OVERVIEW: What every practitioner needs to know
Are you sure your patient has a lysosomal storage disease? What are the typical findings for this disease?
Lysosomal storage disorders (LSDs) are genetic diseases caused by defects in lysosomal proteins or lysosomal related-proteins, which results in dramatic dysfunction of lysosomes.
Lysosomes are cellular organelles required for recycling various molecules and compounds including glycosaminoglycans, glycoproteins and glycolipids. To execute this essential physiologic function, lysosomes harbor several enzymes that are capable of functioning in the acidic lysosomal compartment. Some of these enzymes are secreted by cells and consequently can be measured in body fluids (ie, serum and urine).
Classically, lysosomal dysfunction can occur by a mutation in genes encoding one of the lysosomal catalytic enzymes, resulting in accumulation of molecules that are normally degraded and consequently leading to a storage disorder.
Other forms of lysosomal dysfunction are caused by defects of lysosomal membrane proteins, errors in enzyme targeting and defective function of lysosomal enzyme activators.
As a result of lysosomal dysfunction and resultant disturbance of cellular homeostasis, LSDs have a broad spectrum of clinical manifestations including dysmorphism, visceromegaly, skeletal and joint abnormalities, hematologic findings and significant central and peripheral nervous system impairment.
Most LSDs can affect predominantly, and often exclusively, the central nervous system, causing progressive neurodegeneration. Therefore, most patients do not present with “storage” clinical phenotype.
The majority of LSDs have an autosomal recessive inheritance. However, for some LSDs the causative gene of the defected enzyme is located on the X chromosome, resulting in an X-linked inheritance pattern (Fabry disease and mucopolysaccharidosis type 2).
LSDs are progressive multisystemic genetic disorders. Thus, the optimal management for these disorders requires a multidisciplinary approach, including constant surveillance of potential complications that can occur during the natural history of each these disorders.
Based on current knowledge about the pathogenesis of these disorders, specific therapeutic modalities have been developed and shown to result in improvement of several symptoms of LSDs. Importantly, since these are progressive diseases, the response to different therapies relies on the stage of disease each patient presents and is diagnosed. In addition, supportive management is a crucial component of the management of patients afflicted with these disorders.
Symptoms are insidious and progressive. Most common symptoms can be grouped in three major categories:
Storage syndrome – which results in dysmorphism (coarse facies, visceromegaly, organ dysfunction).
Bone syndrome – which can be characterized in short stature, severe joint and spine abnormalities and severe bone pain.
Neurologic syndrome – mostly chronic and progressive encephalopathy including global delay, seizures, ataxia and dysarthira.
Age of onset of symptoms: any time during the entire life span, from fetal period to late adulthood; age at onset of first symptoms depends on the residual function of the deficient lysosomal enzyme.
Clinical symptomatology of each LSDs overlaps and some characteristic differences may guide the diagnosis (Table I).
Storage Syndrome in LSDs
Storage syndrome is present in several LSDs, especially mucopolysaccharidoses (MPSs). The storage syndrome includes a constellation of symptoms/signs in connective tissue (subcutaneous and osteochondral joints), skeleton and visceral organs. Each of these findings may indicate an LSD:
– Coarse facies: macrocephaly, prominent forehead and supra-orbital ridges, mild puffiness of eyelids, broadening and flattening of nasal bridge, anteverted nostrils, thickness of lips, thickened and fleshy pinnae, prognathism.
– Other head/neck findings: corneal clouding, macroglossia with prominent tongue fissures, gingival hypertrophy, and short neck. Recurrent ear infections and symptoms and signs of hydrocephalus can also occur in LSDs. Fundoscopy can reveal important sign of “cherry red spot,” which is a prominent macula surrounded by a pale retina (full of storage sphingolipids in ganglion cells obscuring choroid vessels).
– Short stature: linear growth occurs in first year with but suddenly slows in the second year. Axial skeleton is often shortened with lumbar lordosis.
– Joint impairment: limitations on passive movement of major joints: interphalangeal (given apperance of claw-like hands), wrists, elbows, shoulders, hips, knees and ankles.
– Digits and toes are thicker and shorter than normal.
Hepatomegaly and/or splenomegaly
Cardiac involvement is characterized by hypertrophic cardiomyopathy and thickened cardiac valves, especially mitral and aortic. Symptoms can progress to cardiac congestive failure.
Adrenal calcifications, which can be seen in Wolman disease.
Pancytopenia can be present and be aggravated by hypersplenism which can be associated with these disorders:
Chronic normocytic anemia
Alder-Reilly bodies in peripheral leucocytes
– Hydrops fetalis (see Table II)
History of recurrent non-immune hydrops fetalis.
Negative investigations for infection etiology, unbalanced chromosomal abnormalities and congenital major malformations (heart, kidneys and vascular system).
Placental morphology appears bulky and pale and histology and ultra-structure examinations may reveal presence of cellular vacuolation.
Coarse facial features can be present in the fetus, along with hepatomegaly and neonatal hepatitis (Niemann-Pick C disease), cardiomyopathy (infantile Pompe disease) and signs of dysostosis multiplex.
Table II describes possible LSDs that can present as hydrops fetalis.
Bone Syndrome in LSDs
Bone syndrome is present in several LSDs, especially in mucopolysaccharidosis (MPSs).
– Spine: flattening and wedging of anterior-inferior lip of the vertebral body, resulting in posterior displacement of upper lumbar vertebrae. Clinically, patients present with an acute angle kyphosis (“gibbus”). Hypoplasia or absence of odontoid process resulting in atlanto-axial instability can be present.
– Hands: shortened and broadened metacarpals and phalanges which result in a “bullet-shaped” digits. Erosion of phalanges with increased coarse trabeculation is noted.
– Carpal tunnel syndrome is often observed in patients with different forms of MPSs.
– Hips: external rotation of ilia of the pelvis and underdeveloped acetabulum is present.
– All these skeletal signs are called multiplex dysostosis, which is the term used to described changes occurring thoughout the entire skeletal system, but manifest primarily in the skull, thorax, pelvis, hands and vertebrae.
– Osteopenia with progression in some disease and can result in pathological fractures as in Gaucher disease type 1.
