Lowe syndrome: Case report of a patient with a novel mutation in the OCRL gene

Introduction The oculocerebrorenal (OCRL) syndrome of Lowe is an X linked, multisystem disorder characterised by a triad of abnormalities in the eyes, the nervous system and the renal tubules. It is caused by a mutation in the OCRL gene which encodes an inositol polyphosphate 5-phosphatase. This enzyme has been detected on vesicular structures of the endosomal system and the Golgi complex, and plays a main role in cellular metabolism. The deficiency of this enzyme impairs the maturation of polarizing epithelium in neurons and glia, renal proximal tubule and lens. Prevalence of this syndrome has been estimated as 1 in 500,000 .


Introduction
The oculocerebrorenal (OCRL) syndrome of Lowe is an X linked, multisystem disorder characterised by a triad of abnormalities in the eyes, the nervous system and the renal tubules 1 . It is caused by a mutation in the OCRL gene which encodes an inositol polyphosphate 5-phosphatase. This enzyme has been detected on vesicular structures of the endosomal system and the Golgi complex, and plays a main role in cellular metabolism. The deficiency of this enzyme impairs the maturation of polarizing epithelium in neurons and glia, renal proximal tubule and lens 2 . Prevalence of this syndrome has been estimated as 1 in 500,000 3 .

Case report
This baby boy was born of a non-consanguineous marriage in January 2013 at the Base Hospital, Kahawatta and bilateral cataracts were detected at birth. On the 4th day of life, baby was referred to the Eye Surgeon, Lady Ridgeway Hospital (LRH), Colombo. He underwent bilateral trabeculectomy at the age of 2 months. At the age of 1 week, baby was referred to the Department of Chemical Pathology for necessary biochemical investigations of cataract by the eye unit. There is a history of delayed milestones. His family tree ( Figure 1) revealed his maternal cousin to share the clinical features.
On physical examination, his weight was 6.2 kg less than -3SD), height was 64 cm (less than -3 SD) and head circumference was 45 cm (10 th _________________________________________ 1 District General Hospital Matara, Sri Lanka, 1 District General Hospital Negombo, Sri Lanka, 3   He was treated with Joule's solution and Polycitra. The clinical diagnosis of Lowe syndrome was confirmed by DNA analysis. This revealed a hemizygous mutation c. 1427C>T (p.Thr476Ile) in exon 14 and carriership was confirmed in the mother. Slit lamp examination of eyes of his mother did not reveal any abnormalities and her renal tubular functions were normal.

Discussion
Patients with OCRL syndrome, typically present in infancy with congenital bilateral cataract, growth failure and mental retardation. Cataract manifests early in embryogenesis. Congenital or childhood glaucoma has been observed in 50% of Lowe syndrome patients 4 . Neurologic manifestations include seizures, repetitive behaviour, intellectual disability and variable degree of mental retardation. Renal tubular dysfunctions include low molecular weight proteinuria, albuminuria, aminoaciduria, hypercalciuria and phosphaturia which may lead to chronic renal failure 5 .
Our patient was clinically diagnosed on the basis of typical occulocerebrorenal manifestations. Impaired proximal tubular reabsorption led to generalised aminoaciduria, proteinuria, phosphaturia, hyperuricosuria and metabolic acidosis. He did not have glycosuria which is consistent with other reported cases of Lowe and indicates selective proximal dysfunction in Lowe syndrome patients 2 . Our patient also had vitamin D deficiency. Usually Lowe patients develop vitamin D dependent rickets due to impaired activation of 1-alpha hydroxylase with normal 25-hydroxy vitamin D level 6 . In our case vitamin D deficiency led to high PTH and ALP levels. X-rays did not show evidence of rickets.
Hyperphosphaturia and metabolic acidosis due to bicarbonate loss are part of the proximal tubulopathy of Lowe syndrome or result from PTH action on renal tubules. Hypercalciuria may be a manifestation of either tubulopathy or vitamin D deficiency. Though our patient had hypercalciuria, there was no radiological evidence of urolithiasis or nephrocalcinosis often reported in OCRL patients 7 . Severe hypotonia is reported in the literature 3 and our patient also had hypotonia with elevated CK, LDH and AST despite of normal liver function. Elevation of these enzymes could be due to muscle involvement. According to the literature carrier mothers with a mild phenotype developed aminoaciduria following ornithine loading 8 and often show eye lesions by slit lamp examination 9 . We could not perform ornithine loading test but eye examination did not detect any abnormalities. As she is a carrier, she has 25% of possibility of having an affected boy and 25% of possibility of having a carrier girl in future pregnancies. His 5year-old cousin was clinically diagnosed as Lowe syndrome and is on treatment however we could not perform genetic analysis on him.
More than 200 mutations in the OCRL gene have been described in Lowe syndrome patients including nonsense, splice-site, missense mutations and insertions and deletions 10 . The missense mutation (c. 1427C>T) in exon 14 of the OCRL gene observed in our patient had not been previously reported. Probably it may be a novel mutation in Sri Lanka.