Journal q[ the Neurological Sciences, 1983, 62 : 95 113

95

Elsevier

MENKES' DISEASE AND SWAYBACK
A Comparative Study of Two Copper Deficiency Syndromes

NOEL TAN and HENRY URICH

Department of Neuropatholog.l', Royal Perth Ho,~pita/, Perth, We.S'lernA ustralkt (,4 ustralia)
(Received 9 June, 1983)
(Accepted 20 July, 1983)

SUMMARY

The neuropathological findings in two siblings with Menkes' disease were
compared with representative material obtained from lambs suffering from swayback
(enzootic ataxia). The aim of the study was to demonstrate the similarity of lesions
in a genetic and a nutritional form of copper deficiency in support of the view that
all lesions in Menkes' disease could be ascribed to simple hypocupraemia. All
lesions of Menkes' disease were shown to have their counterpart in swayback,
with exception of the abnormal arborisations of the Purkinje cell dendrites. These
have often been interpreted as malformations and cited in evidence of the prenatal
origin of the cerebral lesions. They are, however, non-specific and similar lesions
have been reported in conditions arising in later life. While there is abundanl
collateral evidence of disturbed copper metabolism in utero, the problem of the
prenatal versus postnatal origin of cerebral damage remains unresolved.

Key words : Copper def~cieno,
- Swa)'baek

-

Enzootic ataxia

-

H37~oeupraernia

Menkes' disease

INTRODUCTION

Menkes' disease (Menkes et al. 1962) is a well established genetic entity,
inherited as a sex-linked recessive, and affecting the central nervous system, skin,
hair, blood vessels and bones. The underlying metabolic defect is copper deficiency
Correspondence to: Dr. N. Tan, Department of Neuropathology, Royal Perth Hospital.
Box X2213 G.P.O., Perth, W.A. 6001, Australia
0022-510X/83/$03,00 a) 1983 Elsevier Science Publishers B.V.

96
caused primarily by malabsorption from the gut ~Danks et al. 19721 Despite
extensive experimental studies many problemsof pathogenesis, particularly of lesions
in the CNS. remain unsolved. The closest animal model is a mouse mutant, the
mottled brindled (Mo "r) mouse and this has been studied both from a morphological
(Nagara et al. 1980; Suzuki and Nagara 1981) and biochemical point of view
(Camakaris et al. 1979 Mann et al. 1979a,b). Genetic conditions, however, pose
the question whether all lesions can be ascribed to the underlying metabolic
disorder or may be independent expressions of the abnormal genome. It is theretbre of interest to compare Menkes" disease with a nutritional copper deficiency
such as swayback, or enzootic ataxia, of lambs. Danks (1980) presented a brief
survey of lesions caused by copper deficiency of different aetiology in a wide range
of species and Smith (1981) reviewed the literature on Menkes' disease, swayback
and the mottled brindled mouse, emphasizing the similarity of findings. What is
lacking is a comparative study of the neuropathology of Menkes" disease and
swayback, based on personal observations on material from both conditions,
MATERIALS AND METHODS

Material for the study of Menkes" disease consisted of two siblings, the elder
of which was already briefly reported by Hockey and Masters (1977). Their findings,
with some additional observations, will be briefly recapitulated and compared
with those in the younger sibling. The material was studied in paraffin sections.
stained with standard neuropathological methods. In addition° Cajal's silver impregnations were carried out on frozen sections of the cerebellum.
Material from swayback was put at our disposal by the Department of
Veterinary Medicine, University of Cambridge, the Central Veterinary Laboratory
of the Ministry of Agriculture. Weybridge, and the Departmenl of Veterinary
Pathology, Murdoch University. Western Australia. It consisted of cases both
of congenital and delayed swayback (classification after Howell et at. t982). In
the former group both cases with and without cerebral involvement were included.
Most of the material consisted of paraffin sections stained with haematoxytin and
eosin. No material was available for silver impregnations.
OBSERVATIONS

