Dismetabolic Cataracts: Clinicopathologic Overview and Surgical Management with B-MICS Technique

Background: Dismetabolic cataract is a loss of lens transparency due to an insult to the nuclear or lenticular fibers, caused by a metabolic disorder. The lens opacification may occur early or later in life, and may be isolated or associated to particular syndromes. We describe some of these metabolic conditions associated with cataract formation, and in particular we report our experience with a patient affected by lathosterolosis that presented bilateral cataracts. Methods: Our patient was a 7-years-old little girl diagnosed with lathosterolosis at age 2 years, through gas cromatography/mass spectrometry method for plasma sterol profile that revealed a peak corresponding to cholest7-en-3β-ol (lathosterol). Results: The lens samples obtained during surgical removal with B-MICS technique were sent to the Department of Pathology and routinely processed and stained with haematoxylin-eosin and PAS; then, they were examined under a light microscope. Histological examination revealed lens fragments with the presence of fibers disposed in a honeycomb way, samples characterized by the presence of homogeneous eosinophilic lens fibers, and other fragments characterized by bulgy elements referable to cortical fibers with degenerative characteristics. These findings were compatible with cortical dismetabolic cataract. Conclusion: We conclude that lathosterolosis is a complex malformative syndrome that can lead to dismetabolic cataract development. This unique case of cataract in such a patient, has been successfully managed with cataract extraction and IOL implant. Galactosemia Mucolipidosis tipe I Mucolipidosis tipe II Fabry disease Galactokinase deficiency Glucose-6-phosphate dehydrogenase deficiency Mannosidosis Refsum disease Lowe syndrome Alport syndrome Familiar hypoparatyroidism Cholesterol biosynthesis defects (Smith-Lemli-Opitz syndrome, lathosterolosis...) Metabolic syndrome Diabete Table 1: The metabolic disorders those are more frequently associated to cataract formation. Citation: Cavallini GM, Forlini M, Masini C, Campi L, Chiesi C, et al. (2013) Dismetabolic Cataracts: Clinicopathologic Overview and Surgical Management with B-MICS Technique. J Genet Syndr Gene Ther 4: 165. doi:10.4172/2157-7412.1000165


Introduction
Dismetabolic cataract is a loss of lens transparency due to an insult to the nuclear or lenticular fibers, caused by a metabolic disorder. The lens opacification may occur early or later in life, and may be isolated or associated to particular syndromes. The exact incidence of this kind of cataract is not known, as it is often numbered in the group of congenital cataracts. Actually, metabolic and systemic disease are found in as many as 60% of bilateral congenital cataracts. Screening for metabolic disorders in all children with bilateral cataracts is essential, as in some inherited metabolic disorders progressive and severe symptoms can be avoided with timely initiation of treatment [1].
The metabolic disorders that are more frequently associated to cataract formation are reported in Table 1.
We describe some of these metabolic conditions associated with cataract formation, and in particular we report our experience with a patient affected by lathosterolosis that presented bilateral cataracts.

Cataract in galactosemia
Classical galactosemia is an autosomal recessive disorder caused by a severe compromission of galactose utilization due to deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). The GALT enzyme is responsible for the conversion of galactose-1-phosphate with UDP glucose to glucose-1-phosphate and UDP galactose. The gene encoding for GALT is located on chromosome 9p13. Patients present with hepatomegaly, liver failure, food intolerance, hypoglycaemia, muscle hypotonia, sepsis and cataract. The typical appearance of galactosemic cataract is an "oil-drop" central opacity (Figure 1), caused by the accumulation of galactitol in the lens. This causes an increase Results: The lens samples obtained during surgical removal with B-MICS technique were sent to the Department of Pathology and routinely processed and stained with haematoxylin-eosin and PAS; then, they were examined under a light microscope. Histological examination revealed lens fragments with the presence of fibers disposed in a honeycomb way, samples characterized by the presence of homogeneous eosinophilic lens fibers, and other fragments characterized by bulgy elements referable to cortical fibers with degenerative characteristics. These findings were compatible with cortical dismetabolic cataract.

