A NOVEL VARIANT IN THE LIPA GENE
ASSOCIATED WITH DISTINCT PHENOTYPE
Sarajlija A.1,6, Armengol L.2, Maver A.3, Kitic I.4,6, Prokic D.4,6, Cehic M.1, Djuricic M.S.5,7, Peterlin B.3
*Corresponding Author: Adrijan Sarajlija, MD, PhD, Mother and Child Health Care Institute of Serbia
“Dr. Vukan Cupic”, School of Medicine, University of Belgrade, Radoja Dakica 6-8, Belgrade, 11070,
Serbia, Tel: +381113108287, E-mail: adrijans2004@yahoo.com
page: 8
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DISCUSSION
It has been observed that the clinical spectrum of LAL
deficiency varies from the classic Wolman phenotype of
early infantile cholestasis to a non-specific presentation of chronic liver disease with much later onset (2). However, a
pattern of clinical (hepatosplenomegaly) and biochemical
(dyslipidemia, elevated liver enzymes) abnormalities is
present in most of the patients (2,7,8). The disease which
affected the two pairs of siblings that we present herein fit
well into the pattern of LAL deficiency, especially after
the exclusion of LSDs with a more common occurrence
among the Serbian population. It has been reported that
approximately two thirds of CESD patients have a disease
onset before the age of 5 years. This corresponds to the age
range of our case series (2 months – 3 years) (18). Clinically,
all patients developed progressive hepatosplenomegaly,
complicated by hypersplenism. Esophageal varices were
present in one pair of siblings. Furthermore, three of our
patients manifested with growth faltering, which has been
previously described as a relatively common finding in late
onset LAL-D (19). A disturbed serum lipid profile is one
of the biochemical hallmarks of LAL deficiency (8). All
of the patients in our series have persistently low serum
HDL cholesterol concentration (Table 1), corresponding to
the proposed diagnosis. Patients 3 and 4 also had elevated
serum concentrations of total cholesterol and LDL fraction
in most of the measurements. Normal serum total and LDL
cholesterol in family 1 does not exclude the possibility of
LAL-D, especially in the presence of typically low HDL
cholesterol (20). Liver enzyme elevation in the serum is
present in the whole series we presented herein and these
findings correspond to previous clinical reports of LAL-D
patients (21). In two of our patients (one from each couple
of siblings), chitotriosidase activity in plasma was obtained,
and in both cases it showed starkly elevated values. Chitotriosidase
is a well-known and widely used marker of LSDs
(12,22). Although not entirely specific to metabolic disorders,
high chitotriosidase in pediatric patients with familial
occurrence of hepatosplenomegaly should direct further
testing toward LSDs. Due to the absence of neurologic
manifestations in our patients, we suspected the possibility
of Gaucher disease type 1 and LAL-D. After negative
results of specific enzyme assays for LSDs, whole exome
sequencing revealed the aforementioned variants in the
LIPA gene, hereby excluding other LSDs. Plasma oxysterol
concentration was available only for patient 1, and its elevation
was in line with the previously described biochemical
abnormalities in certain LSDs, including LAL-D (13).
Uniform microvesicular steatosis on light microscopy,
liquid crystals of cholesteryl esters with Maltese
cross-type birefringence in frozen section and staining with
Oil Red O or Sudan Black are the features of liver pathology
that strongly suggest CESD (10). Foamy macrophages
rich in lipid and ceroid content are one of the hallmarks
of histopathology in younger patients (2). Immunohistochemistry
reveals lysosomal markers, such as cathepsin
D, LAMP1, LAMP2 and LIMP2 (10).
Histology changes in the liver biopsies of patients 3
and 4 were entirely in accordance with the CESD diagnosis.
Progression to fibrosis and micronodular cirrhosis
is probable in untreated patients (2), and despite the early
age at the time of biopsy of patients 3 and 4 (3 and 5 years,
respectively), portal fibrosis was pronounced. The case of
patient 4 has already been reported in an article describ-ing the usefulness of histopathology in diagnosis of this
particular lysosomal storage disorder (23).