Neurological Syndrome in LSDs
Characteristics of neurological manifestations of LSDs are:
– Most children have normal development for an initial and variable period.
– At the onset of disease, global developmental delay is usually very subtle.
– Once the delay becomes obviously, neurodeterioration begins and becomes progressive.
– The clinical picture is of chronic encephalopathy, which is characterized by both gray and white matter involvement.
– Common neurological symptoms observed in LSDs:
More common in sphingolipid disorders, known as sphingolipidosis. However, in some types of mucopolysaccharidosis, as MPS type III (Sanfilippo syndrome), seizures is a common symptom.
Seizures are usually associated with rapid progression of the disease.
Myoclonus may be more specific to a group of LSDs (See Figure 1).
It is usually global and characterized by impairment of several cognitive functions including gross-motor, fine-motor, socio-adaptive and linguistic skills.
Irritability, impulsivity, aggressiveness and hyperactivity are present.
In adolescents and adults, a progressive dementia occurs with impairment of cognitive functions.
Psychomotor involvement is usually progressive. An apparent period of normal development can precede the regression.
It is usually associated with other neurological signs including hypotonia, seizures, pyramidal or extra-pyramidal signs.
Signs of central and peripheral white matter disease:
Motor disturbances, gross motor weakness and spasticity.
Brain magnetic resonance imaging (MRI) shows moderate to severe attenuation of white matter signal.
Peripheral neuropathy can present as initial symptoms of gait impairment; stumbling, clumsiness can resemble ataxia.
Signs of distal muscle atrophy in upper and lower extremities can be present.
Peripheral muscular involvement:
Progressive proximal muscular weakness with respiratory dysfunction can be observed in late onset Pompe disease.
In patients with MPSs, the progressive compression of spinal cord can result in cervical myelopathy, which is caused by the thickening of dura, also know as hypertrophic pachymeningitis cervicalis.
Communicating hydrocephalus and its complications can be seen in severe MPS I.
It may occur with insidious onset.
Recurrent acute cerebral ischemic events are typically seen in patients with Fabry disease.
Tremors, rigidity and other symptoms of Parkinson’s disease have been identified in five times higher frequency in adult patients and carriers of mutations in the gene GBA encoding glucocebrosidase (enzyme deficiency in Gaucher disease).
Other Manifestations of LSDs
Most of the pathogenesis is secondary of the accumulation of glycosaminoglycan or glycolipid in respiratory system.
Obstructive upper airways disease (MPSs and Farber disease).
Obstructive sleep apnea is progressive in several MPSs and can result in pulmonary hypertension and cor pulmonale if not treated.
Chronic obstructive and restrictive pulmonary disease can be observed in several LSDs especially MPSs as the mobility of thoracic cage is compromised.
Congenital pulmonary lobar emphysema is described in patients with Niemmann-Pick type B.
Restrictive pulmonary disease is characteristic in late onset Pompe disease.
Thickening of left heart valves (mitral and aortic)
Arteriopathy and aorta coarctation are noted in some MPSs due to accumulation of glycosaminoglycans in intima of endothelium.
Coronary artery disease is often seen in Fabry disease and MPS type 1.
Patients with Fabry disease can present with progressive end-stage renal disease associated with other symptoms (hypertrophic cardiomyopathy, arrhythmias, hearing impairment, acroparesthesias) and X-linked inheritance in family history.
Progressive cirrhosis is observed in patients with MPSs.
Early presentation of liver impairment in some LSDs can present as neonatal hepatitis.
Gastrointestinal dysmotility is usually observed in patients with Fabry disease, Pompe disease and Gaucher disease.
Abdominal, inguinal and scrotal hernias are common in MPSs and need prompt intervention but often recur.
Secondary hyperparathyroidism associated with severe osteopenia can occur as a deficiency of calcium transport across the placenta and it has been observed in mucolipidosis type 2 (ML2).
Visual impairment can be initial symptoms of LSDs.
Retinal abnormalities including retinitis pigmentosa can be detected and preceded by late response in electroretinogram (ERG) in a group of diseases called neuronal ceroid-lipofuscinosis. Retinal degeneration is also seen in MPSs.
Optic atrophy is an important finding, indicating white matter disease in some LSDs (Krabbe disease and metachromatic leukodystrophy).
A prominent fovea within pale retina, also known as “cherry-red spot” can be detected in several LSDs including infantile form of GM2 and GM1 gangliosidosis and sialidosis type I.
Corneal clouding is seeing as a steamy or ground-glass appearance of lens, which is observed in many mucopolysaccharidoses (MPSs).
Corneal worms, also known as corneal verticillata, is asymptomatic and mostly an ophthalmological finding in Fabry disease. This is an important diagnostic finding for females affected with this condition.
Glaucoma can occur in some MPSs.
Characteristic oculomotor dysfunction is observed in chronic neuronopathic Gaucher type 3.
Combination of Eustachian dysfunction, dysostosis of the ossicles of middle ear and eighth nerve cause hearing loss in MPSs.
Cranial facial abnormalities secondary to storage syndrome can result in decreased drainage though Eustachian tubes and recurrent otitis media in LSDs.
Rhinorrhea can be significant symptoms in MPSs.
In the context of other associated symptoms, this can an important diagnostic clue for LSDs.
Angiokeratomas are small, dark red micro vessel telangectasias, which can be mistaken by regular petechiae. It can become papular and rough on exam.
Ichthyosis is often seen in early presentation of some LSDs including multiple sulfatase deficiency and neuronopathic Gaucher disease type 2.
Papular-erythema with a reticulum pattern can be noted in patients with MPS1 and MPS2.
Xanthomas and brownish discoloration of lesions can be seen in Niemann-Pick type A.
Diffuse hirsutism is often seen in patients with MPSs.
What other disease/condition shares some of these symptoms?
