Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders.

Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols. Case reports from 10 patients (8 infants) with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride (MCT) oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support (ventilation, ECMO, vasopressors) and, in some cases, resuscitation. The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction (EF) was assessed. EF was moderately to severely impaired prior to triheptanoin treatment, ranging from 12-45%. Improvements in EF began between 2 and 21days following initiation of triheptanoin, and peaked at 33-71%, with 9 of 10 patients achieving EF in the normal range. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy. The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Two of the case histories illustrate that cardiomyopathy may also develop later in childhood and/or persist into adulthood. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD.

Dental abnormalities in Schimke immuno-osseous dysplasia.

Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFß1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD.

Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry.

The Fabry Registry is a global observational research platform established to define outcome data on the natural and treated course of this rare disorder. Participating physicians submit structured longitudinal data to a centralized, confidential database. This report describes the baseline demographic and clinical characteristics of the first 1765 patients (54% males (16% aged < 20 years) and 46% females (13% < 20 years)) enrolled in the Fabry Registry. The median ages at symptom onset and diagnosis were 9 and 23 years (males) and 13 and 32 years (females), respectively, indicating diagnostic delays in both sexes. Frequent presenting symptoms in males included neurological pain (62%), skin signs (31%), gastroenterological symptoms (19%), renal signs (unspecified) (17%), and ophthalmological signs (11%). First symptoms in females included neurological pain (41%), gastroenterological symptoms (13%), ophthalmological (12%), and skin signs (12%). For those patients reporting renal progression, the median age at occurrence was 38 years for both sexes, but onset of cerebrovascular and cardiovascular events was later in females (median 43 and 47 years, respectively) than in males (38 and 41 years, respectively). This paper demonstrates that in spite of the considerable burden of disease in both sexes that begins to manifest in childhood or adolescence, the recognition of the underlying diagnosis is delayed by 14 years in males and 19 years in females. The Fabry Registry provides data that can increase awareness of common symptoms in all age groups, as well as insight into treated and untreated disease course, leading to improved recognition and earlier treatment, and possibly to improved outcomes for affected individuals.

The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease.

The effect of enzyme replacement therapy (ERT) on bone crisis and bone pain was investigated in patients with Gaucher disease (GD) type 1 followed over 4 years. Data from the International Collaborative Gaucher Group Gaucher Registry were used. Only patients with bone crisis and/or bone pain data for 1 year prior to ERT, and for each of 3 years after the start of ERT, were included. Bone crises were reported in 17% of patients during the year before starting ERT. The frequencies of bone crises decreased to 5%, <1% and 3% for 1, 2, and 3 years after initiation of treatment, respectively (p < 0.0001). Bone pain followed a similar pattern of response. Bone pain was reported in 49% of patients the year before treatment and decreased to 30% in the first year, 29% in the second year, and 30% in the third year of ERT (p < 0.0001). ERT is associated with a reduction in bone crisis and bone pain in patients with GD type 1 . This study shows that significant improvements in symptoms of skeletal disease are achievable clinical outcomes and treatment goals in GD type 1.

Knowledge and attitudes toward a free education and Ashkenazi Jewish carrier testing program.

Carrier testing is offered on the basis of Ashkenazi Jewish background in both the prenatal and preconception settings, with the goal of decreasing the prevalence of affected individuals and allowing informed decision-making during childbearing. The purpose of this study was to (1) document the demographic characteristics of individuals who attended a free education and screening program, (2) learn how the education program changed attendees' knowledge and attitudes by learning more about these disorders, and (3) determine how participants perceived their carrier status risk. One hundred seventy-four individuals completed questionnaires at the beginning and end of an educational program about the Ashkenazi Jewish genetic disorders. There was a statistically significant difference in the participant's level of knowledge from the pre- to post education (p < .001). Females reported a significantly higher level of concern about the disorders (p = .004) and their carrier status (p = .006) before the education, as well as about their carrier status post education (p = .05). Finally, having one or more parent affiliated with Orthodox Judaism was related to higher knowledge before the education program (p = .05). In conclusion, this study demonstrated that an educational carrier screening program increased knowledge about the disorders and also produced mild anxiety regarding personal and reproductive risks.

