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Volume 12 Supplement 1



Gaucher Disease: The Metabolic Defect, Pathophysiology, Phenotypes and Natural History

Hagit N. Baris1 MD, Ian J. Cohen1 MB, ChB, Pramod K. Mistry2 MB, BS, PhD, FRCP


Gaucher disease (GD), a prototype lysosomal storage disorder, results from inherited deficiency of lysosomal glucocerebrosidase due to biallelic mutations in GBA. The result is widespread accumulation of macrophages engorged with predominantly lysosomal glucocerebroside. A complex multisystem phenotype arises involving the liver, spleen, bone marrow and occasionally the lungs in type 1 Gaucher disease; in neuronopathic fulminant type 2 and chronic type 3 disease there is in addition progressive neurodegenerative disease. Manifestations of Gaucher disease type 1 (GD1) include hepatosplenomegaly,

cytopenia, a complex pattern of bone involvement with avascular osteonecrosis (AVN), osteoporosis, fractures and lytic lesions. Enzyme replacement therapy became the standard of care in 1991, and this has transformed the natural history of GD1. This article reviews the clinical phenotypes of GD, diagnosis, pathophysiology and its natural history. A subsequent chapter discusses the treatment options.

Ref: Ped. Endocrinol. Rev. 2014;12(Suppl 1):72-81

Key Words: Gaucher disease, Lysosomal storage disorder, GBA, Neuronopathic Gaucher disease, Ashkenazi Jews, Bone disease, Enzyme therapy


Management of Gaucher Disease: Enzyme Replacement Therapy

Ari Zimran MD, Deborah Elstein PhD


Starting in 1994, 3 years after the first approval of the placental-derived enzyme replacement therapy (ERT) with alglucerase, the recombinant form imiglucerase was the introduced and became the standard of care for the visceral symptoms of Gaucher disease. For patients with non-neuronopathic (type 1) Gaucher disease, ERT is safe, with few adverse/side events, and effective in reducing hepatosplenomegaly, improving hematological parameters such as anemia and thrombocytopenia, and to a lesser degree, ameliorating lung- and bone-referred disease. Dosage differences are appreciated mainly as differences in the initial slope in achieving improvements before plateauing. Because ERT does not pass the blood-brain barrier, for patients with the acute neuronopathic form (type 2), there is no substantial change in the life-threatening neurological parameters and hence ERT is not seen as efficacious; but for patients with sub-acute neuronopathic forms (type 3), ERT for the often devastating visceral symptoms, improved quality of life, and longevity make ERT part of the standard care.

Due to a world-wide reduction in imiglucerase availability mid-2009 that was not resolved quickly, patients were ERT-stopped or dose-reduced, re-invigorated the movement to provide additional therapeutic options. Early access programs of two new ERTs, then at the pre-license stage, were initiated at regulatory authorities' request for patients requiring ERT. At that point, velaglucerase alfa which has the native-enzyme sequence produced in a (proprietary) human cell line, and taliglucerase alfa, which is plant-cell-derived and produced in an inexpensive platform, were completing Phase 3 clinical trials. Velaglucerase alfa was FDA-approved in February 2010 while taliglucerase alfa was approved in May 2012. Marketing of these ERTs has also targeted the extraordinarily high cost of imiglucerase. However, with > 20 years' experience with infusible ERTs, many patients are eager to consider oral options including substrate reduction and/or pharmacological chaperone treatments taken as pills or possibly oral formulations of an ERT.

Ref: Ped. Endocrinol. Rev. 2014:12(Suppl 1):82-87

Key Words: Enzyme Replacement Therapy (ERT), Gaucher disease, Glucocerebrosidase, Imiglucerase, Taliglucerase alfa, Velaglucerase alfa



Fabry Disease

Alison S. Thomas MRCP, FRCPath, MD(Res)

