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Amyotrophic leteral sclerosis Part 2. Etiopathogenesis

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NEUROLOGICAL PROGRESS
Amyotrophc Lateral Sclerosis:
Part 2. Etipathogenesis*
Rup Tandan, MD, MRCP, and Walter G. Bradley, DM, FRCP
The pathogenesis of the motor neuronal degeneration in amyotrophic lateral sclerosis (ALS) is unclear, though several
possible etiological factors are currently being investigated. A unifying hypothesis will have to explain the diverse
geographical occurrence, clinical features, and selective vulnerability and relative resistance of different neuronal
populations in the disease. It is possible that different biochemical defects underlie this diversity, or alternatively that
the many factors incriminated in the etiology may act upon an underlying genetic-biochemical abnormality to trigger
premature neuronal death. Viruses, metals, endogenous toxins, immune dysfunction, endocrine abnormalities, impaired DNA repair, altered axonal transport, and trauma have all been etiologically linked with ALS, but convincing
research evidence of a causative role for any of these factors is yet to be demonstrated.
Tandan R, Bradley WG: Amyotrophic lateral sclerosis: Part 2. etiopathogenesis.
Ann Neurol 18:419-431, 1985
The pathogenesis of the syndrome of amyotrophic lateral sclerosis (ALS) is still obscure, but intensive research in the last decade has identified several clues to
its possible etiology. A unifying hypothesis will have to
explain the diversities of geographical occurrence and
clinical presentation, the clinical course, and the selective vulnerability and relative resistance in different
neuronal populations. It is possible that different
biochemical defects account for this diversity. Alternatively, the multitude of factors incriminated in the causation of ALS may act in concert with an underlying
biochemical-genetic defect in triggering premature
neuronal degeneration.
The contribution by each of these potential trigger
factors in the etiology of ALS is discussed.
cies, immunoglobulin allotypes (discussed later), dermatoglyphic patterns [58), and red cell enzyme or
serum protein markers 123) have been unproductive.
Etiological Factors
Genetics
A recent comprehensive review [47) confirmed earlier
reports that almost 95% of patients with classic ALS
lack a family history of the disorder and therefore represent sporadic cases. However, recognition of autosomal dominant inheritance in familial adult-onset ALS
12, SO], of autosomal dominant and recessive transmissions in familial juvenile-onset ALS 1471, and of ALS
in both members of twin pairs 1491 implicates a genetic predisposition in some patients. A search for genetic markers has produced conflicting results from
histocompatibility antigen (HLA) studies (discussed
later), and extensive analyses of blood group frequen-
Aging
The concept of “abiotrophy” {66] or “premature aging” underlying many progressive neuronal degenerations remains poorly understood. Progressive neuronal
loss occurs in the ventral horns of the spinal cord with
normal human aging [175]. Loss of motor units and
single-fiber electromyographic abnormalities have also
been demonstrated electrophysiologically in humans
after the age of 60 years [ill, 170). The basis of this
attrition process is not clear, but reduction in cellular
ribonucleic acid (RNA) content 11781, intraneuronal
lipofuscin accumulation { 1071, and accumulated desoxyribonucleic acid (DNA) damage [60) are some
factors incriminated. The ability to compensate for this
neuronal loss by distal axonal sprouting may become
impaired with advancing age 1142). Premature loss of
motor neurons in ALS could represent an age-related
phenomenon that is accelerated by exogenous factors,
even though the principal determinant is genetic. An
age-related deficiency of a neurotrophic hormone
elaborated by muscle that stimulates anterior horn cell
(AHC) function by means of retrograde axonal transport has been postulated {8], though this hypothesis
fails to explain the lack of AHC involvement in endstage primary muscle disease. Peak onset of ALS between 5 5 and 60 years of age, reduced motor neuronal
From the Department of Neurology, University of Vermont College of Medicine, Burlington, VT 05401.
“Part 1 appeared in the September issue of the Annals.
Received Nov 26, 1984, and in revised form Mar 28, 1985. Accepted for publication Mar 28, 1985.
Address reprint requests to Dr Bradley.
RNA content 142,433, and an increase in the observed incidence rate of ALS with advancing age 1861
all favor the concept of premature aging, though the
precise mechanism remains unclear.
Metals and Minerals
Several recent reviews have discussed the role of metals in the pathogenesis of ALS [36, 189, 1931. Increased exposure to lead, mercury 11441, or heavy
metals as a group 11531 has been reported in ALS
patients, though not by a l l investigators 194,991. However, significant exposure to lead can sometimes be
unknown, overlooked, or denied. Increased lead content in blood and cerebrospinal fluid (CSF) 137, 1551
has been demonstrated in ALS patients as compared
with controls, but this has not been noted universally
Il081. The initial observation of markedly increased
lead levels in the spinal cords of both lead-exposed and
-unexposed ALS patients [143] has since been duplicated 1971. A positive correlation has been achieved
between cord lead level and duration of the disease.
