Non-Endocrine Metabolic Disorders Julio A. Urrets-Zaval´ıa MD, PhD, Evangelina Esp´osito MD, Iliana Garay MD, Rodolfo Monti MD, Alejandro Ruiz-Lascano MD, PhD, Leandro Correa MD, Horacio M. Serra PhD, Andrzej Grzybowski MD, PhD, MBA PII: DOI: Reference:
S0738-081X(15)00252-7 doi: 10.1016/j.clindermatol.2015.12.002 CID 7011
To appear in:
Clinics in Dermatology
Please cite this article as: Urrets-Zaval´ıa Julio A., Esp´osito Evangelina, Garay Iliana, Monti Rodolfo, Ruiz-Lascano Alejandro, Correa Leandro, Serra Horacio M., Grzybowski Andrzej, Non-Endocrine Metabolic Disorders, Clinics in Dermatology (2015), doi: 10.1016/j.clindermatol.2015.12.002
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Non-Endocrine Metabolic Disorders
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Julio A. Urrets-Zavalía, MD, PhD,1 Evangelina Espósito, MD,1 Iliana Garay, MD,2 Rodolfo Monti, MD,1 Alejandro Ruiz-Lascano, MD, PhD,2 Leandro Correa, MD,1 Horacio M. Serra, PhD,3* Andrzej Grzybowski, MD, PhD, MBA4,5*
Department of Ophthalmology, University Clinic Reina Fabiola, Catholic University of
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1
Córdoba, Argentina.
Department of Dermatology, Hospital Privado Centro Médico de Córdoba and Instituto
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2
de Ciencias Biomédicas de Córdoba, Argentina.
CIBICI-CONICET, Faculty of Chemical Sciences, National University of Córdoba,
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3
Argentina.
Department of Ophthalmology, Poznań City Hospital, Poland.
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Department of Ophthalmology, University of Warmia and Mazury, Olsztyn, Poland.
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4
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*These two authors contributed equally to this work.
Correspondance: Dr. Julio A. Urrets-Zavalía, Centro de la Visión, Clínica Universitaria Reina Fabiola, Universidad Católica de Córdoba, Oncativo 1248, Córdoba
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5000, Argentina.
Phone/Fax: +54 (351) 4142150. Email address
[email protected]
Conflicts of interest: All authors declare no financial or proprietary interests, as well as no public or private support in this work.
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ACCEPTED MANUSCRIPT Abstract As metabolism is controlled by the input of genes and the environment, metabolic disorders result from some disturbance in the interaction between genes and
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environmental factors. Many metabolic disorders consist in congenital enzyme deficiencies, also known as “inborn errors of metabolism”, that may be disabling or cause severe illness and death, and are predominantly inherited in an autosomal recessive fashion. The deposit in cells and tissues of storage substances from errors in
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metabolic processes may produce a wide variety of disorders affecting different organs and functions, with different degrees of severity and frequently present around the time
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of birth or early childhood. Distinctive ocular and skin manifestations accompany many
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metabolic diseases and may provide clues for their diagnosis and evolution.
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ACCEPTED MANUSCRIPT Outline I. Uric acid metabolism disorders Gout
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Lesch-Nyhan disease II. Porphyrias III. Amino acids disorders Alkaptonuria
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Cystinosis Phenylketonuria
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Homocystinuria
Homocystinuria and methylmalonic aciduria cobalacin C type Tyrosinemia type II (Richner-Hanhart syndrome)
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Hartnup’s disease Prolidase deficiency
Gaucher disease
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IV. Lysosomal lipid storage diseases
Niemann-Pick disease Fabry disease
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Farber disease Krabbe disease
GM1 Gangliosidoses
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GM2 Gangliosidosis Tay-Sachs disease Sandhoff disease
V. Carbohydrates storage disorders Lysosomal mucopolysaccaharide storage disorders (mucopolysaccharidoses) Mucopolysaccharidosis I Galactosemia VI. Protein deposition diseases Amyloidosis Lipoid proteinosis
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I. Uric acid metabolism disorders Gout
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Gout is one of the most common causes of arthritis. It is a disease of the uric acid metabolism, characterized by the rise of serum urate, intraarticular and connective tissues (tophi) deposition of monosodium urate crystal, urate urolithiasis, and, rarely, gouty nephropathy.1 The first acute manifestation of gout is preceded by asymptomatic
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hyperuricemia for many years (up to 20 years) in the absence of gout or uric acid nephrolithiasis, and it usually occurs between the ages of 40 and 60 in men and after age metabolism or renal urate transport.2,3
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65 in women.2 Onset in young adulthood is often related to an inherited defect in purine
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In acute gouty arthritis, more than 50% of initial episodes present as oligoarticular podagra, an acute inflammation of the first metatarsophalangeal joint; the ankles, knees, and feet, can also be affected.4 The joint is usually very tender and
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swollen, and the attack may lasts a few days, relapsing from time to time.4 The chronic stage of gout is represented by tophi formation that usually occurs ten or more years after the onset of the disease.4 Tophi, a pathognomonic feature of gout, are yellowish and non-tender nodules ranging in size from 1 mm to 7 cm, observed mainly in articular, periarticular, bursal, bone, auricular, and cutaneous tissues.4 Tophi themselves
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are generally painless, but they can trigger local inflammation.5 Without treatment, joint destruction and large tophi deposition can result in grotesque deformities as a result of
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the chronic surrounding inflammation.5 Although infrequent, ophthalmological manifestations of gout are varied and generally observed in longstanding disease. Urate crystals may be found in eyelids, tarsal plates, extraocular muscle tendons, conjunctiva, cornea, sclera, iris, and lens. They appear as irregular, flake-like white crystals. Other findings consisting in tortuous conjunctival and episcleral blood vessels, some of them spiral-shaped, and transparent conjunctival vesicles with metal-like shine, have been observed.6-15
Lesch-Nyhan disease Lesch-Nyhan disease and its variants are X-linked inborn errors of metabolism of the uric acid that are caused by a defect in the hypoxanthine-guanine phosphoribosyltransferase HPRT gene.16 Congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in marked 4
ACCEPTED MANUSCRIPT overproduction of uric acid, severe motor handicap resembling dystonic cerebral palsy, intellectual disability, and recurrent self-injurious behaviors such as biting of lips, tonge and fingers, and head banging.17
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One of the first signs of the disease may be the observation of orange crystals in the diapers, or crystalluria with obstruction of the urinary tract. Other uncommon forms of presentation include renal failure or acidosis with repeated vomiting.17 Psychomotor delay, when present, becomes evident within 3 to 6 months.17
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All characteristic findings associated with gout may be present in these patients: acute arthritis, tophi, nephrolithiasis or urolithiasis, and renal disease. If the diagnosis
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and treatment is delayed, tophi and renal failure may appear.17 Patients with severe enzyme deficiency may present mild blepharospasm and abnormal eye movements, such as unwanted and voluntary ocular saccades, the latter
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being preceded by an initial head movement and/or eyeblink.18 These abnormal eye movements are consistent with a dysfunction of the basal ganglia or their connections
II. Porphyrias
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with ocular motor centers in the prefrontal brain cortex or midbrain.18
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Porphyrias are a group of inherited metabolic disorders of heme biosynthesis and metabolism, each one resulting from a specific enzymatic alteration in its biosynthesis pathway. Porphyrias are often classified as hepatic or erythropoietic,