Derralynn. A. Hughes MA, DPhil, FRCP, FRCPath


Fabry disease (FD) is an X-linked disorder caused by deficiency of the enzyme alpha-galactosidase A, required for the degradation of globotriaosylceramide. Accumulation of substrate occurs in multiple cell types resulting in a multi-system disorder, affecting both males and females. Clinical features include neuropathic pain and angiokeratoma, with subsequent development of proteinuria, renal failure, left ventricular hypertrophy, arrhythmias and stroke. Beyond palliative therapies for organ involvement and pain control, enzyme replacement therapy directed at the underlying metabolic defect became available in 2001-2003. Knowledge of the pathophysiology and clinical features of FD is vital for assessing the rationale and evidence of efficacy of therapies for FD and their limitations. Whilst ERT improves many of the symptoms of FD, its effect on the natural history of the disorder has yet to be fully demonstrated. Improved understanding of the appropriate use of adjunctive therapies and the development of new treatment strategies, including pharmacologic chaperone therapy and gene therapy, coupled with long term clinical outcome data on the effects of ERT are all key components of optimising treatment for FD.

Ref: Ped. Endocrinol. Rev. 2014;12(Suppl 1):88-101

Key Words: Fabry, Enzyme, Therapy, α-galactosidase A, Chaperone


Mucopolysaccharidosis Type I

J.E. Wraith1 MB ChB FRCPCH, Simon Jones2, MBChB BSc MRCPCH


Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal hydrolase α-L-Iduronidase leading to accumulation of the GAGs, dermatan sulfate, and heparan sulphate, The disease spectrum includes a disorder with severe involvement and CNS disease Hurler disease (HPS I H) a chronic disease without CNS disease Scheie disease (HPS I S) and the intermediate Hurler/Scheie disease(HPS I H/S).The urine GAGs pattern. confirmed by Iduronidase enzyme assay is diagnostic. Over 200 mutations exist. Genotype/phenotype correlation is poor but two nonsense mutations results in Hurler disease.The skeletal disease dysostosis multiplex (DM) is seen in severe variants of MPS I. The hypoplastic odontoid putting these patients at high risk of cervical cord damage.

MPS IH (Hurler Disease) affected infants develop a spinal ‘gibbus’ deformity, persistent nasal discharge, middle ear effusions and frequent upper respiratory infection. They have “coarse”, facial features, and an enlarged tongue. . Progressive upper airway disease leads to obstructive sleep apnoea. Corneal clouding and cognitive impairment appears, growth ceases. Joint stiffness and contractures limit mobility. Cardiac disease is universal. Death occurs before 10 years. SCHEIE patients are diagnosed as teenagers with hepatomegaly, joint contractures, cardiac valve abnormalities and corneal clouding . Prolonged survival with considerable disability without cognitive impairment is usual.

MPS IH/S Hurler/Scheie. is diagnosed by 6.5 years, with variable skeletal and visceral manifestations without cognitive involvement. Joint stiffness, corneal clouding, , umbilical hernia, abnormal facies , hepatomegaly, joint contractures, and cervical myelopathy occur. Patients die in their 20s .Haematopoietic stem cell transplantation (HSCT) the standard treatment of MPS IH for 30 years is unpredictable .When performed before 2 years it can stabilize cognitive impairment. Hepatosplenomegaly, urine GAGs excretion, upper airways obstruction and cardiomyopathy improve . The coarse hair and facial features soften and corneas partly clear,but dysostosis multiplex and cervical instability are not improved.

Enzyme replacement therapy (ERT) in patients with MPS IH is associated with improved GAG excretion, left ventricular hypertrophy,sleep studies and liver size. The standard treatment of MPS IH/S and MPS IS is ERT, α-L-Iduronidase, laronidase, a life-long therapy. GAG excretion is reduced, respiratory function and physical endurance improve. Joint mobility improves but not dural thickening, cardiac valve lesions or eye changes. MPS I mice have been successfully treated with IDUA-expressing mesenchymal stem cells . Gene therapy may be developed for MPS I, via an ex vivo approach demonstrated to improve even skeletal outcomes in animal models.

