Christian J Hendriksz

• MB ChB,M Sc, FRCPCH
• Professor at Steve Biko Academic Hospital

The cornerstone treatment of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) is a lifelong low-protein diet with phenylalanine (Phe) free L-amino acid supplements. However, the PKU diet has significant shortcomings, and there is a clinically unmet need for new therapeutics to improve patient outcomes. CDX-6114 is a modified phenylalanine ammo...

Fucosidosis (OMIN# 230000) is a rare lysosomal storage disorder (LSDs) caused by mutations in the FUCA1 gene, leading to alpha-L-fucosidase deficiency; it is inherited as an autosomal recessive trait. Fucosidosis represents a disease spectrum with a wide variety of clinical features, but most affected patients have slow neurologic deterioration. M...

Background Patients are the most important stakeholders in the care of any disease and have an educational need to learn about their condition and the treatment they should receive. Considering this need for patient-focused materials, we present a directed approach for mucopolysaccharidosis (MPS) VI and MPS IVA, a pair of rare, inherited diseases t...

Mucopolysaccharidosis VII (or Sly syndrome) is an autosomal recessive disorder characterised by a deficiency in the enzyme Beta-glucuronidase (GUSB). Partial degradation of glycosaminoglycans (GAGs); chondroitin sulfate (CS), dermatan sulfate (DS) and heparan sulfate (HS) results in the accumulation of these fragments in the lysosomes of many tissu...

Low– and middle–income countries (LMIC) represents an enormous challenge to the worldwide rare disease community at a time when it is faced with huge new challenges, including the COVID 19 pandemic. This chapter outlines what is known about the challenge: its breadth, its elements, and strategies for tackling it. It also addresses, lack of awarenes...

The mucopolysaccharidoses (MPSs) are a group of lysosomal diseases, each characterized by a specific enzyme deficiency related to a specific gene defect that affects one of the steps of the stepwise degradation pathway of glycosaminoglycans, leading to progressive storage of these compounds in tissues and organs. These diseases are genetically very...

Mucopolysaccharidosis (MPS) disorders are a group of rare, progressive lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) and classified according to the deficient enzyme. Enzyme replacement therapy of MPS VI has limited effects on ophthalmic, cardiovascular, and skeletal systems. Odiparcil is an orally-availa...

Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secre...

Background Patients are the most important stakeholders in the care of any disease and have an educational need to learn about their condition and the treatment they should receive. Considering this need for patient-focused materials, we present a directed approach for mucopolysaccharidosis (MPS) VI and MPS IVA, a pair of rare, inherited diseases t...

Late-onset Pompe disease (LOPD) is a rare disease, defined as a progressive accumulation of lysosomal glycogen resulting in muscle weakness and respiratory problems. Anecdotally, individuals often have difficulties walking, yet, there is no three-dimensional data supporting these claims. We aimed to assess walking patterns in individuals with LOPD...

The North-West University's Centre for Human Metabolomics (CHM) is in the process of establishing the first rare disease (RD) biobank in South Africa and Africa. The CHM Biobank's main focus is on the collection of samples and information for rare congenital disorders. Approximately 72% of all RDs have a genetic origin, of which 70% have an exclusi...

Background: Mucopolysaccharidoses (MPS) are rare, inherited disorders associated with enzyme deficiencies that result in glycosaminoglycan (GAG) accumulation in multiple organ systems. Management of MPS is evolving as patients increasingly survive to adulthood and undergo multiple surgeries throughout their lives. As surgeries in these patients ar...

An outcome measure of toileting skills, the Toileting Abilities Survey or TAS, with sensitivity to detect change in a neurodegenerative disorder such as MPS II, was developed. The TAS was used in a research study of patients (n = 86) with the neuronopathic form of MPS II to measure treatment benefit of intrathecal idursulfase. Treatment with idursu...

A R T I C L E I N F O Keywords: Mannose phosphate isomerase-congenital disorder of glycosylation MPI-CDG Phosphomannose isomerase Adult Clinical outcomes A B S T R A C T The mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) is caused by phospho-mannose isomerase deficiency. Clinical features include hyperinsulinaemic hypogl...

Mitochondrial dysfunction is emerging as an important contributory factor to the pathophysiology of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs appears to be multifactorial, although impaired mitophagy and oxidative stress appear to be common inhibitory mechanisms shared amongst these heterogeneous disorders....

Marshall et al1 correctly identify some of the challenges and changes that the SARS-CoV-2 pandemic has brought to General Practice (GP), however the perpetual shift of work away from hospital care into primary care will likely intensify. Inherited metabolic diseases (IMDs) are a group of rare genetic disorders resulting principally from enzyme def...

Patients with Mucopolysaccharidosis (MPS) have an increased risk of cardiovascular complications, conduction tissue abnormalities and arrhythmia; all rare but underestimated. It has been reported that conduction system defects are progressive in this group of patients and may result in sudden cardiac death. The aim of this study is to review our cu...