We have referred samples of one patient from each
pair of siblings (patients 1 and 3) to referent metabolic
laboratories (Mainz, Glasgow, Hamburg) and received
results stating that LAL activity in plasma was below the
normal range in both cases. However, LAL activity was
above the cut-off value defined as diagnostic for CESD.
Different methods of activity measurement have been employed
as diagnostic tools for LAL deficiency worldwide,
making it difficult to compare the findings of individual
patients. A residual enzyme activity of 2-11% is considered
as diagnostic for CESD (24). However, there has been a
report of severe LAL-D phenotype associated with substantially
higher LAL-D of 16% (25). Therefore, the predictive
value of enzymatic activity in regard to the clinical
course is not firmly established. Certain authors suggest
that precise cutoffs for low LAL activity are still dubious
for late-onset CESD, and that clinicians dealing with LSDs
should take into account other biomarkers (chitotriosidase,
serum transaminases, lipid profile) during the diagnostic
process (26-28). Over the years, assays of enzyme activity
employed in the diagnostics of different lysosomal storage
disorders have been subjected to critical evaluation,
pointing out the reduced possibility of false negativity with
a more recent methodology (29). Therefore, a borderline
enzyme result in the case of LSD suspicion, such as in
cases from our report, is recommended for further evaluation
by molecular genetic testing (30).
In patients 1 and 2 from our report, two variants
were detected in the LIPA gene in a compound
heterozygous state by clinical exome sequencing:
NM_000235.4:c.419G>A (p.Trp140Ter) (designated as
pathogenic) and NM_000235.4:c.851C>T (p.Ser284Phe)
(designated as VUS), while segregation testing confirmed
the carrier status of the parents. Both brothers share the
clinical pattern resembling LAL and have the same genotype.
The same VUS was detected in a homozygous state
in siblings from family 2 (patients 3 and 4) presented in
this study. However, the final diagnosis could not be made,
despite clinical and biochemical findings, in absence of
an indisputable enzyme deficiency and in the context of
uncertain nature of the c.851C>T (p.Ser284Phe) variant
in the LIPA gene. In a very recent study of infants treated
for severe LAL deficiency, a diagnosis based on a clinical
phenotype and supported by the variant of uncertain
significance (VUS) was reported in at least one case (31).
More authors address the possibility of the impact of VUS
in patients with probable lysosomal storage disease (32).
There are estimates that approximately a quarter of variants
designated as VUS contribute significantly to enzyme
deficiency in Mucopolysaccharidosis type III (33).
The pathogenic c.419G>A (p.Trp140Ter) variant in
the LIPA gene, present in heterozygous state in one pair
of siblings from our study, is considered as a severe null
variant (24). As recently stated by Reiner et al., the clinical
importance of heterozygosity (carriership) for variants in
the LIPA gene has yet to be elucidated in the future (34).
On the other hand, pathogenicity of LIPA gene variants is
a subject of critical reevaluation, primarily by means of
in vitro functional studies (17). There have been reports
that even polymorphisms in the LIPA gene can contribute
significantly to the occurrence of metabolic complications
in patients with obesity (35). The interpretation of
genetic findings in the context of the clinical condition is
further complicated in CESD due to the lack of genotypephenotype
correlation in this specific disorder (9).
The possibility of incongruence between genetic
findings and enzyme activity, as observed in this series
of patients, prompts further investigations. Nonsense,
frameshift, and splice mutations typically cause severe
(Wolman) forms of the disease (36) while the effect of
missense mutations (typically causing the milder CESD)
has recently been shown to be related with the structural
domain compromised (37). In the case of the missense
mutation described herein, we could speculate that it could
be related to the compromised ability of the mutated enzyme
to reach the optimal subcellular location, while the in
vitro biological activity remains normal, since the catalytic
domain is not compromised. A similar pathophysiologic
scenario has been described in several different rare genetic
diseases (38,39).
When confronted with a challenge of confirming the
diagnosis of a treatable inherited metabolic disorder, a
clinician should consider a multitude of aspects: clinical
manifestations, specific biomarkers, enzyme assay results,
and molecular genetic findings. We hope that this report
calls cases with considerable discrepancy between those
aspects to attention.
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