Review
SjgrenLarsson
syndrome
Neil Gordon MD FRCP Hon FRCPCH
Correspondence to author at Huntlywood, 3 Styal Road,
Wilmslow, Cheshire SK9 4AE, UK.
E-mail: neil-gordon@doctors.org.uk
SjgrenLarsson syndrome is a recessively inherited
syndrome caused by deficiency of fatty aldehyde
dehydrogenase. The most common symptoms and signs are
described, especially ichthyosis, spastic diplegia, and severe
learning difficulties; but also other less frequent ones. Special
investigations include sensory evoked potentials,
electromyography, and proton magnetic resonance
spectroscopy. Post-mortem examination shows, in particular,
an accumulation of lipid substances in specific regions of the
brain. The diagnosis depends on the measurement of fatty
aldehyde dehydrogenase in cultured fibroblasts from skin
biopsies, and by identifying known mutations by allele-
specific polymerase chain reaction assay. Prenatal diagnosis is
possible by using the same technique. The disorder is located
on gene 17, and many mutations have been identified. Most
mutations are unique to an affected family, but clinical
variations may be due to unknown genetic and environmental
factors. The deficiency of the enzyme impairs the oxidation of
medium and long chain fatty aldehydes, and this may explain
the link between the brain and skin disorders. The treatment
of affected children needs input from a number of specialists,
and their contributions are discussed.
152 Developmental Medicine & Child Neurology 2007, 49: 152154
SjgrenLarsson syndrome is an autosomal recessive disor-
der with 100% penetrance, characterized by ichthyosis, spastic
diplegia, and severe learning difficulties. It is caused by the
deficiency of fatty aldehyde dehydrogenase, a component of
the fatty alcohol:nicotinomide adenine denucleotide oxidore-
ductase complex. The diagnosis is usually apparent from the
clinical findings, and can be confirmed by appropriate tests.
The skin condition can certainly be treated, and so can the
complications of spasticity. Its incidence worldwide has been
estimated to be 0.4 per 100 000.
Clinical presentation and course
The symptoms and signs will be those of a child with cerebral
palsy (CP), usually spastic diplegia or tetraplegia, although a
generalized dystonia has been reported.1 There will also be
severe learning difficulties and ichthyosis. The latter is likely
to be present from birth, with a slight hyperkeratosis, which
then progresses to a generalized ichthyosis, especially on the
neck, the flexures, and the lower abdomen.2 Pruritus is a promi-
nent feature that is not found in other types of ichthyosis.
The hair and nails are normal.3 Seizures occur in about 40%
of patients.4 Less common features are short stature, kyphosco-
liosis, nystagmus, and retinal changes,5 consisting of perivas-
cular glistening white dots.6 Affected children can become
wheelchair-bound, and then orthopaedic management can
be essential; starting with physiotherapy and splintage, and
followed by surgical procedures such as lengthening of ten-
dons and muscle release.
Clinical findings can be variable, even among siblings, and
it is suggested that deficiency of the responsible enzyme is
considered to be part of the definition of the syndrome,
which will almost certainly include ichthyosis, severe learning
difficulties, and spasticity.7 This variability, no doubt linked
to genetic influences, makes it especially difficult to give a
prognosis, apart from the fact that any child with CP can be at
greater risk from factors such as intercurrent infections, so
that life expectancy will almost certainly be affected.
Brainstem auditory evoked potentials, visual evoked poten-
tials, and short-latency somatosensory evoked potentials can
be impaired, so that children with SjgrenLarsson syndrome
can suffer from dysfunction of three sensory modalities at dif-
ferent levels of the sensory pathways, from peripheral areas to
central regions.8
Magnetic resonance imaging (MRI) can show evidence of
delayed myelination, and proton magnetic resonance spectro-
scopy can reveal an abnormal lipid peak in the periventricular
white matter, suggesting an accumulation of lipids, periventric-
ular gliosis, delayed myelination, and a mild, permanent myelin
deficit. The monitoring of the lipid peak may offer a way of
assessing the effects of treatment.9,10 Proton magnetic reso-
nance spectroscopy can also be a powerful tool in the screening
of SjgrenLarsson heterozygotes.11,12 The electroencephalo-
gram shows only non-specific slow wave activity.13
Post-mortem examination of the brain can confirm the
accumulation of lipid substances in the subpial, subependy-
mal and perivascular glial layers, the subpial and perivascular
spaces, and the white matter of the cerebrum and brainstem.
