameters. Electromyography (EMG) revealed discrete interference patterns in right deltoid, hence a possibility of anterior horn cell degeneration. EMG of left deltoid and vastus lateralis of both sides did not reveal any abnormality. Magnetic resonance imaging of brain and spine were normal. Muscle biopsy did not reveal neurogenic pattern. Immunohistochemistry for dystrophin 1, 2 and 3 was negative. Genetic studies for the exon 7 deletion on telomeric SMN gene of chromosome 5q were negative. Diagnosis of JALS was made on the basis of clinical findings and exclusion of spinal muscular atrophy, muscular dystrophy, thyroid myopathy, any cerebral or cerebellar structural abnormality or extrapyramidal involvement.
Discussion
Amyotrophic lateral sclerosis (ALS) is a form of motor neuron disease characterized by clinical and pathological features of upper and lower motor neuron degeneration. Presentation before 25 years of age is usually termed as juvenile ALS. Its authenticity has been difficult to establish because of the lack of comprehensive study in a large series.[1] Gregg et al[2] described 2 brothers presenting in first decade of life with ALS symptom complex, distal muscular atrophy, increased deep tendon reflexes, spasticity and fasciculations, as seen in the case presented in this paper. Only other case with presentation in first decade was reported by Refsum and Skillicon,[3] hence the rarity of our case.
The combination of upper motor neuron (UMN) and lower motor neuron (LMN) signs distinguishes this condition from the spinal muscular atrophies. In our case, combination of fasciculations, spasticity and wasting was seen. Spinal muscular atrophy and dystrophy was ruled out by biochemical studies, muscle biopsy and genetic studies. Patients of ALS usually have bulbar involvement, though involvement of respiratory and bulbar muscles may not be seen as in our case.[4] The El Escorial Criteria are the two most widely accepted sets of electrodiagnostic criteria for ALS.[5] The electrodiagnostic diagnosis must be supported by appropriate history and physical examination findings. Other diseases that may mimic a generalized disorder of the motor neurons must be excluded by neuroimaging and laboratory testing. Usually, the normal nerve conduction velocities are normal and there is a neurogenic pattern on EMG.[5] There was a discrete interference pattern in left deltoid i.e. a neurogenic pattern on EMG. Nerve conduction velocities were normal. There are reports on atypical forms of juvenile ALS, specially with deafness, monomelic amyotrophy involving one upper extremity and wasted leg syndrome restricted to one lower limb.[5],[6],[7],[8]
Approximately 90% of amyotrophic lateral sclerosis are sporadic and 10% are familial, but majority of the cases of JALS are familial.[9] About 20% of families with familial ALS carry mutation in superoxide dismutase gene (SOD1).[10] Most cases of JALS are autosomal recessive, though an autosomal dominant inheritance patterns have been described.[1] Recessive forms of juvenile ALS have been mapped to chromosome regions 2q33 and 15q12-21.[11] Genetic linkage to the chromosome 9q34 region is seen in the dominantly inherited form.[4] Recently it has been suggested that dominant ALS and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder.[12] Genetic studies could not be carried out in our case due to lack of facilities. Detailed family history did not reveal any evidence of similar illness in the family, hence we assumed our case to be sporadic. A sporadic case of JALS is rare.
The familial cases do not differ in their symptoms and clinical course from nonfamilial ones, although as a group the former has a somewhat earlier age of onset, an equal sex distribution and a slightly shorter survival. Death usually occurs due to respiratory failure or infections in a debilitated patient. Progression of disease is not very rapid in sporadic form of juvenile ALS .
There is no effective treatment for the disease, though thyrotropin release hormone, ganglioside therapy and plasmapheresis have been tried in adults without much benefit.[13], [14] Hence, juvenile amyotrophic lateral sclerosis is a diagnosis of exclusion and should be suspected in a child presenting with a combination of upper and lower motor neuron signs. Sporadic presentation of JALS is rare but has better prognosis than the familial variety.
References
1. Ben Hamida M, Hentati F, Ben Hamida C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Brain 1990; 13 : 347-363.
2. Bradley WG, Krasin F. A new hypothesis of etiology of amytrophic lateral sclerosis: the DNA hypothesis. Arch Neurol 1982; 39 : 677-680.
3. Refums, Skillicon SA. Amyotrophic familial spastic paraplegia. Neurology 1954; 4 : 40-47.
4. Rabin BA, Griffin JW, Crain BJ. Autosomal dominant juvenile amyotrophic lateral sclerosis. Brain 1999; 122 : 1539-1550.
5. World Federation of neurology research group on motor neuron disease. Revised criteria for diagnosis of amytropic lateral sclerosis. www.wfnals.org/Articles/esescorial 1998.htm.
6. Gouriedevi M, Suresh TG, Shankar SK. Pattern of motor neuron disease in south India and monomelic amyotrophy.(A benign atypical form). In Gouriedevi M, eds. Motor Neuron Disease . Oxford and IBH Publishing Co Pvt Ltd India 1984; 171-190.