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according to the organ in which heme precursors accumulate. Classification based on clinical presentation as acute porphyrias, cutaneous porphyrias, and rare recessive porphyrias, is directly related to a simple biological diagnosis strategy and is more practical.19 Porphyria cutanea tarda, erythropoietic protoporphyria, and congenital erythropoietic porphyria, have predominantly cutaneous manifestations. Hereditary coproporphyria and variegate porphyria are classified as mixed as they may have both cutaneous and neuropsychiatric features.19 Porphyrin molecules absorb visible light, generating excited states with consequent lipid peroxidation and protein cross-linking leading to cell membrane damage and death.19 Porphyria cutanea tarda (PCT) type 1 (sporadic) is the most frequent type worldwide, accounting for 80-90% of all cases of PCT, and presents predominantly 5
ACCEPTED MANUSCRIPT with skin symptoms.20 Possible etiological factors include alcohol, estrogens, iron, chemicals (e.g. hexachlorobenzene), hepatitis C and HIV infection.21 Type 2 (familial) PCT, an autosomal dominant disease with incomplete penetrance, is heterozygous for
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UROD mutations, and asymptomatic patients have approximately half-normal enzyme activity systemically.22 Many of the risk factors related to type 1 PCT may contribute with the expression of type 2 disease.22
PCT usually presents in adults and is characterized by blistering skin lesions that
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appear most commonly on the backs of the hands.21 These blisters rupture and crust over, leaving areas of atrophy and scarring (Fig 1, Fig 2).22 Lesions may also occur on
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the forearms, face (Fig 3), legs, and feet.23 Skin friability and small white papules termed milia are common, especially on the back of the hands and fingers.23 Hypertrichosis (Fig 4) and hyperpigmentation (Fig 5), particularly on the face, are
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especially troublesome in women.24 Occasionally, in sun-exposed areas the skin becomes severely thickened with scarring and calcification, which resembles systemic
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sclerosis.25 Neurologic features are absent.23
Erythropoietic protoporphyria (EPP), the most common erythropoietic porphyiria and the most common porphyria in children, is essentially an autosomal dominant disorder due to an inherited partial deficiency of ferrochelatase, the last
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enzyme in the heme biosynthetic pathway.26 The EPP phenotype is characterized by acute, painful, cutaneous photosensitivity and elevated erythrocyte protoporphyrin levels.26 Severe cutaneous photosensitivity and bullous eruption begins in early infancy
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in most cases.27-29 Clinical suspicion of EPP should be alerted by a history of screaming or skin pain when going outdoors.30 Erosions on the face, healing with scars, or waxy thickening of the skin of the nose and knuckles may be present.30 The face and dorsa of the hands (Fig 6) are frequently affected areas, but photosensitivity reactions can also appear on any exposed skin area, persisting for hours up to several days.30 The appearance of vesicles or bullous lesions characteristic of other forms of cutaneous porphyria is unusual but may occur.30 Nail lesions (photonycholysis and transversal leuconycholysis) are possible associated manifestations.30 Chronic skin changes may include lichenification, leathery pseudovesicles, labial grooving, and nail changes.30 Severe scarring is rare, as are pigment changes, friability, and hirsutism.30 Congenital erythropoietic porphyria (CEP), or Günther's disease, is a very rare form of porphyria of autosomal recessive inheritance.31 It results from a pronounced deficiency of uroporphyrinogen III synthase enzymatic activity (UROS).19 The clinical 6
ACCEPTED MANUSCRIPT spectrum ranges from non-immune hydrops fetalis as a result of severe hemolytic anemia in utero, to the development of moderate to severe photosensitivity with pink to red urine during the first few months of life.32 At the time of teeth and bone
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development erythrodontia occurs due to deposition of porphyrins in the developing teeth.32 Secondary infection and bone resorption may lead to disfigurement of the face and hands.32 Uroporphyrin-I is a toxic compound that accumulates in erythrocytes causing hemolysis and turns the urine pink-red. Pink staining diapers allows early
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diagnosis in infancy.33 Repeated episodes of blistering result in mutilation of ears, nose and hands, and lesions healed over time with scarring, milia, hypo and
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hyperpigmentation.33,34
Ocular manifestations of porphyrias are rare, and are caused as the consequence
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of deposition of photosensitive porphyrins in ocular and periocular tissues.35 In acute intermitent porphyria, transmited as an autosomal dominant trait and characterised by abdominal pain, renal and neurological manifestations, severe neuro-ophthalmological
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complications such as oculomotor paralysis (especially those of the IIIrd nerve) and cortical blindness (occipital cortex infarction), and ischemic retinopathy, may manifest during a crisis.35
Porphyria cutanea tarda presents rarely with ocular manifestations, but they
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may be sight threatening.36 In this disease, bilateral inferior symblepharon, superior tarsal conjunctival scarring and concretions, and recurrent conjunctival and episcleral injection, have been described,37 as well as scleral necrosis in the interpalpebral
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area.36,38 Also, a progressive bilateral, peripapillary, geographic chorioretinal atrophy has been observed in a case of porphyria cutanea tarda with high iron stores, chronic hepatitis C, and a history of alcoholism.39 Congenital erythropoietic porphyria may be complicated by cicatricial ectropion, photophobia, keratoconjuntivitis, corneal ulceration, and scleromalacia.38,40-42 Porphyrins, especially uroporphyrin and coproporphyrine, have been detected in teardrops in four patients with congenital erythropoietic porphyria, and severity of ocular involvement was linked to the level of porphyrins accumulated in teardrop.43
III. Amino acids disorders Alkaptonuria Alkaptonuria is a rare hereditary disorder of homogentisic acid (HGA) metabolism.44 It affects about one in every 250,000 to 1 million persons, with an equal 7
ACCEPTED MANUSCRIPT distribution between males and females, symptoms begining earlier and more severe in males.45,46 Individual collagen fibres become decorated, with pigment binding to specific sites within the fibrillar structures.47 The ochronotic tissue becomes stiff and
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brittle and it is this change in mechanical properties of connective tissue that results in the multisystem morbidity, dominated by spondyloarthropathy.48 Near half of the patients suffering alkaptonuria have clinical evidence of ochronosis.49
Ocular ochronosis consists of dark spots in the exposed parts of the sclera
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immediately adjacent to the cornea that take the form of pigmented globules, whereas farther from the limbus they are ill-defined.50 These pigmented spots have diagnostic
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value but cause no visual or ocular impairment.50 They may be related to elastic tissue and probably predominate in the exposed parts of the eye because of a light-induced
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oxidation.50
Alkaptonuria may initially present with palmo-plantar hyperpigmentation or gray nail plate discoloration.51,52 The axillae, groin, and ears are the most common sites
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of pigmentation; sweat glands are commonly affected and dark brown sweat may stain clothing.52-54 The neck, nose, and dorsum of the hands are also affected.51-53 All are areas of either thin or actinically damaged skin that may overlie pigmented cartilage or tendons.52-54 A case of acrokeratoelastoidosis (hyperkeratotic linearly arranged blue papules along the lateral aspects of fingers of the hand and feet) has been reported in
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association with alkaptonuria.55 The upper respiratory tract is often involved, although patients are asymptomatic.52-54
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Diagnosis of alkaptonuria is often based on clinical findings and family history, but testing a urine sample for presence or absence of HGA by gas chromatography-mass spectrometry is the gold standard for confirmation of the diagnosis.56-58