Conclusion:
We conclude that lathosterolosis is a complex malformative syndrome that can lead to dismetabolic cataract development. This unique case of cataract in such a patient, has been successfully managed with cataract extraction and IOL implant. P2, in the trans-Golgi network is responsible for the disease. Bilateral cataract and severe hypotonia are present at birth. In the subsequent weeks or months the ocular picture may be complicated by glaucoma and cheloids. Psychomotor retardation is evident in childhood, while behavioural problems prevail and renal complications arise in adolescence [5].
Typically complete opacification and discoid deformation of the lenses (microphakia) are seen, indicating a developmental defect in early embryogenesis ( Figure 2). Patients with mild Lowe syndrome phenotype may show incomplete lenticular opacities without visual impairment [6].

Cataract in mannosidosis
Mannosidosis is a rare disorder of glycoprotein metabolism. The primary metabolic defect in mannosidosis is the deficiency of the acidic alpha-mannosidase A and B activites which results in the lysosomal accumulation of mannose-rich substrates. People with mannosidosis appear normal at birth and that their typical phenotype develops by two years of age. This is characterized by a distinctive coarse facies and dysostosis multiplex. Although recurrent infections, hearing loss and mental retardation occur, the course in this storage disorder generally is stable and is compatible with adult life [7]. Alpha-mannosidosis in the human has been associated with cataract development in infancy [8]. The lens opacities do not have typical appearance, but may be nuclear or capsular, or total.

Cataract in hypoparatiroidism
Cataract is a well-known complication of hypoparathyroidism, albeit the mechanism is obscure. The typical appearance is characterized by cuneate radial opacities ( Figure 3). The progression of cataract is typically slow in patients with idiopathic hypoparathyroism. Anyway, there are also cases in which the typical hypocalcemic cataracts have an extremely rapid evolution, in particular when hepatic and renal failure occurs, with alteration in the serum calcium and phosphorus levels [9]. Physicians and ophthalmologists must be aware of cataracts developing rapidly in the setting of such metabolic derangements.

Cataract in lathosterolosis
Lathosterolosis is a singular defect of cholesterol biosynthesis due to the lack of lathosterol-5-desaturase (SC5D), the enzyme that catalyzes the conversion of lathosterol to 7-dehydrocholesterol in the cholesterol synthetic pathway. Cholesterol is an abundant lipid in eukaryotic membranes, implicated in different structural and functional capacities, and its partial or complete lack as well as the accumulation in the osmotic pressure within the lens, with a subsequent osmotic water inflow and lens opacification. The ophthalmologist may play an important role in this disease, since early recognition of cataract development followed by the initiation of a galactose-free diet may lead to clearing of lenticular opacities [2]. Treatment involving the total restriction of lactose-containing foods is also life-saving but many patients develop late complications such as problems of mental development, disorders of motor function, disorders of speech and hypergonadotrophic hypogonadism [3].

Cataract in galactokinase deficiency
Galactokinase (GALK1) deficiency is an autosomal recessive disorder, which involves the first enzyme of galactose metabolic chain. Galactokinase deficiency results from mutation in the GALK1 gene mapped on 17q24. Cataract and, rarely, pseudotumor cerebri caused by galactitol accumulation seem to be the only consistently reported abnormalities in this disorder [4]. Cataracts may develop during infancy or may be presenile in the adult population. The lens opacity has typically a lamellar shape.
As cataract and pseudotumor cerebri appear to be the only complications of galactokinase deficiency, the outcome for patients with galactokinase deficiency is much better than for patients with classical galactosemia.