Ref: Ped. Endocrinol. Rev. 2014;12(Suppl 1):102-106

Key Words: Glycosaminoglycans (GAGs), Heparan sulfate (HS), Dermatan sulfate (DS), Hurler, Scheie, Haematopoietic Stem Cell Transplant (HSCT), Enzyme Replacement Therapy (ERT)


Mucopolysaccharidosis Type II, Hunter’s Syndrome

Anna Tylki-Szymańska MD, PhD


H unter syndrome is caused by deficiency of the lysososmal enzyme iduronate-2-sulphatase that cleaves O-linked sulphate moieties from dermatan sulphate and heparan sulphate and leads to accumulation of GAGs. The disease is a X-linked condition affecting males and rarely females, clinically divided into severe (2/3) and attenuated types. Children with severe form, diagnosed at 12-36 months, have coarse facial feature, short stature, joint stiffness, short neck, broad chest, large head circumference, watery diarrhea, skeletal changes, progressive and profound mental retardation, retinal degeneration’ hearing loss, cardiomyopathy, valvular involvement, with progressive thickening and stiffening of the valve leaflets leading to mitral and aortic regurgitation and stenosis . Recurrent and prolonged rhinitis with persistent nasal discharge are the first symptoms of airway disease that manifests itself as noisy breathing and later sleep apnea. Some patients develop ivory-colored skin lesions on the upper back and sides of the upper arms, pathogenomic of Hunter syndrome. The scalp hair becomes coarse, straight and bristly. Inguinal and umbilical hernias occur caused by the disturbed structure of connective tissue and increased liver and spleen volume. Patients with attenuated form have normal intelligence and a milder phenotype. Physical features diagnosed later are similar but less pronounced but progress to severe disease. Sceening is by quantitative assessment of urinary GAGs excretion. Qualitative assessment of GAG by electrophoresis can distinguish the type of mucopolysaccharidosis. Definitive diagnosis is based on enzyme activity assay in leukocytes, fibroblasts or plasma. Molecular testing is recommended mainly for genetic counseling and carrier detection. Limited experience of Haematopoietic stem cell therapy in MPS II showed progressive neurodegeneration. Recombinant I2S Idursulfase, is indicated for long-term treatment. The response appears to depend on the severity of the disease and the age treatment is started, Improvements in a composite endpoint comprising: change in walking distance percentage of predicted forced vital capacity (%FVC) ,decrease in liver and spleen volume and urinary GAG levels were encouraging. Current research is focused on pharmacological chaperones, gene therapy and substrate reduction therapy and therapies that, unlike Idursulfase, do cross the blood–brain barrier.

Ref: Ped. Endocrinol. Rev. 2014;12(Suppl 1):107-113

Key Words: Hunter syndrome, Mucopolysaccharidosis type II, Clinical features treatment



New Therapeutic Approaches for Pompe Disease: Enzyme Replacement Therapy and Beyond

Priya S. Kishnani, MD, Alexandra A. Beckemeyer, BA


P ompe disease is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Prior to 2006, therapy was palliative. Severely affected infants with Pompe succumbed to cardiomyopathy or respiratory failure by one year of age. Enzyme replacement therapy (ERT) with alglucosidase alfa (Genzyme, Cambridge, MA, USA) is currently the only approved treatment for Pompe disease which has improved overall survival, ventilator-free survival, cardiomyopathy, and motor development in infants. In patients with late onset Pompe disease, ERT has resulted in disease course stabilization with motor and pulmonary improvements. Factors impacting outcome include age at start of ERT, muscle fiber type, underlying genotype and a multidisciplinary approach to care. This article highlights the lessons learned from infants and adults treated with ERT, limitations of ERT, and the development of adjunctive and alternative therapies, including immune modulation, upregulation of receptor expression, diet and exercise, second-generation recombinant ERT, chaperone therapy, substrate reduction therapy and gene therapy.

Ref: Ped. Endocrinol. Rev. 2014;12(Suppl 1):114-124

Key words: Pompe disease, Alglucosidase alfa, ERT, Chaperones, Small molecule therapy, Substrate reduction, Gene therapy


Lysosomal Acid Lipase Deficiency: Diagnosis and Treatment of Wolman and Cholesteryl Ester Storage Diseases

