Agnieszka Jurecka

Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3-year follow-up

Aim:  We present a 3‐year follow‐up of a boy with mucopolysaccharidosis type II (MPS II) who had idursulfase therapy initiated at the age of 3 months and compare his clinical course to his healthy twin brother.

Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency

Adenylosuccinate lyase (ADSL) catalyzes two steps in purine nucleotide metabolism-the 8th step in the de novo pathway: conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR), and conversion of adenylosuccinate (S-AMP) to adenylate (AMP) in the purine nucleotide cycle. To date, over 50 patients have been reported suffering from ADSL deficiency. We report all seven so far diagnosed Polish patients with this defect. Most of our patients shared intractable seizures and psychomotor retardation since the neonatal period and had biochemical evidence of severe (type I) deficiency. Two patients with type II suffered only from mild/moderate psychomotor retardation and showed a transientvisual contact disturbance. One patient had a fatal neonatal form of ADSL deficiency with lack of spontaneous movement, respiratory failure, severe encephalopathy and intractable seizures. Analysis of the ADSL gene showed that four apparently unrelated patients carried a R426H mutation (two homozygous and two compound heterozygous). With the exception of the latter mutation, a Y114H mutation that had been reported previously, and a novel mutation T242I, all other mutations (including D268H and three novel S23R, D215H and I351T mutations) were found only in single families in single alleles. A search for this disorder should be included in the screening program of all infants with unexplained neonatal seizures, severe infantile epileptic encephalopathy, developmental delay, hypotonia, and/or autistic features.

Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA)

Background Resistance to thyroid hormone is characterised by a lack of response of peripheral tissues to the active form of thyroid hormone (triiodothyronine, T3). In about 85% of cases, a mutation in THRB, the gene coding for thyroid receptor β (TRβ), is the cause of this disorder. Recently, individual reports described the first patients with thyroid hormone receptor α gene (THRA) defects. Methods We used longitudinal clinical assessments over a period of 18 years at one hospital setting combined with biochemical and molecular studies to characterise a novel thyroid hormone resistance syndrome in a cohort of six patients from five families. Findings Using whole exome sequencing and subsequent Sanger sequencing, we identified truncating and missense mutations in the THRA gene in five of six individuals and describe a distinct and consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia and constipation), specific facial features (round, somewhat coarse and flat face) and macrocephaly. Laboratory investigations revealed anaemia and slightly elevated cholesterol, while the thyroid profile showed low free thyroxine (fT4) levels coupled with high free T3 (fT3), leading to an altered T4 : T3 ratio, along with normal thyroid-stimulating hormone levels. We observed a genotype–phenotype correlation, with milder outcomes for missense mutations and more severe phenotypical effects for truncating mutations. Interpretation THRA mutations may be more common than expected. In patients with clinical symptoms of mild hypothyreosis without confirmation in endocrine studies, a molecular study of THRA defects is strongly recommended.

Growth pattern and growth prediction of body height in children with mucopolysaccharidosis type II

Aim:  Our goal was to evaluate the level, degree and direction of deviation in the ontogenesis of patients with mucopolysaccharidosis type II (MPS II) in comparison with the healthy population.

Adenylosuccinate lyase deficiency

Adenylosuccinate lyase ADSL) deficiency is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways. Biochemically this defect manifests by the presence in the biologic fluids of two dephosphorylated substrates of ADSL enzyme: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). More than 80 individuals with ADSL deficiency have been identified, but incidence of the disease remains unknown. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The fatal neonatal form has onset from birth and presents with fatal neonatal encephalopathy with a lack of spontaneous movement, respiratory failure, and intractable seizures resulting in early death within the first weeks of life. Patients with type I (severe form) present with a purely neurologic clinical picture characterized by severe psychomotor retardation, microcephaly, early onset of seizures, and autistic features. A more slowly progressing form has also been described (type II, moderate or mild form), as having later onset, usually within the first years of life, slight to moderate psychomotor retardation and transient contact disturbances. Diagnosis is facilitated by demonstration of SAICAr and S-Ado in extracellular fluids such as plasma, cerebrospinal fluid and/or followed by genomic and/or cDNA sequencing and characterization of mutant proteins. Over 50 ADSL mutations have been identified and their effects on protein biogenesis, structural stability and activity as well as on purinosome assembly were characterized. To date there is no specific and effective therapy for ADSL deficiency.

Molecular analysis of mucopolysaccharidosis type VI in Poland, Belarus, Lithuania and Estonia

Mucopolysaccharidosis VI (MPS VI) is a rare autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (ARSB). Over 130 ARSB gene mutations have been identified thus far and most mutations are unique to individual families. We aimed to analyze the spectrum of mutations in the ARSB gene responsible for the disorder in Poland, Belarus and Baltic States. Twenty one families with MPS VI patients, in whom diagnosis was confirmed biochemically and enzymatically, were studied. Direct sequencing of patient genomic DNA was used to identify ARSB mutations. In total, fourteen different disease-causing mutations were found. Three novel mutations included insertion c.375_376insT, a missense mutation c.499G>A (p.G167R) and deletion/insertion c.750_754delinsCCTGAAGTCAAG. We also report 11 previously described mutations (p.A33V, p.W57C, p.Q88X, p.T92K, p.Q97X, p.R152W, p.R160Q, p.R160X, p.Y210C, p.Y266S, p.G302R). The mutation p.R152W was present at a high prevalence of 50% (21/42) the mutated alleles in this group of patients. High prevalence of p.R152W mutation in Poland, Belarus and Baltic States indicates a possible founder effect and suggests that screening for this mutation may be appropriate in MPS VI patients from this region. Our study has also provided evidence to support genotype-phenotype correlation.