Many conditions share some of the clinical features of the lysosomal storage diseases:
Storage Syndrome (coarse facies)
Some chromosomal rearrangement syndromes including 1p36 deletion, 1q41q42 microdeletion and 20p duplication
Donohue syndrome (leprechaunism)
Hepatosplenomegaly and hematological complications:
Autoimmune syndromes (i.e. immune thrombocytopenic purpura)
Infections (congenital or acquired infections)
Hematologic (i.e. hemophagocytic lymphohistiocytosis) or oncologic etiologies
Nonimmune Hydrops Fetalis:
Cardiac malformations (left heart hypoplasia, single ventricules, etc)
Chromosomal abnormalities (aneuploidies)
Chondrodysplasias (thanotophoric dysplasia, short rib polydactylies, hypophosphatasia, Saldino-Noonan syndrome)
Hematological (alpha-thalassemia, pyruvate kinase deificiency, red cell aplasias)
Infectious (CMV, Parvo B19, Toxoplasmosis, Rubella, Coxsackeivirus, syphilis)
Thoracic (congenital lung malformations, chylothorax, pulmonary lymphagiectasia)
Twin pregnancy (twi-twin transfusion syndrome)
Urinary tract malformations (urethral atresia or stenosis, posterior urethral valve, Prune belly syndrome, etc)
1p36 deletion syndrome
Sickle cell disease
Cogan’s syndrome (keratitis)
Drug-adverse reaction (nitisinone – treatment of tyrosinemia type I)
Lecithin cholesterol acyltransferase deficiency
Tyrosinemia type II (associated with keratitis)
Trauma (corneal abrasion or corneal foreign bodies)
Biopterin defects (hypsarrhythmia, autistic features, dystonia)
Congenital disorders of glycosylation
Congenital infection (toxoplasmosis, rubella, CMV, HSV, varicella, syphilis)
Cobalamin metabolic disorders
Creatinine deficiency (low cerebral creatine)
DNA repair disorders (Cokayne syndrome)
Pyrimidine and purine disorders including Lesch-Nyhan disease (choreoatetosis and self-mutilation), adenylosuccinate lyase deficiency (austitic features, microcephaly and white matter abnormalities)
Maternal phenylketonuria (PKU)
Menkes disease (X-linked) – steely brittle hair
Mitochondrial disorders (Leigh syndrome, respiratory chain defects)
Neurotransmitor defects (serine deficiency, P5C synthase deficiency, etc)
Panthotenate kinase 2 deficiency (extra-pymramidal signs and dementia)
Pelizaeus-Merzbacher syndrome (leukoduytrophy, nystagmus)
Peroxisomal disorders (X-linked adrenoleukodystrophy, Refsum disease and peroxisomal biogenesis disorders)
Sjogreen-Larson syndrome (ichthyosis, paraplegia)
What caused this disease to develop at this time?
LSDs are genetic conditions that can present at any period of life.
Based on current knowledge of the pathogenesis of these disorders, specific therapeutic modalities have been developed and shown to improve of several symptoms of LSDs.
Symptoms of progressive diseases can be storage symptoms (coarse facies, hepatosplenomegaly), hematological (anemia, or thrombocytopenia) and neurological (global delay, seizures, peripharal neuropathy).
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Over 60 lysosomal enzymes and proteins exist. When one of them is deficient, a specific LSD can result.
As it would be impossible to perform a single test for all lysosomal enzymes, the clinical history along with an attentive physical and neurological examination are still useful clinical tools to guide the clinician to the final etiology.
In most LSDs the diagnosis follows a comprehensive multi disciplinary management that ultimately results in improvement in the care of LSDs patients. In some LSDs, the time of diagnosis has important implications in specific therapeutic options that can be offered to patients.
Ancillary tests that are usually helpful in guiding the diagnosis include the following: brain imaging studies, comprehensive metabolic and biochemical investigations including tests for renal and hepatic functions and electrophysiological tests.
Laboratory investigations for LSDs includes 4 areas of diagnostic studies. Investigation should be pursued in the following order: histological and ultra-structural studies; detection of accumulated compound secondary to the lysosomal enzyme deficiency; specific biochemical enzyme assays and molecular genetic studies.
Histological and ultra-structural studies:
In general, these are not diagnostic but can indicate strongly the diagnostic work-up for an LSD.
Alder-Reily bodies in peripheral leucocytes can indicate a LSDs.
Bone marrow biopsy and/or aspiration can identify characteristic cells, including Gaucher cells (“wrinkled-tissue” cytoplasm) or lipid-laden cells (foam-cells) as seen in Niemman-Pick C disease and cholesterol ester storage disease.
Conjunctival biopsy can reveal important findings of curvilinear and fingerprinting cellular inclusions in neuronal ceroid-lipofuscinosis and mucolipidosis type 4.
Skin biopsies can be indicative of LSDs revealing curvilinear and fibrogranular flocculent material, known as membranous cytoplasmatic bodies. However, currently skin biopsies have been done mostly for establishment of cell lines for biochemical enzyme assays.
Detection of accumulated substrate (sphingoolipid or mucopolysaccharide).
Urine is a valuable specimen for the diagnosis of a group of LSDs that manifest with storage syndrome, known as mucopolysaccharidosis (MPSs).
Urinary mucopolysaccharides are very useful when suspecting of a MPSs in a patient presenting with storage syndrome (as above described and in Table I).
The urinary mucopolysaccharides can be done in a randomly collected urine and can classify the type of MPS based on the relative proportion of specific mucopolysaccharide (See Table I).
Urinary oligosaccharides are useful for some LSDs including GM1 gangliosidosis, galatosialidosis, sialidosis, Schindler disease, where the excretion of urine oligosaccharides are obvious. However, it has been shown to be non-specific and with low sensitivity and specificity. Patients with alpha-mannosidosis, alpha-fucosidosis and Sandhoff disease can present very subtle increases of oligosaccharides.
Both mucopolysaccharide and oligosaccharide tests can be done in amniotic fluid in prenatal investigation or when signs of hydrops fetalis.
Biochemical enzymatic assay:
For most LSDs the diagnosis is based on a biochemical test, which is an enzyme assay from patient specimens.
Peripheral leukocytes can be used for most lysosomal assays. However, confirmation of the enzyme deficiency in other patient specimens, most commonly cultured skin fibroblasts, is usually required to confirm the diagnosis.