Anthony F. Porto MD, MPH


Lysosomal acid lipase (LAL) is responsible for the hydrolysis of cholesterol esters and triglycerides. LAL is coded by the LIPA gene on chromosome 10q23.31. Its deficiency leads to two autosomal recessive disorders, Wolman disease (WD) and Cholesteryl Ester Storage Disease (CESD). WD has an estimated incidence of 1 in 500,000 live births and is the result of a complete loss of LAL and presents in infancy with vomiting, diarrhea, poor weight gain and hepatomegaly subsequently leading to death. CESD is the result of partial loss of LAL and its presentation is more variable. Patients may be asymptomatic or present with non-specific gastrointestinal symptoms, hepatomegaly, elevated transaminases and dyslipidemia which may be confused with the diagnosis of Non-alcoholic Fatty Liver Disease. CESD is currently underdiagnosed and has an estimated prevalence as high as 1 in 40,000 individuals. Radiologic findings in WD is calcification of the adrenal glands. Hepatomegaly is noted on CT scan in both WD and CESD. MRI may demonstrate accumulation of cholesterol esters and may be useful to study effects of potential medical therapies. The diagnosis of WD and CESD is based on LIPA gene sequencing and the measurement of LAL levels in peripheral blood leukocytes. Treatment of LAL deficiency is currently limited to control of cholesterol levels and to prevent premature atherosclerosis. Use of enzyme replacement therapy with recombinant human LAL in short-term studies has shown to be safe and effective.

Ref: Ped. Endocrinol. Rev. 2014;12(Suppl 1):125-132

Key Words: LIPA gene, Lysosomal Acid Lipase (LAL) deficiency, CESD, Wolman, Fatty liver, Non-Alcoholic Fatty Liver Disease, (NAFLD)


Mucopolysaccharidosis III (Sanfilippo Syndrome) – Disease Presentation and Experimental Therapies

Janine A. Gilkes, MS, Coy D. Heldermon, MD, PhD


Sanfilippo Syndrome or Mucopolysaccharidosis III (MPS III) is a group of lysosomal storage diseases resulting from a deficiency of one of four lysosomal enzymes: Type A - heparan N-sulfatase (SGSH), Type B - α-N-acetylglucosaminidase (NAGLU), Type C - acetyl CoA α-glucosaminide acetyltransferase (HGSNAT) and Type D - N-acetylglucosamine-6-sulfatase (GNS). Each of these enzymes is necessary for degradation of heparan sulfate. Deficiency of any of these enzymes manifests as a neurodegenerative disorder with accompanying somatic manifestations. Typically this presents early in life with developmental delays followed by developmental regression and usually results in death sometime during the second decade of life, though several less severe cases have been described living into late adulthood (30’s to 60’s). Often there is a delay of several years from time of symptom onset to diagnosis. Currently treatment is limited to supportive care. We will briefly discuss the typical natural history and presumed pathophysiology of the disease. We will also discuss current experimental therapies being pursued for treatment of this devastating disease. These include enzyme replacement, gene therapy, stem cell therapy, and substrate reduction approaches.

Ref: Ped. Endocrinol. Rev. 2014;12(Suppl 1):133-140

Key Words: Mucopolysaccharidosis, MPS III, Sanfilippo Syndrome, Gene therapy, Stem cell


Morquio A Syndrome: Diagnosis and Current and Future Therapies

Shunji Tomatsu1 MD PhD, Eriko Yasuda1 MS, Pravin Patel1, Kristen Ruhnke1, Tsutomu Shimada1 PhD, William G. Mackenzie1 MD, Robert Mason1 PhD, Mihir M. Thacker1 MD, Mary Theroux1 MD, Adriana M. Montaño2 PhD, Carlos J. Alméciga-Díaz3 PhD, Luis A. Barrera3 PhD, Yasutsugu Chinen4 MD, William S. Sly5 MD, Daniel Rowan2, Yasuyuki Suzuki6 MD PhD and Tadao Orii7 MD


Morquio A syndrome is an autosomal recessive disorder, one of 50 lysosomal storage diseases (LSDs), and is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Deficiency of this enzyme causes specific glycosaminoglycan (GAG) accumulation: keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The majority of KS is produced in the cartilage, therefore, the undegraded substrates accumulate mainly in cartilage and in its extracelluar matrix (ECM), causing direct leads to direct impact on cartilage and bone development and leading to the resultant systemic skeletal spondyloepiphyseal dysplasia. Chondrogenesis ,the earliest phase of skeletal formation that leads to cartilage and bone formation is controlled by cellular interactions with the ECM, growth and differentiation factors and other molecules that affect signaling pathways and transcription factors in a temporal-spatial manner. In Morquio A patients, in early childhood or even at birth, the cartilage is disrupted presumably as a result of abnormal chondrogenesis and/or endochondral ossification. The unique clinical features are characterized by a marked short stature, odontoid hypoplasia, protrusion of the chest, kyphoscoliosis, platyspondyly, coxa valga, abnormal gait, and laxity of joints.

