51.1 Clinical Features
and Laboratory Investigations Lowe syndrome, or oculocerebrorenal syndrome of Lowe (OCRL), is a rare, X-linked hereditary disease. It is present in all races, with a predominance in those of Caucasian and Asian ancestries. Rarely females are affected like males.
Males with OCRL present with congenital ocular manifestations including cataract, often associated with glaucoma and miotic pupils. Buphthalmos may be present. Sight is poor and eye movements are nys- tagmoid. Additional early features include muscle hy- potonia, hyporeflexia, or areflexia and hypermobility of the joints. During the first year of life psychomotor developmental delay becomes evident. The infants have excessive crying with a high-pitched scream.
Asymptomatic amino aciduria and proteinuria are usually found during this stage.
During early childhood the symptoms of renal tubular dysfunction develop with metabolic acidosis and losses of calcium and phosphate. Severe deminer- alization and rickets may develop and lead to fre- quent fractures, pain, and delay of normal physical development. Many patients develop scoliosis. Linear growth decreases after 1 year of age, and between 1 and 3 years of age height falls below the third per- centile. Head circumference is either normal or bor- derline microcephalic. Noninflammatory arthro- pathy of unknown pathogenesis with pain, joint swelling, and contractures may occur, affecting both large and small joints. Mental retardation is usually moderate, but intelligence varies between normal and profoundly decreased. Some patients have epilepsy.
Unusual stereotypic movements are often seen, espe- cially repetitive shaking of limbs. Maladaptive behav- ior is frequently present and consists of temper tantrums, high-pitched scream, and stubbornness. A later occurring ocular complication is corneal keloid, consisting of scar-like opacifications of the cornea that can develop spontaneously or following trauma.
The frequency of corneal keloid increases with age in OCRL patients.
Patients with OCRL continue to grow in early adulthood. Final height, however, remains below the third percentile of normal values. Severe bone disease leads to orthopedic disability. Renal dysfunction is slowly progressive with decreasing glomerular filtra- tion rates. Terminal renal failure occurs in the mid-
thirties. Death may occur between the first and the fourth decade, secondary to inanition, pneumonia, or uremia.
Laboratory findings show renal tubular dysfunc- tion similar to Fanconi syndrome. The tubular dys- function leads to urinary loss of bicarbonate, glucose, calcium, phosphorus, protein, and amino acids. The results are metabolic acidosis, hypophosphatemia, secondary hyperparathyroidism, and rickets. Urinary excretion of carnitine is increased with decreased serum carnitine. The serum muscle enzymes creatine kinase, aspartate aminotransferase, and lactate dehy- drogenase are sometimes elevated. Over the years progressive glomerular dysfunction develops with uremia. A linear relation between reciprocal serum creatine level and age reflects the progressive renal failure. Abnormalities of blood chemistry values are mitigated by replacement therapy for renal tubular losses.
Skeletal X-ray examinations reveal rachitic changes.
EEG often shows nonspecific abnormalities, some- times epileptic activity.
Progressive lenticular opacities are present in OCRL carriers, and even young carriers can be identified reliably in this way in known OCRL families. Lack of opacities in females cannot be considered as proof of not being a carrier, but is suggestive.
The biochemical assay for deficiency of phos- phatidylinositol 4,5-biphosphate 5-phosphatase in cultured fibroblasts is the definitive laboratory test for diagnosing patients and can be used for prenatal diagnosis. DNA techniques are available for diagnos- tic confirmation in patients, for carrier detection, and for prenatal diagnosis. De novo mutations or sporadic cases are frequent. Somatic and germline mosaicism has been described and must be taken into account for genetic counseling.
51.2 Pathology
In OCRL, data on neuropathological findings are lim- ited. The brain weight is usually below normal. Mod- erate, diffuse atrophy may be seen with cerebral vol- ume loss, some ventricular enlargement and thinning of the corpus callosum. The meninges are diffusely fibrotic without inflammatory changes.
Variable cortical changes have been described ranging from normal to neuronal loss in combination
Lowe Syndrome
with gliosis. Evidence of aberrant neuronal migration with pachygyria or polymicrogyria has also been re- ported.
The white matter changes described are variable.
The most frequent finding is gliosis. More or less prominent myelin paucity has been described, either focal or diffuse. White matter abnormalities are most pronounced in the centrum semiovale and periven- tricular white matter. Spongy changes have been observed, frequently associated with perivascular lacunes. Active myelin breakdown has never been reported, and the myelin paucity is usually ascribed to deficient myelination. In rare cases, the white mat- ter is normal.
The cerebellum may be atrophic or normal. Gliosis of the cortex and white matter have been observed.
Variable and inconsistent abnormalities of the pe- ripheral nervous system have been reported. Nerve biopsy has been found to exhibit signs of axonal neu- ropathy in several, but not all patients. Muscle biopsy has indicated selective type 1 fiber atrophy with mild type 1 fiber predominance, considered to be consis- tent with congenital fiber type disproportion myopa- thy or, alternatively, to abnormal neuronal influence upon muscle. In other patients, muscle biopsy re- vealed no abnormalities.
