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Lowe Syndrome
Lowe syndrome, also known as oculocerebrorenal syn-
drome, is a rare X-linked recessive disorder. It was
initially recognized in 1952 by Lowe and colleagues
who described the triad of congenital cataracts, mental
retardation, and generalized aminoaciduria. In 1954,
a renal Fanconi syndrome was recognized as being
associated with the syndrome (Bickel & Thurshby-
Pelnam 1954) and in 1965, an X-linked recessive pattern
of inheritance was determined (Richards et al. 1965).
Its prevalence is estimated to be several cases per
100,000 males.
Synonyms and Related Disorders
Dent-2 disease; Oculocerebrorenal syndrome
Genetics/Basic Defects
1. Inheritance
a. X-linked recessive disorder predominantly
affecting males, although several affected
females have been reported
b. New mutations in 31.6% of affected males
c. Germline mosaicism in 4.5%
2. The gene involved (OCRL1)
a. Map locus: Xq26.1, based on
i. Balanced X-autosome translocations with
a break-point in band Xq25-q26 in two
unrelated female patients
ii. Linkage analysis with RLFP in families with
multiple affected individuals
b. Mapped in 1977
c. Cloned in 1992
d. Encoding OCRL1, a 105-kD enzyme
with phosphatidylinositol 4,5-bisphosphate 5-
phosphatase (PtdIns-4,5-P2) activity localized
to the Golgi complex
i. Loss or reduction of the enzyme demon-
strated in affected males
ii. Carrier status of OCRL in females not readily
determined by assays of the enzyme due to
the X-linked nature of OCRL1 and random
X inactivation
3. Mutations of OCRL1 gene responsible for Lowe
syndrome
a. Nonsense mutations and deletions causing
frameshifts and premature termination
b. Deletions
c. Missense mutations in domains conserved
among all the known PtdIns(4,5)P25-phosphatases
4. Carrier females with typical lens opacities
5. Affected females as a result of
a. Unfavorable lyonization
b. Turner syndrome
c. X-autosome translocation through the relevant
gene
6. Dent-2 disease (a mild variant of Lowe syndrome
(Bokenkamp et al. 2009)
a. Dent disease
i. An X-linked tubulopathy charac-
terized by low-molecular-weight proteinuria,
hypercalciuria, and nephrolithiasis/
nephrocalcinosis (1)
ii. In more than half the patients, Dent disease is
caused by mutations affecting the voltage-
gated chloride channel and chloride/proton
antiporter (ClC-5).
H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_150,# Springer Science+Business Media, LLC 2012
1301
b. Dent-2 disease
i. In approximately 15% of patients with a Dent
phenotype, mutations in the oculocer-
ebrorenal syndrome of Lowe gene
(OCRL) encoding a phosphatidylinositol
4,5-bisphosphate 5-phosphatase, have been
found (Hoopes et al. 2005; Utsch et al.
2006; Sekine et al. 2007; Cho et al. 2008).
ii. These patients are classified as having “Dent
disease-2” to distinguish them from most
patients with an OCRL mutation who have
the more severe oculocerebrorenal syndrome
of Lowe phenotype (Charnas et al. 1991)
which is characterized by a proximal
tubulopathy (Bockenhauer et al. 2008; Kleta
2008), congenital cataract, severe mental
retardation, and behavioral disturbances.
Clinical Features
1. Variable age of onset and severity of clinical
manifestations
2. Eye abnormalities
a. Congenital cataracts (the hallmark of the disease)
i. Developed prenatally
ii. Always present prior to birth
b. Congenital glaucoma with or without
buphthalmos (50–60%)
c. Microphthalmos
d. Nystagmus
e. Decreased visual acuity (blindness)
f. Corneal scarring and keloid formation
i. Develops spontaneously without trauma
ii. Onset usually after age 5
iii. Causes significant visual impairment
3. Renal abnormalities
a. Fanconi syndrome of renal tubules (the cardinal
features)
i. Bicarbonaturia
ii. Proximal tubular acidosis
iii. Generalized aminoaciduria
iv. Hyperphosphaturia leading to osteomala-
cia, renal rickets, and pathologic fractures
v. Hypercalciuria
vi. Proteinuria
vii. Glycosuria (not a feature of the renal tubu-
lar dysfunction)
viii. Impairment in urine-concentration
(polyuria)
ix. Carnitine wasting
b. Variable age of onset and severity of the tubular
dysfunction
i. Failure to thrive
ii. Recurrent infections
iii. Metabolic collapse
iv. Severe hypokalemia or hypocalcemia requir-
ing replacement therapy in a minority of
patients. This is probably a part of preterminal
exacerbation of tubular dysfunction.
v. Slowly progressive renal failure may occur
in the second to fourth decade of life.
