8
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-P 2 ) 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)P 2 5-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 (Bo ¨kenkamp 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

Atlas of Genetic Diagnosis and Counseling || Lowe Syndrome

  • Upload
    harold

  • View
    213

  • Download
    0

Embed Size (px)

Citation preview

Page 1: Atlas of Genetic Diagnosis and Counseling || Lowe Syndrome

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

Page 2: Atlas of Genetic Diagnosis and Counseling || Lowe Syndrome

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

Page 3: Atlas of Genetic Diagnosis and Counseling || 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

Page 4: Atlas of Genetic Diagnosis and Counseling || Lowe Syndrome

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

Page 5: Atlas of Genetic Diagnosis and Counseling || 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

References

Abbassi, V., Lowe, C. U., & Calcagno, P. L. (1968). Oculo-

cerebro-renal syndrome: A review. American Journal ofDiseases of Children, 115, 143–168.

Al-Uzri, A. Oculocerebrorenal dystrophy (Lowe syndrome).

Medscape Reference. Updated July 14, 2009. Available at:

http://emedicine.medscape.com/article/946043-overview.

Attree, O., Olivos, I. M., Okabe, I., et al. (1992). The Lowe’s

oculocerebrorenal syndrome gene encodes a protein highly

homologous to inositol polyphosphate-5-phosphatase.

Nature, 358, 239–242.Bickel, H., & Thursby-Pelnam, D. C. (1954). Hyper-amino-

aciduria in Lignac Fanconi disease, in galactosemia and in

an Obscure syndrome. Archives of Disease in Childhood, 29,224–231.

Bockenhauer, D., Bokenkamp, A., Van’t Hoff, W., et al. (2008).

Renal phenotype in Lowe syndrome: A selective proximal

tubular dysfunction. Clinical Journal of the American Soci-ety of Nephrology, 3, 1430–1436.

Bokenkamp, A., Bockenhauer, D., & Cheong, H., II. (2009).

Dent-2 disease: A mild variant of Lowe syndrome. Journalof Pediatrics, 155, 94–99.

Charnas, L. R., Bernardini, I., Rader, D., et al. (1991). Clinical

and laboratory findings in the oculocerebrorenal syndrome

of Lowe, with special reference to growth and renal func-

tion. The New England Journal of Medicine, 324,1318–1325.

Charnas, L. R., & Gahl, W. A. (1991). The oculocerebrorenal

syndrome of Lowe. Advances in Pediatrics, 38, 75–107.Cho, H. Y., Lee, B. H., Choi, H. J., et al. (2008). Renal manifes-

tations of Dent disease and Lowe syndrome. PediatricNephrology, 23, 243–249.

de Carvalho-Neto, A., Ono, S. E., de Melo Cardoso, G., et al.

(2009). Oculocerebrorenal syndrome of Lowe. Magnetic

resonance imaging findings in the first six years of life.

Arquivos de Neuro-Psiquiatria, 67, 305–307.Demmer, L. A., Wippold, F. J., 2nd, & Dowton, A. B. (1992).

Periventricular white matter cystic lesions in Lowe

(oculocerebrorenal) syndrome. A newMR finding. PediatricRadiology, 22, 76–77.

Elliman, D., & Woodley, A. (1983). Tenosynovitis in Lowe

syndrome. Journal of Pediatrics, 103, 1011.Gardner, R. J., & Brown, N. (1976). Lowe’s syndrome: Identi-

fication of carriers by lens examination. Journal of MedicalGenetics, 13, 449–454.

Gazit, E., Brand, N., Harel, Y., et al. (1990). Prenatal diagnosis

of Lowe’s syndrome: A case report with evidence of de novo

mutation. Prenatal Diagnosis, 10, 257–260.Ginsberg, J., Bove, K. E., & Fogelson, M. H. (1981). Patholog-

ical features of the eye in the oculocerebrorenal (Lowe)

syndrome. Journal of Pediatric Ophthalmology and Strabis-mus, 18, 16–24.

