Hernán Amartino

Treatment of Fabry’s Disease with the Pharmacologic Chaperone Migalastat

BACKGROUND Fabrys disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabrys disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

Timing of diagnosis of patients with pompe disease: Data from the pompe registry

Diagnostic delays in Pompe disease are common. The diagnostic gap (the time from the onset of symptoms to the diagnosis of Pompe disease) and factors associated with diagnostic delays were examined among Pompe Registry patients in three onset categories: Group A, onset ≤12 months of age with cardiomyopathy; Group B, onset ≤12 months without cardiomyopathy and onset >12 months to ≤12 years; and Group C, onset >12 years. Of 1,003 patients, 647 were available for analysis. In all groups, musculoskeletal signs and symptoms were among the most frequent presenting signs and symptoms, in addition to cardiomyopathy in Group A, which was part of the groups definition. Diagnostic gaps existed in all three groups. Patients presenting with respiratory and musculoskeletal signs and symptoms concurrently had the shortest diagnostic gap, while those presenting with neither respiratory nor musculoskeletal signs and symptoms had the longest. Independent factors influencing the probability of a long diagnostic gap included presenting signs and symptoms (all three groups) and year of diagnosis and age at symptom onset (Groups B and C). Group B, which represents the infantile patients without cardiomyopathy and juvenile Pompe cases, had the longest median gap (12.6 years). Diagnostic testing methods used also were reviewed. Despite the availability of blood‐based assays that can be used to quickly and accurately diagnose Pompe disease, diagnostic gaps in Pompe patients across the disease spectrum continue.

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

BACKGROUND In X‐linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem‐cell transplantation. METHODS We enrolled boys with cerebral adrenoleukodystrophy in a single‐group, open‐label, phase 2–3 safety and efficacy study. Patients were required to have early‐stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti‐D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft‐versus‐host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS A total of 17 boys received Lenti‐D gene therapy. At the time of the interim analysis, the median follow‐up was 29.4 months (range, 21.6 to 42.0). All the patients had gene‐marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment‐related death or graft‐versus‐host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem‐cell transplantation and later died from transplantation‐related complications. CONCLUSIONS Early results of this study suggest that Lenti‐D gene therapy may be a safe and effective alternative to allogeneic stem‐cell transplantation in boys with early‐stage cerebral adrenoleukodystrophy. Additional follow‐up is needed to fully assess the duration of response and long‐term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102; ClinicalTrialsRegister.eu number, 2011‐001953‐10.)

p.[G576S; E689K]: pathogenic combination or polymorphism in Pompe disease?

We discuss four cases of acid α-glucosidase deficiency (EC, 3.2.1.3/20) without evident symptoms of Pompe disease (OMIM No 232300) in individuals of Asian descent. In three cases, the deficiency was associated with homozygosity for the sequence variant c.[1726G>A; 2065G>A] in the acid α-glucosidase gene (GAA) translating into p.[G576S; E689K]. One of these cases was a patient with profound muscular atrophy, another had cardio-myopathy and the third had no symptoms. The fourth case, the mother of a child with Pompe disease, was compound heterozygote for the GAA sequence variants c.[1726G>A; 2065G>A]/c.2338G>A (p.W746X) and had no symptoms either. Further investigations revealed that c.[1726A; 2065A] is a common GAA allele in the Japanese and Chinese populations. Our limited study predicts that approximately 4% of individuals in these populations are homozygote c.[1726A; 2065A]. The height of this figure in contrast to the rarity of Pompe disease in Asian populations and the clinical history of the cases described in this paper virtually exclude that homozygosity for c.[1726A; 2065A] causes Pompe disease. As c.[1726A; 2065A] homozygotes have been observed with similarly low acid α-glucosidase activity as some patients with Pompe disease, we caution they may present as false positives in newborn screening programs especially in Asian populations.

Sulthiame add‐on therapy in children with focal epilepsies associated with encephalopathy related to electrical status epilepticus during slow sleep (ESES)

Purpose:  In children with symptomatic or idiopathic focal epilepsies, their disease may evolve into an epileptic encephalopathy related to continuous spike and wave during slow sleep (CSWS) or electrical status epilepticus during slow sleep (ESES). ESES syndrome implies serious risks of neuropsychologic impairment, and its treatment has frequently been disappointing. The aim of this study is to present our experience using sulthiame as add‐on treatment in 53 patients with ESES syndrome that was refractory to other antiepileptic drugs (AEDs).