There is also proliferation of perivascular macrophages con-
taining lipofuscin-like pigments, spheroid bodies in brain-
stem nuclei, and reduction of myelinated nerve fibres in the
cerebral and cerebellar white matter. The findings suggest
that peculiar lipid substances can accumulate in specific regions
of the brain and interfere with normal function.14
Diagnosis
The diagnosis depends on measurements of fatty aldehyde
dehydrogenase or of the oxidoreductase complex in cultured
fibroblasts from skin biopsies, but now can be confirmed by
identifying known mutations by allele-specific polymerase
chain reaction assay. Identification of abnormal urinary excre-
tion of leukotriene B4 and its metabolites can also be use-
ful.13,15,16 Enzymatic confirmation of the diagnosis is important
because only about half of the patients with cutaneous and
neurological symptoms resembling the SjgrenLarsson syn-
drome have a deficiency of fatty aldehyde dehydrogenase.4,17
The differential diagnosis is from conditions such as Ruds
syndrome and Refsums disease, combining neurological
and dermatological disorders, and from other slowly progres-
sive neurological disorders such as carbohydrate-deficient gly-
coprotein syndrome type 1, multiple sulphatase deficiency,
neural lipid storage disorder, and mitochondrial disorders.
Prenatal diagnosis of the syndrome is possible, by measur-
ing the conversion of phytol into phytenic acid in chorionic
villus biopsy samples,18 or by a polymerase chain reaction-
based mutation analysis of the sample.19
Genetics
This autosomal recessive disorder is located at gene 17p11.2.2
Mutations in the homozygous state in several exons of this
aldehyde dehydrogenase isoenzyme gene can result in a defi-
ciency of the microsomal enzyme fatty aldehyde dehydroge-
nase. This enzyme is involved in epidermal lipid synthesis,
and its deficiency can result in a disruption of the function of
the stratum corneum as a water barrier.15 Most mutations are
unique to each affected family6 and clinical variations, even
among siblings, may be due to unknown genetic or environ-
mental factors.20 The possibility of genetic heterogeneity is
not excluded21 and missence mutations comprise the largest
class of the many mutations.22,23
Biochemistry
The exact pathogenesis is uncertain, but the deficiency of
fatty aldehyde dehydrogenase in this syndrome impairs the
process which catalyzes the oxidation of medium- and long-
chain fatty aldehydes. Leukotriene B4, a potent pro-inflam-
matory mediator, plays a role in a variety of disease
processes, and its metabolism is disordered in this syndrome
as normally it is inactivated by the dehydrogenase enzyme. It
may, therefore, offer an explanation for some aspects of the
pathophysiology.24,5,16 The enzyme is necessary for the oxi-
dation of fatty aldehyde derived from metabolism of fatty
alcohol and wax esters, a pathway that is important in epider-
mal lipid synthesis, and its deficiency may disrupt the water
barrier and cause the skin to dry. Also, it may be that the accu-
mulation of aldehyde-modified lipids or fatty alcohol in
white matter, corresponding to the lipid peaks seen on pro-
ton magnetic resonance spectroscopy, interferes with the
functional integrity of myelin, thus explaining the link
between the skin and brain disorder.4,17
Evidence has been found for the defective inactivation of
leukotriene B4 among patients with this syndrome, and this
may be the reason for the frequent preterm births among
affected children. It certainly supports the concept of
preterm labour as an intrauterine inflammatory response as
leukotriene B4 is a potent proinflammatory mediator.16,25
Treatment of children
Treatment of affected children should be multidisciplinary,
with advice from a variety of specialists, including neurologists,
dermatologists, ophthalmologists, orthopaedic surgeons, and
physiotherapists. Surgical treatment of joint contractures
may be needed.26,27
Special diets can be tried early in the disease to reduce
total fatty intake, and with supplements of both n-3 and n-6
fatty acids to obtain a linoleic/linolenic acid ratio of 6, but
with limited effect.28,29
Treatment of skin lesions will require abundant hydration
with emollient baths and keratolytic agents; and certain types of
ichthyosis have been treated with significant improvement by
the topical application of calcipotriol, a vitamin D analogue.5
In view of the role of defective leukotriene B4 metabolism
in this syndrome, therapeutic trials of zileuton, a 5-lipoxyge-
nase inhibitor, are justified, especially if pruritis is severe.30,31,32
Also, gene therapy may be possible, as it has been shown that,
using cell lines from hamsters, adeno-associated virus vec-
tors, can target relevant tissues and are able to restore fatty
aldehyde dehydrogenase deficiency.33
Conclusions
Although a rare disorder, much can be done to help the affected
child and the family, especially in the treatment of the skin
condition and in the giving of genetic advice. The recent dis-
coveries of the responsible biochemical abnormalities have
explained many of the different symptoms and signs, in par-
ticular the links between the brain and the skin.
Accepted for publication 24th October 2006.
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