Inositol polyphosphate 5-phosphatase OCRL

Function

Disease

Disease Lowe syndrome, formally called oculocerebrorenal syndrome, oculocerebrorenal syndrome of Lowe or OCRL, is an X-linked multisystemic disorder mainly involving eyes, nervous system (both the central and the peripheral) and kidneys. However, defects in other systems are observed as well. The syndrome is quite rare, its prevalence is 1 in 500 000 in the general population (based on the observations of the American Lowe Syndrome Association and the Italian Association of Lowe syndrome). Almost all of the patients are male. The syndrome is believed to occur worldwide as there are documented cases in America, Europe, Australia, Japan and India.^[1][2]

There is quite a wide range of different phenotypes in Lowe syndrome patients so the individual cases may vary a lot. Amongst the hallmarks of Lowe syndrome are dense congenital cataracts, some degree of intellectual impairment and mental retardation (usually severe), severe growth retardation and generalized hypotonia, proximal renal tubular dysfunction of the renal Fanconi type, which is slowly progressing towards renal failure/end-stage renal disease (ERSD) in adulthood.^[1][2]

Renal tubular dysfunction is accompanied by low-molecular-weight (LMW) proteinuria in all patients. Aminoaciduria, phosphaturia, hypercalciuria, polyuria, bicarbonate, sodium and potassium wasting, renal tubular acidosis are often present as well. All affected people have impaired vision even after cataracts are removed. Hypotonia may improve a little with age, but normal state is never achieved. Hypotonia is connected with joint hypermobility which can result in joint dislocation. Almost all patients suffer from osteopenia, some patients suffer from repeated bone fractures with poor healing and in about 50 % of patients, scoliosis is present. Other frequent physical complications of Lowe syndrome are arthritis, dental malformations, bleeding disorder (platelet malfunction) and cryptorchidism (undescended testes). In some cases cysts on the skin, in the mouth, kidneys and brain were found.^[1][2]

Some kinds of seizures occur in up to 50 % of patients. Behavioral problems are usually present in Lowe syndrome patients. Those may include maladaptive behaviors, obsessive-compulsive behaviors, stubbornness, repetitive behavior (such as repetitive purposeless movements), tantrums and aggressive or self-abusive behavior.^[1][2]

Some of the defects, such as congenital cataracts and hypotonia, are present at birth while others evolve later. The absence of deep tendon reflexes is often observed soon after birth as well which may point to hypotonia and together with cataracts it is the first diagnostic clue. LWM proteinuria is also detected soon after birth and it is the first symptom of tubular dysfunction that appears. LMW proteinuria is present in all patients. Usually, life span is not longer than 40 years. ^[1][2][3]

As for heterozygous females, most of them have lens opacities in post-pubertal age. Besides that, manifestations of the Lowe syndrome are usually not observed.^[1]

Diagnosis and treatment

Lowe syndrome is inherited in an X-linked manner. About two-thirds of cases are transmitted by maternal carriers. Affected males are not known to reproduce. Female carriers show heterozygous female phenotype, which might indicate the need for genetic counseling. The remaining one third (approximately) is attributed to a de novo variant. There is a high risk (4,5%) of germline mosaicism in Lowe syndrome families. If OCRL pathogenic variant has been identified in a family member, prenatal genetic testing can be performed. Unfortunately, it can not say anything about the severity of the disease. ^[1][2][3]

Treatment is only symptomatic. Patients usually require more than one medical specialist to manage various clinical problems.^[1][2][3] Regular surveillance by many specialists is also needed in many fields for the whole lifetime. ^[1][2]

Structural highlights

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