Biomarkers for the mucopolysaccharidoses: Discovery and clinical utility☆

The mucopolysaccharidoses (MPSs), a group of inherited lysosomal storage diseases, are complex, progressive, multisystem disorders with extreme clinical heterogeneity. The introduction of therapies that target the underlying enzyme deficiency in a number of the MPSs has brought to light the need for biomarkers that would aid in the evaluation of disease burden and as a means to objectively measure therapeutic response in individual patients. It is increasingly recognized that due to the extraordinarily complex pathogenesis of the MPSs, achieving these goals with a single analyte, such as urinary glycosaminoglycans, is unlikely. This recognition has created an impetus for the search for clinically useful biomarkers that reflect the disease pathogenesis and that are stage- or organ-specific. In this review, the current state of MPS biomarker research is discussed, with a focus on clinical utility in the MPSs.

Pompe disease (glycogen storage disease type II) in Argentineans: Clinical manifestations and identification of 9 novel mutations

Pompe disease is an autosomal recessive disorder caused by a deficiency in 1,4-alpha-glucosidase (EC.3.2.1.3), the enzyme required to hydrolyze lysosomal glycogen to glucose. While previous studies have focused on Pompe patients from Europe, the United States, and Taiwan, we have analyzed a group of South American Pompe patients to better understand the molecular basis of their disease. From 14 Argentinean patients diagnosed with either infantile or late-onset disease, we identified 14 distinct mutations in the acid alpha-glucosidase (GAA) gene including nine novel variants (c.236_246del, c.377G>A, c.1099T>C, c.1397T>G, c.1755-1G>A, c.1802C>G, c.1978C>T, c.2281delGinsAT, and c.2608C>T). Three different families displayed the c.377G>A allelic variant, suggesting a higher frequency among a subset of Argentineans. Comparison of patients with similar or identical variations in the GAA gene highlights the phenotypic diversity of late-onset disease and supports a role for other genetic and environmental factors in disease presentation.

Methods of Diagnosis of Patients with Pompe Disease: Data From The Pompe Registry

Pompe disease is a rare, autosomal recessive disorder characterized by deficiency of lysosomal acid alpha-glucosidase and accumulation of lysosomal glycogen in many tissues. The variable clinical manifestations, broad phenotypic spectrum, and overlap of signs and symptoms with other neuromuscular diseases make diagnosis challenging. In the past, the diagnosis of Pompe disease was based on enzyme activity assay in skin fibroblasts or muscle tissue. In 2004, methods for measuring acid alpha-glucosidase activity in blood were published. To compare how diagnostic methods changed over time and whether they differed by geographic region and clinical phenotype, we examined diagnostic methods used for 1059 patients enrolled in the Pompe Registry in three onset categories (Group A: onset of signs/symptoms ≤ 12 months of age with cardiomyopathy; Group B: onset ≤ 12 months without cardiomyopathy and onset >1 year to ≤ 12 years; Group C: onset >12 years). Enzyme activity-based assays were used more frequently than other diagnostic methods. Measuring acid alpha-glucosidase activity in blood (leukocytes, lymphocytes, or dried-blood spot) increased over time; use of muscle biopsy decreased. The increased use of blood-based assays for diagnosis may result in a more timely diagnosis in patients across the clinical spectrum of Pompe disease.