7. Prabhakar S, Chopra JS, Banerjee AK et al. Wasted leg syndrome. A clinical, electrophysiological and histological study. Clinical Neuro Neurosurg 1981; 83 : 19.
8. Panagariya A, Garg A, Sharma B. Juvenile amyotrophic lateral sclerosis with unusual presentation: A case report. Neurol India 2003; 51 : 413-414.
9. Emery AEH, Holloway S. Familial motor neuron disease. In Rowland LP, ed. Human motor neuron disease. Advances in Neurology. New York; Raven Press; 1982. Vol. 36. 139-47.
10. Rossen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A et al. Mutations in the Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362 : 59-62.
11. Hentati A, Bejaoui K, Pericak-Vance MA, Hentati F, Speer MC, Hung W-Y et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat Genet 1994b; 7 : 425-428.
12. Jonghe PD, Grumbach MA, Wagner IK, Plecko B, Kennerson M, Zhu D et al. Autosomal dominant juvenile amytrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for same disorder. Brain 2002; 125 : 1320-1325.
13. Engel WK, Siddique T, Nicloff JT. Effect on weakness and spasticity in amyotropic lateral sclerosis of thyrotropin releasing hormone. Lancet 1983; 73-75.
14. Olarte MR, SchoenfeldtMG, Rowland LP. Plasmapheresis in amytrophic lateral sclerosis. Ann Neurol 1980; 8 : 644-645.(Aggarwal Anju, Shashiraj)
Abstract
Juvenile amytrophic lateral sclerosis (JALS) is a type of motor neuron disease presenting before 25 years of age. It is characterized by a combination of upper and lower motor signs. It may be familial or sporadic. We are reporting a sporadic case of JALS with onset of symptoms at 4 years of age. Diagnostic criteria and a brief review of literature are presented.
Keywords: Juvenile amyotrophic lateral sclerosis; Early onset
Juvenile amyotrophic lateral sclerosis (JALS) is a form of chronic motor neuron disease with gradual weakness of voluntary muscles resulting from the destruction of neural cells. It is characterized by a combination of upper and lower motor neuron signs. The term JALS has been used for patients with onset of disease before 25 years of age. They usually have a prolonged survival.[1] It may be sporadic or familial. This paper presents a sporadic case of JALS with the onset of symptoms at 4 years of age.
Case Report
A 10-year-old male child presented with progressive weakness of all four limbs since the age of 4. He had difficulty in combing hair, putting on clothes and climbing stairs, suggesting a proximal muscle weakness. The child used to fall while walking and the frequency of falls was gradually increasing. He did not experience any difficulty in swallowing and speech. Bowel and bladder functions were normal. There was no family history of similar illness. He was the first born of a non-consanguineous marriage. Birth was uneventful. On examination, the child was underweight; but height for age was normal. Examination revealed normal intelligence and memory. He had difficulty in getting up from sitting position (Grower's sign positive). Upper and lower limb muscles were wasted bilaterally, more so in proximal muscles, deltoid and glutei. Fasciculations were seen on tongue and upper limbs in the region of deltoid muscle. Tone in the neck extensors was decreased; tone was decreased in the lower limbs as well. There was tightening of tendoachilles, and dorsiflexion of ankle was limited. Tendon reflexes were brisk in all four limbs. Plantar was extensor. Abdominal reflexes were present. Gag reflex was present. There were fine tremors of hands which increased on activity. There were no cerebellar signs or sensory involvement. Evaluation of other organ systems was normal.
Total creatine kinase was 564 U/L. Thyroid function tests were within normal limits. Nerve conduction studies revealed normal motor conduction parameters. Electromyography (EMG) revealed discrete interference patterns in right deltoid, hence a possibility of anterior horn cell degeneration. EMG of left deltoid and vastus lateralis of both sides did not reveal any abnormality. Magnetic resonance imaging of brain and spine were normal. Muscle biopsy did not reveal neurogenic pattern. Immunohistochemistry for dystrophin 1, 2 and 3 was negative. Genetic studies for the exon 7 deletion on telomeric SMN gene of chromosome 5q were negative. Diagnosis of JALS was made on the basis of clinical findings and exclusion of spinal muscular atrophy, muscular dystrophy, thyroid myopathy, any cerebral or cerebellar structural abnormality or extrapyramidal involvement.
Discussion
Amyotrophic lateral sclerosis (ALS) is a form of motor neuron disease characterized by clinical and pathological features of upper and lower motor neuron degeneration. Presentation before 25 years of age is usually termed as juvenile ALS. Its authenticity has been difficult to establish because of the lack of comprehensive study in a large series.[1] Gregg et al[2] described 2 brothers presenting in first decade of life with ALS symptom complex, distal muscular atrophy, increased deep tendon reflexes, spasticity and fasciculations, as seen in the case presented in this paper. Only other case with presentation in first decade was reported by Refsum and Skillicon,[3] hence the rarity of our case.