However, the report by Petkau and colleagues 11431
of elevated levels of lead in skeletal muscle remains
unconfirmed [145}. The precise mechanism underlying lead-induced neurotoxicity is unclear, but interference with synaptic activity, intracellular calcium
homeostasis, and cholinergic function have been
suggested 11671. The exact mode of entry of lead into
the nervous system is also obscure, but may involve
initial capillary endothelial damage 1657 or retrograde
axonal and transsynaptic transport [ 161.
A moror neuron disorder resembling ALS has followed outbreaks of organic mercury intoxication
caused by use of fungicides, and after brief but intense
exposure to elemental mercury 11, 121. In some autopsied cases in which there was exposure to organic
mercury, motor neuronal and pyramidal tract degeneration has been demonstrated 1361. A significantreduction
in neuronal RNA seen in experimental mercury intoxication 1341 suggests that selective inhibition of protein
synthesis may be the basis of mercury neurotoxicity.
Experimental aluminum-induced neurofibrillary degeneration in susceptible laboratory animals 11771
shares the topographical and morphological characteristics of axonal swellings encountered in some ALS
patients [3 11. Neutron activation analysis has detected
aluminum in values that are higher than control in the
spinal cords of Chamorro ALS and Parkinson’s disease
patients 11891 and Japanese patients with ALS 11961.
Electron-probe x-ray microanalysis has demonstrated
significant amounts of aluminum in the nucleoli of
lumbar AHCs from some ALS patients and has also
shown perivascular deposits of calcium, aluminum, and
manganese in ALS cervical spinal cords {195}. The
relevance of these observations to the etiology of ALS
is currently unknown.
420 Annals of Neurology Vol 18 No 4 October 1985
Several observations suggest that manganese is involved in the pathogenesis of ALS. Chamorro miners
in Guam who had had heavy exposure to manganese
were more likely to develop the endemic ALSparkinsonism-dementia complex 11911. ALS has been
reported following manganese intoxication in miners
in another study [ 1791. Relatively high concentrations
of manganese and aluminum and low concentrations of
calcium and magnesium exist in water and soil samples
from Guam [82), the Kii peninsula of Japan (1901, and
West New Guinea 1543, three high-incidence foci of
ALS. However, the determination of manganese in
ALS spinal cord tissue has revealed conflicting results
[97, 120, 1961. Skeletal muscle manganese levels were
not different from controls in one study 11451.
There are similar discordant results of copper levels
in ALS spinal cord 197, 1961. The report of ALS cases
in a small community in South Dakota where affected
subjects excreted abnormal amounts of urinary
selenium 1901 could not be confirmed by other investigators {132). The wide range of selenium levels in
spinal cords from ALS patients and controls 1977 probably represents a difference in dietary intake.
The discrepancies in these studies make it difficult
to assign an etiopathogenetic role to metals in ALS.
Inconsistent control levels of tissue metals reported by
different investigators cause concern about reliability,
and may depend on the analytical techniques employed. Moreover, the increased concentration of
some metals in ALS tissues could be a consequence of
atrophy, or could represent a phenomenon secondary
to cellular damage or alteration in the blood-brain barrier ClO51. Nevertheless, further research is needed in
this area to elucidate the involvement of metals and
minerals in the pathogenesis of ALS.
Calcium, Phosphate, and Bone Metabolism
The several lines of evidence implicating disordered
calcium, phosphate, and bone metabolism in ALS have
been reviewed recently [137, 1891. Abnormal blood
calcium levels, deranged intestinal calcium absorption,
elevated parathyroid hormone values (PTH), and reduced 1,25-dihydroxyvitamin D levels have all been
found in some ALS patients 1137, 1901. Clinical
similarities between ALS and neuromuscular involvement in primary and secondary hyperparathyroidism
and phosphate deficiency (reviewed in [1371), an increased incidence of fractures, and frequent radiological skeletal abnormalities in ALS patients 11371
further indicate that disturbed metabolism of bone
minerals may be relevant in the pathogenesis.
Increased calcium levels in brain and spinal cord
tissue have been demonstrated by neutron activation
analysis in ALS patients from Japan {1961 and Guam
11971, and in the spinal cords of patients in the U.S.
1971. Further analysis of the perivascular deposits of
calcium, aluminum, and manganese from ALS cervical
spinal cords 11951has revealed a pattern similar to that
of calcium-hydroxyapatite 1811. Hgher concentrations
of calcium-hydroxyapatite have been reported in ALS
as compared with control spinal cords 1192).
Yase 11931 has suggested that the chronic nutritional deficiency of calcium and magnesium and relative excess of trace metals such as manganese and
aluminum, as have been documented in the hghincidence foci [54,82, 1911, may induce secondary
hyperparathyroidism with consequent mobilization of
calcium and other metals from bone and deposition in
nervous tissue as calcium-hydroxyapatite. Experimental evidence favoring this hypothesis comes from the
demonstration of calcium and aluminum deposition
in spinal cords of rats on calcium and magnesiumdeficient diets 11271. The occurrence of enhanced calcium and aluminum accumulation in central nervous
system (CNS) tissue in the presence of PTH IllO), of
abnormalities in mineral metabolism, and of elevated
levels of FTH seen in some patients suggests that PTH
is involved in the pathogenesis of ALS.