Guidelines for diagnosis and treatment of Hunter Syndrome for clinicians in Latin America

This review aims to provide clinicians in Latin America with the most current information on the clinical aspects, diagnosis, and management of Hunter syndrome, a serious and progressive disease for which specific treatment is available. Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient. Clinical manifestations vary widely in severity and involve multiple organs and tissues. An attenuated and a severe phenotype are recognized depending on the degree of cognitive impairment. Early diagnosis is vital for disease management. Clinical signs common to children with Hunter syndrome include inguinal hernia, frequent ear and respiratory infections, facial dysmorphisms, macrocephaly, bone dysplasia, short stature, sleep apnea, and behavior problems. Diagnosis is based on screening urinary glycosaminoglycans and confirmation by measuring I2S activity and analyzing I2S gene mutations. Idursulfase (recombinant I2S) (Elaprase®, Shire) enzyme replacement therapy (ERT), designed to address the underlying enzyme deficiency, is approved treatment and improves walking capacity and respiratory function, and reduces spleen and liver size and urinary glycosaminoglycan levels. Additional measures, responding to the multi-organ manifestations, such as abdominal/inguinal hernia repair, carpal tunnel surgery, and cardiac valve replacement, should also be considered. Investigational treatment options such as intrathecal ERT are active areas of research, and bone marrow transplantation is in clinical practice. Communication among care providers, social workers, patients and families is essential to inform and guide their decisions, establish realistic expectations, and assess patients’ responses.

Benign familial infantile seizures: further delineation of the syndrome.

Benign familial infantile seizures are an autosomal dominant epilepsy disorder that is characterized by convulsions, with onset at age 3 to 12 months and a favorable outcome. Benign familial infantile seizures have been linked to chromosome 19q, whereas infantile convulsions and choreoathetosis syndrome, in which benign familial infantile seizure is associated with paroxysmal choreoathetosis, has been linked to chromosome 16p12-q12. Many additional families from diverse ethnic backgrounds have similar syndromes that have been linked to the chromosome 16 infantile convulsions and choreoathetosis syndrome region. Moreover, in one large pedigree with paroxysmal kinesiogenic dyskinesias only, the syndrome has also been linked to the same genomic area. Families with pure benign familial infantile seizures may be linked to chromosome 16 as well. In this study, we present a series of 19 families and 24 otherwise healthy infants with benign familial infantile seizures. Two of these families include members affected with benign familial infantile seizures and paroxysmal choreoathetosis. We included patients with normal neurologic examinations, who started having simple partial seizures, complex partial seizures, or apparently generalized seizures without recognized etiology between 2 months and 2 years of age. Neurologic studies were normal, but in all patients, there was a history of similar seizures and age at onset in either the father or the mother. Twenty-four patients (14 girls and 10 boys) were evaluated at our hospital between February 1990 and February 2001. Age at onset, sex, family history of epilepsy and/or paroxysmal dyskinesias, neurologic examination, semiology, distribution, and frequency and duration of seizures were evaluated. Electroencephalographic (EEG) and neuroradiologic studies were also performed. Seizures began between 3 and 22 months of life, with a median age of 5½ months. Nine patients (37.5%) had only apparently generalized seizures, 5 patients (20.8%) had only partial seizures, and 10 patients had both partial and apparently generalized seizures (41.6%). Seizures were invariably brief, occurred during the waking state (100%), and presented mainly in clusters in 12 patients (50%). Interictal EEG was normal in 23 patients (95.8%). Sixteen patients (66.6%) had a confirmed history of convulsions in family members other than parents. Twenty-two patients became seizure free after 30 months of life. Two brothers in the same family had brief paroxysmal episodes of choreoathetosis in the hemibody triggered by stress while awake at 15 and 17 years old, respectively. One of them had paroxysmal choreoathetosis only, and the other was associated with benign familial infantile seizures. One father had brief spontaneous episodes of paroxysmal choreoathetosis when awake at age 18 years. All of them had a good response to antiepilepsy drugs, and neurologic examination and EEG and neuroradiologic studies were normal. Benign familial infantile seizure is a genetic epilepsy syndrome with autosomal dominant inheritance. It may be associated with paroxysmal choreoathetosis (infantile convulsions and choreoathetosis syndrome), which has been linked to the chromosome 16 infantile convulsions and choreoathetosis syndrome region. Patients in families with infantile convulsions and choreoathetosis syndrome could display either benign familial infantile seizures or paroxysmal choreoathetosis or both. It is likely that the disease in families with pure benign familial infantile seizures may be linked to the infantile convulsions and choreoathetosis region as well. We cannot exclude the possibility that the youngest patients may develop choreoathetosis or other dyskinesias later in life. (J Child Neurol 2002;17:696-699).