Mucopolysaccharidosis Type VI (Maroteaux–Lamy syndrome) with a predominantly cardiac phenotype

We present here the first literature description of a predominantly cardiac phenotype in a patient homozygous for missense mutation p.R152W in the N-acetylogalactosamine-4-sulfatase (arylsulfatase B, ARSB) gene. An adult Caucasian woman, who displayed very few symptoms up to her late thirties, was diagnosed with mucopolysaccharidosis type VI (MPS VI) after her hospitalization due to acute heart failure originating mainly from valve disease. In addition to her cardiac phenotype some musculoskeletal involvement without other MPS characteristic features were found. Despite the common pharmacologic treatment and implementation of enzyme replacement therapy with galsulfase the patient died at the age of 38 years because of decompensation of chronic heart failure.

Mucopolysaccharidosis type II in females and response to enzyme replacement therapy.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X‐linked lysosomal storage disease caused by a deficiency of iduronate‐2‐sulfatase (IDS). Two affected girls with moderate and severe forms of MPS II with normal karyotypes and increased urinary dermatan sulphate and heparin sulphate excretion and marked deficiencies of IDS activity are reported. Molecular studies showed that case 1 has a heterozygous mutation c.1568A > G (p.Y523C) associated with almost totally skewed inactivation of the normal maternal X chromosome, and case 2 has a heterozygous deletion that includes exons 1–4 of IDS (minimal deletion range c.1–103_184del). The multi‐exon deletion correlated with early onset of the disease and severe phenotype with intellectual disability, whereas the missense mutation was associated with moderate developmental delay. Although genotype–phenotype correlation in MPS II is difficult, gene deletions seem to correlate with more severe clinical manifestation of the disease. Enzyme replacement therapy (ERT) in these two females resulted in disease stabilization in both.

Prevalence rates of mucopolysaccharidoses in Poland

The aim of this study was to determine the prevalence rates of mucopolysaccharidoses in Poland and to compare them with other European countries. A retrospective epidemiological survey covering the period between 1970 and 2010 was implemented. Multiple ascertainment sources were used to identify affected patients. The overall prevalence of mucopolysaccharidoses in the Polish population was 1.81 per 100,000. Five different mucopolysaccharidoses were diagnosed in a total of 392 individuals. MPS III was the most frequent mucopolysaccharidosis, with a birth prevalence of 0.86 per 100,000 live births. A prevalence of approximately 0.22 cases per 100,000 births was obtained for MPS I. For MPS II, the prevalence was estimated as 0.45 cases per 100,000 births; for MPS IV A and B as 0.14 cases in 100,000 births; and that for MPS VI as 0.03 cases per 100,000 births. 1. The prevalence pattern of mucopolysaccharidosis in Poland is lower when compared to the prevalence reported for other European countries, such as the Netherlands, Czech Republic, or Germany, but similar to countries like Sweden and Denmark. 2. Different frequencies of the various forms of mucopolysaccharidosis were observed. 3. In the case of MPS VI, the incidence values for Poland were the lowest of all the studies previously published so far.

Osteoimmunology in mucopolysaccharidoses type I, II, VI and VII. Immunological regulation of the osteoarticular system in the course of metabolic inflammation

BACKGROUND Mucopolysaccharidoses (MPSs) are rare genetic diseases caused by a deficient activity of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. These metabolic blocks lead to the accumulation of GAGs in various organs and tissues, resulting in a multisystemic clinical picture. The pathological GAG accumulation begins a cascade of interrelated responses: metabolic, inflammatory and immunological with systemic effects. Metabolic inflammation, secondary to GAG storage, is a significant cause of osteoarticular symptoms in MPS disorders. OBJECTIVE AND METHOD The aim of this review is to present recent progress in the understanding of the role of inflammatory and immune processes in the pathophysiology of osteoarticular symptoms in MPS disorders and potential therapeutic interventions based on published reports in MPS patients and studies in animal models. RESULTS AND CONCLUSIONS The immune and skeletal systems have a number of shared regulatory molecules and many relationships between bone disorders and aberrant immune responses in MPS can be explained by osteoimmunology. The treatment options currently available are not sufficiently effective in the prevention, inhibition and treatment of osteoarticular symptoms in MPS disease. A lot can be learnt from interactions between skeletal and immune systems in autoimmune diseases such as rheumatoid arthritis (RA) and similarities between RA and MPS point to the possibility of using the experience with RA in the treatment of MPS in the future. The use of different anti-inflammatory drugs requires further study, but it seems to be an important direction for new therapeutic options for MPS patients.