Endogenous Toxins
In a report of in vitro cytotoxicity in neonatal
mouse cultures, the antineuronal factor, believed to
be present in 75% of ALS sera, was characterized
as nondialyzable, heat-labile, apparently complementindependent, and possibly associated with the immunoglobulin G (IgG) fraction 11541. In the same
study, cytotoxicity seen also with sera from 25% of
neurological controls, several family contacts of ALS
patients, and an “occasional investigator” was unexplained. However, other laboratories were unable to
find this cytotoxic effect with different tissue culture
systems 1101, 1031. Touzeau and Kato 11761were unsuccessful in demonstrating functional toxicity of ALS
sera to dissociated monolayer cultures of chick ciliary
ganglia neurons.
Schauf and associates 11641 have shown neuroelectric blocking activity in A L S sera using ventral root
response-inhibition in the isolated perfused frog
spinal cord model. However, its significance to functional impairment in A L S is not clear. More recently,
Denys and colleagues 1451 were unable to demonstrate any electrophysiological or microscopic effects
in mice injected intraperitoneally with either whole
plasma or isolated Ig fraction from ALS patients.
The questions of endogenous toxins in the pathogenesis of ALS remain unanswered.
Virases
POLIOMYELITIS VIRUS.
The recognition of several
progressive neurological diseases caused by chronic
persistent or slow viral infections [lo}, coupled with
selective degeneration of motor neurons in both
poliomyelitis and ALS,raises the possibility that ALS
may be caused by a chronic infection, poliovirus, or a
poliolike virus 1831. In both paralytic polio and ALS a
familial predisposition is recognized, and an increased
frequency of HLA-A3 15, 1461 may identify susceptible individuals who have neurons bearing receptor
sites for a virus or viruses, or other damaging agents.
There are several reports of a slowly progressive ALSlike syndrome developing many years after acute
paralytic polio (reviewed in [4)), though patients with
rapid deterioration, upper motor neuron signs, and
bulbar involvement have also been recognized {156}.
A prior history of polio was elicited in 2 to 5% of
patients with motor neuron disease 1149, 1531, which
is about ten times the expected incidence 11491. In a
recent case-controlled study, however, polio had not
occurred previously in any of the 35 ALS patients
1861.
Serological studies have not documented raised
complement-fixing or neutralizing antibody titers to
poliovirus, in either the CSF 187,981 or serum 1871 of
ALS patients, but it is now known that asymptomatic
mice with prolonged inuacerebral poliovirus infection
also fail to generate neutralizing antibody titers 11151.
Persistent CNS infection following either poliovirus
vaccination 1441 or other enteroviral infections { 1131
is well recognized in immunodeficient individuals.
Nevertheless, infectious poliovirus 118, 1561, virusrelated antigens as demonstrated by indirect immunofluorescence [1561, and virus-related nucleic acid
sequences as detected by sensitive hybridization techniques [92, 116, 156, 182) have never been reported
in ALS tissue. Several explanations have been offered
11161: the pathogenesis of the disease may be immune-mediated to polio antigens elsewhere (e.g., the
intestine); human motor neurons may be obligatory for
the growth of virus; the virus may only be present
early, with either no or very little nucleotide in later
autopsy specimens which is undetected by current assays; or the virus may exist as defective particles 1791,
making detection difficult.
Several studies in ALS patients
have reported antibody titers similar to control values
for herpes simplex, mumps, coxsackie and arbor viruses, and type C murine retrovirus 140, 57, 87, 88).
Virus-like particles reported in some ALS tissues have
never been confirmed by positive viral isolates in these
patients, though several other reports of positive viral
cultures are notable (reviewed in 183)). Transmission
studies in nonhuman primates, utilizing multiple tissue
specimens (always including brain) from Guamanian
patients and patients with the sporadic type of ALS,
have, to date, been negative 1631 and fail to support
the view that ALS is a slow viral infection. Claims by
Soviet scientists of the successful transmission of ALS
OTHER VIRUSES.
Neurological Progress: Tandan and Bradley: ALS: Part 2
421
to rhesus monkeys {56, 1991 remain unsubstantiated
by study of the material in the U.S. 162, 751.
H L A Antigens
HLA antigens serve as genetic markers for immune
responsiveness in several species, particularly in viral
and autoallergic diseases. One of the etiological factors
suggested in ALS is a persistent or slow viral infection,
thus leading several investigators to study HLA antigens. Results, unfortunately, have been conflicting.
