Catherine Caillaud

Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece

Sanfilippo syndrome, or mucopolysaccharidosis type III (MPSIII) is a lysosomal storage disease with predominant neurological manifestations in affected children. It is considered heterogeneous with respect to prevalence, clinical presentation, biochemistry (four biochemical forms of the disease referred to as MPSIIIA, B, C, and D are known), and causative mutations. The perspective of therapeutic options emphasizes the need for better knowledge of MPSIII incidence and natural history. We performed parallel retrospective epidemiological studies of patients diagnosed with MSPIII in France (n = 128), UK (n = 126), and Greece (n = 20) from 1990 to 2006. Incidences ranged from 0.68 per 100,000 live‐births in France to 1.21 per 100,000 live‐births in UK. MPSIIIA, which predominates in France and UK, was absent in Greece, where most patients have MPSIIIB. The study confirmed the large allelic heterogeneity of MPSIIIA and MPSIIIB and detected several yet undescribed mutations. Analysis of clinical manifestations at diagnosis and over a 6–7 years follow‐up indicated that almost all patients, whatever the disease subtype, expressed neurological manifestations before the age of 5 years, including language acquisition delay, cognitive delay, and/or abnormal behavior. In contrast to relatively homogeneous early onset manifestations, disease progression showed significant variation depending on subtype and age at diagnosis. Different severities of disease progressions and different allele distribution between France and UK suggested that mutations are not equally deleterious, although genotype–phenotype correlation could not be established. Notwithstanding the rapidity of further clinical deterioration, all MPSIII patients suffer early onset devastating neurological manifestations that deserve early treatment when available.

Dystonia and parkinsonism in GM1 type 3 gangliosidosis.

GM1 gangliosidosis is due to β‐galactosidase deficiency. Only patients with type 3 disease survive into adulthood and develop movement disorders. Clinical descriptions of this form are rare, particularly in non‐Japanese patients. We describe four new patients and systematically analyze all previous reports found by a literature search and contacts with the authors for additional information. Generalized dystonia remained the predominant feature throughout the disease course and was often associated with akinetic–rigid parkinsonism. GM1 gangliosidosis must be considered as a cause of early‐onset generalized dystonia, particularly in patients with short stature and skeletal dysplasia.

The pulvinar sign: frequency and clinical correlations in Fabry disease

Fabry disease is an X-linked lysosomal deficiency of α-galactosidase A that results in cellular accumulation of galactoconjugates, mainly globotriaosylceramide, particularly in blood vessels. Neuroradiological findings include ischemic stroke, white matter lesions, vascular abnormalities (vertebrobasilar dolichoectasia and vessel tortuosity), and posterior thalamus involvement (the so called pulvinar sign). The purpose of our study was to investigate the presence of the increased pulvinar signal intensity on T1-weighted imaging – pulvinar sign and its relationship with other clinical findings, in a non-selected cohort of Fabry patients.MethodsWe performed a prospective analysis of two populations of patients (36 subjects) with Fabry disease. Patients were followed-up at the Department of Internal Medicine of the Bichat Hospital in Paris (France) and at the Neurological Clinic of the University Hospital of Padova (Italy). Brain MR studies of each patient included T1- and T2- weighted images, FLAIR sequences, and in some cases diffusion weighted images.ResultsA total of 36 patients (16 males, 20 females) were investigated in 14 families. The pulvinar sign was found in 5 male patients, but not in female patients. Seven patients had had at least one stroke (territorial or lacunar). There was no correlation between stroke and the pulvinar sign. All patients with the pulvinar sign had hypertrophic cardiomyopathy. Four patients out of five with the pulvinar sign were on dialysis or had a kidney transplantation.ConclusionsOur findings suggest that the pulvinar sign is a highly specific sign of Fabry disease, found in male patients with cardiac signs and severe kidney involvement.