Hayashi, Y., Hanioka, K., Kanomata, N., et al. (1995). Clinico-

pathologic and molecular-pathologic approaches to Lowe’s

syndrome. Pediatric Pathology & Laboratory Medicine, 15,389–402.

Hodgson, S. V., Heckmatt, J. Z., Hughes, E., et al. (1986).

A balanced de novo X/autosome translocation in a girl with

manifestations of Lowe syndrome. American Journal ofMedical Genetics, 23, 837–847.

Holtgrewe, J. L., & Kalen, V. (1986). Orthopedic manifestations

of the Lowe (oculocerebrorenal) syndrome. Journal of Pedi-atric Orthopaedics, 6, 165–171.

Hoopes, R. R., Jr., Shrimpton, A. E., & Knohl, S. J. (2005). Dent

disease with mutations in OCRL1. American Journal ofHuman Genetics, 76, 260–267.

Kawano, T., Indo, Y., Nakazato, H., Shimadzu, M., &Matsuda, I.

(1998). Oculocerebrorenal syndrome of Lowe: Three

mutations in the OCRL1 gene derived from three patients

with different phenotypes. American Journal of MedicalGenetics, 77, 348–355.

Kenworthy, L., & Charnas, L. (1995). Evidence for a discrete

behavioral phenotype in the oculocerebrorenal syndrome

of Lowe. American Journal of Medical Genetics, 59,283–290.

Kleta, R. (2008). Fanconi or not Fanconi? Lowe syndrome

revisited. Clinical Journal of the American Society ofNephrology, 3, 1244–12445.

Lane, D., Baujat, G., Mirault, T., et al. (2010). Bleeding disor-

ders in lowe syndrome patients: Evidence for a link between

OCRL mutations and primary hemostasis disorders. BritishJournal of Haematology, 150(6), 685–688.

Laube, G. F., Russell-Eggitt, I. M., & Van’t Hoff, W. G. (2004).

Early proximal tubular dysfunction in Lowe’s syndrome.

Archives of Disease in Childhood, 89, 479–480.Lavin, C. W., &McKeown, C. A. (1993). The oculocerebrorenal

syndrome of Lowe. International Ophthalmology Clinics,33, 179–191.

Lewis, R. A., Nussbaum, R. L., Breewer, E. D. (2008). Lowe

syndrome. GeneReviews. Updated March 12, 2008. Avail-

able at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?

book¼gene&part¼lowe.

Lin, T., Lewis, R. A., & Nussbaum, R. L. (1999). Molecular

confirmation of carriers for Lowe syndrome.Ophthalmology,106, 119–122.

Lowe Syndrome 1305

Page 6: Atlas of Genetic Diagnosis and Counseling || Lowe Syndrome

Lin, T., Orrison, B. M., Leahey, A. M., et al. (1997). Spectrum of

mutations in the OCRL1 gene in the Lowe oculocerebrorenal

syndrome. American Journal of Human Genetics, 60,1384–1388.

Loi, M. (2006). Lowe syndrome (review). Orphanet Journal ofRare Diseases, 1, 16–20.

Lowe, C. U., Terrey, M., & MacLachan, E. A. (1952). Organic

aciduria, decreased renal ammonia production,

hydrophthalmos, and mental retardation: A clinical entity.

American Journal of Diseases of Children, 83, 164–184.Mueller, O. T., Hartsfield, J. K., Jr., Gallardo, L. A., et al. (1991).

Lowe oculocerebrorenal syndrome in a female with

a balanced X;20 translocation: Mapping of the

X chromosome breakpoint. American Journal of HumanGenetics, 49, 804–810.

Nussbaum, R. L., Orrison, B. M., Janne, P. A., et al. (1997).

Physical mapping and genomic structure of the Lowe syn-

drome gene OCRL1. Human Genetics, 99, 145–150.Nussbaum, R. L., & Suchy, S. F. (2001). The oculocerebrorenal

syndrome of lowe (lowe syndrome). In C. R. Scriver, A. L.

Beaudet, W. S. Sly, & D. Valle (Eds.), The metabolic andmolecular bases of inherited disease, Ch 252 (8th ed.,

pp. 6257–6266). New York: McGraw-Hill.