A significantly increased frequency {5, 951 of HLAA3 in classic ALS may correlate with rapid progression
151. It is suggested that the decreased occurrence of
HLA-A3 in Mexicans and American blacks 131 may
account for the apparently low rates of ALS in these
populations 1241. The increased frequency of HLAB12 in patients with slower progression 15, 1741 may
serve to identify “benign” ALS 151. Reports of the
more common occurrence of HLA-A2 and A28 1191,
and HLA-B40 1851 in sporadic ALS remain uncorroborated. Over-representation of HLA-Bw35 in
sporadic ALS was observed by several investigators
{7, 15,953, and in one study, non-Jewish patients had
a significantly increased frequency of HLA-B35 as
compared with non-Jewish controls {l51. About 20%
of Guamanian ALS patients with HLA-Bw35 showed
impaired cell-mediated immunity and T cell mitogen
reactivity, low IgA and high IgM levels, and a shorter
disease duration, while patients with normal cellmediated immunity lacked this antigen 1771. In contradistinction, a lack of significant correlation between
HLA haplotypes and ALS in some studies is noteworthy 176, 1401. Inconsistent results among patients and
controls from different series demand additional and
more extensive analyses.
Other Immune Factors
Serum and CSF immunoglobulins {7, 141; serum autoantibodies, lymphocytotoxic antibodies, and C3 complement levels 114, 1801; and peripheral blood B and
T lymphocyte (including T cell subset) studies 17, 141
have all been normal in ALS patients. A false-positive
immunoassay of acetylcholine-receptor antibody may
occur in patients who have undergone modified
neurotoxin therapy 11191. Hoffman and associates
1781 recorded increased IgA and IgG levels in male
Guamanian ALS patients. Westall {183] identified
slower progression of ALS in patients with high or low
IgA and low IgG levels, and fast progression in patients with high T suppressor cell counts.
Circulating immune complexes, uncorrelated with
the disease course, have been reported in sporadic and
Guamanian ALS {14, 129,1331. Bartfeld and associates {14] were unable to detect immune complexes
in the CSF. Deposits of immune complexes containing
Ig and C3 complement have been documented in
422
Annals of Neurology
Vol 18 No 4 October 1985
biopsied kidney tissue { 133, 1361 but not skin or muscle specimens 11361, and may correlate with the rapid
disease course 11361. Poliovirus antigens 17, 1331 or
other specific antigens 171 have not been identified in
these immune complexes. In the jejunum, deposits of
immune complexes containing poliovirus antigens as
demonstrated by immunofluorescence, but exhibiting
no virus particles on electron microscopy examination,
{ 18, 141) probably represent a nonspecific staining
phenomenon {531.
Cell-mediated immunity 1141, IgG secretion (1091,
and blastogenesis 1141 by B lymphocytes following
pokeweed mitogen stimulation, and T lymphocyte responses to mitogens 17, 141 are normal in classic ALS,
though Behan and colleagues 1181 found decreased T
lymphocyte responsiveness to phytohemagglutinin.
Suppressor T lymphocyte activity, including that following activation with concanavalin A, is normal in
classic ALS (141. Increased in vitro cell-mediated immunity to pooled polio antigens 114,951 and to isolated antigens from poliovirus types 2 and 3 [14] has
been demonstrated, thus suggesting a relationship
between exposure to poliovirus and the subsequent
development of ALS. Cunningham-Rundles and
colleagues (411, on the contrary, found decreased
lymphocyte transformation to poliovirus type 1 antigen in ALS patients but not in controls. In v i m cellmediated immunity to measles and coxsackie A9 virus
antigens was similar in ALS cases and controls 1141.
Bartfeld and associates { 141 believe that the increased
cell-mediated immunity to brain extract and CNS myelin seen in some of their ALS patients probably represents an epiphenomenon, resulting from the primary
breakdown of CNS tissue.
The relevance of these immunological abnormalities
in ALS is uncertain, but increased cell-mediated immunity to poliovirus antigens and the presence of
circulating and renal immune complexes provide
evidence for an immune-mediated mechanism in the
pathogenesis of ALS.
Neurobistocbemical Analyses
Lttle is known about the deranged chemistry of the
motor neurons in ALS. The inability to study viable
human brain or spinal cord tissue makes dynamic analyses of biochemical changes impossible. Furthermore,
postmortem changes in tissues necessitate cautious interpretation of results.
In an amino acid analysis of frozen tissue from the
ventral horns of ALS spinal cord, Patten and colleagues [I397 found increased levels of ornithine and
ammonia, the latter correlating inversely with disease
duration. They postulated a possible defect in the urea
cycle and an adverse effect of ornithine and ammonia
on motor neuron function, perhaps through energy
depletion. Hayashi and Tsubaki 1731 documented de-
creased citrate synthase activity in isolated AHCs but
not in dorsal root ganglia from ALS lumbar spinal
cords examined within 6 hours of death. They suggested that this results in deficient production of acetyl
coenzyme A, and consequently acetylcholine, thereby
compromising energy metabolism and function of the
cholinergic AHCs.
Patten and co-workers [138} demonstrated significant alterations in serum and CSF amino acids in
ALS, correlating with disease activity and severity.