4. CNS (prominently involved organ) and behavioral
abnormalities
a. Cardinal features
i. Neonatal/infantile hypotonia
ii. Delay in motor milestones
iii. Cognitive impairment
iv. Areflexia by 1 year of age
b. Mental retardation (common but not cardinal
feature)
c. Seizures
d. Neuropathologic and neuroimaging abnormalities
e. Stereotypic behaviors
i. Temper tantrum (Lowe tantrum)
ii. Aggression
iii. Irritability
iv. Stubbornness
v. Rigidity of thought
vi. Self injury
vii. Repetitive nonpurposeful movements
5. Musculoskeletal abnormalities
a. Secondary consequences of hypotonia, renal
tubular acidosis, and/or hypophosphatemia
i. Short stature
ii. Joint hypermobility
iii. Dislocated hips
iv. Genu valgum
v. Scoliosis
vi. Kyphosis
vii. Platyspondylia
viii. Fractures
b. Primary abnormality of excessive connective
tissue growth
i. Nontender joint swelling
ii. Subcutaneous nodules
1302 Lowe Syndrome
6. Typical facies
a. Frontal bossing
b. Characteristic deep-set eyes
c. Inattentiveness
7. Other features
a. Increased hemorrhagic risk (Lane et al. 2010)
b. Cryptorchidism
8. Natural history
a. Succumb to either severe renal insufficiency and
dehydration or infection
b. Survival to adulthood if metabolic abnormalities
are adequately treated
9. Manifestation in the carriers
a. Lens involvement
i. Micropunctate cataracts clustered in a radial
wedge pattern
ii. Occasional dense posterior cortical cataract
b. Sensitivity of carrier detection by slit-lamp
examination (>90%), due to random inactiva-
tion of Lowe syndrome allele in the proportion of
cells in the lens of female carriers
c. Germ line or somatic mosaicism documented
d. Positive family history of early cataracts in
mother, maternal female relatives, and institu-
tionalized maternal uncles
Diagnostic Investigations
1. Blood chemistry
a. Blood gas for metabolic acidosis
b. Electrolyte disturbances (likely absent in
neonates and young infants)
2. Urine
a. Aminoaciduria
b. Hyperphosphaturia
c. Low-molecular-weight (LMV) proteinuria:
characterized by the excretion of proteins such
as retinal binding protein and N-acetyl
glucosaminidase, is seen in
i. Lowe syndrome: LMW proteinuria can be
seen early in life even in the absence of clin-
ically significant aminoaciduria or other renal
tubular abnormalities (Laube et al. 2004)
ii. The allelic disorder Dent disease
iii. Many other diseases associated with the
Fanconi syndrome
d. Glycosuria
e. Low urine osmolality
f. Elevated 24-h volume
3. Serum enzyme values
a. Elevated CK
b. Elevated SGOT
c. Elevated LDH
d. Elevated a2-globulin4. Measurement of inositol polyphosphate
5-phosphatase OCRL1 activity in cultured skin
fibroblasts (Lewis et al. 2008)
a. Males: to confirm the diagnosis in affected males
(Suchy et al. 1995; Zhang et al. 1995)
i. Affected males have less than 10% normal
activity of the enzyme.
ii. Such testing is abnormal in more than 99% of
affected males.
b. Carrier females. The activity is not accurate for
carrier detection because of lyonization (random
X-chromosome inactivation), which results in
a wide range of “normal” activity in females
(Lin et al. 1999).
5. Karyotype. Translocations between an autosome
and an X chromosome with a breakpoint through
the OCRL locus (Xq26.1) have been observed
(Hodgson et al. 1986; Mueller et al. 1991)
6. Radiography
a. Rickets/osteoporosis
b. Pathological fractures
c. Frontal bossing
d. Kyphoscoliosis
e. Cervical spine anomalies
f. Platyspondyly
g. Hip subluxations/dislocation
7. Neuroimaging
a. Cranial MRI
i. Mild ventriculomegaly (33%)
ii. Multiple tiny periventricular cysts (no clini-
cal significance)
iii. Two patterns of brain lesions (de Carvalho-
Neto et al. 2009)
a) Hyperintensities on T2-weighted images
b) Periventricular cystic lesions
b. Neuropathologic examination of the brain
i. Normal in some cases
ii. Diffuse or focal myelin pallor without mye-
lin breakdown
iii. Ventriculomegaly
iv. Mild cerebral abnormalities
Lowe Syndrome 1303
v. Isolated cases of subependymal cysts
vi. Mesencephalic porencephaly
vii. Postencephalitic changes
viii. Blunted and foreshortened frontal lobes
ix. Acute pontine necrosis
x. Cerebellar hypoplasia
xi. Aberrant neuronal migration
xii. Multiple tiny cysts without inflammatory
changes
8. Affected male patients
a. Biochemical assay of reduced activity (<10%)
of PtdIns (4,5)P2 5-phosphatase in cultured
fibroblasts to confirm diagnosis of patients with
OCRL. Peripheral blood cannot be tested since
the enzyme is not present in lymphocytes.