Cystinosis Cystinosis is a rare autosomal recessive lysosomal storage disease produced by an intracellular, multiorgan accumulation of cystine that is due to a defect in the membrane transport protein, cystinosin.59 Its prevalence is 1:100,000 to 1:200,000, and has been found worldwide affecting all ethnic groups.59 Prior to renal transplant and the advent of cystine-depleting medical therapy cystinosis was a fatal disease, having nowadays a life expectancy over 50 years.59 Three types of cystinosis have been recognized: 1) nephropathic (or classic infantile) cystinosis, the most frequent (95%) and severe form, leading inevitably to 8
ACCEPTED MANUSCRIPT renal failure in the first decade of life, being the major identifiable cause of Fanconi syndrome; 2) intermediate cystinosis, with onset at adolescence and with all the manifestations of the infantile form; 3) non-nephropathic or ocular cystinosis,
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characterized by corneal deposition of crystals and photophobia; in this form the kidneys are spared probably because the mutant allele produces residual cystinosin.59 Photophobia develops by the age of 10 years as the consequence of corneal crystals deposition.60 Infantile nephropathic cystinosis develops eye posterior segment
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complications such as retinal crystal deposits, and pigment epithelium degeneration that leads to nyctalopia, constriction of the visual field, and significant visual handicap; they
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are correlated directly with time not receiving oral cyseamine therapy.61 The mechanism by which crystal accumulation in the retinal pigment epithelium and choroid leads to
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retinal degeneration remains unknown.61
In infantile nephrogenic cystinosis cystine crystal deposits have been evidenced as scattered bright particles within the papillary dermis by means of in vivo reflectance
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confocal microscopy of the skin, being more prominent in older individuals.62 No correlation has been observed between renal disease or hypopigmentation and the density of dermal cystine deposits, but high levels of deposition are associated with
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extrarenal manifestations such as photophobia.62
Phenylketonuria
Phenylketonuria is an inherited autosomal recessive error in amino acid
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metabolism caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH) that converts the essential amino acid phenylalanine (Phe) into tyrosine, resulting in elevated plasma and tissue concentrations of Phe, negatively impacting on cognitive development and function.63 The nature and position of the mutation dictates its effect on the activity of PAH enzyme, which determines the hyperphenylalaninemia phenotype of the patient. Little or no enzyme activity results in the classic phenylketonuria phenotype.63 It is a rare disease, but its incidence varies significantly worldwide, with the highest rates found in Ireland and Eastern Europe (1:4500 to 1:9000), and the lowest in Finland, Japan and Thailand (1:100,000, 1:108,000 and 1:212,000, respectively), and with an approximately incidence of 1:10,000 in North America.64 Untreated, phenylketonuria leads to severe mental retardation, with an intelligence quotient below 30, severe behavioral problems and seizures.65,66 9
ACCEPTED MANUSCRIPT Fair skin and hair resulting from impairment of melanin synthesis is the most characteristic cutaneous manifestation of PKU.67 Patients often have typical pigmentation, light sensitivity, increased incidence of pyogenic infections, increased
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incidence of keratosis pilaris, hair loss, and eczema.68 Visual and ocular manifestations in phenylketonuria are rare. Albinism with iris (50%) and ocular fundus hypopigmentation (42.8%) may be responsible for photophobia but not for reduced visual acuity, nystagmus or strabismus, as occur
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frequently in classical albinism.68,69 Cataract may be observed in middle-aged patients, in patients with a history of severe self-induced trauma, or in patients under treatment
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with high doses of thioridazine hydrochloride.68
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Homocystinuria
Although rare, homocystinuria is the most common inborn error of methionine metabolism, and is caused by cystathionine β-synthase (CBS) deficiency.70 It is
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transmitted in an autosomal recessive trait with variable expressivity for all the clinical signs, and usually manifests in infancy.70 Classic manifestations of the disease include fair skin and hair, malar flush, neurological complications such as mental retardation, epilepsy, dolicostenomelic marfanoid features, ectopia lentis (displacement of the lens; Fig 7), and vascular
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changes represented mostly by thromboembolic events.70 These symptoms may present separately or in various combinations.70 Behavior disturbances are observed in almost
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50% of patients during their lives, and almost 3% may present a psychiatric symptom as the initial manifestation of the disease.71 Thromboembolic events are the major cause of early death and morbidity, and can manifest as peripheral vein thrombosis, pulmonary embolism, stroke, peripheral artery occlusion, and myocardial infarction.72 Hypopigmentation is a feature of homocystinuria and can be shown to be reversible in patients with pyridoxine-responsive homocystinuria.73,74 Usually, lens displacement manifests by the age of 8 years, and generally occurs towards the inferior quadrants, with not infrequent dislocation to the anterior chamber. Other important ocular findings include increased axial length and myopia, chronic open angle glaucoma, and areas of peripheral vitreo-retinal degeneration that predispose to retinal detachment.75,76
Homocystinuria and methylmalonic aciduria cobalacin C type 10
ACCEPTED MANUSCRIPT This rare disease is the most common inborn vitamin B12 (cobalamin) metabolism error, in which the cause is an impaired conversion of vitamin B12 into its two active forms, adenosylcobalamin and methylcobalamin, with the consequent
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increased plasma homocystine, decreased methionine synthesis, and methylmalonic aciduria.77 Two distinct clinical forms have been identified: 1) early-onset (before the age of 1 year) with developmental delay, feeding difficulties, hypotonia, seizures, and hematologic (anemia, neutropenia and thrombocytopenia), ocular, renal, pulmonary,
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and cardiac manifestations; and 2) late-onset disease, in which patients present a milder clinical phenotype, with neurological and behavioral disturbances.78
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Ocular manifestations are typical and include decreased visual acuity, nystagmus, atrophic maculopathy, peripheral pigmentary abnormalities, optic atrophy,
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and strabismus.79
Tyrosinemia type II (Richner-Hanhart syndrome)
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Tyrosinemia type II, or oculocutaneous tyrosinemia, is an inborn error of tyrosine metabolism due to a block in the transamination reaction converting tyrosine to p-hydroxyphenylpyruvate by defective hepatic enzyme tyrosine aminotransferase (TAT), leading to increased levels of serum and urine tyrosine.80 The main characteristics of the disease are bilateral keratitis, painful palmoplantar hyperkeratosis,
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and mild to moderate mental retardation (60% of cases).81,82 Skin lesions occur in 80% of cases, and age of onset can range from the first
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week of life to the second decade.83 The typical dermatologic findings are painful, welldemarcated hyperkeratosis on the palms and soles, although the palms can be unaffected.84,85 On the palms the distribution usually involves the fingertips, the thenar and the hypothenar eminences, while the lesions on the soles are on the weight-bearing areas.84,85 The lesions, which may begin as bullae and erosions that progress to crusted, hyperkeratotic plaques, are often associated with hyperhydrosis.85 In the skin, tyrosine in the keratinocyte cytoplasm leads to crystal formation with subsequent cell injury and rupture, followed by fusion of two or more keratinocytes.85 Ocular manifestations are present in 75% of cases, and are dominated by epiphora, photophobia, blepharospasm, and painful, bilateral pseudo-dendritic lesions that stain poorly with fluorescein, and may be the initial manifestation of the disease.81,86 Keratitis is unresponsive to antiviral therapy, and resolves spontaneously with a relapsing course, leaving a corneal haze that involves de mid-lower quadrant.81 11