Gaucher Disease: The Origins of the Ashkenazi Jewish N370S and 84GG Acid β-Glucosidase Mutations

Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder, results from the deficient activity of acid beta-glucosidase (GBA). Type 1 disease is panethnic but is more prevalent in individuals of Ashkenazi Jewish (AJ) descent. Of the causative GBA mutations, N370S is particularly frequent in the AJ population, (q approximately .03), whereas the 84GG insertion (q approximately .003) occurs exclusively in the Ashkenazim. To investigate the genetic history of these mutations in the AJ population, short tandem repeat (STR) markers were used to map a 9.3-cM region containing the GBA locus and to genotype 261 AJ N370S chromosomes, 60 European non-Jewish N370S chromosomes, and 62 AJ 84GG chromosomes. A highly conserved haplotype at four markers flanking GBA (PKLR, D1S1595, D1S2721, and D1S2777) was observed on both the AJ chromosomes and the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common to both populations. Of note, the presence of different divergent haplotypes suggested the occurrence of de novo, recurrent N370S mutations. In contrast, a different conserved haplotype at these markers was identified on the 84GG chromosomes, which was unique to the AJ population. On the basis of the linkage disequilibrium (LD) delta values, the non-Jewish European N370S chromosomes had greater haplotype diversity and less LD at the markers flanking the conserved haplotype than did the AJ N370S chromosomes. This finding is consistent with the presence of the N370S mutation in the non-Jewish European population prior to the founding of the AJ population. Coalescence analyses for the N370S and 84GG mutations estimated similar coalescence times, of 48 and 55.5 generations ago, respectively. The results of these studies are consistent with a significant bottleneck occurring in the AJ population during the first millennium, when the population became established in Europe.

Widespread distribution of beta-hexosaminidase activity in the brain of a Sandhoff mouse model after coinjection of adenoviral vector and mannitol.

Sandhoff disease is a severe inherited neurodegenerative disorder resulting from deficiency of the β-subunit of hexosaminidases A and B, lysosomal hydrolases involved in the degradation of GM2 ganglioside and related metabolites. Currently, there is no viable treatment for the disease. Here, we show that adenovirus-mediated transfer of the β-subunit of β-hexosaminidase restored Hex A and Hex B activity after infection of Sandhoff fibroblasts. Gene transfer following intracerebral injection in a murine model of Sandhoff disease resulted in near-normal level of enzymatic activity in the entire brain at the different doses tested. The addition of hyperosmotic concentrations of mannitol to the adenoviral vector resulted in an enhancement of vector diffusion in the injected hemisphere. Adenoviral-induced lesions were found in brains injected with a high dose of the vector, but were not detected in brains injected with 100-fold lower doses, even in the presence of mannitol. Our data underline the advantage of the adjunction of mannitol to low doses of the adenoviral vector, allowing a high and diffuse transduction efficiency without viral cytotoxicity.

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

Gaucher disease (GD, ORPHA355) is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 gene should be identified as they may be of prognostic value in some cases. Patients with type-1 GD—but also carriers of GBA1 mutation—have been found to be predisposed to developing Parkinson’s disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat).

A French experience of type 3 Gaucher disease: Phenotypic diversity and neurological outcome of 10 patients

OBJECTIVE To describe the clinical presentation of 10 patients with type 3 Gaucher disease and the clinical evolution of nine of them following specific therapy regimes. METHODS The follow-up of these 10 patients was between 2 and 15 years. The clinical history was provided by each patients general practitioner and a final clinical evaluation was made by two different physicians including a neurologist. One patient received no treatment, eight received enzyme replacement therapy (ERT) and one received ERT combined with substrate reduction therapy (SRT, miglustat). RESULTS The clinical presentations were heterogeneous and most phenotypes reported for type 3 Gaucher disease were represented. The neurological involvement stabilized or improved in six patients under ERT with a follow-up of 2-15 years. Four of them showed isolated oculomotor signs only that improved or remained unchanged during the follow-up. Of two patients with progressive myoclonic epilepsy, the outcome was clearly unfavorable in one receiving ERT and disputable for the other receiving ERT+SRT. An unfavorable neurological outcome was observed in another patient in whom the ERT dose had been reduced before clinical decline. CONCLUSION The stabilization of the clinical course in most patients is noteworthy. Though further evidence is needed from a larger series in order to draw any definite conclusions, our data suggest that ERT may be effective in preventing the evolution of neurological disturbances associated with type 3 Gaucher disease in some patients. However, the clinical course of the two patients with progressive myoclonic epilepsy was not influenced by ERT, as previously reported. In accordance with that reported in the literature, data from our series suggest that the outcome of patients undergoing ERT depends on the type of clinical involvement, treatment onset and dose. Genotype may also be an important factor, with p.L444P/p.L444P possibly indicating a better outcome.