Late-onset optic pathway tumors in children with neurofibromatosis 1.

Identification of new optic pathway tumors (OPTs) and progression of pre-existing OPTs in children with neurofibromatosis 1 (NF1) have been reported infrequently after age 6. The authors present eight children with NF1 (mean age 12.2 years) seen in three NF1 centers who had either late-onset (four of eight) or late-progressive (seven of eight) OPT. Continued monitoring of individuals with NF1 into adulthood for the development of OPTs and for progression of known OPTs is warranted.

Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.

PURPOSE: Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid alpha-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder. METHODS: The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II. rhGAA used in this study was purified from genetically engineered Chinese hamster ovary (CHO) cells overproducing GAA. Adverse effects and efficacy of rhGAA upon cardiac, pulmonary, neurologic, and motor functions were evaluated during 1 year of the trial period. The primary end point assessed was heart failure-free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age. RESULTS: The results of more than 250 infusions showed that rhGAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants have well passed the critical age of 1 year (currently 16, 18, and 22 months old) and continue to have normal cardiac function. Improvements of skeletal muscle functions were also noted; one patient showed marked improvement and currently has normal muscle tone and strength as well as normal neurologic and Denver developmental evaluations. Muscle biopsies confirmed that dramatic reductions in glycogen accumulation had occurred after rhGAA treatment in this patient. CONCLUSIONS: This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.

The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease.

BACKGROUND: The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy. METHODS: Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review. RESULTS: Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2. 3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. CONCLUSIONS: The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.

Neural tube defects and the 13q deletion syndrome: evidence for a critical region in 13q33-34.

Neural tube defects (NTD) are common findings in the 13q deletion syndrome, but the relationship between the 13q- syndrome and NTDs is poorly understood. We present a child with a 13q deletion and lumbosacral myelomeningocele. This was a boy with microcephaly, telecanthus, minor facial anomalies, and ambiguous genitalia. Cytogenetic and fluorescence in situ hybridization analysis showed a de novo 46,XY,del(13)(q33.2-->qter) with no visible translocation. By using microsatellite markers, the deletion breakpoint was mapped to a 350-kb region between D13S274 and D13S1311 and was paternal in origin. An analysis of 13q deletions with NTDs, including the present case, suggests that a deletion in 13q33-34 is sufficient to cause an NTD. The deletions associated with NTDs are distal to and nonoverlapping with the previously defined critical region in 13q32 for the major malformation syndrome [Brown et al., 1999: Am J Hum Genet 57: 859-866]. Our analysis also suggests that one or more genes in 13q33-34 produces NTDs by haploinsufficiency.

Myelocystocele-cloacal exstrophy in a pedigree with a mitochondrial 12S rRNA mutation, aminoglycoside-induced deafness, pigmentary disturbances, and spinal anomalies.

A large Filipino-American family with progressive matrilineal hearing loss, premature graying, depigmented patches, and digital anomalies was ascertained through a survey of a spina bifida clinic for neural crest disorders. Deafness followed a matrilineal pattern of inheritance and was associated with the A1555G mutation in the 12S rRNA gene (MTRNR1) in affected individuals as well as unaffected maternal relatives. Several other malformations were found in carriers of the mutation. The proband had a myelocystocele, Arnold-Chiari type I malformation, cloacal exstrophy, and severe early-onset hearing loss. Several family members had premature graying, white forelock, congenital leukoderma with or without telecanthus, somewhat suggestive of a Waardenburg syndrome variant. In addition to the patient with myelocystocele, two individuals had scoliosis and one had segmentation defects of spinal vertebrae. The syndromic characteristics reported here are novel for the mitochondrial A1555G substitution, and may result from dysfunction of mitochondrial genes during early development. However, the mitochondrial A1555G mutation is only rarely associated with neural tube defects as it was not found in a screen of 218 additional individuals with spina bifida, four of whom had congenital hearing loss.

