Eniko K. Pivnick

Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease

Purpose: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease.Methods: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3–43 months old (median 13 months) with minimal acid α-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort.Results: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid α-glucosidase; no patients withdrew from the study because of safety concerns.Conclusions: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.

Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome.

We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat–mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events.

Jacobsen syndrome: report of a patient with severe eye anomalies, growth hormone deficiency, and hypothyroidism associated with deletion 11 (q23q25) and review of 52 cases.

We have evaluated a patient with Jacobsen syndrome. The patient presented with growth retardation, hypotonia, trigonocephaly, telecanthus, downward slanting palpebral fissures, bilateral inferior colobomas (of the iris, choroid, and retina), hydrocephalus, central nervous system (CNS) abnormalities, and an endocardial cushion defect, features commonly seen in Jacobsen syndrome. Endocrine evaluation showed growth hormone deficiency and central hypothyroidism. Chromosome analysis showed a 46,XX,del(11)(q23q25) de novo karyotype. Cytogenetically, the deletion appeared to include most of bands 11q23 and q24 and a portion of q25. Using chromosome specific paint probe, a combination of chromosome 11 centromere, telomere, and region specific cosmid probes from 11q14.1-14.3, 11q23.3, and 11q24.1, we have localised the deletion breakpoint to q24.1. Phenotype-karyotype correlation of patients with Jacobsen syndrome and specific deletions of chromosome 11q has enabled us to suggest that the critical region for this syndrome lies in close proximity to cytogenetic band 11q24. Although growth retardation is a consistent finding in 11q deletion syndrome, the presence of hypothalamic-pituitary hormone deficiency has not been reported previously.

Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: Report of five new cases and review

The neonatal progeroid syndrome (NPS), or Wiedemann-Rautenstrauch, is a rare autosomal recessive disorder comprised of generalized lipoatrophy except for fat pads in the suprabuttock areas, hypotrichosis of the scalp hair, eyebrows, and eyelashes, relative macrocephaly, triangular face, natal teeth, and micrognathia. We report on 5 new patients who demonstrate phenotypic variability and who represent the single largest series of NPS reported to date. Two of the patients are from an African-American kindred, an ethnic occurrence not reported previously. The fact that there are 2 pairs of sibs among the 5 patients further supports that NPS is an autosomal recessive condition. This report also includes a review of the previously reported 16 patients and compares them with the 5 new patients. Abnormalities in endocrine and lipid metabolism were found in 3 of 5 patients. Skeletal findings in 2 of our patients demonstrated some new findings as well as the typical radiological abnormalities previously noted in NPS. It is apparent, based on the 21 cases, that mild to moderate mental retardation is common in NPS. Long term follow-up of patients with NPS should provide more information relative to their ultimate psychomotor development. NPS is usually lethal by 7 months; however, on rare occasions, patients have survived into the teens. Our 3 surviving patients range in age from 16-23 months. Variability in the phenotype of NPS is clear; however, the phenotype remains distinct enough to allow a secure diagnosis.

The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature

Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism‐associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been identified. We performed a phenotype/genotype analysis of individuals with interstitial 15q duplications to broaden our understanding of the 15q syndrome and investigate the contribution of 15q duplication to increased autism risk. All subjects were recruited solely on the basis of interstitial duplication 15q11.2‐q13 status. Comparative array genome hybridization was used to determine the duplication size and boundaries while the methylation status of the maternally methylated small nuclear ribonucleoprotein polypeptide N gene was used to determine the parent of origin of the duplication. We determined the duplication size and parental origin for 14 int dup(15) subjects: 10 maternal and 4 paternal cases. The majority of int dup(15) cases recruited were maternal in origin, most likely due to our finding that maternal duplication was coincident with autism spectrum disorder. The size of the duplication did not correlate with the severity of the phenotype as established by Autism Diagnostic Observation Scale calibrated severity score. We identified phenotypes not comprehensively described before in this cohort including mild facial dysmorphism, sleep problems and an unusual electroencephalogram variant. Our results are consistent with the hypothesis that the maternally expressed ubiquitin protein ligase E3A gene is primarily responsible for the autism phenotype in int dup(15) since all maternal cases tested presented on the autism spectrum. Autism Res 2013, ●●: ●●–●●.