Establishment of cultured fibroblasts, which are obtained by a skin biopsy, are usually done in the setting of a lysosomal enzyme deficiency detected in peripheral leucocytes.
The selection of enzyme assay to be performed is based on clinical findings and other investigations including morphological and detection of accumulated enzyme substrates (See Table I).
Some lysosomal enzyme assays can be performed in cultured amniocytes from amniotic fluid for a prenatal diagnosis or investigation of etiology of hydrops fetalis.
Molecular genetic studies:
With the identification of genes encoding many of the lysosomal enzymes and advances in DNA sequencing technology, detection of specific mutations have been useful for diagnostic confirmation and, especially in the identification of female carriers with Fabry disease. However, some of the alterations (mutations) in specific genes can be novel, which may affect the interpretation of test results. Thus, biochemical testing to evaluate for significant reduction of lysosomal enzyme activity is still diagnostic for LSDs.
The availability of a specific mutation in a gene encoding a lysosomal enzyme can be helpful in the molecular investigation in a chronic villous specimen obtained in early gestation for prenatal diagnostic purpose.
Would imaging studies be helpful? If so, which ones?
Radiographs – Skeletal survey
Complete skeletal surveys are important to detect signs of multiplex dysosotosis. Relevant findings may include:
– Skull films may show craniosynostosis, macrocephaly and thickened calvarium with a “j” sella turcica.
– Dysplasia of C2 resulting in atlantoaxial instability (common in several MPSs).
– Shortening and thickening of long bones (MPS) with sign of hyperostotic metaphysis.
– Flared iliac bones with a flattened acetabulum and coxa valga deformity.
– Long bone cortical thinning with flared metaphyseal regions Erlenmeyer deformity (distal femur and proximal tibia – remodeling process; typical in Gaucher disease).
– Distal humerus and ulna have an abnormal angulation and tilting of the distal epiphyses.
– Narrow metacarpals proximally with erosions in distal ends.
– Avascular necrosis of bones of wrist bones and acetabulum (Gaucher disease).
– Anterosuperior hypoplasia of lower thoracic and upper lumbar vertebral bodies with beaking, resulting in vertebral slippage and dorsal acute kyphosis.
– Generalized osteopenia.
– Narrowing of ribs close to vertebral junction and with broadening close to the sternal junction, resulting in decreased intercostal spaces.
– Clavicle may have widened ends.
– Demyelination with T2-weight images in white matter.
– Communicating hydrocephalus (as in MPS).
– Virchow spaces in corpus callosum, basal ganglia and white matter regions of the brain (perivascular enlargement due to accumulated GAGs).
– Cerebellar atrophy is prominent sign in juvenile forms of GM2 (Tay-Sachs and Sandhoff diseases) and GM1 gangliosidosis.
Ultrasound, CT scan and MRI of thorax and abdomen:
– Multiple mediastinum adenomegaly (Gaucher disease).
– Congenital pulmonary lobar emphysema (Niemann-Pick type A).
– Liver or spleen nodular lesions called “gaucheromas” (seen in Gaucher disease).
– Cystic lesions in distal femur or proximal tibia.
– Nodular lesions in extremities of long bones, which are also called “gaucheromas” (Gaucher disease).
– Signs of avascular necrosis in spine, hips and extremities of long bones.
Confirming the diagnosis
See Table I for description of LSDs with characteristic differences in different clinical and diagnostic areas.
If you are able to confirm that the patient has a lysosomal storage disease, what treatment should be initiated?
The treatment of LSDs can be divided in supportive and specific treatment categories. After diagnosis a comprehensive evaluation of potential complications above described should be done and appropriate management should be adopted. Treatment modalities complement each other and together aim the best quality-of-life for the affected patients and their families.
Supportive treatment involves multi disciplinary care by many specialties. Subspecialties, such as cardiology, anaesthesia, orthopaedics, otorhinolaryngology, ophthalmology and neurosurgery, as well as many paramedical groups including, for example, physiotherapy, occupational therapy, audiology, speech therapy and psychology, will all have an important input.
The following potential complications should be promptly assessed and treated:
Control can be achieved with conventional antiepileptic drugs including benzodiazepines, phenytoins, barbiturates.
However, seizures are progressive and change in type and severity; thus, increasing doses and different combination of antiepilectic drugs may be necessary for optimal seizure control.
Psychomotor retardation –
Early physiotherapy and occupational therapy can be very beneficial for patients.
Predictions regarding development should be avoided and the basic concept is the earlier the presentation the faster is the disease progression.
Consideration of psycho-educational assessment of children with attenuated disease prior to primary school entry.
Adult onset of some LSDs present with psychiatric and behavior symptoms for which conventional antipsychotic or antidepressant therapy may be used. Unfortunately, the clinical response is unpredictable and generally poor (classically seen in patients with MPS3).
The use of lithium salts and electroconvulsive therapy has been reported to be beneficial, at least in ameliorating for a period the episodes of psychotic depression (i.e. late-onset GM2 gangliosidosis).
Skeletal manifestations –
Physical therapy is a critical aspect of skeletal manifestations in LSDs.
Range of motion exercises appear to offer some benefit in preserving joint function, and should be started early.
Joint replacement and atlanto-occipital stabilization may be necessary.
Carpal tunnel syndrome, which can be asymptomatic should be treated in LSDs as soon as diagnosed by detection of abnormal nerve conduction velocities. Surgical decompression of the median nerve results in variable restoration of motor hand activity. Intervention at an early stage, prior to severe nerve damage, optimizes outcome; repeated surgery may be required.
Ocular manifestations –
Wearing peaked caps or eye-shades can reduce glare resulting from corneal clouding.
Corneal transplantation is successful for individuals with attenuated disease, although donor grafts eventually become cloudy.
Intraocular pressure should be monitored and specific surgical intervention including trabeculoplasty and iridotomy.
Cardiac valve replacement should be considered early.
Cardiomyopathy should be followed closely.
Arrhythmias should be investigated and pacemaker or implantable cardioverter defibrillator (ICD) may be required.
Coronary lesions involve the entire course of the vessels. Obstruction may result in sudden death. Vigilance should be employed in suspicion of coronary disease, even in young children, as the clinical presentation is atypical, and coronary angiography may not predict the severity of the disease.