Background: Mucopolysaccharidoses (MPS) are rare, inherited disorders associated with enzyme deficiencies that result in glycosaminoglycan (GAG) accumulation in multiple organ systems. Management of MPS is evolving as patients increasingly survive to adulthood and undergo multiple surgeries throughout their lives. As surgeries in these patients are...

Background: Mucopolysaccharidoses (MPS) are rare, inherited disorders associated with enzyme deficiencies that result in glycosaminoglycan (GAG) accumulation in multiple organ systems. Management of MPS is evolving as patients increasingly survive to adulthood and undergo multiple surgeries throughout their lives. As surgeries in these patients are...

Introduction: Mucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance...

Introduction: Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present nume...

Mucopolysaccharidoses (MPS) are rare disorders associated with enzyme deficiencies, resulting in glycosami-noglycan (GAG) accumulation in multiple organ systems. As patients increasingly survive to adulthood, the need for a smooth transition into adult care is essential. Using case studies, we outline strategies and highlight the challenges of tran...

Background: There is a growing awareness of the risk of learning disability (LD), progressive cognitive disorders and psychosis as a result of Inherited Metabolic Disorders (IMDs) in adult patients. Anxiety and depression are common features that may manifest before and after a diagnosis is made. Yet the rarity of IMDs makes it challenging to under...

Introduction: Alpha-mannosidosis is an ultra-rare lysosomal storage disorder resulting from the deficient activity of lysosomal alpha-mannosidase. Alpha-mannosidosis presents as a highly heterogenous condition with large variations in symptom severity and disease progression rates. Quantitative and qualitative data for alpha-mannosidosis patients...

Urea cycle disorders (UCD) are a group of rare inherited metabolic conditions of amino acid catabolism caused by an enzyme deficiency within the hepatic ammonia detoxification pathway. The presentation of these disorders ranges from life‐threatening intoxication in the neonate to asymptomatic status in adults. Late‐onset UCDs can present for the fi...

Aim To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E‐HOD) international web‐based registry. Results This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofo...

Management of mucopolysaccharidosis (MPS) is complicated, therefore robust independent guidance is required. This program used a modified-Delphi methodology to develop evidence-based, expert-agreed recommendations for the management of patients with MPS IVA/VI. The program was led by an international, multidisciplinary Steering Committee (SC) of 29...

The multiple clinical manifestations and progressive nature of CLN2 disease, a major form of the neuronal ceroid lipofuscinoses or Batten disease, make the management of patients challenging. Although guidelines are available, the methodology used to formulate clinical recommendations has come under increased scrutiny, highlighting a need for robus...

Mucopolysaccharidoses (MPS) are rare disorders associated with enzyme deficiencies, resulting in glycosaminoglycan (GAG) accumulation in multiple organ systems. Because of improvements to the diagnosis and treatment of MPS, patients are increasingly surviving to adulthood, and a smooth transition into adult care is essential. We present transition...

Mucopolysaccharidosis (MPS) IVa is a lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfatase leading to progressive accumulation of glycosaminoglycans (GAGs) in musculoskeletal system, patients manifest with an impaired gait pattern, reduced levels of physical endurance, muscular weakness, arrhythmias and upper a...

Background Rare and ultra-rare diseases (URDs) are often chronic and life-threatening conditions that have a profound impact on sufferers and their families, but many are notoriously difficult to detect. Niemann-Pick disease type C (NP-C) serves to illustrate the challenges, benefits and pitfalls associated with screening for ultra-rare inborn erro...

Aim To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. Results This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofo...

We characterized cognitive function in two metabolic diseases. MPS–IVa (mucopolysaccharidosis IVa, Morquio) and tyrosinemia type III individuals were assessed using tasks of attention, language and oculomotor function. MPS–IVa individuals were slower in visual search, but the display size effects were normal, and slowing was not due to long reactio...

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of ERT in people with LOPD.

Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease...

Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestatio...

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness, safety and appropriate dose regimen of ERT in people with MPS IV A. To determine whether evidence from NRSIs (which potentially offers longer follow-ups) can contribute to the ERT efficacy evidence-base, and to determine the potentia...

Totally implantable vascular access devices (TIVADs) are commonly used in conjunction with enzyme replacement therapy (ERT) for lysosomal storage disorders (LSDs). This case series describes potential complications associated with long-term TIVAD use, such as compromise of skin integrity, infection, or port failures. Best practices and skilled spec...

Objective To estimate clinical progression and resource utilisation together with the associated costs of managing children and adults with LAL Deficiency, at a tertiary referral centre in the UK. Methods A retrospective chart review was undertaken of patients in the UK with a confirmed diagnosis of LAL Deficiency who were managed at a LAL Deficie...

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.gov NCT0...

Background Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III) is an inherited monogenic lysosomal storage disorder divided into subtypes A, B, C and D. Each subtype is characterized by deficiency of a different enzyme participating in metabolism of heparan sulphate. The resultant accumulation of this substrate in bodily tissues causes va...

Tay-Sachs disease is a rare metabolic disease caused by a deficiency of hexosaminidase A that leads to accumulation of GM2 gangliosides predominantly in neural tissue. Late-onset Tay-Sachs disease variant is associated with a higher level of residual HexA activity. Treatment options are limited, and there are a few described cases who have undergon...

Background: Long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) were assessed in 173 patients with Morquio A syndrome (mucopolysaccharidosis IVA) in a 96-week, open-label, multi-center, phase 3 extension study (MOR-005) of the pivotal 24-week, placebo-controlled study (MOR-004). Changes in efficacy endpoints were eval...

Niemann-Pick type C (NP-C) is a rare recessive disorder associated with progressive supranuclear gaze palsy. Degeneration occurs initially for vertical saccades and later for horizontal saccades. There are studies of oculomotor degeneration in adult NP-C patients [1, 2] but no comparable studies in children. We used high-resolution video-based eye...

Port-a-cath is a widely used device in patients with long-term venous access demand such as frequent or continuous administration of medications such as Enzyme Replacement Therapy (ERT), chemotherapy delivery, blood transfusions, blood products, and fluids. Patients with Lysosomal Storage Diseases (LSDs) often require recurrent courses of ERT. We r...

Objectives This 109-week, nonrandomized, observational study of mucopolysaccharidosis II (MPS II) patients already enrolled in the Hunter Outcome Survey (HOS) (NCT00882921), assessed the long-term immunogenicity of idursulfase, and examined the effect of idursulfase-specific antibody generation on treatment safety (via infusion-related adverse even...

Introduction: Phenyloketonuria is a rare metabolic disorder caused by a deficiency of the phenylalanine (Phe) hydroxylase enzyme. A reduced intake of natural proteins helps optimise plasma Phe concentration. A relationship between high plasma Phe level and the inhibition of cholesterol synthesis was previously observed but the mechanisms are unclea...

Background Fabry disease, an X-linked genetic condition, results from alpha-galactosidase deficiency and increased accumulation of glycosphingolipids in cardiovascular tissues. Clinical manifestation includes vasculature associated complications. Hyperlipidaemia is one of the cardiovascular risk factors however it has never been well defined in Fab...

Glycogen Storage Disease type IX is a heterogeneous condition caused by mutations in the phosphorylase b kinase subunits, which has a major regulatory role in the breakdown of glycogen. Two patterns of inheritance for deficiency are observed, X-linked and autosomal recessive. Described mutations were associated with variable severity of symptoms. C...

Background: Mucopolysaccharidoses (MPS) are a group of rare inherited disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) within the myocytes and coronary arteries. Little is known about hyperlipidaemia as a potential cardiovascular risk factor in these patients. Baseline cholesterol data in adults are scarce. Therefore, t...

Background: Inborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches. Methods: We designed and validated a next-generation sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based subpanels and tested 1...

Niemann–Pick type C (NP-C) disease is a rare neurodegenerative lysosomal storage disorder. It is highly heterogeneous, and there is limited awareness of a substantial subgroup that has an attenuated adolescent/adult-onset disease. In these patients psychiatric features, often a psychosis, may dominate the initial impression, although often there is...

Objective: To determine whether Hunter syndrome (MPS II) affects the crystallographic texture (preferred orientation) of enamel. Design: Synchrotron X-ray diffraction, being a state of the art technique, has been used to determine the enamel crystallite orientation in enamel affected by Hunter syndrome (MPS II). The incisal, lingual and cervical...

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnor...

https://doi.org/10.1016/j.ymgme.2016.11.372

Background: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral or psychiatric manifestations. The incidence of NP-C is underestimated due to under-recognition or misdiagnosis across a wide range of...

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The mucopolysaccharidoses (MPS) comprise a heterogeneous family of rare, genetic lysosomal storage disorders that result in severe morbidity and reduced life expectancy. Emerging treatments for several of these disorders have triggered the search for clinically relevant biomarkers and clinical markers associated with treatment efficacy in populatio...

Background: Niemann-Pick disease Type C (NP-C) is a genetic lipid storage disorder characterised by progressive neurovisceral symptomatology. Typically, disease progression is more pronounced in patients with early onset of neurological symptoms. Heterogeneous clinical presentation may hinder disease recognition and lead to delays in diagnosis. He...

Introduction: Morquio A syndrome is a rare, autosomal recessive, lysosomal storage disorder caused by a deficiency in the enzyme N-acetylgalactosamine-6-sulfatase (GALNS). In 2014, the use of recombinant human GALNS, elosulfase alfa, was approved in Europe, Canada, the United States, Australia, and Brazil for the treatment of Morquio A syndrome. El...