Neural crest anomaly syndromes in children with spina bifida.

A hereditary contribution to the etiology of neural tube defects (NTDs) has been suggested by clinical studies and animal models. To evaluate the hypothesis that common genes are important for both neural tube defects and neural crest anomalies, we examined children with developmental abnormalities of the spinal cord for anomalies of neural crest-derived structures. Neural crest anomalies, particularly auditory and pigmentary disorders, were identified and classified according to inheritance and type of anomaly. Of the 515 children screened, 44 (8.5%) had neural crest anomalies, 20 (3.9%) of which were apparently familial. Another 19 (3.7%) families had neural crest anomalies in two or more close relations, but the NTD subject was unaffected. Sixteen (3.1%) children with NTDs had a recognizable syndrome, including nine (1.7%) with a subtype of the Waardenburg syndromes. The coincidence of familial neural crest anomaly syndromes in subjects with spina bifida implies that defects in genes underlying neural crest development may contribute to the etiology of neural tube defects in a fraction of cases. The rate of anomalies and familial syndromes of neural crest-derived structures must be assessed in an adequate control sample to evaluate whether or not these abnormalities constitute risk factors for NTDs.

Intracranial gliomas in neurofibromatosis type 1.

Optic pathway gliomas and brainstem gliomas are the predominant intracranial neoplasms associated with neurofibromatosis type 1 (NF1). Before the past 15 years, studies of optic pathway gliomas in NF1 were hampered by the inaccurate diagnosis of NF1, the unavailability of noninvasive neuroimaging techniques, and the frequent rendering of what would now be considered unnecessary, overly aggressive therapy. When studied systematically, these tumors behave in a much more benign fashion than their counterparts in children who do not have NF1. While they may cause symptoms in as many of 50% of cases, progression to the point where specific intervention is deemed necessary is unusual. Consequently, screening neuroimaging of asymptomatic patients is unwarranted. Because optic pathway tumors universally arise in children younger than 7 years of age, all such children should undergo yearly ophthalmologic evaluations and annual assessments of growth to monitor for signs of precocious puberty. Am. J. Med. Genet. (Semin. Med. Genet.) 89:38-44, 1999.

Carboplatin therapy for optic pathway tumors in children with neurofibromatosis type-1.

Symptomatic optic pathway tumors (OPT) occur in 7% of children with neurofibromatosis type-1 (NF-1). Although tumor progression following diagnosis is unusual in such children, specific therapy may be necessary for patients with either severe or progressive disease. We reviewed the records of 9 children (6 girls, 3 boys) with NF-1 associated OPT who were treated with the second generation platinum compound carboplatin. Carboplatin was given at a dose of 560 mg/mm2 every 4 weeks for a mean of 15 cycles. The mean age at presentation of the OPT was 3.4 years. Eight children had abnormal ophthalmologic examinations at the time of diagnosis. Only 4 patients had documented evidence of progressive disease prior to the institution of therapy. No patient had evidence of progressive disease following therapy. Four patients had radiologic evidence of tumor shrinkage and 2 patients had definite improvement in vision. There was only minimal toxicity. In conclusion, carboplatin is a safe and effective treatment for OPT in children with NF-1. However, as disease stabilization of NF-1 associated OPT often occurs following clinical presentation, the clinician should document tumor progression or visual deterioration prior to the institution of therapy.

Gaucher disease: recommendations on diagnosis, evaluation, and monitoring.