The French Gaucher’s disease registry: clinical characteristics, complications and treatment of 562 patients

BackgroundClinical features, complications and treatments of Gaucher’s disease (GD), a rare autosomal–recessive disorder due to a confirmed lysosomal enzyme (glucocerebrosidase) deficiency, are described.MethodsAll patients with known GD, living in France, with ≥1 consultations (1980–2010), were included in the French GD registry, yielding the following 4 groups: the entire cohort, with clinical description; and its subgroups: patients with ≥1 follow-up visits, to investigate complications; recently followed (2009–2010) patients; and patients treated during 2009–2010, to examine complications before and during treatment. Data are expressed as medians (range) for continuous variables and numbers (%) for categorical variables.ResultsAmong the 562 registry patients, 265 (49.6%) were females; 454 (85.0%) had type 1, 22 (4.1%) type 2, 37 (6.9%) perinatal–lethal type and 21 (3.9%) type 3. Median ages at first GD symptoms and diagnosis, respectively, were 15 (0–77) and 22 (0–84) years for all types. The first symptom diagnosing GD was splenomegaly and/or thrombocytopenia (37.6% and 26.3%, respectively). Bone-marrow aspiration and/or biopsy yielded the diagnosis for 54.7% of the patients, with enzyme deficiency confirming GD for all patients. Birth incidence rate was estimated at 1/50,000 and prevalence at 1/136,000. For the 378 followed patients, median follow-up was 16.2 (0.1–67.6) years. Major clinical complications were bone events (BE; avascular necrosis, bone infarct or pathological fracture) for 109 patients, splenectomy for 104, and Parkinson’s disease for 14; 38 patients died (neurological complications for 15 type-2 and 3 type-3 patients, GD complications for 11 type-1 and another disease for 9 type-1 patients). Forty-six had monoclonal gammopathy. Among 283 recently followed patients, 36 were untreated and 247 had been treated during 2009–2010; 216 patients received treatment in December 2010 (126 with imiglucerase, 45 velaglucerase, 24 taliglucerase, 21 miglustat). BE occurred before (130 in 67 patients) and under treatment (60 in 41 patients) with respective estimated frequencies (95% CI) of first BE at 10 years of 20.3% (14.1%–26.5%) and 19.8% (13.5%–26.1%).ConclusionThis registry enabled the epidemiological description of GD in France and showed that BE occur even during treatment.

GM1 gangliosidosis and Morquio B disease: expression analysis of missense mutations affecting the catalytic site of acid β‐galactosidase

Alterations in GLB1, the gene coding for acid β‐D‐galactosidase (β‐Gal), can result in GM1 gangliosidosis (GM1), a neurodegenerative disorder, or in Morquio B disease (MBD), a phenotype with dysostosis multiplex and normal central nervous system (CNS) function. While most MBD patients carry a common allele, c.817TG>CT (p.W273L), only few of the >100 mutations known in GM1 can be related to a certain phenotype. In 25 multiethnic patients with GM1 or MBD, 11 missense mutations were found as well as one novel insertion and a transversion causing aberrant gene products. Except c.602G>A (p.R201H) and two novel alleles, c.592G>T (p.D198Y) and c.1189C>G (p.P397A), all mutants resulted in significantly reduced β‐Gal activities (<10% of normal) upon expression in COS‐1 cells. Although c.997T>C (p.Y333H) expressed 3% of normal activity, the mutant protein was localized in the lysosomal‐endosomal compartment. A homozygous case presented with late infantile GM1, while a heterozygous, juvenile case carried p.Y333H together with p.R201H. This allele, recently found in homozygous MBD, gives rise to rough endoplasmic reticulum (RER)‐located β‐Gal precursors. Thus, unlike classical MBD, the phenotype of heterozygotes carrying p.R201H may rather be determined by poorly active, properly transported products of the counter allele than by the mislocalized p.R201H precursors. Hum Mutat 30, 1–8, 2009.

Rigid spine syndrome revealing late-onset Pompe disease

The authors describe a 50-year-old man who was evaluated for a rigid spine syndrome with onset at age 15, and subsequent walking difficulties. Cardiac and pulmonary functions were normal. Deltoid biopsy revealed the presence of small vacuoles and increased glycogen with Periodic Acid Schiff staining in a limited number of fibers. Acid alpha-glucosidase staining was decreased in leucocytes, and genetic analysis identified the presence of two mutations in that gene. This observation suggests that Pompe disease should be considered in the differential diagnosis of rigid spine syndrome, even in patients without respiratory involvement or with a muscle biopsy showing only mild histopathological changes.