Tonsillectomy and adenoidectomy correct Eustachian tube dysfunction and decrease upper airway obstruction.
Early placement of ventilating tubes should be done in severely affected individuals.
Hearing aids should also be considered in MPS patients.
Sleep apnea may require tracheotomy or high-pressure continuous positive airway pressure (CPAP) with supplemented oxygen.
Tracheostomy is often required to maintain the airway and control pulmonary hypertension and right heart failure.
Careful positioning and avoidance of hyperextension of the neck during anesthesia is required.
Use of smaller endotracheal tubes and fiber-optic laryngoscope is required.
Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.
Gastrointestinal system –
GI dysmotility can be controlled by diet, including control of the amount of roughage.
Increased roughage and the conservative use of laxatives may ease constipation.
Renal complications –
The nephrologist has a major role in managing patients with Fabry disease presenting with renal impairment.
Hemodialysis and renal transplantation may be required at end-stage renal disease in Fabry disease.
Cerebrospinal fluid (CSF) pressure and progressive ventricular enlargement indicate need for a shunting procedure.
Ventriculoperitoneal shunting in individuals with MPS1 who have moderate to severe hydrocephalus is generally palliative and improves quality of life.
Hypertrophic pachymeningitis cervicalis – it should be aggressively and quickly evaluated in patients with attenuated disease as early surgical intervention, as spinal cord decompression, may prevent severe neurological complications.
Specific treatments aim to target specific components of the pathogenesis of LSDs:
Enzyme-augmentation therapy, substrate reduction therapy and enzyme-enhancement therapy are three modalities to tackle the pathogenesis of LSDs.
Enzyme-augmentation therapy –
Hematopoietic stem cell transplantation (HSCT)
The aim is to use donor derived cells as a source of enzyme. Using either bone marrow or umbilical cord cells, donor macrophages can infiltrate diverse patients’ tissues including the central nervous system. These donor-cells secrete lysosomal enzyme (normal levels) which is taken up by neighboring host disease cells, reaching the lysosomes and correcting the biochemical defect. When done before the patient affected with a severe clinical form starts to develop neuroregression, HSCT has shown to be efficacious in one specific LSDs, MPS type 1 (see Figure 1). However, it has not proven to have the same result in most LSDs. In addition, in medical literature, most data on the clinical outcome for other LSDs are anecdotal or described in small case series.
In Krabbe disease and metachromatic leukodystrophy, initial benefit has been demonstrated, preventing the fulminant course of these neurodegenerative diseases. However, the long-term follow-up patients still present significant neurological disability.
Enzyme-replacement therapy (ERT):
Six LSDs are have ERT agents that are FDA-approved. ERT was originally developed for Gaucher disease using glucocerebrosidase purified from human placentas. The development of recombinant enzyme produced in mammalian cells increased the scale of the production. The major limitation of ERT is its inability to treat neurological symptoms of most LSDs since the ERT agent is unable to cross the blood-brain barrier. The cost is high for a life-therapy: average of 300,000 US$/year (for a 70kg weight individual).
Gaucher disease type 1:
This is the only LSD which three FDA-approved ERT agents are available:
-imiglucerase (Cerazyme –Genzyme-Sanofi produced in Chinese Hamster Ovarian, CHO cells) – administered I.V. at 60 units per kg every 2 weeks.
-velaglucerase alfa (VPRIV – Shire Human Genetics Therapeutics, HGT; produced in human cells) – administered I.V. at 60 units per kg every 2 weeks.
-tagliglucerase alfa (ELELYSO – Pfizer-Protalix Inc.; plant cell-expressed of human glucocerebrosidase) – administered I.V. at 60 units per kg every 2 weeks.
Both ERT agents are uptaken by macrophages residing in the reticulum endothelium system and shown to improve, in 6-12 months time, the fatigue, visceromegaly (hepatomegaly and splenomegaly), and pancytopenia. In long term follow-up, ERT has some mild effect in bone density in GD1 patients. ERT has also been efficacious in controlling acute bone crisis as well as splenic infarcts.
Biomarkers to control treatment response include frequent measurement of plasma chitotriosidase (CHITO), angiotensin converting enzyme (ACE) and tartrate-resistance phosphatase (TRAP).
Limitations of these drugs include the poor efficacy in controlling the bone disease progression and inability to treat neurological symptoms. A prolonged drug shortage has affected treatment of a significant number of patients in 2009-2010.
Once the stabilization of the disease is achieved, lower doses of imiglucerase (up to 7.5 mg/kg IV administered every 2 weeks) have shown to keep the disease stabilized in patients with Gaucher disease type 1.
ERT agent imiglucerase can also be used in chronic neuronopathic Gaucher disease type 3 to treat visceral and hematological aspects of this condition. The dose may need to be increased from time to time to control visceral disease, e.g. increase in hepatosplenomegaly, exacerbation of pulmonary disease, or unexplained systemic symptoms such as malaise or irritability accompanied by a significant deterioration of biomarkers including CHITO, ACE and TRAP.
One FDA-approved ERT agent is available for treatment of Fabry disease: agalsidase beta (Fabrazyme – Genzyme-Sanofi – produced in CHO cells) is administered I.V. at 1mg/kg dose every 2 weeks.
Another non-FDA approved agent named agalsidase alfa (Replagal – Shire HGT; produced in human cells) is approved by several drug regulatory bodies from more than 50 countries. Both drugs have shown to be efficacious in treating the neuropathic pain, decreasing the progression of renal impairment, improving and/or stabilizing cardiomyopathy and reducing gastrointestinal complications, e.g. nausea, diarrhea and abdominal pain.
Monitoring biomarkers to evaluate treatment response include measurement of urinary and plasma globosyltriasylceramide (GL3). Serum antibodies are recommended to be monitor periodically.
The limitations are the inability to reduce the risk of cerebrovascular events, cost of the medication and current prolonged shortage (patients have been taking ½ standard dose for over 2 years since 2009).
Two FDA-approved ERT agents are available:
-alglucosidase alfa (Myozyme – Genzyme-Sanofi produced in CHO cells) – administered I.V. to infantile Pompe disease (patients < 8 years old) at 20-40 mg/kg/dose every 2 weeks.