Cataract in lowe syndrome
The oculo-cerebro-renal syndrome of Lowe (OCRL) is a rare X-chromosomal disorder characterised by the triad of congenital cataracts, renal tubular dysfunction, and mental retardation. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol [4,5] bisphosphate 5 phosphatase, PtdIns [4,5]    of precursors, may lead to a group of malformative syndromes of recent identification [10]. Lathosterolosis is a rare disorder that leads to developmental abnormalities, including mental retardation, and to date has only been identified in two patients [11,12] one of which died at 18 weeks of age with diffuse intracellular storage.
We describe a unique case of cataract in a lathosterolosis patient who underwent cataract surgery. Our patient was a 7-years-old little girl diagnosed with lathosterolosis at age 2 years, through gas cromatography/mass spectrometry method for plasma sterol profile that revealed a peak corresponding to cholest-7-en-3β-ol (lathosterol). The biosynthesis of cholesterol in her fibroblasts was defective, showing a block in the conversion of lathosterol into 7-dehydrocholesterol. Physical examination revealed dismorphic features, including severe microcephaly, receding forehead, anteverted nares, micrognathia, prominent upper lip, high arched palate, haxadactyly and syndactyly of the left foot. Severe psychomotor delay became increasingly evident with age; conductive deafness was found at the auditory evoked potentials. She also had liver disease with signs of cholestasis [11]. At the first ophthalmic evaluation, carried out in June 2005, the little patient presented with bilateral posterior subcapsular cataracts at byomicroscopy and bilateral pale optic nerve head at fundus examination. In November 2005, after a severe gastroenteric Rotavirus infection with subsequent metabolic decompensation, a marked worsening in the lens opacity of the left eye occurred. There was no history of ocular trauma reported by parents, and Eco-B scan examination revealed normal vitreous-retinal structures. Marked subconjunctival jaundice was evident at biomicroscopy, due to a severe intrahepatic cholestasis. After metabolic improvement, the little patient was encouraged to surgery for left cataract extraction. Surgery was performed on February 2006, under general anaesthesia. We performed a bimanual microphacoemulsification mainly working in aspiration mode; an acrylic hydrophobic flexible IOL was inserted (Acri.Smart 48S-Acri.Tec, Co. Berlin, Germany) and manual posterior continuous curvilinear capsulorhexis (PCCC) and optic entrapment of the IOL were performed [13]. No intraoperative or postoperative complications occurred. After surgery, refraction was +0.75 sph with an astigmatism of +0.50 (90°) diopter, remaining stable during the whole follow-up; biomicroscopic evaluation revealed absence of significant inflammation and good IOL centration; no posterior capsule opacification occurred 2 years after surgery. Visual acuity was not assessable due to complete lack of patient's collaboration; anyway, we noted a better orientation of the proband during the subsequent control visits, and parents referred a greater confidence and autonomy in her daily life attitudes.
The lens samples obtained during surgical removal were sent to the Department of Pathology and routinely processed and stained with haematoxylin-eosin and PAS; then, they were examined under a light microscope. Histological examination revealed lens fragments with the presence of fibers disposed in a honeycomb way, samples characterized by the presence of homogeneous eosinophilic lens fibers, and other fragments characterized by bulgy elements referable to cortical fibers with degenerative characteristics (Figures 4 and 5). These findings were compatible with cortical dismetabolic cataract ( Figure 6).
The relationship between abnormal cholesterol metabolism and disturbed morphogenesis have been extensively studied in recent years [14,15], and it has been questioned whether cholesterol deficiency or increased levels of intermediate sterols are responsible for the abnormal functioning of the pathway in these syndromes. The prototypical example is the Smith-Lemli-Opitz syndrome (SLOS), a complex malformation syndrome including the presence of congenital cataracts [14]. Our proband presented with bilateral subcapsular posterior cataracts, with rapid worsening in the left eye after a severe metabolic decompensation. Hystopathologic examination confirmed the presence of a dismetabolic cortical cataract. We don't really know the exact pathologic mechanism involved; in two cases of dismetabolic cataracts in patients with SLO syndrome, it has been advocated a dysfunction or rupture of the lens capsule leading to acute osmotic shifts [16]. We can hypothesize the same pathogenetic mechanism for our case. We conclude that lathosterolosis is a complex malformative syndrome that can lead to dismetabolic cataract development. This unique case of