Menkes' disease
Case 1 X74-338
Clinical history: M.B.. a male and first child of Maltese and Australian parent~ was born

after a 33 weeks' gestation. The prenatal and perinatal periods were uneventful. At 2 months he
appeared floppy and developed generafised seizures. The scalp hair was lustreless, depigmented and
showed pill torti and triehorrhexis nodosa. His further physical and mental development was retarded.
punctuated by feeding problems and episodes of hypothermia His reflexes were brisk with ankle
clonus. Serum copper was 6.2 .umolll Inormal 11-25t and copper oxidase 0.06 g/l fnormal 0.21 0,431.
A diagnosis of Menkes' disease was made. During the following year he became progressively retarded
in physical growth and mental development, had constant myoclonus and respiratory problems until
his death ai 2 years.

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Post mortem examhmtion: confirmed bronchopneumonia. The long bones showed thickening
of the periosteum witb numerous erosions of the cortical bone and osteoclastic activity. Microscopy
of representative systemic and cerebral arteries disclosed no significant changes.
Neuropatholo<v: The brain weighed 521 g (normal for age 1100 g) and showed severe generalised atrophy with ventricular dilatation and areas of cortical softening in the frontal, temporal and
parietal lobes. The cerebellar folia, particularly those of the vcrmis, were severely atrophic.
~licroscOl?_V: There was diffuse, bul not unii'orm, atrophy of the cerebral cortex. Neuronal loss
was severe in placcs, with almost total loss of small neurons in layer IV, and patchy status spongiosus m layer V. The white matter was poorly myelinated and contained reactive astrocytes. Mild
neuronal loss was also present in the basal ganglia and thalamus.
In the brain stem the most striking lesion was the presence of chromatolytic neurons in lhe
reticular formation (Figs. IA and B). These were large, tip to about 35 ,am in diameter, with homogeneons acidophilic cytoplasm and small l~agments of Nissl bodies in the periphery. Their nuclei
were cnlarged and distorted, with ill defined nuclear membrane and a large, eosinophilic nucleolus.
Some were represented by ghost cells which had lost all their cytoplasmic and nuclear structures.
The cerebellar cortex showed severe loss of granule cells and moderate loss of Purkinje cells
with corresponding Bergmann gliosis. In silver impregnations the remaining Purkinje cells showed
abnormal dentritic ramilications in the lbrm of antler-like expansions (Fig. 2A). Polydentritic neurons

l'ig, I. Menkes" disease ICase l ) (A and B, seep, 98). T w o c h r o m a t o l y t i c c e l l s f i - o m reticular subslauce
in medulla. H&E. ×450.

9~
~ere also present and formed to patterns: numerous free processes radiating from thc cell bod~,
(Fig. 2B) or several coarse, branching dendrites (Fig. 2C~. Occasional axonal swellings I t o r p e d o e s " )
were also seen. Basket fibres were absent. Mild gliosis of the dentate nucleus was apparem.
In the spinal cord the most striking lesion was neuronal loss and gliosis of Clarke's column
Occasional chromatolvtic cells were seen m Clarke's column and the large celled nucleus o f the posterior horn. Degeneration o f the dorsal spinocerebellar and corticospinal tracts was present.~hroughout
the cord.
Case 2 FY79-162
Clinical history: S.B. the brother of the first patient, was delivered by caesar~an secuon at
34 weeks o f gestation because of placenta praevia. He had feeding problems, hypotonia and episodes
of hypothermia almost since birth. His hair was sparse and stubby with piti torti. Serum copper was
2 #mol/l and the caeruloplasmin concentration 0.02 optical density units. The child did not thrive
and succumbed to suppurative p n e u m o n i a a! the age of 51/2 months.
Post mortem examination: confirmed the presence of suppurative bronchitis and pneumonia.
Otherwise lesions were confined to blood vessels. Sections of the aorta, c o m m o n carotid, coronary
and itiac arteries showed duplication and fraying o f the internal elastic laminae, intimal fibrosis and
stenosis of the lumen. The cerebral arteries were free from these c h a n g e s
Neuropathology: The brain weighed 719 g and was swollen and congested. Coronal sections
of the fixed brain showed focal necrosis o1 the cerebral cortex and softening of the subeortical and

Fig. |B.