-alglucosidase alfa (Lumizyme – Genzyme-Sanofi produced in CHO cells)- administered I.V. to patients with late onset Pompe disease (≥ 8 years old ) at 20 mg/kg/dose every 2 weeks.
In patients who initiated before age 6 months and before need for ventilatory assistance, Myozyme resulted in improvement of survival, ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills.
Lumizyme showed improved walking distance and stabilization of pulmonary function over an 18-month period.
Limitation of this therapy includes anaphylactic reactions to Myozyme, which causes serious acute exacerbation of cardiac or respiratory associated with the underlying condition. Clinical evidence suggests that patients developing sustained elevated anti-alglucosidase alfa antibodies titers may have a poorer clinical response to treatment. Identification of these patients who may benefit from immunomodulation therapy is crucial. The response of skeletal musculature seems not to correlate to the response of respiratory musculature. Patients on ERT treatment can progress to respiratory insufficiency and become ventilatory-dependent.
Mucopolysaccharidosis type 1 (Hurler and Scheie syndromes):
One FDA-approved ERT agent is available for treatment MPS type I: laronidase (Aldurazyme – manufactured by Biomarin Pharm. Inc and commercialized by Genzyme-Sanofi; produced in CHO cells) – administered I.V. 0.58 mg/kg every week.
Decreases of hepatomegaly, improved shoulder mobility, pulmonary function (forced vital capacity) and reduction of glycosaminoglycan excretion are observed.
Monitoring of urinary glycosaminoglycans (GAGs) is recommended to be done periodically to evaluate treatment response. Plasma antibodies should be measured periodically.
Limitations are inability to treat the neurological complications of the severe clinical form, along with the inability to treat bone disease and the elevated cost of the ERT agent.
See the treatment algorithm for MPS1 in Figure 1.
Mucopolysaccahridosis type 2 (Hunter syndrome):
One FDA-approved ERT agent is available for treatment of MPS type II: idursulfase (Elaprase, Shire HGT – produced in human cells) – administered I.V. 0.5 mg/kg every week.
Increased mobility (increased 6-min walking test), improvement of pulmonary function (forced vital capacity), reduction of urine GAG excretion and liver and spleen volumes are observed in patients on therapy.
Monitoring of urinary glycosaminoglycans (GAGs) is recommended to be done periodically to evaluate treatment response. Plasma antibodies should be measured periodically.
Limitations are inability to treat the neurological complications of the severe clinical form, bone disease and the elevated cost of the ERT agent.
Mucopolysaccharidosis type 6 (Maroteaux–Lamy syndrome):
One FDA-approved ERT agent is available for treatment of MPS type VI: galsulfase (Naglazyme – Biomarin Pharm. Inc. – produced in CHO cells) administered at 1mg/kg/dose every week.
Patients under treatment show reduction of hepatosplenomegaly, urinary GAG levels and decreased pain, as well as improvements in cardiopulmonary and joint functions.
Monitoring of urinary glycosaminoglycans (GAGs) is recommended to be done periodically to evaluate treatment response. Plasma antibodies should measured periodically.
Limitations are inability to treat severe bone complications and the elevated cost of the ERT agent.
Substrate Reduction Therapy (SRT):
This therapeutic modality is based on the reductions of the accumulating substrate of a deficient lysosomal enzyme.
Miglustat (Zavesca – Actelion Inc.) is the only SRT agent available and FDA-approved solely for patients who are unable to tolerate ERT for Gaucher disease type 1.
Miglustat taken at 100 mg orally three times daily has shown reduction of liver and spleen volumes, improvement of hematological parameters and fatigue.
Biomarkers to control treatment response include frequent measurement of plasma chitotriosidase (CHITO), angiotensin converting enzyme (ACE) and tartrate-resistance phosphatase (TRAP).
Since miglustat is an inhibitor of the ceramide glucosyltransferase which catalyses the first step of glycosphingolipid biosynthesis, it is therefore a potential treatment for a variety of LSDs, including Gaucher disease, Fabry disease and the gangliosidoses.
In patients with Niemann–Pick type C disease, miglustat demonstrates stabilization of disease progression, and is now licensed in Europe for the treatment of this disease; however, miglustat failed to be efficacious in GM2 gangliosidosis.
Enzyme enhancement therapy:
In most LSDs, the disease only becomes clinically evident once residual enzyme activity falls below 10–15%. For this reason, another therapeutic approach is to try to enhance the activity of mutant enzyme. Increasing residual mutant enzyme activity by only a small percentage may have profound clinical effects.
Enzyme enhancement therapy is based on a small molecule that is capable of rescuing lysosomal mutant proteins so that they can be delivered to the lysosome where they can express their catalytic enzymatic activity. These therapeutic agents are small molecules (<500 Da) that generally physically interact with the lysosomal mutant enzyme and are called pharmacological chaperones.
In many cases, these mutant lysosomal enzymes are unstable proteins; they are recognized by the cell as being unstable and misfolded and then are targeted to the proteasome for degradation.
Clinical trials on are currently on going with specific pharmacological chaperones for alpha-galactosidase (deficient in Fabry disease), beta-hexosamidase A (deficient in GM2 gangliosidosis – Tay-Sachs and Sandhoff) and glucocerebrosidase (deficient in Gaucher disease).
What are the adverse effects associated with each treatment option?
Adverse events related to supportive treatment is specifically related to each management (e.g., anticonvulsivants for seizures, orthopedic or otolaryngologic procedures).
For HSCT, a combination of transplant-related morbidity and mortality, persistence of pretransplant damage, and development of disease-related problems continue to cause clinical problems in patients who have had a successful transplant. HSCT has been establish as a therapeutic option for early-onset clinical forms of MPS1, and specific criteria has been developed to select patients with potential better outcomes (Figure 1).
Adverse events include the following:
HSCT complications or adverse events due to drugs related to this procedure (infections, graft-versus host disease, pulmonary and multi-organ complications).
In MPS 1 patients undergoing HSCT are at high risk and prevalence of pulmonary hemorrhages is observed.