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Hartnup’s disease Hartnup´s disease is an autosomal recessive disorder with varied clinical
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expression and is caused by the defective transport of neutral amino acids, with a frequency of one in 24,000.87
Most patients are asymptomatic, and clinical symptoms usually appear in childhood between 3 to 9 years of age, but sometimes may manifest as early as a few
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days after birth, or as late as early adulthood.88 A protein-rich diet compensates the failure of amino acids resorbtion.88 However, with a poor amino acids diet and other
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factors the disease manifests classically with pellagra-like dermatitis and neurological involvement (cerebellar ataxia, intention tremor, persistent headache, and psychiatric
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symptoms).88
Skin compromise manifests as red and scaly rash appearing over the face, neck, hands, external surface of the arms, and dorsal surface of the feet.89 The skin is
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photosensitive and burning pain appears after exposure to direct sunlight, followed by peeling, hiperkeratosis, fissuring, and pigmentation.89 Fever, diarrhea, inadequate diet, or psychological stress, constitute possible precipitating factors of the dermatologic symptoms and signs.89 Exfoliative erythema of malnutrition may be caused by a
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combination of multiple deficiencies in essential fatty acids, amino acids and vitamins.90 Ophthalmological manifestations include horizontal, vertical or torsional nystagmus that is exacerbated in an ataxic crisis. Sometimes, the disease may manifest
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with episodes of diplopia, exotropia, convergence insufficiency, and palpebral myoclonia or ptosis.88,91
Prolidase deficiency Prolidase deficiency is a rare autosomal recessive disease with an estimated incidence of 1 to 2 per 1 million births. The dipeptidase prolidase is involved in the latter stages of degradation of dietary and endogenous proteins, and is particularly important in collagen catabolism. Phenotypic expression is highly variable and includes mental retardation, dysmorphic facies, splenomegaly, systemic lupus erythematosus, and recurrent respiratory infections. But the most distinctive feature is a chronic intractable ulceration of the skin, in particular on the lower limbs. The age of onset varies from birth to 20 years of age, but some cases may remain asymptomatic.92
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ACCEPTED MANUSCRIPT IV. Lysosomal lipid storage diseases Lysosomal lipid storage diseases, also known as lipidoses, are a group of inherited errors in metabolism in which certain complex lipids accumulate within cells
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and tissues.93 Lysosomal accumulation occurs predominantly in cells and organs with the highest rates of biosynthesis or uptake of the undegradeable sphingolipids and their precursors.94 Hence, blockade in ganglioside catabolism results principally in neuronal degeneration, blockade in sulfatide and galactosylceramide degradation leads to myelin
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diseases, and blockade in glucosylceramide catabolism leads to glucosylceramide and glucosylsphingosine accumulation in macrophages (blood, spleen, and liver), generating
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Gaucher´s cells.94
Sphyngolipids are ubiquitous membrane lipids that are present in every cell and
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found most abundantly in neural tissues.95 Sphingolipidoses are autosomal recessive (with the exception of X-linked recessive Fabry´s disease) inherited lipid storage diseases caused by defects in genes encoding proteins involved in the lysosomal
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degradation of sphingolipids and glycosphingolipids.96 Liver, spleen, lungs, heart and central nervous system are commonly involved.97
Gaucher disease
Gaucher disease is the most common form of sphingolipidosis. It is an inherited
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deficiency of the lysosomal enzyme glucosylceramide β-glucocerebrosidase leading to accumulation of glucosylceramide, and is commonly divided into three subtypes based
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on the presence and progression of neurological manifestations.93 Gaucher type 1 is the attenuated form, with no neuronopathic involvement, and is the most frequently observed form of the disorder.93 Its frequency is one in 50,000 to 200,000 births, being most frequent among Ashkenazi Jewish individuals (1:1000); patients usually develop an extrapyramidal disease resembling parkinsonism in middle life.98,99 Gaucher type 2 is the acute form, and is a very rare though worldwide distributed disease characterized by an additional accumulation of glucosylsphingosine with involvement of the nervous system, early involvement and a life expectancy of less than two years.93,100 Gaucher type 3 is the subacute or juvenile form, being an intermediate form of the other two types. In all three variants, patients may present hepatosplenomegaly, anemia, thrombocytopenia and skeletal and pulmonary diseases, the severity of symptoms varying widely and being inversely correlated to the residual enzyme activity determined in skin fibroblasts of patients.93,99 13
ACCEPTED MANUSCRIPT Gaucher disease type 2 may manifest with congenital ichthyosis, and ultrastructural and biochemical alterations are present in the epidermis of affected infants, even when skin clinical signs are not.101 The clinical spectrum of skin
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compromise ranges from mild skin peeling and scaling that resolves quickly, to a “collodion baby” phenotype.102,103 The abnormal skin is erythematous and shiny, and is present all over the body but predominately over the palms and soles or in flexural folds.104 Skin manifestations frequently precede severe neurologic manifestations in
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Gaucher disease type 2.101
Ocular manifestations are very rare. In neuronopathic forms, strabismus may be
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observed in conjunction with other neurological manifestations such as mild mental retardation, behavioural difficulties, choreoathetosis and cramp episodes.105 More infrequently, other ocular manifestations such as small, linear or dot-like stromal
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corneal opacities,106 white deposits in the peripheral corneal endothelium, chamber angle and pupillary margin,107 conjunctival masses infiltrated by Gaucher cells beneath
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a normal epithelium,108 vitreous opacities and vascular abnormalities,109 and bilateral exoftalmos, have been observed.110
Niemann-Pick disease
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Niemann-Pick disease includes a group of fatal diseases with common features of hepatosplenomegaly and sphingomyelin storage in reticuloendothelial and parenchymal tissues, with or without neurological involvement.111 They are caused by
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mutations in sphyngomyelin phosphodiesterase gene that result in partial or complete deficiency of acid sphyngomyelinase and the consequent storage of sphyngomyelin.112 Niemann-Pick disease type A is a severe neurodegenerative disorder of infancy, death occurring usually between ages 2 and 4 years. Corneal opacity, brown color of lens anterior capsule, retinal opacity and macular cherry-red spot may be observed.112 Niemann-Pick disease type B is a milder, no-neuropathic, late disease, with longer survival but with considerable morbidity (especially cirrhosis, pulmonary, coronary artery and valvular heart disease) and mortality (pneumonia, liver failure and hemorrhage), the latter before the age of 21 years in the majority of patients.113 Ocular manifestations are circumscribed to macular whitening and cherry-red spot as the consequence of lipid deposit in the retinal ganglion cell layer (Fig 8).114,115 Niemann-Pick disease type C is a complex lipid storage disease characterized by the accumulation of unesterified cholesterol in the lysosoma/endosoma of the cell, 14
ACCEPTED MANUSCRIPT and is caused by mutations in either of the genes of the NPC1 or the NPC2 protein that cause the impaired cholesterol transport out of the endosomes.116 It is biochemically, genetically, and clinically distinct from the other two forms of Niemann-Pick disease.