They suggested that these abnormalities may be due to
either abnormal membrane transport or poor cellular
utilization, and also speculated that excitatory activity
(fibrillations and fasciculations) in ALS might be related to the increased aspartate level they found. Festoff and Fernandez 15 11 identified normal levels of red
cell acetylcholinesterase ( A C E ) in ALS, but found
plasma levels to be twice control values, and explained
this on the basis of “progressive interruption of
neuromuscular integrity and interrelationships.” However, Conradi and associates [35] found normal levels
of AChE in red cells and plasma in ALS. Poloni and
colleagues El481 noted decreased plasma thiamine and
thiamine monophosphate levels, and a greater reduction in thiamine monophosphate than in thiamine
levels in the CSF of ALS patients. They concluded that
reduced plasma levels could be due to either malnutrition or malabsorption, and the greater reduction in
thiamine monophosphate could result from its reduced
neuronal synthesis from thiamine (under the influence
of thamine pyrophosphatase) from either neuronal depletion or dysfunction.
Several histochemical and biochemical abnormalities
have recently been reported in ALS muscle. Antel and
co-workers 161 found increased acid protease activity
in ALS deltoid muscle biopsies, which correlated with
severity of disease, extent of weakness and muscle atrophy, and the histological presence of target fibers.
They suggested that muscle proteolytic activity may be
an early indicator of the disease. Sufit and associates
1172) found a decrease of carnitine in ALS muscle to
71% of control values, but were unable to demonstrate an abnormality of blood lipids.
Corbett and colleagues 1381 noted an elevated 24hour urinary 3-methylhistidine-to-creatinine excretion ratio in patients with ALS and adult-onset chronic
spinal muscular atrophy (SMA), suggesting enhanced
skeletal muscle breakdown. Urinary creatinine excretion decreased with progressive deterioration and muscle atrophy in ALS, but not in patients with SMA who
also showed relative preservation of muscle bulk and
strength. These researchers inferred that anabolic compensation for accelerated catabolism of skeletal muscle
seemingly occurs in SMA, thus preventing rapid muscle wasting, but that this might not be as effective in
ALS.
Hexosaminidase Dejcienq
The clinical syndromes associated with hexosaminidase
A (Hex A) deficiency are heterogeneous 19, 841, but
two phenotypes of recessively inherited motor neuron
disease are recognized. In one, reported in young Ashkenazi Jewish patients 19, 841, the clinical picture is
similar to that of juvenile SMA; on rectal biopsy, ganglion cells contain membranous cytoplasmic bodies
similar to those seen in classic Tay-Sachs disease, and
submucosal histiocytes are filled with granules that
stain positively with periodic acid-Schiff {84]. Hex A
values in serum and leukocytes 19,841 and slun
fibroblasts C91 are markedly reduced in the patients
and partially reduced in other family members. The
grandchild of one patient’s paternal aunt had classic
infantile Tay-Sachs disease 1841.
The second variety, a slowly progressive ALS-like
syndrome, has been reported both in young Ashkenazi
Jewish males [9, 187) and in a non-Jewish male [168}.
Both Jewish patients had membranous cytoplasmic
bodies in rectal ganglion cells and very low Hex A
levels; one patient’s healthy parents exhibited partial
Hex A deficiency C187) and the other patient’s mother
and sister had other neurological syndromes C91.
Quantitative Hex A activity was markedly diminished
in the non-Jewish patient, but assays using artificial
GM2 ganglioside disclosed activity intermediate between controls and patients with Tay-Sachs disease, in
both the patient and his parents Cl681. Argov and Navon 191 also noted high Hex I activity in their patients,
and explained this as arising because of a relative excess of p subunits of the enzyme.
The identification of Hex A deficiency in these patients suggests that atypical ALS may rarely be due to a
specific biochemical abnormality. Phenotypic variability in this motor neuron syndrome, even in a single
family {9}, might result from modifier genes [84} or
from variable expression of a single gene 197. Hex A
deficiency is unlikely in patients with features of ALS
who are beyond their fifth decade, in those with a
dominant family history, and in those with rapidly progressive disease.
Neurotransmitters
Many recent reports have raised the possibility of abnormal neurotransmitter function in ALS. Nagata and
colleagues [1267 noted reduced muscarinic receptor
sites in the ventral horns of ALS spinal cords. In
a combined in vitro morphologic-autoradiographic
study of ALS and control spinal cords, Whitehouse
and co-workers 11861 found a considerable reduction
in the number of receptors in areas of motor neuron
loss in ALS and inferred that these receptors are
located mainly on motor neurons. High-affinity muscarinic cholinergic receptors were strihngly reduced in
number, particularly in Rexed lamina IX of the ventral
Neurological Progress: Tandan and Bradley: ALS: Part 2 423
horns but also in laminae I1 and I11 of the dorsal horns.
Glycine and benzodiazepine receptor densities in the
ventral horns were less decreased in number. However, Hayashi and colleagues 172) found reduced binding of glycinergic receptors in the anterior gray matter
of ALS thoracic spinal cords, but no decrease in muscarinic cholinergic, dopaminergic, y-aminobutyric acid
(GABA)-ergic, or p-adrenergic receptor binding. Determination of substance P activity in ALS spinal cords
has yielded inconsistent results 164, 1341.