Renal pathology demonstrates dilated tubules with atrophy of tubular epithelium. Many tubules contain eosinophilic, granular protein casts. Interstitial fibro- sis is present. Glomerular changes have been ob- served, in particular on ultrastructural examination.
Glomerular endothelial cells may be swollen with a reduction in the number of endothelial slit pores, fusion of endothelial foot processes, and thickening of the glomerular basement membrane.
51.3 Pathogenetic Considerations
OCRL is caused by defects in the OCRL1 gene, located on chromosome Xq25–26. The gene product is phosphatidylinositol 4,5-biphosphate (PIP2) 5-phos- phatase, an inositol polyphosphate 5-phosphatase be- longing to the type II 5-phosphatase family. The type II phosphatases hydrolyze both water-soluble and lipid inositol polyphosphate substrates, whereas the type I phosphatases only hydrolyze water-soluble substrates. However, PIP25-phosphatase prefers the lipid substrate phosphatidylinositol 4,5-biphosphate.
Many different mutations of the OCRL1 gene have been described in patients, most of which are truncat- ing mutations or missense mutations in conserved domains of the protein. In highly exceptional cases, the OCRL phenotype has been observed in female patients. In some of these female patients there is a mutation in the OCRL1 gene on one chromosome, whereas there is a deletion of the region on the other
X chromosome. OCRL may also occur in XO patients.
Unfortunate X inactivation is another possibility explaining exceptional female patients.
Inositol containing phospholipids are collectively referred to as phosphoinositides or phosphatidyli- nositols. They are minor but ubiquitous components of eukaryotic membranes. Phosphoinositides are important in signal transduction. The subcellular localization of PIP2 5-phosphatase is in the trans- Golgi network. The substrate of this enzyme, phos- phatidylinositol 4,5-biphosphate, serves as a sub- strate for the production of second messengers, pro- motes the polymerization of actin cytoskeleton, and plays a role in vesicular trafficking. In fibroblasts of Lowe patients a decrease in long actin stress fibers, enhanced sensitivity to actin depolymerizing agents, and an increase in actin staining in a distinctly anom- alous distribution in the center of the cells have been demonstrated. Two actin-binding proteins, gelsolin and a-actinin, proteins regulated by both PIP2and Ca2+, have been found to have an abnormal distribu- tion. Actin polymerization plays a key role in the for- mation, maintenance, and proper function of tight junctions and adherens junctions, which are critical in renal proximal tubule function and the differentia- tion of the lens. The relationship with the encephalo- pathy is less clear.
51.4 Therapy
The nephrologist should manage both the tubular and glomerular complications associated with the renal disease in OCRL. In renal tubular acidosis and rickets a combination of sodium-potassium citrate, phosphorus, and large doses of vitamin D has a ben- eficial effect. Ocular surgery is essential to prevent total blindness. The retina in patients with OCRL is usually well-formed and capable of receiving a light stimulus.
51.5 Magnetic Resonance Imaging
MRI in OCRL shows a more consistent pattern of abnormalities than would be suggested by the neu- ropathology. In patients with an advanced degree of myelination patchy, small and larger, isolated and partially confluent white matter changes are visible, suggestive of gliosis (Figs. 51.1 and 51.2). During the first months of life these white matter abnormalities may not be noticeable within the still unmyelinated white matter. The changes are most pronounced in the periventricular area and centrum semiovale, whereas the U fibers, corpus callosum, internal cap- sule, brain stem, and cerebellum are spared. The white matter abnormalities are highly variable in extent. In
Chapter 51 Lowe Syndrome 388
some patients only a few, small white matter lesions are present (Fig. 51.1), whereas in other patients the lesions are much more extensive (Fig. 51.2). The dis- tribution of the white matter changes is symmetrical globally, but not in detail. Often multiple small cystic lesions are seen within the abnormal white matter.
Mild ventriculomegaly may be present. No major cor- tical abnormalities have been reported.
The MRI pattern of multifocal, irregular, patchy white matter abnormalities with small cysts is remi- niscent of the patterns seen in hypomelanosis of Ito and some mucopolysaccharidoses.
Fig. 51.1. MR study of a 17-month-old boy with OCRL. There are multifocal small lesions in the periventricular white matter and small cysts within the abnormal white matter
Chapter 51 Lowe Syndrome 390
Fig. 51.2.
Fig. 51.2. An 8-year-old boy with OCRL. The T2-weighted im- ages (second and third rows) show multifocal small and larger, partially confluent lesions in the periventricular and deep white matter. The sagittal T1-weighted (first row) and axial FLAIR images (fourth row) reveal a multitude of small cysts within and outside the abnormal white matter. Courtesy of Dr.
L. Charnas, Department of Pediatric Neurology, and Dr. C Peter, Department of Pediatric Hemato-Oncology and Bone Marrow Transplantation, University of Minnesota, Minneapolis, USA
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