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Massive storage of glycosphingolipids in the nervous system produces structural changes, namely meganeurite formation and ectopic dendritogenesis.117 Typically, neurologic involvement consists in cerebellar ataxia, dysarthria, dysphagia and progressive dementia.111 A clinical hallmark of type C is supranuclear vertical gaze
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palsy, and optic nerve pallor and retinal perimacular discoloration are also observed.117 As observed in other neurodegenerative diseases, activation of the innate
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immune system occurs in the brain resulting in neuro-inflammation. A combined treatment with substrate reduction therapy and non-steroidal anti-inflammatory drugs has resulted in additive benefit in an experimental mouse model, supporting the
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important role of inflammation in the pathogenesis of the disease.118
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Fabry disease
This rare metabolic X-linked hereditary disorder is caused by partial or complete deficiency of the activity of the lysosomal enzyme a-galactosidase A, resulting in a progressive accumulation of glycosphingolipids, principally globotriaosylceramide (GL 3) throughout the body.119 The estimated incidence of Fabry´s disease is about one per
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80,000 to 117,000.120 Clinical manifestations seem to be influenced by the residual enzyme activity depending on the type of mutation, but a clear genotype-phenotype
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correlation has not been established.121 Absent or reduced activity of the enzyme causes a progressive accumulation of glycosphingolipids with terminal a-galactosyl residues, especially globotriaosylceramide (Gb3), within lysosomes of different cell types with a preferential involvement of endothelial cells, epithelial cells of glomeruli and tubules of the kidneys, cardiac myocites, ganglion cells of the autonomic system, cornea, endothelial, perithelial and smooth muscle cells of blood vessels, and histiocytic and reticular cells of connective tissue.122 Most patients remain clinically asymptomatic during early infancy.123 Initial manifestations include gastrointestinal disturbances, pain in the hands and feet, altered sweating, and fever.123-125 Pain is not only the earliest manifestation of Fabry disease but also one of the most disabling complications, especially during the first two decades of life.126 In adulthood, morbidity is associated with cardiac left ventricular hypertrophy,127 renal (proteinuria gradually progressing to
15
ACCEPTED MANUSCRIPT end stage renal failure),128 and central nervous system involvement and stroke.122 Average life expectancy is reduced to 50–55 years in males and 70 years in females.122 Cutaneous manifestation hallmark of Fabry disease is angiokeratoma.129
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Although easily overlooked, angiokeratomas are commonly seen at presentation and are rarely associated with relevant medical disorders.129 They will develop in about 40% of male adolescents with classic Fabry’s disease at a median age of onset of 14 to16 years. They tend to increase in number and size with age, and are present in 66% of male and
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36% of female patients.130 Appearing as non-blanching red to blue-black lesions from 1 to 5 mm in diameter, they are not always covered by fine white scales as their name
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would suggest, being also macular or just palpable, tending to cluster around the umbilicus and swimming trunk regions.131 They can also present around the mouth or other parts of the body like on the genitals, involving the penis, scrotum and groins in
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men.131 Later, they can appear on the lips, umbilicus, and periungual areas and palms.131,132 A proportion of patients have no cutaneous vascular lesions, and others
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have macular angiomas (cherry angiomas).133
Telangiectasia is the second commonest skin manifestation, and occurs most commonly on photodamaged areas such as the face and the V of the neck.134 They appear later than angiokeratomas and may be seen at unusual sites such as the flanks,
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groins, elbow, and knee flexures.134 The presence of cutaneous vascular lesions (telangiectasias and or angiokeratomas) has been associated with higher disease severity scores and a higher prevalence of mayor organ involvement.131 Hypohidrosis (decreased
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sweating) is another common problem in Fabry´s disease, which has been attributed to both a main effect on the sweat glands and to autonomic neuropathy.135 More than 50% of men and 25% of women have proved to have decreased sweating or heat intolerance, or both, in childhood.135 Hyperhidrosis (excessive sweating) has also been described more commonly in females than in males, and it affects palms and soles and is not generalized.135 Edema and lymphedema in lower limbs is frequently observed in Fabry´s patients.136 Patients have characteristic facial features that include periorbital fullness, prominent lobules of the ears, bushy eyebrows, recessed forehead, shallow midface, full lips, prominent nasal bridge, and coarse features, among others.137,138 Ocular manifestations of Fabry disease are highly characteristic. However, they produce no symptoms, and are frequently overlooked.139 Most Fabry female gene carriers, including those who have no symptoms of the disease, have ocular signs 16
ACCEPTED MANUSCRIPT typical of Fabry´s disease.139 The conjunctival vessels may be dilated and show ampullary out-pouchings.50,139 The cornea has a superficial haze with a whorl-like distribution (cornea verticillata) as the consequence of glycolipids deposition in the
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basal epithelial cells, and this aspect is present in up to 95% of male and 88% of female gene carriers.50 This corneal compromise begins in childhood, being earlier in boys than in girls.140 Cataract is found most commonly in male patients, with posterior lens opacities somewhat more frequent than anterior opacities in both sexes. Linear, whitish,
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almost translucent spoke-like deposit of GL-3 on, or near the posterior lens capsule are unique to Fabry´s disease, the lens showing a characteristic octopus-like silhouette in its
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posterior cortical zone.141 The retinal vessels show unusual distension, tortuosity and occasional telangiectases, and are found in approximatly 77% of males and 19% of
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females, usually starting in adolescence.140 Fabry's disease is a sex-linked genetic trait that achieves full expression only in males. Ophthalmologists should be aware of the clinical signs of Fabry´s disease as they could greatly reduce diagnostic delays and thus
Farber disease
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reducing the morbidity and mortality of the disease.139
Farber disease (or Farber lipogranulomatosis) is a rare, autosomal recessive disease consisting in a lysosomal acid ceramidase deficiency that results in an
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accumulation of Cer in the liver, central nervous system, joints, throat, and retina.142 The clinical presentation is characterized by very painful subcutaneous skin nodules
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appearing near the joints, most frequently interphalangeal, wrist, elbow and ankle joints, or over mechanical pressure points, leading to progressive joint stiffness, immobilization and deformation of the affected joints.142 Classically, newborns develop symptoms within the first weeks of life, including retinal macular whitening and cherryred spot.117 Abnormal accumulation of Cer in the laryngeal tissues produces a progressive hoarseness with a characteristic cry in infancy.142 Seven different phenotypes that differ in severity and additional organ involvement (lungs, nervous system, heart and lymph nodes) have been described, with a variable degree of central nervous system involvement depending on residual lysosomal ceramidase turnover.142
Krabbe disease Known also as globoid cell leukodystrophy or galactosyl ceramide lipoidosis, Krabbe disease is an autosomal recessive disorder that occurs as the consequence of a 17
ACCEPTED MANUSCRIPT deficiency in ß-galactosylceramidase, resulting in monoglycosylsphingolipid (also known as psychosine, a downstream product of galactosylceramide) accumulation that causes death of oligodendrocytes, hence disrupting the development of the myelin
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sheath.117 The disease manifests initially by irritability and stiffness, episodic fevers, and seizures, and eventually severe motor and mental deterioration leading to early death.117 Retrograde neuronal degeneration leads to thinning of ganglion cell and nerve fiber layers, and blindness may be present in later stages of the disease because of
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degeneration of afferent visual pathways.143 A cherry-red spot in a whitish macula may
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also be observed in the course of Krabbe disease.144
GM1 Gangliosidoses
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This disease is caused by an inherited autosomal recessive deficiency of the lysosomal enzyme GM1-ß-galactosidase that leads to storage of GM1-gangliosides within lysosomes and subsequent neuronal apoptosis, demyelination, and gliosis.91