Based on previous clinical studies, the most severe adverse event is death which can occur in 20-25% of LSDs patients who undergo HSCT. Several disease comorbidities will contribute to patient specific risk.
Adverse events related to ERT are mostly related to infusion-related events, which can occur in 5-7% of patients on ERT. The reactions include one or more of the following: chills, fever, feeling hot or cold, dyspnea, nausea, flushing, headache, vomiting, paresthesia, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, back pain, pallor, bradycardia, urticaria, hypotension, face edema, rash, and somnolence.
Adverse events associated with SRT (miglustat) include gastrointestinal problems (diarrhea, stomach pain or bloating and weight loss) and muscle cramps, especially in lower extremities associated with tremors, unsteady gait, and dizziness.
What are the possible outcomes of lysosomal storage diseases?
In LSDs, symptoms are insidious and progressive. Most common symptoms described above progress over time and result in complications in several organs and systems.
The possible outcomes are ultimately related to the impairment of different organs and systems with the consequent related-symptoms observed in each LSDs.
The neurological symptoms can bring severe impairment and debilitation, as the brain disease is progressive in the majority of LSDs.
In general, the earlier the onset of symptoms, the more rapid is the disease progression and ultimately the severity of symptoms. The onset of symptoms can occur during the entire life span, from fetal period to late adulthood which ultimately depend on the residual enzymatic activity of the deficient lysosomal enzyme.
Clinical symptomatology of each LSDs overlaps and some characteristic differences may guide the diagnosis (See Table I).
What causes this disease and how frequent is it?
LSDs are genetic diseases caused by defects in lysosomal proteins or lysosomal related-proteins, which results in dramatic dysfunction of lysosomes.
Classically, lysosomal dysfunction can occur by a mutation in genes encoding one of the lysosomal catalytic enzymes, resulting in accumulation of molecules that are normally degraded and consequently leads to a storage disorder. Other forms of lysosomal dysfunction are caused by defects of lysosomal membrane proteins, errors in enzyme targeting and defective function of lysosomal enzyme activators.
Almost 60 LSDs exist. Individually, lysosomal storage disorders are rare genetic diseases, the prevalence ranging from 1/50,000 (Gaucher disease) to 1/4.2×10^6 live births (sialidosis). However, the combined prevalence has been estimated can range from 1/4,000 to 1/7,000.
How do these pathogens/genes/exposures cause the disease?
LSDs are genetic disorders caused by mutation in specific genes encoding proteins important for physiological lysosomal function.
What complications might you expect from the disease or treatment of the disease?
All potential complications in different organs and systems are described above.
Are additional laboratory studies available; even some that are not widely available?
Screening and diagnostic tests available are described in Table I.
How can lysosomal storage diseases be prevented?
Most LSDs are autosomal recessive diseases in which parents are obligate carriers for this condition. Heterozygous individuals are asymptomatic.
Some LSDs are X-linked. In Fabry disease, females are also affected with the same condition. MPS2 (Hunter syndrome) is also an X-linked LSDs, but heterozygous female are asymptomatic. Danon disease is also a X-linked LSDs caused by the deficiency of lysosomal-associated membrane protein 2 (LAMP-2) – a lysosomal membrane protein involved in the autophagy process (cellular self-digestion mechanism to recycled damage organelles). In this LSDs, male are afffected and females can also be affected with later onset of symptoms (hypertrophic cardiomyopathy and proximal weakness).
What is the evidence?
The following references are evidence of the proposed management and are cited and recommended for reading:
Walkley, S.U. ” Pathogenic cascades in lysosomal disease – Why so complex”. J Inherit Metab Dis. vol. 32. 2009. pp. 181-9. (This is an excellent review on molecular disturbances secondary to the primary lysosomal enzyme deficiency that have clinical relevance and therefore can be used as targets to develop therapeutic approaches.)
Meikle, P.J. ” Prevalence of lysosomal storage disorders”. JAMA. vol. 281. 1999. pp. 249-54. (This is a classical study on the epidemiology of LSDs in a large population [Australia].)
Pinto, R. ” Prevalence of lysosomal storage diseases in Portugal”. Eur J Hum Genet. vol. 12. 2004. pp. 87-92. (Another epidemiology study in an European country confirms the prevalence observed in other countries.)
Mechtler, TP, Stary, S, Metz, TF, De Jesús, VR, Greber-Platzer, S, Pollak, A. “Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria”. Lancet. vol. 379. 2012 Jan 28. pp. 335-41. (This is article reports the incidence of four LSDs (Gaucher, Fabry, Niemann-Pick A and B and Pompe disease) in Austria. The study is based on nationwide newborn screening of almost 35,000 live-births in Austria from a 7-month period.)
Nelson, J. ” Foamy changes of placental cells in probable beta glucuronidase deficiency associated with hydrops fetalis”. J Clin Pathol. vol. 46. 1993. pp. 370-1.
Kooper, A.J. ” Lysosomal storage diseases in non-immune hydrops fetalis pregnancies”. Clin Chim Acta. vol. 371. 2006. pp. 176-82. (Description of several cases of LSDs diagnosed in newborns and stillborns with hydrops fetalis.)
Taylor, D.B. “Arteriopathy and coarctation of the abdominal aorta in children with mucopolysaccharidosis: imaging findings”. AJR Am J Roentgenol. vol. 157. 1991. pp. 819-23. (This is a classical article describing several cases of MPS with different types of large arteriopathies.)
Muenzer, J, Wraith, J.E, Clarke, L.A. “Mucopolysaccharidosis I: management and treatment guidelines”. Pediatrics. vol. 123. 2009. pp. 19-29. (The article describes current guidelines for follow-up and management of patients with MPS type I.)
Malatack, J.J, Consolini, D.M, Bayever, E. “The status of hematopoietic stem cell transplantation in lysosomal storage disease”. Pediatr Neurol. vol. 29. 2003. pp. 391-403.
Boelens, J.J. ” Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders”. Pediatr Clin North Am. vol. 57. 2010. pp. 123-45. (The two above are excellent reviews on the use of hematopoietic stem cell transplantation for treatment of lysosomal storage disease.)
