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amyotrophic lateral sclerosis (ALS); Lou Gerig's disease

Etiology: 1) degeneration of motor neurons at all levels of the CNS a) anterior horn cells in the spinal cord b) brainstem motor nuclei c) neurons in the motor cortex d) variants in TP73 correlate with risk for ALS& suggest a role for apoptosis in pathology of ALS [27] 2) frontotemporal dementia sometimes a comorbidity [2] 3) familial forms 4) risk factors - pesticides (RR=5.1) [14] - pentachlorobenzene, cis-chlordane, polychlorinated biphenyl (PCB) 175, PCB 202, & polybrominated diphenyl ether (PBDE) 47 - lead exposure, PCB 151 & PBDE 66 with protective effects [14] - exposure to diesel exhaust (RR=1.2-1.4) [22] - physical activity (RR=1.06-1.07) [23] - professional soccer, 3.2 cases per 100,000 person-years (RR=2) [24] Epidemiology: - 5.0 per 100,000 Americans, 1.7 per 100,000 [24] - 20 per 100,000 among Americans in their 70s [21] Pathology: 1) upper & lower motor neuron degeneration in cranial, cervical, thoracic & lumbosacral regions 2) the most striking changes are seen in affected muscles & anterior spinal nerve roots 3) some cases show selective atrophy of the precentral gyrus 4) loss of large motor neurons with gliosis most easily seen in anterior horns of the lumbar & cervical spinal cord 5) neurofilament (NF)-rich inclusions in neurons of the spinal cord & brain, colocalization of MAP6 6) spinal cord: a) degeneration of crossed & uncrossed pyramidal tracts b) diffuse loss of myelin in anterior & lateral columns c) intact posterior columns, sometimes some cell loss in Clarke's column 7) neurochemical changes: a) antiganglioside antibodies b) reduced muscarinic cholinergic, glycinergic, benzodiazepine, & TRH receptors c) decreased fibers containing enkephalin, neurokinin, somatostatin, substance P, & TRH in some cases d) accumulation of cholesterol esters & ceramides (globosides ?) [3] Genetics: - mutation in SOD1 in one familial form - genetic variation in DPP6 may influence susceptibility to ALS - defects in NEFH are a cause of susceptibility to ALS - defects in ANG are the cause of susceptibility to ALS type 9 - defects in TARDBP/TDP43 are the cause of ALS type 10 - pathogenic mutation in ARPP21 identified in 12 patients from Spain [31] - variants in TP73 correlate with risk for ALS & suggest a role for apoptosis in pathology of ALS [27] - hexanucleotide-repeat expansion in the C9ORF72 gene in ~10% of patients - other implicated genes: RNF19A - relative of patients with ALS at increased risk of schizophrenia & other psychiatric disorders [20] Clinical manifestations: 1) onset usually mid-life 2) most cases rapidly progressive with death in 3-5 years 3) upper motor neuron signs + lower motor neuron signs 4) presentation may be asymmetric with single limb involvement [2] 5) hands & arms involved more than legs a) hand muscles involved early b) muscle weakness c) muscle wasting/muscle atrophy (lower motor neuron sign) d) muscle stiffness, muscle rigidity may be asymmetric e) muscle cramping, muscle spasms f) muscle twitching g) hyperreflexia/hyporeflexia, reflexes may be preserved h) spasticity i) + Babinski's sign j) fasciculations (lower motor neuron sign) - fasciculations occur in association with muscle weakness or muscle atrophy [2] k) clonus 6) brainstem involvement a) dysarthria b) dysphagia c) pseudobulbar palsy d) wasting of tongue e) fasciculations of tongue [11] 7) preserved intellect 8) lack of sensory abnormalities 9) extraocular muscles intact, no weakness 10) absence of bowel or bladder dysfunction 11) progressive respiratory deterioration Laboratory: 1) cerebrospinal fluid (CSF): normal 2) elevated muscle enzymes: a) serum creatine kinase b) serum aldolase 3) serology: - antibodies to gangliosides: anti-GM1 & anti-GD1b - dipeptidyl peptidase 6 IgG in CSF - dipeptidyl peptidase 6 IgG in serum 4) arterial blood gas (ABG): hypercapnia 5) lipid panel - higher HDL cholesterol in serum & higher HDL/total cholesterol associated with reduced risk for ALS [28] - higher apolipoprotein A1 in serum associated with reduced risk for ALS [28] 6) exclusion testing: a) heavy metals in urine & serum - serum copper b) thyroid function tests c) serum protein electrophoresis d) lysosomal enzyme activities e) serum vitamin B12 & serum folate levels f) serologic tests for syphilis g) Lyme serology h) complete blood count (CBC) i) erythrocyte sedimentation rate (ESR); serum C-reactive protein (CRP) j) chemistry profile: 1] serum glucose 2] serum calcium, serum PTH if elevated 3] serum chloride 7) genetic testing - SOD1 gene mutation Special laboratory: 1) electromyography is diagnostic test of choice a) muscle denervation with chronic reinnervation b) involvement of different peripheral nerves & nerve roots c) fasciculation potentials 2) pulmonary function tests (PFT) - ventilation management 3) polysomnography may be helpful in titrating ventilation management (BiPap) [2,7] 4) swallowing evaluation if bulbar signs [2] Radiology: - magnetic resonance imaging (MRI) better than computed tomography a) not diagnostic b) T2 bright signal bilateral in corticospinal tract may be observed c) exclude spinal cord lesions 1] spinal cord compression 2] cervical spondylosis d) cervical spine lesions can produce bulbar signs & symptoms if the brainstem is also involved Differential diagnosis: - secondary motor neuron disorders (see motor neuron disease) - chronic traumatic encephalopathy - Lyme disease - hyperparathyroidism - thyroxicosis - sensory symptoms or pain, cognitive impairment or extaocular muscle weakness suggest an etiology other than ALS [2] - fasciculations without muscle weakness or muscle atrophy or muscle weakness/muscle atrophy with fasciculations is not ALS Complications: 1) respiratory failure is the cause of death in most cases 2) nocturnal ventilatory impairment may precede awakend-state hypoventilation 3) aspiration 4) 20% of patients with develop frontotemporal dementia [2] Management: 1) supportive care a) goals - prolong independence - improve quality of life [2] b) non-invasive ventilatory support for symptoms of respiratory insufficiency (BiPap) [2,7] - early diaphragm pacing hastens the need for BiPap & increases mortality [17] c) occupational therapy for energy-conservation techniques to maintain function [30] d) physical therapy for muscle stretching to maintain function [30] e) strength training, endurance exercise & balance training not helpful [30] d) enteral feeding (percutaneous encoscopic gastrostomy) [2] e) high-carbohydrate, high calorie diet may improve survival* [10] 2) riluzole may be effective in slowing the progression of ALS - increases survival by 3 months on average [2] 3) edaravone (Radicava) FDA-approved May 2017 [2,18] - may benefit mildly symptomatic patients 4) lithium carbonate, therapeutic range 0.4-0.8 meq/L [4] {investigational} 5) IV or intrathecal thyrotropin-releasing hormone (TRH) 6) dextromethorphan/quinidine (Nuedexta) may be useful for treatment of pseudobulbar palsy [6] 7) agents in clinical trials a) ciliary neurotrophic factor (CNTF) b) insulin-like growth factor-1 (IGF-1) c) sodium phenylbutyrate/taurursodiol (AMX0035) [26] 8) other investigational therapies - repeated intrathecal antisense oligonucleotides that selectively blunt expression of G4C2 repeat-containing transcripts & effectively suppress CSF levels of poly(GP) dipeptides [29] (see C9ORF72) * mildly obese patients with ALS have longer survival [10]