Ziegler and associates [1983 observed reduced
levels of CSF GABA and increased levels of norepinephrine in the CSF and plasma, most notably in
bedridden ALS patients. They postulated that these
changes probably affect spinal neurotransmission, and
that the increased sympathetic tone from higher levels
of plasma norepinephrine may explain the resistance to
bedsores 1527 and high incidence of nonatherosclerotic
angiopathy 1171) in ALS. Belendiuk and colleagues
120’)found a slightly increased concentration of serotonin in platelets, significantly increased monoamine oxidase activity, and decreased levels of free and bound
plasma tryptophan, all correlating with disease severity.
They concluded that raised platelet monoamine oxidase activity may be related to elevated plasma levels
of norepinephrine 11987, and the increased platelet
serotonin and low plasma tryptophan levels may be an
attempt to compensate either for dysfunction of the
monoaminergic neurons that normally facilitate motor
function 11851 or for motor neuron degeneration.
Nucleic Acids
Mann and Yates [ 1061 first reported reduced levels of
cytoplasmic RNA in ALS AHCs and trigeminal motor
neurons, in parallel with decreases in nuclear and nucleolar volumes. They postulated that this was related
to a primary heterochromatization of nuclear DNA
with resultant impaired synthesis of messenger RNA.
Davidson and associates 142,431 likewise demonstrated a 31 to 42% reduction in neuronal RNA content in lumbar and cervical cord motor, but not in the
nucleus dorsalis (Clarke’s) neurons. The reduction in
RNA content was independent of disease duration and
extent of cell loss. The base composition of RNA was
also abnormal in ALS cords as compared with controls
t70). Using gel fractionation of RNA from motor
neurons, Hartmann and Davidson 170) concluded that
in ALS ribosomal RNA levels are markedly reduced
but transfer RNA values are normal.
We have demonstrated decreased protein synthesis
and increased turnover in cervical motor neurons of
the wobbler mouse, an animal model of motor neuron
disease 1122). We have also noted decreased nuclear
volume of motor neurons with advancing disease, and
an approximately 30% reduction of RNA content and
nuclear RNA synthesis, even in normal-appearing
424 Annals of Neurology
Vol 18 No 4
October 1985
neurons 1123). Actinomycin D (a highly specific RNA
polymerase inhibitor) and the fluoropyrimidines
(which inhibit protein synthesis by reducing RNA synthesis) are known to produce neuronal degeneration in
cats when injected intrathecally 1911.
It is possible that in ALS a number of different
mechanisms might result in reduced levels of ribosomal RNA, and consequently decreased protein synthesis, which would thus predispose to motor neuronal
degeneration. These include heterochromatization of
DNA, and deficiency of RNA polymerase or of precursor nucleotides. We have recently suggested that
the RNA changes in motor neurons in ALS may
reflect aberrant transcription caused by accumulation
of unrepaired D N A damage 128). Cloning and quality
of DN A synthesis following irradiation were reportedly normal in cultured ALS s h n fibroblasts
11021, as was survival following irradiation in cultured
lymphoblastoid cell lines 11521. However, Kidson and
associates 1891 have recently observed an increased
sensitivity of ALS cells to ionizing radiation.
Our studies of skin fibroblast cell lines from 6 ALS
patients and 6 age-matched normal controls have
shown an impaired DNA repair capacity in ALS
11731. In these studies, unscheduled DNA synthesis
and alkaline elution were used as two different techniques to investigate DN A damage and repair. This
impaired capacity appears to be a specific defect restricted to repair of base damage produced by the alkylating agent methyl methanesulfonate; repair of
damage produced by mitomycin C (a DNA-DNA
interstrand crosslinking agent), ultraviolet light (which
produces cyclobutane pyrimidine dimers), and x-rays
(which cause D N A single-strand breaks) appears to be
normal. We hypothesize that the basic defect in ALS is
a deficiency of the repair of apurinic and apyrimidinic
sites 11731. If this DNA hypothesis is correct, it might
represent the first biochemical abnormality through
which all the other etiopathogenetic factors discussed
here could produce their effect.
Endocrine
The role of parathyroid gland dysfunction and deranged bone mineral metabolism in the etiopathogenesis of ALS has already been discussed (see
the section Calcium, Phosphate, and Bone Metabolism). The cases of several patients with thyrotoxicosis and a clinical picture simulating ALS have been
reported 1121, 1281; in some, the ALS-like syndrome
occurred several years after achieving euthyroidism
133, 157). Considerable diagnostic difficulty may occur
in patients with “thyrotoxic myopathy” who exhibit
pronounced fasciculations of the muscles including the
tongue 169, 1211, pyramidal tract signs 11211, or histochemical fiber-type grouping in muscle biopsies
t481. There is, however, no convincing evidence that
thyrotoxicosis predisposes to the development of ALS
1112).