b. Molecular analysis to detect mutations in the
OCRL gene in about 95% of affected males
i. Sequence analysis
ii. Fluorescence in situ hybridization analysis
(FISH), with cosmid probes that span the
entire OCRL1 gene
9. Carrier females
a. Karyotyping to rule out X-autosome transloca-
tion with a breakpoint through the OCRL locus
b. Carrier detection
i. Biochemical assay of reduced activity of
PtdIns (4,5)P2 5-phosphatase in cultured
fibroblasts is not suitable for determining
OCRL carrier status, since random
X inactivation could result in a wide range
of enzyme activity that may overlap with the
normal range.
ii. An obligatory carrier based on evaluation of
the family pedigree
iii. Slit-lamp examination for numerous punc-
tate opacities, especially in prepubertal
females, is a better method and it has a low
false-negative rate.
iv. By direct detection of mutations when the
mutation is previously identified (in about
95% of carrier females)
v. By mutation scanning of high-risk females
by denaturing high performance liquid chro-
matography (DHPLC) when:
a) The affected male is not available
b) The diagnosis has been confirmed by
enzyme analysis
vi. By linked markers when the mutation is
unknown
Genetic Counseling
1. Recurrence risk
a. Patient’s sib
i. A 25% risk of having an affected boy and
a 25% risk of having a carrier daughter if the
mother is a carrier
ii. A low but finite recurrence risk (estimated to
be about 1.5%) in case of a new mutation due
to possibility of nonpenetrance or gonadal
mosaicism in the mother
b. Patient’s offspring: affected males not known to
reproduce
2. Prenatal diagnosis available for pregnancies at
risk
a. Determine fetal gender by amniocentesis or CVS
b. Biochemical assay for deficiency of PtdIns(4,5)
P2 5-phosphatase from cultured amniotic fluid
cells or cultured CVS if the fetal karyotype
shows 46,XY (not suitable for determining
OCRL carrier status for females)
c. Molecular analysis
i. By direct detection of mutations when the
OCRL disease-causing mutation in the family
is known
ii. By linked markers in informative families
when the mutation is unknown
d. Offer prenatal diagnosis by enzymatic analysis
to every mother of a son with Lowe syndrome
because of the relatively high rate (4.5%) of
germline mosaicism, even with the following
situations:
i. Negative family history
ii. Negative dilated slit-lamp examination
iii. DNA testing showing that the mother is not
a carrier
3. Management
a. Ocular management
i. Cataract extraction to avoid amblyopia
ii. Refraction for aphakia
iii. Control of glaucoma
iv. Removal of corneal keloids: often with
recurrence and enlargement of the lesions
b. Speech and physical therapy for developmental
delay
c. Medications
i. Anticonvulsants
ii. Behavior-modifying medications if needed
1304 Lowe Syndrome
d. Replacement/supplementation
i. Phosphate and sodium-potassium citrate for
renal tubular acidosis (urinary bicarbonate,
water, and phosphate losses) and bone dis-
ease (rickets)
ii. L-carnitine
iii. Vitamin D supplements as indicated
e. Anesthetic risks
i. Chronic metabolic acidosis
ii. Existing hypokalemia, a risk for serious car-
diac arrhythmia
iii. A risk of glaucoma
iv. Hypophosphatemic rickets causing fragility
of bone structures
1. Requires attention while positioning
2. Difficulty in maintaining the airway due
to craniofacial abnormalities and abnor-
mal teeth structure
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Lowe Syndrome 1305
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1306 Lowe Syndrome
a
c d
bFig. 1 (a–d) One and half
year-old boy with Lowe
syndrome showing frontal
bossing and deep-set eyes. He
had a history of profound
hypotonia, failure to thrive,
cataracts, glaucoma, seizures,
and generalized
aminoaciduria. The diagnosis
was confirmed by assay of
markedly deficient
phosphatidylinositol
bisphosphate phosphatase
activity in the cultured
fibroblasts (0.05, control:
2–5 mmol/min/mg protein).
The recent photos were taken
at 6 and 9 years of age
Lowe Syndrome 1307
a b
Fig. 2 (a, b) A 10-year-old boy with Lowe syndrome showing
short stature and visual impairment. The diagnosis was con-
firmed by assay of markedly deficient phosphatidylinositol
bisphosphate phosphatase activity (0.05 with normal control of
2–5 nmol/min/mg protein) in the cultured fibroblasts
1308 Lowe Syndrome