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Three different clinical forms may be distinguished: the early infantile form (type 1), with developmental arrest and progressive deterioration of the nervous system; the infantile/juvenile form (type 2), characterized by progressive neurological symptoms; and the adult or chronic form (type 3), occurring in young adults. As the consequence of its changed substrate specificity, a defective GM1-ß-galactosidase can also lead to
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Morquio disease type B.91 Characteristic clinical features include coarse facies, hepatosplenomegaly, skeletal dysostosis, and a whitish macula with cherry-red spot
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(50% of cases).114 Other ophthalmological manifestations may be observed such as corneal clouding, tortuous retinal vessels, retinal hemorrhages, and optic nerve atrophy.451
GM2 Gangliosidosis GM2 gangliosidosis are a group of three sphingolipidoses resulting from defects in degradation of ganglioside GM2 and related glycolipids.93 As with GM1 gangliosidosis, the severity of the disease and its progression reflects the degree of enzymatic dysfunction.117 Accumulation of GM2 gangliosides in the brain results in early neuronal cell death and progressive neurodegeneration. The B-variant of this disease, is characterized by a deficiency in an alfa chain and the subsequent deficiency of hexosaminidases A and S, but with normal hexosaminidase B (that gives the name of this variant), and it may be subclassified into 18
ACCEPTED MANUSCRIPT infantile, juvenile, chronic, and adult forms, corresponding to increasing residual enzyme activity.93,145 Tay-Sachs disease corresponds to the infantile form of the B-variant GM2
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gangliosidosis, and has a higher prevalence among Ashkenazi Jews, with a heterozygote frequency of 1 in 27.93 Clinical features include ataxia, muscle wasting with motor degeneration, spasticity, convulsions, deafness, blindness, and death by the age of 3 years.117 The optic disc is pale, and the macula presents the characteristic white opacity
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of the internal neurosensory retina with the central cherry-red spot, as the consequence of accumulation of gangliosides within the retinal ganglion cells, spearing the central
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fovea as it lacks ganglion cells.117 This characteristic macular appearance is common to many of the lysosomal storage diseases. Long-term follow-up of patients with a cherryred spot macula has shown a decrease in prominence of this appearance as the result of
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ganglion cell death and gliosis.146 The loss of ganglion cells seems to parallel the progressive visual loss experienced by these patients.147
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Sandhoff disease corresponds to the o-variant of GM2 gangliosidosis, and it is produced by a functional loss of both hexosaminidases A and B. It is charachterized by accumulation of negatively charged glycolipids similar to those of Tay-Sachs disease, but also by elevated levels of uncharged glycolipids such as glycolipid GA2 in the
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brain, and globoside in visceral organs.93 Sandhoff disease shares many of the ophthalmological manifestations described in Tay-Sachs disease, such as optic atrophy and retinal macular whitening with the central cherry red spot appearance. Elevated pro-
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inflammatory cytokine production (TNF alfa, IL-1B and TGFB1) have been observed in Sandhoff disease as well as in late-onset Tay-Sachs disease; macrophage activation and enhanced MHC class II expression leads to microglial activation, increased nitric oxide formation, and increased oxidative damage, with a correlation with disease severity.147 The A-B variant of GM2 gangliosidosis is characterized by normal ßhexosaminidase A, B, and S activities, but with a deficient GM2-activator protein (lipid binding protein). Clinical picture resembles that of Tay-Sachs disease.93
V. Carbohydrates storage disorders
Lysosomal mucopolysaccaharide storage disorders (mucopolysaccharidoses) The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, characterized by a functional deficiency caused by genetic mutation of one of the 19
ACCEPTED MANUSCRIPT particular lysosomal enzyme that act in the sequential catabolism of glycosaminoglycans (GAGs, known as mucopolysaccharides).149 Individuals with one of these rare metabolic disorders are affected by progressive accumulation of
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incompletely degraded GAGs, and excessively excreted in the urine.149 The type of GAG stored depends on the specific enzyme deficiency and classification of the disorders is now based upon these deficiencies, rather than clinical features. Four different pathways of lysosomal degradation of GAGs depending on the molecule to be
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degraded have been individualized: dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate.150 The overall incidence for all types of MPS is approximately
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one in 20,000 live births, and they are transmitted in an autosomal recessive form, except MPS II (Hunter´s disease), which is X-linked.150,151
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The typical symptoms include organomegaly, dysostosis multiplex, and a characteristic abnormal facies. Hearing, vision, and cardiovascular function may also be affected.152
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Mucopolysaccharidosis I is caused by a deficiency of α-L-iduronidase, resulting in a wide range of phenotypic involvement with three major recognized clinical entities: Hurler (early infancy; very severe; mentally retarded), Hurler-Scheie (youth; moderately severe; mentally retarded), and Scheie (adult, mild, normal intelligence, claw hand) syndromes.152 Clinical spectrum ranges from death in early infancy due to
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cardiomyopathy to near normal adult patients.152 Affected patients have characteristic coarse facies, macroglossia, hearing loss, hydrocephaly, and hepatosplenomegaly, but
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the clinical course is dominated by airway problems with frequent upper and lower respiratory infections in the most severe forms in children.152 Umbilical and inguinal hernias are very frequent, and mobility may be limited by progressive joint stiffness.152 In addition, the accumulation of GAGs in rigid structures and paraspinal ligaments increases the potential for morbidity, resulting in major risks to the cervical column.152154
Dermal melanocytosis and corneal clouding are characteristic in Hurler´s disease.152 Mucopolysaccharidosis II (Hunter's syndrome) consists in a deficiency of the
lysosomal enzyme iduronate sulfatase, which is fundamental for the correct degradation of dermatan and heparan sulfate, with the consequent accumulation of glycosaminoglycans in nearly all organs and tissues.155 Patients may have a wide spectrum of severity.155 Severe forms are infantile and have progressive mental retardation and physical disability, with death occurring before the age of 15 in the majority of cases. In contrast, mild or attenuated forms are compatible with minimally 20
ACCEPTED MANUSCRIPT impaired intellect and survival to adulthood.155 Patients exhibit upper respiratory tract dysfunctions, either obstructive or restrictive, sleep apnea, dysostosis multiplex in various bones, hepatomegaly (associated or not with splenomegaly), umbilical and
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inguinal hernias, recurrent otitis and some degree of hearing loss, dental abnormalities, gingival hypertrophy and hyperplasia, and cardiologic manifestations.155 Mongolian spot, and papular lesions, caused by GAG deposits and considered typical of this type of MPS, although not exclusive to it.156,157
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Mucopolysaccharidosis III (Sanfilippo's syndrome), observed in late infancy, is caused by impaired degradation of heparan sulfate, and includes 4 subtypes, each one
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due to the deficiency of a different enzyme: heparan N-sulfatase, α-Nacetylglucosaminidase, acetyl CoA: α-glucosaminide acetyltransferase , and N-
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acetylglucosamine-6-sulfatase . At a clinical level, the four subtypes are quite similar, with characteristic associated severe central nervous system degeneration, with mild somatic disease and no ophthalmological manifestations.152
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Mucopolysaccharidosis IV (Morquio's syndrome) is caused by impaired degradation of keratan sulphate.152 Two known enzyme deficiencies cause two different subtypes of Morquio's syndrome: deficiency in N-acetylglucosamine-6-sulfatase, that plays a role in the degradation in keratan and chondroitin sulphate (Morquio type A, with normal intelligence, short trunk dwarfism, fine corneal deposits, spondylo-
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epiphyseal dysplasia, and cervical myelopathy), and deficiency in β-galactosidase, involved in degradation of keratan sulphate (Morquio type B; similar clinical features
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than type A).152
Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) results from a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase (arylsulfatase B).158 Intelligence is within normal ranges but cornea, skin, liver, spleen, brain, meninges, and skeletal (short trunk and a thoracolumbar gibbus) and cardiopulmonary systems are affected.158 Coarse facial features including frontal bossing, a depressed nasal bridge, enlarged tongue, gingival hypertrophy, delayed dental eruption, and hirsutism are observed.158 Hypoacusia may be present, and obstructive sleep apnea and respiratory involvement results from extrinsic and intrinsic alterations to the airways (short neck, elevated epiglottis, deep cervical fossa, hypoplastic mandible, and tracheobronchomalacia).158 Cardiovascular involvement is a significant component of this disease and is responsible for a large part of the patients' morbidity and mortality.159
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ACCEPTED MANUSCRIPT Mucopolysaccharidosis VII (SLY) is very rare disease and is caused by deficiencies of ß-glucuronidase, resulting in accumulation of dermatan, heparan, and chondroitin sulphate.160 It often presents as non-immune hydrops foetalis and affected
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patients rarely survive more than a few months.160 The systemic features of MPS VII are middle ear disease and deafness, caries and dental abscesses, upper airway obstruction and obstructive sleep apnea, cardiomyopathy and valve lesions, hepatosplenomegaly, hernias, hydrocephalus, learning difficulties, and dysostosis
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multiplex.160
Progressive corneal opacity due to abnormal corneal GAG deposition can affect
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all subgroups of MPS, but is a prominent feature of patients with MPS I (more than 80% of patients) and MPS VI (more than 94% of cases).161 Patients often manifest
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photophobia and visual impairment.161 The accumulation of GAGs occurs both intra and extracellularly in the corneal epithelium, keratocytes, stroma, and endothelium, with subsequent disruption of the optically important arrangement of collagen.162 GAG
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deposition increases corneal thickness, particularly in patients with MPS I Hurler and MPS VI.163 Elevated intraocular pressure may occur because of GAG accumulation in the angle of the anterior chamber, impairing outflow and leading to open-angle glaucoma.164 Secondary angle-closure glaucoma may also occur because of thickening
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of the iris and peripheral cornea as a result of GAG deposition.164 Optic nerve involvement is more common in MPS I Hurler, Hurler/Scheie and MPS VI, and are a significant cause of severe visual loss.165 The optic nerve abnormalities in MPS include
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an infiltrative swelling because of GAG accumulation within the nerve and the meningeal sheaths.164 GAG deposition in the central nervous system may cause obstructive hydrocephalus and true papilledema.166 Optic atrophy may be secondary to accumulation of GAG within ganglion cells and eventual degeneration of the optic nerve fibers, secondary to optic nerve compression, or as the consequence of retinal degeneration.166 Progressive pigmentary retinopathy is particularly noticeable in all MPS I subtypes, and MPS III. GAG deposition within retinal pigment epithelial cells and in the photoreceptor matrix leads to progressive photoreceptor loss, retinal degeneration, and dysfunction.165 Patients may experience nyctalopia and visual field constriction, although this may go unnoticed, particularly in patients with MPS Hurler and Hurler/Scheie because of advanced corneal opacity.165 The majority of patients with MPS is hypermetropic because of reduced axial length as a result of storage of GAG in the sclera.164 Hyperopia might also be due to increased corneal rigidity resulting from 22
ACCEPTED MANUSCRIPT storage of GAG that straighten the curvature of the cornea and reduce the refractive power.165 Strabismus, in particular esotropia as the consequence of raised intracranial pressure, and acquired Brown syndrome due to mechanical limitation of movement of
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the superior oblique tendon.165 Also, GAG infiltration of the extraocular muscles may contribute.165
Galactosemia
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Of complex and still not completely understood pathophysiology, galactosemia is an autosomal recessive disease caused by the deficiency of galactose-1-phosphate
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uridyltransferase (GALT), one of the key enzymes in the Leloir pathway of galactose metabolism, leading to galactose-1-phosphate (gal-1P) accumulation.167 It affects 1 in
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50,000 births. Untreated patients with classic galactosemia in the newborn period manifest vomiting, diarrhea, poor feeding, failure to thrive, liver disease, jaundice, Escherichia coli sepsis, cataratcs, and neonatal death.168 Newborn screening for
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galactosemia and galactose restriction by immediate removal of lactose help to prevent neonatal morbidity and mortality of the disease in most of cases.167 However, long-term complications are frequent and usually include mental retardation, speech abnormalities, reduced bone density, depression, anxiety, cataracts and ovarian insufficiency in most girls.169
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Cataract is almost the unic ophthalmic finding in galactosemia,170 affecting 30% of patients, the majority remaining mild or transient, and only a few requiring surgical
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treatment.171 In treated patients a cataract has been observed in 21% of adult galactosemic patients,169 and no direct correlation between the degree of noncompliance with the diet and the occurence of cataract.172 The intralenticular accumulation of galactose-1-phosphate and galacticol seem to have a hyperosmotic effect on crystalline fibers, producing vacuolated opacities (oily droplets) that may be present even at birth.170 More exceptionally, a vitreous hemorrhage has also been associated with galactosemia in newborns without related obstetric or delivery complications, and the coexistence of coagulation disorders might predispose to retinal hemorrhages and their subsequent progression to a vitreous hemorrhage.173-175 The unsatisfactory outcomes especially concerning intelligence quotient sequels and ovarian insufficiency of treated patients with classic galactosemia, calls for new
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ACCEPTED MANUSCRIPT treatments that may include selective galactokinase (GALK) inhibition (it eliminates the accumulation of gal-1P from endogenous production and dietary sources).167
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VI. Protein deposition diseases Amyloidosis
Amyloidosis refers to a variety of conditions wherein normally soluble proteins
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become insoluble (amyloid) and are deposited within the extracellular space of different tissues and organs, affecting their architecture and function.176
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Systemic amyloidosis can be classified into a primary type, caused by an occult plasma cell dyscrasia and a myeloma-associated type.176 Secondary type or reactive
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amyloidosis occurs in association with chronic inflammatory systemic disease or chronic dermatoses.177 Other systemic forms include hemodialysis-related and multiple heredofamilial forms, including familial Mediterranean fever, Muckle-Wells syndrome,
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and familial amyloid polyneuropathy.178
Localized cutaneous amyloidosis can either be primary or secondary. Primary cutaneous amyloidosis consists of three types: nodular, macular, and lichenoid.179 Secondary cutaneous amyloid deposits are found as incidental findings in multiple
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benign and malignant cutaneous tumors and after PUVA therapy.179,180 AL (primary) amyloidosis results from extra-cellular deposition of fibril-forming
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monoclonal immunoglobulin (Ig) light chains (LC), most commonly of lambda isotype, usually secreted by a small plasma cell clone.181 Patients may have nonspecific constitutional symptoms, such as macroglossia, carpal tunnel syndrome, or edema.181 Less common presentations include sicca syndrome.181 Skin or mucous membrane lesions are seen in 40% or less of cases.182 The most common lesion is purpura, seen in 15% to 17% of patients.183 It occurs after minor trauma (pinch purpura) particularly in areas such as eyelids, axilla, umbilicus, and anogenital regions.184 Facial purpura can occur after a Valsalva maneuver or proctoscopy.185 Purpura results from amyloid deposition in vessel walls, and the deposits can leave cutaneous vessels thickened and cordlike.185 Bleeding dyscrasia arise as a result of vascular infiltration by amyloid, and the production of a dysfunctional fibrinogen molecule by the amyloid-impaired liver (dysfibrinogenemia), abnormal platelet aggregation, and deficiencies of factors II, V, VII, IX, and particularly factor X.185 Factor X has a predilection to bind to amyloid
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ACCEPTED MANUSCRIPT fibrils, and its resultant deficiency cannot easily be corrected by administering plasma because the infused factor X rapidly binds to large amyloid deposits in the liver and spleen without causing a concomitant rise in blood’s factor X level.183,186
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Asymptomatic papules, plaques, and nodules with a waxy, hemorrhagic appearance occur less commonly and are located in flexural areas, the central area of the face, the retroauricular fold, and the oral cavity, especially the tongue.187 Facial plaques may coalesce, resulting in a leonine appearance; a sclerodermatous infiltration also may