In spite of many descriptions of the unique clinical manifestations, diagnosis delay still occurs. The pathogenesis of systemic skeletal dysplasia in Morquio A syndrome remains an enigmatic challenge. In this review article, screening, diagnosis, pathogenesis and current and future therapies of Morquio A are discussed.

Ref: Ped. Endocrinol. Rev. 2014;12(Suppl 1):141-151

Key Words: Mucopolysaccharidosis IVA, Enzyme assay, Keratan sulfate, Tandem mass spectrometry, GALNS, Enzyme replacement therapy, Bone marrow transplantation, Pathogenesis, Morquio tissue repository bank


Therapy for Mucopolysaccharidosis VI: (Maroteaux-Lamy Syndrome) Present Status and Prospects

Roberto Giugliani1,2,3, MD, PhD, Silvani Herber4, RN, PhD, Louise Lapagesse de Camargo Pinto5, MD, PhD and Guilherme Baldo2,3, PhD


Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disorder caused by deficient activity of Arylsulphatase B (ARSB). The disease is progressive and multisystemic, usually leading to death in the first decades of life. In addition to supportive management, specific treatments for MPS VI are the hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). Both are effective for some aspects of the disease, but fail in correcting important clinical features, such as bone deformities and heart valve thickening. Based on that, new treatments are currently being tested to be used alone or in combination with the current therapies. Here we summarize some of these new approaches and the preliminary results obtained, reporting their limitations and indicating possible future trends in MPS VI treatment. We discuss intrathecal ERT, gene therapy and therapies based on anti-inflammatory molecules, among other approaches. Finally, we highlight the importance of early treatment and diagnosis for a better outcome in these patients.

Ref: Ped. Endocrinol. Rev. 2014:12(Suppl 1):152-158

Key Words: Mucopolysaccharidosis VI, Maroteaux-Lamy syndrome, Glycosaminoglycans, Lysosomal storage diseases, Enzyme replacement therapy, Therapy of genetic disorders


Mucopolysaccharidosis Type VII: A Powerful Experimental System and Therapeutic Challenge

Mark S. Sands, PhD


Mucopolysaccharidosis type VII (MPSVII) is an inborn error of metabolism caused by a deficiency in the lysosomal enzyme β-glucuronidase (GUSB). As such, MPSVII is one of a larger class of inherited diseases referred to as lysosomal storage diseases (LSD).(1) The absence of GUSB activity leads to the progressive accumulation of undegraded glycosaminoglycans (GAGs) in many tissues of the body. Mucopolysaccharidosis VII has a complex clinical phenotype, including skeletal dysplasia, hepatosplenomegally, sensory deficits, cognitive impairment, and premature death. Although the natural history of the human disease is not precisely defined, small and large animal models of MPSVII have played a major role in our understanding of the disease process and towards effective treatments. The mouse model of MPSVII is a particularly powerful system due to its similarity to the human disease and the ability to generate large numbers of genetically defined animals. It has been shown in the murine model of MPSVII that recombinant enzyme replacement therapy (ERT) can ameliorate most of the clinical signs of disease if initiated during the neonatal period. Progenitor cell transplantation (hematopoietic, neuronal, mesenchymal) can correct many of the pathological signs of disease in MPSVII mice. Viral-mediated gene therapy has also been shown to decrease the severity of the disease in both the murine and canine models of MPSVII. Although pre-clinical experiments have shown that a number of approaches can effectively treat MPSVII, translation of those therapies into the clinic has lagged behind other LSDs. This is due in large part to the ultra-rare nature of MPSVII. Encouragingly, a clinical trial of ERT for MPSVII has recently been initiated. It will be interesting to determine if the positive pre-clinical data gathered in animal models of MPSVII translate to affected children. This clinical trial may also establish a paradigm for the treatment of other ultra-rare disorders.