Fig. 2. Menkes" disease (Case 1). Abnormalities of Purkmje cell dendrites. ,4: "'Antler" or "'staghorn'"
deformity: B: Polydendritic cell with numerous fine perisomatic processes: (': Polydcndritic cell wilh
several course branching dendrites. Ca.jaFs silver impregnalion, × 450.

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Fig. 2C.

central white matter, most pronounced in the lateral and inferior parts of the frontal, lemporal and
parietal lobes. The basal ganglia and thalamus were preserved and the ventricles reduced in size.
The cerebellum showed generalised atrophy, the brainstem and spinal cord appeared normal.
Microscopy: The cortex showed extensive laminar necrosis involving predominantly bayers 1[I
and V. Large areas o f white mattcr were devoid of myelinated fibres a n d replaced by a -meshwork o f
astroglia, containing scattered small cavities with sharply demarcated edges and devoid o f liptd macrophages (Fig. 3/. The white matter of the severely damaged insula and the adjacent basal ganglia
contained several dilated tortuous veins.
Chromatolytic neurons were less conspicuous than in Case I. bul some werc present in the
reticular substance of the medulla.
In the cerebellar cortex abnormalities were seen in all layers (Fig. 4~. The internal granular
was severely depleted. Purkinje ceils were abundant, but m a n y o f them were necrotic, and some
showed coarse vacuolation o f their cytoplasm. The external granular layer was present at a thickness
appropriate for the age, but showed peculiar rosette-like clusters irregularly dispersed in t h e molecular
layer Silver impregnauons showed abnormal arborisations o f t h e Purkinje celt dendrites. ~ome o f
which divided high in the molecular layer with secondary and tertiary branches directed towards the
deeper layers of the cortex fthe "'weeping willow" patternl (Fig. 5) A few cells shoxved short and
stubby perisomatic dendrites.
The spinaI cord showed minimal changes. There was no appreciable loss of neurons in Clarke's
column, but some reactive astrocyles were present. Some degenerating neurons were seen in various

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Fig, 3. Mcnkes" disease (Case 2). Cavitation of white matter. Luxol-lhst blue and neutral red, x 25.

parts of the cord, but none showed the typical chromatolytic pattern. A lcw vacuolated neurons
were seen in the intcrmedio-lateral group in the thoracic cord. No definite abnormality was seen in
the long tracts.

5"~ra.rhack
In eases of congenital swayback with cerebral involvement both the cerebral cortex and the
white matter were involved. In the oedematous variant, laminar or patchy neuronal necrosis was
present in the cortex with rarefaction and vacuolation of the ncuropil. The white matter showed
extensive loss of myclinated fibres with replacement by a loose glial meshwork of reactive astrocytes
and their processes. These lesions could be unilateral or bilateral. In the more common type cavitation
of the white matter was the most prominent feature. The cavities had sharply demarcated edges with
a thin glial wall, and showed very little, if any, evidence of microglial activity or phagocytosis. In some
cases there was laminar loss of neurons in the cortex with status spongiosus and scattered ferruginated cells. In one case focal aggregations of lipid macrophages were prominent in thc cortex.
In the brainstem the main feature was the presence of large chromatolytic neurons, mainly
in the red nucleus, the vestibular nuclei and the reticular substance. These changes were not ticcompanicd by obvious tract degenerations.

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Fig. 4. Menkes' disease /Case 2L Cerebellar cortex showing clusters of cells ill external granular layer.
depletion of internal granular layer ~nd vacuolation of Purkinje cells. H&E. Y 25¢~

The cerebellum was affected in onty a few cases, either m a patchy or a diffuse fashion. The
characteristic lesion consisted of widening of the normally thin external granular layer and corresponding
thinning and rarefaction of the internal granular layer (Figs. 6A. B). Some of the cells of the external
layer showed degenerative changes and in some places that layer had disappeared completely (Figs.
7A. B). The Purkinje cells were generally well preserved, but some loss. necrosis or coarse vacuolation were found in places. Malorientation a n d displacement of Purkinje cells into the molecular layer
were fairly common.
The spinal cord was affected in all cases, both congenital and delayed. The constant: features
were degeneration of the white matter a n d chrornatolysis of neurons m the grey matter. The tract
degeneration involved both axons and myelin sheats and was confined to the ventrolateral columns
with preservation of the dorsal columns. Chromatotytic neurons were conspicuous in the ventral h o r n s
(Fig. 8) with a less prominent involvement of Clarke's column.