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occur.187,188
Macroglossia is pathognomic of AL amyloidosis and is seen in around 10% of
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patients, being the most frequent cause of macroglossia in adults.189 Other rare cutaneous alterations seen in AL amyloidosis are hyperpigmentation, verticis girata in the scalp.190-194
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alopecia areata or universal, nail dystrophies, cutis laxa, and lesions similar to cutis
Localized AL amyloidosis is a localized phenomenon, related to deposition of
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monoclonal LC close to their synthesis by a focal plasma cell clone.195,196 Most patients do not have evidence of monoclonal gammopathy.195,196 Nodular cutaneous amyloidosis presents as firm subcutaneous nodules up to several centimeters in diameter that are brown-pink, waxy, often with overlying telangiectasias.197,198 They occur on the face, extremities, and trunk or genitalia and can appear atrophic, anetodermic, or bullous,
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possibly from dermal destruction of elastic and collagen fibers.199 The nodular variant is the most rare of the cutaneous amyloidosis.199 In nodular cutaneous amyloidosis, an
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atrophic epidermis overlies large, amorphous, clefted, masses of amyloid, extending from the papillary and reticular dermis into the subcutaneous fat.198 Deposits can also be seen around adnexa, blood vessels, and fat cells.199 Lichen amyloidosis has been considered a highly pruritic dermatosis, and the deposition of fibrillar material has generally been considered to be secondary to the scratching induced by other subjacent pruritogenic processes.200 It is commonly seen as red brown pruritic hyperkeratotic papules on the shins, with a subsequent spread to the dorsa of the feet and thighs.201 The papules at times may coalesce to form plaques resembling hypertrophic lichen planus, lichen simplex, or nodular prurigo.201 The lesions may localize to a single area or may involve various body sites.201 Although the most commonly affected area is the pre-tibial region, it has also been observed on the abdominal and chest wall, the ear auricula,202,203 the anosacral region, the scalp, and the interscapular region.204,205 25
ACCEPTED MANUSCRIPT Macular amyloidosis is seen as gray-brown pruritic patches anywhere on the trunk or extremities, but especially on the upper back.206 Small papules may coalesce into a rippled pattern.206 Macular amyloidosis occurs more commonly in Central and
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South American, Asian, and Middle East populations.207 Neither macular nor lichen amyloidosis has been reported to progress to systemic disease.207 Lichen and macular amyloidosis have deposits in the papillary dermis, usually within the dermal papillae.208 Lichen amyloidosis can sometimes be distinguished from the macular form by the
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presence of hyperkeratosis, acanthosis, and larger deposits.208 The amyloid may be circumscribed and globular, consistent with colloid bodies, and may be in contact with
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basal cells at the basement membrane zone.209
Ocular amyloidosis can occur as a primary form, where the deposits occur without systemic compromise, or as a secondary form, which is associated with
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systemic involvement.210 The deposition of amyloid may occur locally in the same place where it originated or rush into other organs or tissues distant from the site of
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production.211,212 Amyloid may accumulate in the eyelid, conjunctiva or anterior orbit.211-214
Conjunctival amyloidosis is the most common form of involvement being primarily a local process, and rarely associated with systemic disease.212 It is apparently
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the most common ophthalmic manifestation of non-familiar amyloidosis.210 It affects principally middle-aged adults and may present with symptoms simulating a malignant or inflammatory entity.211 Conversely, malignant conjunctival lesions can lead to
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amyloidosis.211 Conjunctival amyloidosis usually starts at the level of the fornices as a vascularized waxy conjunctival mass, and then extending to the bulbar and palpebral conjunctiva.215 Subconjunctival hemorrhage is another sign that is often present, and occurs as the consequence of the accumulation of amyloid in the substantia propria and around blood vessels of the conjunctiva that weakens the walls, facilitating bleeding.211 Blepharoptosis is caused by stretching and dehiscence of the levator aponeurosis secondary to edema and recurrent bleeding.211 It has been suggested that conjunctival amyloidosis could be an early manifestation of a systemic amyloidosis, indicating that a general assessment to rule out the primary form of the disease might be advisable.211,213
Lipoid proteinosis Lipoid proteinosis, also known as Urbach-Wiethe syndrome, or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder caused by mutations in the gen 26
ACCEPTED MANUSCRIPT encoding extracellular matrix protein 1 on chromosome 1q21,216 affecting most frequently light-pigmented-skin race individuals.217 Typical manifestations include hoarseness due to laryngeal involvement that
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produces a typical hoarse cry during infancy, and skin and mucous membrane involvement that become apparent during the first two years of life.218 Pox-like vesicles, pustules, bullae, and hemorrhagic crusted eruptions on the face and limbs that are more extensive in areas of trauma that heal with acneiform atrophic scars.219 The skin
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becomes thick, yellowish and waxy, and the scalp may show alopecia areata.219 The infiltration includes certain mucous membranes, and the infiltrates in the tongue and its
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frenulum may limit lingual movements, causing speech difficulties.219 A pathognomonic sign is a row of beaded papules along the eyelid margins, resembling a string of pearls, termed “moniliform blepharosis”, recognized in 50% of
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patients, but may not be apparent in early infancy.220 Recently, in one series of lipoid proteinosis patients, prominent stromal corneal nerves without other visual or ocular
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manifestations were detected in all of them, in some without detectable eyelid lesions.221
Life expectancy is in general good unless respiratory tract involvement with
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severe airway obstruction occurs.220
Figure legends
Fig.1 Porfiria cutanea tarda-scars of blistering lesions in hands
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Fig.2 Porfiria cutanea tarda Fig.3 Porfiria cutanea tarda-blistering lesions in face Fig 4 Porfiria cutanea tarda-hypertrichosis in face Fig 5 Porfiria cutanea tarda – hyperpigmentation in face Fig 6 Porfiria cutanea tarda-scleroderma Fig 7 Lens displacement in homocystinuria Fig 8 Macular cherry red spot in lysosomal lipid storage disease
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ACCEPTED MANUSCRIPT References 1. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the
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EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1312–1324.
2. Rasaratnam I, Christophitis N. Gout: “a disease of plenty.” Austr Fam Phys. 1995;24:849-60.
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3. Burns CM, Wortmann RL. Latest evidence on gout management: what the clinician needs to know. Ther Adv Chronic Dis. 2012; 3:271–286.
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4. Eggebeen AT. Gout: an update. Am Fam Physician. 2007;76:801–808. 5. Dalbeth N, Aati O, Gao A, et al. Assessment of tophus size: a comparison
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Am J Ophthalmol. 1952;35:1778–1783.
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10. Slansky HH, Kubara T. Intranuclear urate crystals in corneal epithelium. Arch Ophthalmol. 1968;80:338–443. 11. Morris WR, Fleming JC. Gouty tophus at the lateral canthus. Arch Ophthalmol. 2003;121:1195–1197. 12. Margo CE. Use of standard hematoxylin-eosin to stain gouty tophus specimens. Arch Ophthalmol. 2004;122:665. 13. Topping NC, Cassels-Brown A, Chakrabarty A, et al. Uric acid crystals presenting as an orbital mass. Eye (Lond). 2003;17:427–429. 14. Coassin M, Piovanetti O, Stark WJ, Green WR. Urate deposition in the iris and anterior chamber. Ophthalmology. 2006;113:462–465. 15. Sarma P, Das D, Deka P, Deka AC. Subconjunctival urate crystals: a case report. Cornea. 2010;29:830–832. Lin J, Zhao G-Q, Che C-Y, et al.
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ACCEPTED MANUSCRIPT Characteristics of ocular abnormalities in gout patients, Int J Ophthalmol. 2013;6:307-311. 16. Jinnah HA, De Gregorio L, Harris JC, et al. The spectrum of inherited mutations
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causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat. Res. 2000;463:309–326.
17. Torres RJ, Puig JG. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet. J. Rare Dis. 2007;2:48.
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18. Jinnah HA, Lewis RF, Visser JE, et al. Ocular motor dysfunction in LeschNyhan disease. Pediatr Neurol. 2001;24:200-204.
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