Ono, J., Harada, K., Mano, T., et al. (1996). MR findings and

neurologic manifestations in Lowe oculocerebrorenal syn-

drome. Pediatric Neurology, 14, 162–164.Peverall, J., Edkins, E., Goldblatt, J., et al. (2000). Identification

of a novel deletion of the entire OCRL1 gene detected by

FISH analysis in a family with Lowe syndrome. ClinicalGenetics, 58, 479–482.

Reilly, D. S., Lewis, R. A., Ledbetter, D. H., et al. (1988). Tightly

linked flanking markers for the Lowe oculocerebrorenal syn-

drome, with application to carrier assessment. AmericanJournal of Human Genetics, 42, 748–755.

Reilly, D. S., Lewis, R. A., & Nussbaum, R. L. (1990).

Genetic and physical mapping of Xq24-q26 markers

flanking the Lowe oculocerebrorenal syndrome. Genomics,8, 62–70.

Richards, W., Donnel, G. N., Wilson, W. A., et al. (1965). The

oculocerebrorenal syndrome of Lowe. American Journal ofDiseases of Children, 109, 185–203.

Roschinger, W., Muntau, A. C., Rudolph, G., et al. (2000).

Carrier assessment in families with Lowe oculocerebrorenal

syndrome: Novel mutations in the OCRL1 gene and correla-

tion of direct DNA diagnosis with ocular examination.

Molecular Genetics and Metabolism, 69, 213–222.Saricaoglu, F., Demirtas, F., & Aypar, €U. (2004). Preoperative

and perioperative management of a patient with Lowe syn-

drome diagnosed to have Fanconi’s syndrome. PediatricAnesthesia, 14, 530–532.

Satre, V., Monnier, N., Berthoin, F., et al. (1999). Characteriza-

tion of a germline mosaicism in families with Lowe syn-

drome, and identification of seven novel mutations in the

OCRL1 gene. American Journal of Human Genetics, 65,68–76.

Sekine, T., Nozu, K., Iyengar, R., et al. (2007). OCRL1 muta-

tions in patients with Dent disease phenotype in Japan. Pedi-atric Nephrology, 22, 975–980.

Silver, D. N., Lewis, R. A., & Nussbaum, R. L. (1987). Mapping

the Lowe oculocerebrorenal syndrome to Xq24-q26 by use of

restriction fragment length polymorphisms. The Journal ofClinical Investigation, 79, 282–285.

Suchy, S. F., Lin, T., Horwitz, J. A., et al. (1998). First report of

prenatal biochemical diagnosis of Lowe syndrome. PrenatalDiagnosis, 18, 1117–1121.

Suchy, S. F., Olivos-Glander, I. M., & Nussbaum, R. L. (1995).

Lowe syndrome, a deficiency of phosphatidylinositol 4,5-

bisphosphate 5-phosphatase in the Golgi apparatus. HumanMolecular Genetics, 4, 2245–2250.

Utsch, B., Bokenkamp, A., Benz, M. R. (2006). Novel OCRL1

mutations in patients with the phenotype of Dent disease.American Journal of Kidney Disease, 48, 942 e1–14.

Wadellius, C., Fagerholm, P., Pettersson, U., et al. (1989). Lowe

oculocerebrorenal syndrome: DNA-based linkage of the

gene to Xq24–q26, using tightly linked flanking markers

and the correlation to lens examination in carrier diagnosis.

American Journal of Human Genetics, 44, 241–247.Zhang, X., Jefferson, A. B., Auethavekiat, V., et al. (1995). The

protein deficient in Lowe syndrome is

a phosphatidylinositol-4,5-bisphosphate 5-phosphatase. Pro-ceedings of the National Academy of Sciences of the UnitedStates of America, 92, 4853–4856.

1306 Lowe Syndrome

Page 7: Atlas of Genetic Diagnosis and Counseling || 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

Page 8: Atlas of Genetic Diagnosis and Counseling || Lowe Syndrome

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