Ref: Ped. Endocrinol. Rev. 2014:12(Suppl 1):159-165

Key Words: Mucopolysaccharidosis VII, Lysosomal storage disease, Inherited metabolic disease, Enzyme replacement therapy, Gene therapy, Stem cell therapy, Animal models.


The Unique Case of The Niemann-Pick Type C Cholesterol Storage Disorder

Andrés D. Klein1 BSc, PhD, Alejandra Alvarez2 BSc, PhD, Silvana Zanlungo3,4 BSc, PhD


N iemann-Pick type C disease (NPC) is a neuro-visceral lysosomal cholesterol storage disorder that arises from loss-of-function mutations in either the NPC1 or NPC2 genes. Both genes code for proteins involved in lysosomal cholesterol efflux.

NPC is often diagnosed in early childhood, with patients typically displaying cerebellar ataxia, difficulties in speaking and swallowing, and progressive dementia. Unfortunately, to date, there is no curative treatment for this devastating and fatal disorder, although several symptomatic manifestations of NPC are treatable.

In this review, we discuss the cell biology of the disease, clinical aspects, diagnostic approaches, and current and potential therapeutic strategies against NPC.

Ref: Ped. Endocrinol. Rev. 2014;12(Suppl 1):166-175

Key Words: Lysosomal storage disorders, Niemann-Pick type C, Cholesterol, Therapeutic approaches, Diagnostic


Cystinosis: Clinical Presentation, Pathogenesis and Treatment

Ekaterina Ivanova1 MS, Maria Giovanna De Leo2 MS,

Maria Antonietta De Matteis2 MD, PhD, Elena Levtchenko1,3 MD, PhD


N ephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in the CTNS gene encoding the lysosomal cystine transporter cystinosin. Cystinosin deficiency leads to accumulation of cystine in the lysosomes of cells throughout the body and deregulation of endocytosis, trafficking of intracellular vesicles and related cell signalling processes. One of the early features of the disease is renal Fanconi syndrome characterized by polyuria, proteinuria and urinary loss of various solutes. Later in life, extra-renal complications become apparent, and decline of kidney function leads to the development of end-stage renal disease. Modern therapy of the disease is based on treatment with cystine-lowering drug cysteamine, which helps to postpone the disease progression and development of extra-renal pathologies, but offers no cure for the Fanconi syndrome. Besides the improvement of cystine-lowering therapy based on new formulations of cysteamine, further development of therapy is necessary. Some steps forward were done in the recent years, including studies of cell signalling abnormalities in cystinosis and development of stem cell and gene therapy approaches.

Ref: Ped. Endocrinol. Rev. 2014:12(Suppl 1):176-184

Key Words: Cystinosis, Lysosomal storage disorder, Cysteamine therapy, Renal pathology, Fanconi syndrome



Alpha-mannosidosis – a Review of Genetic, Clinical Findings and Options of Treatment

Line Borgwardt MD, Allan Meldgaard Lund MD, DMSc, Christine I Dali, MD


Alpha-mannosidosis (OMIM 248500) is a rare, autosomal recessive, multisystemic, progressive lysosomal storage disorder caused by a deficiency of alpha-mannosidase.

It has been described in humans, cattle, domestic cats, mice and guinea pigs. In humans, alpha-mannosidosis results in progressive facial- and skeletal abnormalities, motor impairment, hearing impairment, intellectual disability, recurrent infections and immune deficiency.

This review provides detailed information regarding the variability of manifestations and a description of current treatment and treatment under investigation for alpha-mannosidosis. The pathology, genetics and clinical pictures, including impairments in the activity of daily living are discussed.

Ref: Ped. Endocrinol. Rev. 2014:12(Suppl 1):185-191

Key Words: Alpha-mannosidosis, MAN2B1, Clinical findings, Enzyme replacement therapy, Haematopoietic Stem Cell Transplantation HSCT., Symptomatic treatment, Activity of daily living




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