Neurofibromatosis type 1 (NF1): a protein truncation assay yielding identification of mutations in 73% of patients.

Neurofibromatosis type 1 (NF1) is caused by mutations in a tumour suppressor gene located on chromosome 17 (17q11.2). Disease causing mutations are dispersed throughout the gene, which spans 350 kilobases and includes 59 exons. A common consequence of NF1 mutations is introduction of a premature stop codon, and the majority of mutant genes encode truncated forms of neurofibromin. We used a protein truncation assay to screen for mutations in 15 NF1 patients and obtained positive results in 11 of them (73%). Sequencing of cDNA and genomic DNA yielded identification of 10 different mutations, including four splicing errors, three small deletions, two nonsense mutations, and one small insertion. Nine mutations were predicted to cause premature termination of translation, while one mutation caused in frame deletion as a result ofexon skipping. In one other case involving abnormal splicing, five different aberrantly spliced transcripts were detected. One germline nonsense mutation (R1306X, 3916C>T) corresponded to the same base change that occurs by mRNA editing in normal subjects. The second nonsense mutation (R2496X) was the sole germline mutation that has been previously described. The subjects studied represented typically affected NF1 patients and no correlations between genotype and phenotype were apparent. A high incidence of ocular hypertelorism was observed.

Rickets Secondary to Phosphate Depletion: A Sequela of Antacid Use in Infancy

Two infants presented with growth failure and were found to have generalized osteomalacia (rickets) due to phosphate depletion from prolonged administration of an aluminum-containing antacid given for the symptoms of colic. One of the infants developed bilateral proptosis due to craniosynostosis related to the underlying metabolic bone disease. The chronic use of aluminum-containing antacids in infants has potential risk for the growing skeleton and is not innocuous. Therefore, antacid therapy should be used in low doses and very cautiously, with routine monitoring of serum calcium and phosphorus in children taking medications which reduce gastrointestinal phosphate absorption.

Infant with midline thoracoabdominal schisis and limb defects

An infant presented with multiple congenital anomalies including a midline thoracoabdominal defect, absence of the sternum, ectopia cordis, right diaphragmatic hernia, right anophthalmia, left microphthalmia, incomplete bilateral cleft lip, and various limb defects including ectrodactyly of the right hand and left foot, and phocomelia of the right lower extremity. The infant expired soon after birth. The radiological findings included absence of the sternum, 11 right-sided ribs, absence of the middle third of the right clavicle, opaque right hemithorax, hypoplastic right tibia, absent right fibula and foot, and ectrodactyly of the right hand and left foot. In addition, the autopsy revealed two distinct diaphragmatic defects, an anterior midline defect of the diaphragm beneath the ectopic heart, and a large Bochdalek hernia, with abdominal contents in the chest. Our case has overlapping features with conditions such as thoracoabdominal syndrome, pentalogy of Cantrell, and limb-body wall complex, but the concurrence of midline body wall defect and ectrodactyly has not been described previously.

Partial duplication of the long arm of chromosome 6: a clinically recognisable syndrome.

Reciprocal translocations involving the short arm of acrocentric chromosomes can segregate to produce partial duplications without associated deletions. We present a case of an infant with a 46,XY,-15,+der(15),T(6;15)(q23;p12)pat chromosome complement. The infant had multiple congenital abnormalities including cranial anomalies, facial dysmorphism, anterior webbing of the neck, cardiac anomalies, and joint contractures. From a comparison of the infants phenotype with 20 other patients with a similar duplication, it is evident that partial duplication of the long arm of chromosome 6 is a clinically diagnosable syndrome.

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype–Phenotype Correlation

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype–phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café‐au‐lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan‐like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1‐patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi‐exon deletion, providing genetic evidence that p.Arg1809Cys is a loss‐of‐function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype–phenotype correlation will affect counseling and management of a significant number of patients.