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Fig. 5. Menkes' disease (Case 2). "Weeping willow" pattern of" Purkinje cell dendrite. Glees and
Marsland's silver impregnation, × 450.

DISCUSSION

The paucity of comparative studies of Menkes' disease and swayback may
perhaps be due to a difference in emphasis on the localisation of the lesions in
the two conditions. Swayback has been presented as a disease affecting primarily
the white matter: a demyelinating condition resembling Schilder's disease (Innes
1939; Innes en Shearer 1940), or different from any human disease (Spais et al.
1961) or due to myelin aplasia rather than demyelination (Howell et al. 1964:
Howell 1968). In Menkes' disease the emphasis has been on grey matter lesions
(~'trichopoliodystrophy", French et al. 1972). It has, however, become increasingly
apparent that lesions are widespread in both diseases. Neuronal lesions are important in swayback (Barlow et al. 1960; Barlow 1963), while degeneration of the
white matter may be sufficiently prominent in Menkes' disease to mimic leucodystrophy (Vagn-Hansen et al. 1973). There is considerable variation in incidence
and severity of the various lesions between the two species and between individuals
in each species.
One may also question the validity of a comparison of a prenatal copper
deficiency in swayback and a predominantly postnatal malabsorption syndrome
in Menkes' disease. However, the brain of newborn ruminants is far more mature
than thai of a human neonate. Myelinalion of the cerebral hemispheres is well
advanced in the lamb and the migration of cerebellar neurons is almost complete.
The last 6 of" the 21 weeks of gestation in sheep are comparable with the postnatal

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Fig. 6. Swayback. Cerebellar cortex showing ~A~ widening of external and thinning of internat granular
layer and vacuolation of Purkinje cells, and (B) normal appearances in adjacent tobule. H&E. - 250.

"7"
rr~"

106

Fig. 7. Swayback.Two adjacent areas of the same cerebetlar folmm. A : Showing broad extertmlgranular
layer, and (B) almost total destruction of this layer. H&E. × 240

development in infants, and it is during that period that the lesions of swayback
develop and can be prevented by administration of copper supplements to the
pregnant ewes (Dunlop et al. 1939). The earliest lesions in the spinal cord were
recorded on the 99th day o f gestation (Smith et al, 1977).
Furthermore, Menkes' disease may not be an exclusively postnatal process.
While malabsorption of copper from the gut is undoubtedly the main defect, other
mechanisms may also be significant, such as reduced levels of copper in the
heterozygous mother, impaired transport of copper through the placenta, or a defect
in intracellular transport of this element, Demonstration of excessive incorporation
of "~Cu into amniotic cells has confirmed the disturbance o f fetal copper metabolism (Horn 1976). Yet its significance in the pathogenesis o f the disease remains
unclear and may have been overstated in an attempt to explain certain apparent
prenatal malformations, particularly in the cerebellum.

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Fig. 7B.

The lesions occurring in both conditions at various levels of the neuraxis
are compared in Table l, and only a few features require further comment.
Chromatolysis of large neurones is one of the most constant features of all
variants of swayback. In the brain stem it is found in the red nucleus, vestibular
nuclei and reticular formation (Barlow et al. 1960). In the spinal cord the cells of
the ventral horns, Clarke's column, ventral grey commissure and lateral horns are
affected (Barlow 1963). The appearance of these cells superficially resembles that
of axonal reaction, but differs from it both histochemically (Barlow and Cancilla
1966) and ultrastructurally (Cancilla and Barlow 1966). Chromatolytic ceils are
rarely seen at birth, but become prominent between 6 and 12 weeks of age (Smith
et al. 1978). This lesion seems to have escaped notice in Menkes' disease and was
found only alter prolonged search in our two siblings. Iwata et al. (1979a,b) found
loss of neurons in the nucleus ventralis oralis of the thalamus, the red nucleus, and