Abnormal glucose metabolism 1125, 15 11, either
from diminished insulin secretion 1162) or from insulin resistance [lsl], has been reported in some ALS
patients, though others have described normal results
of the glucose tolerance test and normal levels of insulin in the CSF and plasma 1111. It seems unlikely that a
disorder of carbohydrate metabolism is primarily involved in the cause of ALS in the majority of cases.
Weiner [1811 has proposed that the degeneration of
motor neurons in ALS may be dependent on the loss
of androgen receptors. Autordiographic analysis of
androgen receptors in male rats has disclosed heavy
labeling in the motor neurons of cranial nerves V, VII,
and XII, and the nucleus ambiguus, and only sparse
binding in cranial nerves 111, IV, and VI, and the dorsal
motor nucleus of X [163}. The latter neuronal groups
ate generally spared in ALS. The highest androgen
receptor concentrations were found around the motor
neurons of the thoracic and lumbar spinal cord and of
cranial nerve IX, populations commonly involved in
ALS 11631. Weiner 1181) has suggested that decreasing levels of total and free testosterone with aging
1147) in combination' with loss of androgen receptors
may be relevant in the pathogenesis. Research to provide data on this hypothesis has, however, not been
reported.
Neopknia
An increased incidence of mdgnancies in ALS was
first reported about two decades ago 1291, and is variously estimated at between 0.7 and 10% in clinical and
postmortem series 1131. A chance association was indicated by a later report of a similar incidence in patients
with ALS and age-matched controls 1131. However,
remission of an ALS-like syndrome following successful treatment of the neoplasm 11171 would support a
causal association, though spontaneous improvement
cannot be excluded.
Paraneoplastic syndromes may occasionally be difficult to distinguish from ALS, but a benign and remitting course, sensory involvement, uncommon pyramidal signs, and elecuodiagnostic evidences of
demyelination in the peripheral nerves may be helpful
in individual cases. Pathologically these syndromes are
distinguished by the presence of neuronophagia and
inflammatory infiltrate 1741 or demyelination in the
central and peripheral nervous systems 11661, features
generally lacking in ALS.
Memhune Properties
Defects in membrane structure or function have been
postulated as being relevant in the pathogenesis of several neuromuscular disorders. Studies of membrane
characteristics in order to identify a generalized defect
that may alter AHC function in ALS are few. Westall
and Jablecki 11841 found increased osmotic fragility in
ALS erythrocytes, while Ronnevi and associates [ l 5 S }
noted similar results when whole blood was incubated
with varying concentrations of lead. Butterfield and
Markesbery 1301, however, found normal membrane
lipid fluidity and physical state of proteins in ALS
erythrocytes as determined by electron-spin resonance. Membrane response to glutaraldehyde as visualized with the scanding electron microscope, and
Nat - and K+-dependent adenosine triphosphatase activity were also normal 1301. Felmus and colleagues
1501 demonstrated normal calcium content in whole
erythrocytes and erythrocyte membranes in ALS, thus
excluding a generalized membrane defect that would
allow excessive calcium influx. Lymphocyte capping,
which is an index of membrane fluidity and cytoskeletal preservation, is increased in the wobbler mouse
1130}, but normal in patients with sporadic and familial
types of ALS 171.
Puruproteinemiu
Paraproteins of the IgG, IgM, and IgA classes have
been identified in the sera of several patients presenting with a neurological illness typical of ALS [loo].
Pathological changes consistent with ALS have been
reported in only a few patients 117, 961. Other cases
studied pathologically have shown a predominantly
motor polyradiculoneuropathy [1591 or myelomatous
infiltration of the lumbosacral dura mater with
chromatolytic changes in the motor neurons [321 and
mild AHC loss 132, 1591.
The precise association between disorders of the
motor neuron and paraproteinemias is unknown but
could simply be coincidental as far as IgG paraproteins
are concerned, as these occur in about 1% of asymptomatic adults and their incidence increases with age.
IgM paraproteins, on the other hand, are known to
possess autoantibody activity against several nervous
system antigens, and the ALS syndrome in such patients could be immune-mediated by antibody activity
against motor neuronal antigens {loo}.
Axonul Transport
The significance of altered axonal transport in relation
to the etiology of ALS has been reviewed previously
1251. Proximal axonal swellings filled with 10-nm
neurofilaments occur in some cases of early, rapidly
progressive ALS 1311, ih hereditary canine spinal muscular atrophy (HCSMA) 1391, and in rats acutely intoxicated with p-p'-iminodipropionitrile (IDPN) 1681.
In both the HCSMA and IDPN model, slow axonal
transport is considerably decreased {67, 1941 and this
obviously raises the question of a similar impairment in
ALS.
Neurological Progress: Tandan and Bradley: A S : Part 2
425
Norris {131) reported a reduction in the rate of
particle movement, as measured by Nomarski optics,
within terminal axons of ALS biopsy specimens taken
from intercostal muscle. In our recent studies {27), we
showed that AChE activity in ALS phrenic nerves was
reduced to about 45% of control values, with
significantly lower values distally as compared to proximally for AChE activity per millimeter and for AChE
activity per milligram of noncollagen protein. Though
the AChE activity per unit length was similar in ALS
and control sural nerves, in ALS the apparent transport
rate was reduced by 44% and the amount of AChE
transported was reduced by 24%. The reduced
amount of AChE transported was probably due to the
30% reduction in myelinated fiber numbers in ALS
sural nerves. However, the decreased apparent transport rate of AChE confirmed Norris’s report 11311.