The combination of upper motor neuron (UMN) and lower motor neuron (LMN) signs distinguishes this condition from the spinal muscular atrophies. In our case, combination of fasciculations, spasticity and wasting was seen. Spinal muscular atrophy and dystrophy was ruled out by biochemical studies, muscle biopsy and genetic studies. Patients of ALS usually have bulbar involvement, though involvement of respiratory and bulbar muscles may not be seen as in our case.[4] The El Escorial Criteria are the two most widely accepted sets of electrodiagnostic criteria for ALS.[5] The electrodiagnostic diagnosis must be supported by appropriate history and physical examination findings. Other diseases that may mimic a generalized disorder of the motor neurons must be excluded by neuroimaging and laboratory testing. Usually, the normal nerve conduction velocities are normal and there is a neurogenic pattern on EMG.[5] There was a discrete interference pattern in left deltoid i.e. a neurogenic pattern on EMG. Nerve conduction velocities were normal. There are reports on atypical forms of juvenile ALS, specially with deafness, monomelic amyotrophy involving one upper extremity and wasted leg syndrome restricted to one lower limb.[5],[6],[7],[8]
Approximately 90% of amyotrophic lateral sclerosis are sporadic and 10% are familial, but majority of the cases of JALS are familial.[9] About 20% of families with familial ALS carry mutation in superoxide dismutase gene (SOD1).[10] Most cases of JALS are autosomal recessive, though an autosomal dominant inheritance patterns have been described.[1] Recessive forms of juvenile ALS have been mapped to chromosome regions 2q33 and 15q12-21.[11] Genetic linkage to the chromosome 9q34 region is seen in the dominantly inherited form.[4] Recently it has been suggested that dominant ALS and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder.[12] Genetic studies could not be carried out in our case due to lack of facilities. Detailed family history did not reveal any evidence of similar illness in the family, hence we assumed our case to be sporadic. A sporadic case of JALS is rare.
The familial cases do not differ in their symptoms and clinical course from nonfamilial ones, although as a group the former has a somewhat earlier age of onset, an equal sex distribution and a slightly shorter survival. Death usually occurs due to respiratory failure or infections in a debilitated patient. Progression of disease is not very rapid in sporadic form of juvenile ALS .
There is no effective treatment for the disease, though thyrotropin release hormone, ganglioside therapy and plasmapheresis have been tried in adults without much benefit.[13], [14] Hence, juvenile amyotrophic lateral sclerosis is a diagnosis of exclusion and should be suspected in a child presenting with a combination of upper and lower motor neuron signs. Sporadic presentation of JALS is rare but has better prognosis than the familial variety.
References
1. Ben Hamida M, Hentati F, Ben Hamida C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Brain 1990; 13 : 347-363.
2. Bradley WG, Krasin F. A new hypothesis of etiology of amytrophic lateral sclerosis: the DNA hypothesis. Arch Neurol 1982; 39 : 677-680.
3. Refums, Skillicon SA. Amyotrophic familial spastic paraplegia. Neurology 1954; 4 : 40-47.
4. Rabin BA, Griffin JW, Crain BJ. Autosomal dominant juvenile amyotrophic lateral sclerosis. Brain 1999; 122 : 1539-1550.
5. World Federation of neurology research group on motor neuron disease. Revised criteria for diagnosis of amytropic lateral sclerosis. www.wfnals.org/Articles/esescorial 1998.htm.
6. Gouriedevi M, Suresh TG, Shankar SK. Pattern of motor neuron disease in south India and monomelic amyotrophy.(A benign atypical form). In Gouriedevi M, eds. Motor Neuron Disease . Oxford and IBH Publishing Co Pvt Ltd India 1984; 171-190.
7. Prabhakar S, Chopra JS, Banerjee AK et al. Wasted leg syndrome. A clinical, electrophysiological and histological study. Clinical Neuro Neurosurg 1981; 83 : 19.
8. Panagariya A, Garg A, Sharma B. Juvenile amyotrophic lateral sclerosis with unusual presentation: A case report. Neurol India 2003; 51 : 413-414.
9. Emery AEH, Holloway S. Familial motor neuron disease. In Rowland LP, ed. Human motor neuron disease. Advances in Neurology. New York; Raven Press; 1982. Vol. 36. 139-47.
10. Rossen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A et al. Mutations in the Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362 : 59-62.
11. Hentati A, Bejaoui K, Pericak-Vance MA, Hentati F, Speer MC, Hung W-Y et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat Genet 1994b; 7 : 425-428.
12. Jonghe PD, Grumbach MA, Wagner IK, Plecko B, Kennerson M, Zhu D et al. Autosomal dominant juvenile amytrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for same disorder. Brain 2002; 125 : 1320-1325.
13. Engel WK, Siddique T, Nicloff JT. Effect on weakness and spasticity in amyotropic lateral sclerosis of thyrotropin releasing hormone. Lancet 1983; 73-75.
14. Olarte MR, SchoenfeldtMG, Rowland LP. Plasmapheresis in amytrophic lateral sclerosis. Ann Neurol 1980; 8 : 644-645.(Aggarwal Anju, Shashiraj)