108
in Clarke's column, associated with degeneration of the dorsal spinocerebeltar tracts,
among the most constant lesions of Menkes' disease. Tract degenerations in the
spinal cord are difficult to compare because of major anatomical differences
between man and sheep, but in both species the dorsal columns remain intact.
White matter lesions, both in the form of gelatinous oedema and frank
cavitation, are undoubtedly more common in swayback. In the oedematous form
(Roberts et al. 1966) the white matter of the affected hemispheres is devoid of
myelinated fibres and replaced by a meshwork of reactive astrocytes and glial
fibres. The cavities, which form the most conspicuous lesions in a proportion of
cases (lnnes and Shearer 1960), are sharply demarcated, surrounded by a thin glial
wall and generally devoid of products of tissue breakdown. In Menkes' disease
there is general poverty of myetination of the centrum semiovate without evidence
of active myelin breakdown(Vagn-Hansenet al. 1973. our Case 1): This suggests impaired myelin formation and supports HoweU's concept of myelin aphasia, although

Fig, 8. Swayback fA and B~ Two chromatolylie cells from ventral horn o! spinal cord. H&E. × 450.

109
loss of cortical and thalamic axons may also play a part. The lesions in Case 2 were
reminiscent of classical swayback with a loose meshwork of glia interspersed with
small cavities. Whether the vascular lesions, conspicuous in Case 2 and absent in
Case 1. were responsible lbr the differences between the siblings remains debatable,
as in swayback lesions of the white matter occur in the absence of any lesions in
the cerebral arteries (Danks 1980).
Cerebellar atrophy is an almost constant feature of Menkes" disease, an
intact cerebellum having been observed only once (Martin et al. 1978). In lambs,
the cerebellum is affected in a minority of cases (Barlow 1963), but the lesion
appears to be more common in copper deficient goats (Owen et al. 1965: Cordy
and Knight 1978). In all species there is a considerable reduction in the number
o1" granule cells associated with a variety of abnormalities in Purkinje cells. Barnard
el al. (1978) noted an abnormal thickness of the external granular layer (EGL)
in the affected parts of the cerebellar cortex in a case el" Menkes" disease and

0

.

o~

kig. 8B.

Q

II

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TABLE 1
C N S L E S I O N S IN M E N K E S '

Type of lesion

DISEASE AND SWAYBACK

Menkes" disease

Swayback

Widespread

Widespread

Vacuolation

Common
P u r k i n j e cells

Common
P u r k i n j e cells

Chromatolysis

Rare (or u n r e c o r d e d ? l

C o n s t a n t in a definite age group

Present in all cases

Present tn all cases
with cerebral involvement

Commoll
Rare
Rare

-Myelin aplasia in oedematous form c o m m o n

Degenerauon of red

Chromatotytic cells in r e d nucleus.
vestibular nuclei and reticular
substance.

Neuronal degenerations

Necrosis
Ferrugination

and cortical neurons

Cortical lesions

Laminar necrosis
Neuronal loss
Status spongiosus
White matter lesions

Hypomyelination
G l i a l meshwork

Cavitation
Brains'tern lesions

nucleus.

Rare chromatolytic cells
Cerebellar lesions

Spinal cord lesions

A l m o s t constant

U n c o m m o n in sheep.
More c o m m o n in goats.