Related

alsin; amyotrophic lateral sclerosis 2 chromosomal region candidate gene 6 protein; amyotrophic lateral sclerosis 2 protein (ALS2 ALS2CR6 KIAA1563) amyotrophic lateral sclerosis [ALS] 2 chromosomal region candidate gene hospice guidelines for determining prognosis, amyotrophic lateral sclerosis (ALS)

Specific

amyotrophic lateral sclerosis type 17 amyotrophic lateral sclerosis type 2; juvenile amyotrophic lateral sclerosis amyotrophic lateral sclerosis with dementia familial amyotrophic lateral sclerosis (ALS) juvenile amyotrophic lateral sclerosis with dementia pagetoid amyotrophic lateral sclerosis (inclusion body myopathy with early-onset Paget disease & frontotemporal dementia, IBMPFD, muscular dystrophy limb-girdle with Paget disease of bone, pagetoid neuroskeletal syndrome, lower motor neuron degeneration with Paget-like bone disease) primary juvenile lateral sclerosis sporadic amyotrophic lateral sclerosis (ALS)

General

motor neuron disease neurodegenerative disease

Database Correlations

OMIM 611895 Kegg hsa/hsa05030

References

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  3. Chemical & Engineering News, Aug 26, 2002
  4. Fornai F et al, Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008, 105:2052 PMID: 18250315
  5. DeJesus-Hernandez M et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011 Oct 20; 72:245. PMID: 21944778 - Renton AE et al A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20;72(2):257-68. Epub 2011 Sep 21. PMID: 21944779
  6. PubMed Health Dextromethorphan and Quinidine http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0016263/
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  20. Kneisel K Relatives of ALS Patients More Apt to Have Mental Health Issues. Irish study suggests ties between pleiotropic genes, ALS, and neuropsychiatric disease. MedPage Today. October 18, 2017 https://www.medpagetoday.com/Psychiatry/Dementia/68620 - Chuquilin M, Wymer S, Wymer J Increasing Evidence for an Association Between Amyotrophic Lateral Sclerosis and Psychiatric Disorders. JAMA Neurol. Published online October 16, 2017 PMID: 29049449 https://jamanetwork.com/journals/jamaneurology/article-abstract/2657320
  21. MedPage Today Staff ALS Prevalence Put at 5.0 per 100,000 (MMWR). Rate hit 20 per 100,000 among Americans in their 70s. MedPage Today. February 22, 2018 https://www.medpagetoday.com/neurology/generalneurology/71322 - Mehta P, Kaye W, Raymond J, et al. Prevalence of Amyotrophic Lateral Sclerosis - United States, 2014. MMWR Morb Mortal Wkly Rep 2018;67:216-218 https://www.cdc.gov/mmwr/volumes/67/wr/mm6707a3.htm
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  32. Amyotrophic Lateral Sclerosis (ALS) Fact Sheet https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet - NINDS Amyotrophic Lateral Sclerosis Information Page https://www.ninds.nih.gov/Disorders/All-Disorders/Amyotrophic-Lateral-sclerosis-ALS-Information-Page