What pathogenetic significance these abnormalities
in axonal transport have in ALS is debatable. In several
experimental disorders, altered axonal transport has
been documented (1141. Normal static levels of AChE
in surd nerves in our studies 127) and only minor
degrees of axonal atrophy and “dying b ack in ALS
phrenic nerves {27) would suggest that a functionally
critical decrease in axonal transport in distal nerves is
probably not the cause of these changes, but is secondary to the underlying biochemical abnormality, as seen
in the experimental neuropathies.
Trauma and Surgery
Back or limb trauma {59,99, 1581, prior skeletal disease or fractures { 1371, “mechanical injuries” before
onset of ALS 194, 991, and exposure to electric shock
or lightning {59] have all been more frequently encountered in ALS patients than in controls. The exact
importance of this relationship is unknown, but may
reflect a vulnerability to injury in the preclinical phase
of ALS or suggest an etiological role for injury in precipitating the disease. However, no significant increase
in prior trauma in cases of ALS was identified in a
recent study 11241.
An increased incidence of previous surgical operations has been observed in ALS patients 1991, though
Kondo 1937 noted no predisposition to ALS following
gastrectomy, and Murros and Fogelholm {1241 were
unable to demonstrate more frequent prior surgery in
ALS patients than in controls.
All these epidemiological retrospective analyses depend on adequate recall of events by ALS patients and
controls, and on correct selection of the control population.
Other Factors
Increased exposure to household pets 11651, farm animals (1501, animal carcasses and hides 1711, and pneu426 Annals of Neurology Vol 18 No 4 October 1985
matic tools {551 have all been reported, but the role of
these factors in the causation of ALS is unclear.
A syndrome resembling motor neuron disease follows irradiation of the lumbar spinal cord in the field
used for the para-aortic lymph nodes in males with
germ-cell tumors of the testes (1041. It can also occur
after radiation to the head and neck region, mediastinum, or the whole neuraxis {135, 161).
Animal Models of ALS
Several spontaneous (26, l60} and experimental
neurotoxic {6l, 68, 169, 1771 disorders in animals
have been identified as appropriate models of human
motor neuron diseases. Animal models enable us to
study the temporal and spatial evolution of diseases
allied to human motor neuron diseases from the early
preclinical stage, utilizing biochemical, neurobiological, and ultrastructural techniques, and thus these
studies using animal models yield better perspectives
on the pathogenesis of human disorders. Unfortunately, no animal model reproduces all the salient features of ALS.
The wobbler mouse is the most extensively studied
animal model, and inherits the disease in an autosomal
recessive pattern 126,461. Extensive studies have characterized the pathological changes {118] and abnormalities in RNA and protein metabolism 1122, 1231 in
wobbler motor neurons. Impaired slow axonal transport has been demonstrated by some ({211; H. Mitsumoto and P. L. Gambetti, personal communication),
but we were not able to find either abnormally fast or
slow transport rates 1261. HCSMA is another wellstudied model of autosomal dominant disease seen in
Brittany spaniels and Brittany spaniel-beagle outcrosses 139, 1601. Neurofilamentous swellings of proximal axons and loss of lower motor neurons occur characteristically; recent studies have shown reduced slow
axonal transport {67]. A spontaneous degeneration of
motor neurons occurring in mature mice, with upper
and lower motor neuron signs and hind limb paralysis,
has been related to a type C retrovirus infection 1571;
vacuolated, noninflammatory degeneration of motor
neurons is also seen in this animal model.
The commonly studied experimental neurotoxins
include those producing a neurofibrillary disorder
similar to thar seen in ALS. Aluminum, the Vinca alkaloids, and the maytansinoids {6l} cause neurofibrillary changes in motor neuronal perikarya; aluminum and IDPN induce neurofilamentous proximal
axonal swellings (68, 177); and acrylamide produces
giant axonal swellings in the distal axon {169}. Acetylethyl tetramethyl tetralin intoxication in rats reveals
features of combined upper and lower motor neuron
degeneration with intraneuronal inclusions which are
ultrastructurally somewhat similar to those found in
ALS 11691. Yamamoto and colleagues 11881produced
nuclear heterochromatization and motor neuronal degeneration with retrograde transport of adriamycin
(doxorubicin hydrochloride) after intraneural injections in rat sciatic nerves. This may provide another
animal model for the study of nucleic acid and protein
changes of the kind described in ALS [42,43, 70,
lOG} and thus may be of relevance to the DNA hypothesis 128).
The DNA repair studies by our group were supported in part by
research grants from the ALS Society of America and the National
ALS Foundation.
The authors are grateful to Susan Soule and Kimberley Morse for
help with preparation of the manuscript.
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