R a r e c h r o m a t o t y t i c cells

Widespread chromatotytic cells.
Degeneration of ventro-lateral

Degeneration of spmocerebellar and pyramidal

columns

tracts

suggested that the depletion of the internal granular layer (IGL) was due to a
migration arrest. Observations on swayback support this view. The EGL in newborn
lambs is only I 2 cells deep, while over the affected areas its thickness may reach
8 10 cells. The arrested cells subsequently undergo degeneration and areas devoid
of the EGL may occur side by side with those of excessive thickness. No evidence
of a uniform broadening of the EGL was found in our Case 2, only focal, rosettelike, aggregates of cells similar to the "cell knots" of Vagn-Hansen et al. ~t973).
Iwata et al. (1979b) expressed doubts about migration arrest and favoured progressive degeneration of the ICL, as they found increasing depletion of granule
cells and. to a lesser extent, Purkinje cells with prolonged survival. The two views,
however, are not mutually exclusive.
The abnormalities of Purkin)e cells have been cited in evidence of the prenatal
origin of the cerebellar lesions (Hockey and Masters 1977; Williams et al. 1977
Smith 1981 ). The relevant deviations from the normal pattern fall into three groups
(1) bizarre arborisations of the apical dendrites. (2) presence of polydendritic

111
neurons, (3) heterotopias. At present there is no evidence of these abnormalities in
other species and they can only be compared with findings in other human diseases.
The expansion, displacement and malorientation of the apical dendrites and their
secondary and tertiary branches are the least specific of these features. They have
been observed in a large variety of conditions associated with depletion of the
granular cell layer, both congenital and acquired, and may be interpreted as a
response of the Purkinje cell to partial deafferentation (Urich 1983). The presence
of polydendritic cells constitutes a more pertinent argument. The fetal perisomatic
dendrites are shed during maturation around the 35th week of gestation (Zccvi~)
and Raki~ 1976). It is therefore reasonable to argue that retention of perisomatic
dendrites implies an arrest in normal maturation and that the responsible factors
must have operated in utero. Yet, as Purpura et al. (1976) remarked, they may
be formed de novo after the fetal dendrites have disappeared. Their presence in
acquired conditions such as industrial organic mercury poisoning (Hunter and
Russell 1954) and olivopontocerebellar degeneration (Fujisawa and Nakamura
1982) supports this view. It is therefore possible to view all dendritic abnormalities
as expression of neuronal plasticity. There are at present no criteria by which one
could confidently distinguish developmental from reactive plasticity.
Subcortical heterotopias of Purkinje cells have been reported in one case
only (Erdohazi el al. 1976: Barnard et al. 1978), This represents a disorder of
migration and is therefore a genuine prenatal malformation. It is, however, one
of the more common cerebellar abnormalities and has been observed in otherwise
normal inlilnts (Rorke et al. 1968). Its relevance to the pathogenesis of Menkes"
disease thus requires further elucidation. The authors claim it as the first mallkwmation recorded in Menkes' disease, thus implying that they consider the
abnormalities of the Purkinje cells to be reactive. Similarly Vagn-Hansen et al.
(1973) dismiss these changes as reactive without further comment.
In conclusion, this study has revealed that all lesions of Menkes" disease
have their conterpart in swayback and can thereti~re be confidently ascribed to
copper deficiency. The problem of the prenatal versus postnatal origin of lesions
remains unresolved. While somc disturbances of copper metabolism are undoubtedly
present ill the fetus their significance in the pathogenesis of the ccrebellar lesions
cannot be deduced from morphological findings alone, as these are not specific,
occur in a variety of conditions, and are open to alternative interpretations.
ACKNOWLEDGEMENTS

We are indebted to Dr. P.J. Pemberton for his clinical records, Dr. G.J,
Cullity lk~r referring material tbr examination, Drs. A. Hockey and C. L. Masters
l\~r permission to re-examine Case 1 of Menkes" disease. We are grateful to Dr.
A.C. Palmer, Department of Veterninary Medicine, Cambridge, Dr. S. Terlecki
and Mr. Martin Jeffrey, Central Veterinary Laboratory, Weybridge and Professor
J. McC. Howell, Department of Veterinary Pathology, Murdoch University lk~r
access to their swayback material and helpful discussions. Our thanks are due to

112

Professor B.A. Kakutas for his interest and encouragement, to the technologists
of the Department of Neuropathology for technical work, Richard -t'imm for
photography and Dianne Chantler and Patsy Cunningham for secretarial help.
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