Duffner, P.K. ” The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: report of the workshop held on July 11 and 12, 2008, Holiday Valley, New York”. Genet Med. vol. 11. 2009. pp. 450-4. (This article describes the long-term follow-up of patients who underwent hematopoietic stem cell transplantation as a treatment for the acute and severe presentation fo Krabbe disease caused by the galactocerebrosidase deficiency)
Burrow, T.A. ” Enzyme reconstitution/replacement therapy for lysosomal storage diseases”. Curr Opin Pediatr. vol. 19. 2007. pp. 628-35. (This is a review of enzyme replacement agents for LSDs. It includes also the costs of the FDA-approved agents.)
Mistry, P.K. ” A reappraisal of Gaucher disease-diagnosis and disease management algorithms”. Am J Hematol. vol. 86. 2011. pp. 110-5. (This is a comprehensive review on the diagnosis and management of Gaucher disease. It includes work-flow sheets which are helpful in patient management decisions.)
Weinreb, N. ” A benchmark analysis of the achievement of therapeutic goals for type 1 Gaucher disease patients treated with imiglucerase”. Am J Hematol. vol. 83. 2008. pp. 890-5. (This article reviews the monitoring parameters and treatment outcomes when treating patients with Gaucher disease type I.)
Mehta, A. ” Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data”. Lancet. vol. 374. 2009. pp. 1986-96. (This article reports a comprehensive study of a large Fabry disease cohort (n=181) on enzyme replacement therapy (ERT) followed for 5-years. Objective data is described on the outcome of ERT for this specific LSDs.)
Kishnani, P.S. ” Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease”. Pediatr Res. vol. 66. 2009. pp. 329-35.
Nicolino, M. ” Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease”. Genet Med. vol. 11. 2009. pp. 210-9.
Banugaria, S.G. ” The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease”. Genet Med. vol. 13. 2011. pp. 729-36. (The three articles above describe the long-term follow-up of patients with the infantile form of Pompe disease who started early treatment with enzyme replacement therapy.)
van der Ploeg, A.T. ” A randomized study of alglucosidase alfa in late-onset Pompe's disease”. N Engl J Med. vol. 362. 2010. pp. 1396-406. (This is the article which lead to the approval of alglucosidase alpha (Lumizyme) as an enzyme replacement agent for late onset Pompe disease.)
Muenzer, J. ” Multidisciplinary management of Hunter syndrome”. Pediatrics. vol. 124. 2009. pp. e1228-39.
Muenzer, J. ” The role of enzyme replacement therapy in severe Hunter syndrome-an expert panel consensus”. Eur J Pediatr. 2011. (The first article reports the most current guidelines for treatment and follow-up of patients with MPS type II [Hunter syndrome]. The second article describes an excellent rationale of the treatment and recommendations of monitoring parameters in patients with MPS type II.)
Giugliani, R, Harmatz, P, Wraith, J.E. “Management guidelines for mucopolysaccharidosis VI”. Pediatrics. vol. 120. 2007. pp. 405-18. (This article reports the guidelines for treatment and follow-up of patients with MPS type VI [Maroteaux-Lamy syndrome].)
Patterson, M.C. ” Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study”. Lancet Neurol. vol. 6. 2007. pp. 765-72.
Maegawa, G.H. ” Substrate reduction therapy in juvenile GM2 gangliosidosis”. Mol Genet Metab. vol. 98. 2009. pp. 215-24. (The above two articles describe two clinical trials with a subtrate reduction agent (SRT) to treat a neurological LSDs, Niemann-Pick C and GM2 gangliosidosis.)
Mistry, P.K. ” Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis”. Br J Haematol. vol. 147. 2009. pp. 561-70. (This article describes the effects of enzyme replacement therapy for the bone disease in Gaucher disease type I.)
Vellodi, A. ” Management of neuronopathic Gaucher disease: a European consensus”. J Inherit Metab Dis. vol. 24. 2001. pp. 319-27. (This is a comprehensive article on the recommendations for management and follow-up of patients with Gaucher disease types II and III.)
Politei, J.M. ” Treatment with agalsidase beta during pregnancy in Fabry disease”. J Obstet Gynaecol Res. vol. 36. 2010. pp. 428-9.
Granovsky-Grisaru, S. “The management of pregnancy in Gaucher disease”. Eur J Obstet Gynecol Reprod Biol. vol. 156. 2011. pp. 3-8. (These articles describe patients with Fabry and Gaucher disease type I disease who were on enzyme replacement therapy during pregnancy. Concerns of ERT agent and pregnancy are discussed in these artcles.)
Ongoing controversies regarding etiology, diagnosis, treatment
ERT has not been effective to treat neurological symptoms in the six LSDs for which this therapy is available.
The time of initiation of specific ERT or SRT for LSDs is still controversial for some LSDs. No controlled studies have shown that treating asymptomatic patients with Fabry disease or nonneuronopathic Gaucher disease type 1 will prevent or delay the development of symptoms or alter the early clinical disease course in these conditions.
As a general rule, the initiation of ERT for Fabry disease, nonneuronopathic Gaucher disease (type I) and late onset Pompe disease should not be determined solely by absolute numbers or parameters, but rather by the combination of symptoms and their progression over time in each patients affected with these three LSDs.
As per consensus, early initiation of treatment for MPS1, MPS2 and MPS6 have resulted in substantial clinical benefit for patients with these conditions.
Although, ERT is not efficacious for neurological manifestations of most LSDs, it can be used to treat the visceromegaly, which can bring a significant improvement in the quality of life of patients with early onset and neurological clinical forms of MPS1, MPS2 and neuronopathic Gaucher disease.
Pregnancy is not considered a contraindication for ERT in nonneuronopathic Gaucher disease type I and Fabry disease. No study or reports exists evaluating the ERT during pregnancy in MPS1, MPS2 and MPS6.
For early onset MPS1, specific criteria for HSCT and ERT decisions are well-established (MPS1 treatment algorithm – See Figure 1.)
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has a lysosomal storage disease? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
- If you are able to confirm that the patient has a lysosomal storage disease, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of lysosomal storage diseases?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can lysosomal storage diseases be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment