Recurrent infections of the airways and ears, inguinal and/or umbilical hernia in combination with joint stiffness and contractures as well as other skeletal abnormalities may lead to the diagnosis of a rare, inherited disease: mucopolysaccharidosis.

The mucopolysaccharidoses (MPS) are one group of lysosomal storage disorders caused by a deficiency of lysosomal enzymes, that are responsible for the degradation of glycosaminoglycans (GAGs), important components of the connective tissues. This is accomplished by complex pathophysiological cascades and results in a storage of GAGs in the cells. Almost all organs and organ systems are affected.

The accumulation of undegraded GAGs leads to a progressive variety of somatic and neurological symptoms, including skeletal, musculoskeletal and cardiorespiratory complications. Some MPS types show also a mental development decline. Early diagnosis, appropriate management and - in some MPS types available- therapies affect the quality of life of patients and can lead to a slowdown or a prevention of irreversible complications.

Since there is not a typical "MPS-symptom", but only the sum of many nonspecific and variable symptoms may lead to the diagnosis, in particular in attenuated / milder MPS types, they are often diagnosed late and mistaken for an (uncharacteristically running) rheumatologic or skeletal disease.

Gaucher disease is an autosomal recessive disorder that is caused by mutations in the GBA1 gene leading to the insufficient activity of the hydrolase acid beta-glucosidase (glucocerebrosidase). Patients are classified into three phenotypes depending on whether the central nervous system (CNS) is involved and on the age of onset of clinical manifestations. NeuronopathicGaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form—Gaucher type 2—from the subacute or chronic form—Gaucher type 3. We recently positively defined the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD.

We discuss the features that suggest nGD and what clinical features differentiate between Gaucher type 2 and type 3.  This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming research studies. Enzyme replacement therapy is the standard medical treatment for nGD. Substrate reduction therapy with venglustat is in clinical trial and gene therapy trials will likely start very soon.

An international registry (NCT01633489; Alexion Pharmaceuticals, Inc.; 2013–ongoing) was established to better understand the natural history of lysosomal acid lipase deficiency (LAL-D) and to evaluate long-term treatment outcomes. Baseline findings for patients enrolled through July 1, 2019, are presented. Of 190 patients enrolled, 35 were excluded from this analysis (LIPA carrier, deceased at enrollment, unconfirmed LAL-D diagnosis); 155 patients with confirmed LAL-D diagnosis were included (12 infants, 143 children/adults). LAL enzyme activity analysis was performed for 145/154 patients (94%) and genetic testing for 128/154 patients (83%). Of 105 children/adults with reported LIPA mutations, 39 were homozygous and 34 were compound heterozygous for the common LIPA mutation E8SJM (c.894G>A); 6 infants with reported LIPA mutations were homozygotes and 2 were compound heterozygotes. Of the 155 patients, 62% were <18 years, 52% were male, and 85% were white. Median (range) age at clinical onset was 0.2 years (0.0–0.7) among infants and 6.0 years (0.0–41.3) among 133 children/adults with data; median (range) age at diagnosis was 0.2 years (−0.1 to 1.2) among infants and 10.8 years (0.2–53.6) among 135 children/adults with data. Manifestations that raised suspicion of LAL-D were reported in 149/155 patients. Infants (12 with data) presented predominantly with hepatomegaly (75%), splenomegaly (58%), nausea/vomiting (58%), and diarrhea (50%), and 50% had a known family history of LAL-D. Children/adults (n=143) presented predominantly with elevated alanine aminotransferase levels (67%), hepatomegaly (66%), and elevated aspartate aminotransferase levels (65%). Of 74 children/adults with baseline liver biopsy, 58% had microvesicular steatosis, 16% had micro- and macrovesicular steatosis and 32% had lobular inflammation. Of the 155 patients, 6% had a medical history of cirrhosis. Analyses exploring the genotype-phenotype relationship will be presented. Registry data of >150 LAL-D patients demonstrate early symptom onset, variable clinical manifestations, and a significant diagnostic delay in children/adults.

Manisha Balwani1; William Balistreri2; Lorenzo D’Antiga3; Shona Fang4; Simon A. Jones5; Emilio Ros6; Florian Abel4; Don P. Wilson7

 1Icahn School of Medicine at Mount Sinai Hospital, New York, New York; 2Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; 3Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; 4Alexion Pharmaceuticals, Inc., Boston, Massachusetts; 5Manchester University Hospital NHS Trust, Manchester, UK; 6Hospital Clinic de Barcelona, Barcelona, Spain; 7Cook Children’s Medical Center, Fort Worth, Texas

Disclosures:  

Balwani: Alexion Pharmaceuticals, Inc., honorarium, advisory board; Lysosomal Acid Lipase Deficiency Registry, scientific advisory board.

Balistreri: Otsuka, Alexion Pharmaceuticals, Inc., consultant; Gilead, AbbVie, Merck, research grants.

D’Antiga: Alexion Pharmaceuticals, Inc., advisory board, honorarium, grants, speaker; Lysosomal Acid Lipase Deficiency Registry, scientific advisory board.

Fang and F. Abel: Alexion Pharmaceuticals, Inc., employment.

S.A. Jones: Alexion Pharmaceuticals, Inc., honorarium, grants, speaker.

Ros: Alexion Pharmaceuticals, Inc., honorarium, grants, speaker; Lysosomal Acid Lipase Deficiency Registry, scientific advisory board.

D.P. Wilson: Osler Institute, National Lipid Association, Insulet Corp., Alexion Pharmaceuticals, Inc., speaker; Aegerion, Alexion Pharmaceuticals, Inc., Merck Sharp & Dohme, Novo Nordisk, advisory board; Merck Sharp & Dohme, Novo Nordisk, research funding.

AVROBIO, a clinical-stage gene therapy company with a mission to free people from a lifetime of genetic disease, aims to develop potential one-time lentiviral-based gene therapies to treat patients with LDs caused by the mutation of a single gene. Our gene therapies employ patient-derived hematopoietic stem cells modified with a lentiviral vector to insert a therapeutic copy of the mutated gene. Our clinical-stage programs include Fabry disease (AVR-RD-01), cystinosis (AVR-RD-04), and Gaucher disease (AVR-RD-02).

AVR-RD-01 is being evaluated in an investigator-sponsored Ph1 trial and AVROBIO-sponsored Ph2 trial. Nine classic male Fabry patients have been dosed to date. Initial data suggest durable effect, including up to 32 months in one patient, as demonstrated by VCN, AGA enzyme activity in leukocytes and plasma, and associated reductions in plasma lyso-Gb3. An 87% reduction in the average number of kidney peritubular cell Gb3 substrate deposits was reported in the first treatment naïve patient at 48 weeks. Per the last safety data cut-off date, there have been no SAEs associated with AVR-RD-01 and the safety profile reported is consistent with conditioning and underlying disease.

AVR-RD-04 is being studied by UCSD collaborators in a Ph1/2 investigator-sponsored trial to treat cystinosis. Three-month data from the first dosed patient demonstrated a reduction in granulocyte cystine levels and positive trends across multiple clinical measures. Per the last safety data cut-off date, no SAEs were reported and AEs were consistent with conditioning and underlying disease.

The Ph1/2 trial in Gaucher disease Type 1 investigating AVR-RD-02 has enrolled the first patient.

 Background: The mucopolysaccharidoses (MPS) are a family of LSD characterised by impaired degradation of glycosaminoglycans (GAG) which subsequently accumulate in affected cells and are excreted in the urine. Rare disorders, with broad clinical heterogeneity, accurate diagnosis of MPS can be protracted and predicting clinical course and treatment response challenging.

Objective: To improve the diagnostic efficiency of MPS through mass spectrometric detection of small, specific GAG fragments with terminal residues characteristic of the enzyme deficiency.

Methods: A derivatizing agent is added to the biological sample (urine, blood, CSF) along with an internal standard and following partial chromatographic separation, GAG fragments (ranging in size from mono- to tetrasaccharides) are quantified by tandem mass spectrometry.

Results: All ten MPS subtypes were identified from a signature GAG fragment yielding 100% sensitivity and specificity for the diagnosis of 90 MPS patients from 2,500 tested. There is no requirement for age related reference ranges or depolymerisation of the high molecular weight GAG. Notably, two siblings were misdiagnosed as a result of normal urinary GAG but were later correctly diagnosed with MPS IVA using the signature GAG fragment. The MPS II GAG fragment confirmed an unaffected fetus in the prenatal setting with an equivocal enzyme activity result and a genetic variant of uncertain significance. A precipitous drop in the concentration of these fragments was shown in MPS I, III, IVA and VI following therapeutic intervention highlighting their utility for biochemical monitoring. Additionally, in 12 MPS IVA patients in receipt of enzyme replacement therapy, concentrations of the signature GAG fragment correlated with urinary keratan sulphate.

Conclusion: Advances in mass spectrometry technologies have enabled simultaneous measurement of small, naturally occurring, GAG fragments, providing a platform for improving the efficiency and accuracy of MPS diagnosis, biochemical monitoring of treatment response and they may also show promise for prognosis.

Brazil is one of the largest and most populous countries in the world, full of inequalities. However, Brazilians are privileged in terms of access to health. They have a large public health system, which includes a unique Policy on Rare Disorders, which covers neonatal screening and reimbursement for high-cost treatments for lysosomal disorders through specific guidelines. These topics, and the need for advances, will be addressed in the lecture.

Established in 1994 as an anarchy of patient advocates, the (then) EGA, now IGA is an umbrella organisation and its members are national patient-led organisation for Gaucher, LSD, or rare diseases. Today we have 56 member organisations representing 54 countries across the globe, with representation geographically across a large majority of the world, although there are still some areas that we lack presence. We recognise that in some countries there is little or no awareness of Gaucher, LSDs, or rare diseases and here we build relationships with individual patients and parents/families to offer support mainly through supporting patients to get treatment through charitable access programmes.

• Built on a strong foundation of volunteers all with a connection to Gaucher disease the IGA board of directors, volunteers and CEO donated 2900 hours of their time to support the work of the IGA in 2019.
• In 2018 we introduced our regional manager programme that seeks to be the eyes and ears of the IGA in regions where there is little or no awareness of Gaucher disease and using volunteers from our ‘Go with Gaucher’ programme (taking forward the next generation of patient advocates) we have programmes in South Asia (north and south), Central America, Caucasus &Central Asia, and Africa).
• Establishing ourselves as an independent, well respected, and trusted organisation we are recognised as a sister organisation to the EWGGD, the ‘go-to’ organisation for stakeholders to consult with regarding all Gaucher projects, and the global voice of the patient community.

Home therapy, international challenges, annual meetings, but also interviews with national media and conferences with political groups. Being a non-profit organization that helps patients with a rare disease is not easy. Their voice needs to be amplified in order to be listed by institutions. Moreover, they need not be left alone.

The story of AIG started 28 years ago and till now we are supporting Gaucher’s patients. We are fighting to allow lysosomal patients to have access to home therapy. The possibility of practicing enzyme replacement therapies at home is not a simple convenience, but a fundamental step to guarantee a dignified quality of life for these people.

Especially during the COVID-19 pandemic, Home Therapy increases the safety of patients and family members by avoiding non-essential movements to hospitals and prevent patients from interrupting Lifesaving Therapy for fear of infection.