BACKGROUND: Timely diagnosis and continued monitoring of patients with type I Gaucher disease is critical because skeletal involvement can permanently disable patients and visceral organ involvement can lead to abdominal pain and secondary hematologic and biochemical complications. OBJECTIVE: To seek clinical consensus for minimum recommendations for effective diagnosis and monitoring of patients with type I Gaucher disease. PARTICIPANTS, EVIDENCE, AND CONSENSUS PROCESS: Contributing authors collaborated in quarterly meetings over a 2-year period to synthesize recommendations from peer-reviewed publications and their own medical experiences. These physicians care for most patients with Gaucher disease in the United States and serve as the US Regional Coordinators for the International Collaborative Gaucher Group Registry, the world's largest database for this disorder. CONCLUSIONS: The definitive method of diagnosis is enzyme assay of beta-glucocerebrosidase activity. Schedules differ for monitoring complications of type I Gaucher disease, depending on symptoms and whether enzyme replacement therapy is used. Hematologic and biochemical involvement should be assessed by complete blood cell count, including platelets, acid phosphatase, and liver enzymes, at baseline and every 12 months in untreated patients and every 3 months and at enzyme replacement therapy changes in treated patients. Visceral involvement should be assessed at diagnosis using magnetic resonance imaging or computed tomographic scans. Skeletal involvement should be assessed at diagnosis using T1- and T2-weighted magnetic resonance imaging of the entire femora and plain radiography of the femora, spine, and symptomatic sites. Follow-up skeletal and visceral assessments are recommended every 12 to 24 months in untreated patients, and every 12 months and at enzyme replacement therapy changes in treated patients.

Myelomeningocele and Waardenburg syndrome (type 3) in patients with interstitial deletions of 2q35 and the PAX3 gene: possible digenic inheritance of a neural tube defect.

From a spina bifida clinic we have identified two patients with a syndrome of myelomeningocele and Waardenburg syndrome type 3 (WS3). The patients each possess a single, de novo, interstitial deletion of chromosome 2 (2q35-36.2), including the PAX3 gene. Deletion of PAX3 was confirmed by fluorescence in situ hybridization (FISH). Analysis with PAX3 and flanking microsatellites shows that the deleted interval of chromosome 2 is of paternal origin and is at least 2 and 6 cM in the two patients. Interstitial deletions in this region result in the Waardenburg syndrome (WS1), but have not been associated with neural tube defects (NTDs). Although other etiologies have not been formally excluded, these patients raise the possibility of a digenic etiology of their NTDs via a genetic interaction of the deleted PAX3 gene with a second unidentified locus.

Acceleration of retarded growth in children with Gaucher disease after treatment with alglucerase.

OBJECTIVES: The incidence and severity of growth retardation in children with type 1 Gaucher disease and the response to enzyme replacement therapy with alglucerase were studied. STUDY DESIGN: A retrospective analysis of growth in 99 children and adolescents with type 1 Gaucher disease before treatment, and in 54 of those subjects during treatment, was done. Growth was compared with gender, age, and dosage of replacement enzyme. RESULTS: Linear growth was normal in the first 1 to 2 years of life and then decelerated. Height was at or below the 5th percentile in 50% of all subjects immediately before treatment. The mean z score was -1.49 (95% confidence interval, -1.83 to -1.16), corresponding to the 6.8th percentile for height. Seventy-two percent were below the 50th percentile and 50% were at or below the 5th percentile for mid-parental height (p <0.001). One and one-half years after treatment was started, the estimated mean z score for all subjects was -1.01, which corresponds to the 16th percentile for height. Normal growth was achieved within 4 to 30 months in eight of nine subjects who were at or below the 5th percentile. It occurred only in those receiving higher doses (60 to 120 U/kg per 4-week period) of alglucerase. There was a significant association between z scores for height before treatment and liver enlargement (r= 0.57; p < 0.01). CONCLUSIONS: Half of the subjects who manifest type 1 Gaucher disease in childhood have growth retardation. Treatment with adequate amounts of modified enzyme replacement was effective in normalizing linear growth.

Optic pathway tumors in children: the effect of neurofibromatosis type 1 on clinical manifestations and natural history.

OBJECTIVE: To distinguish the clinical manifestations and natural history of optic pathway tumors (OPT) associated with neurofibromatosis type 1 (NF-1 OPT) from that of OPT not associated with NF-1 (non-NF-1 OPT). METHODS: Two groups of children with OPT were compared: (1) 17 children with NF-1 OPT who were followed prospectively, and (2) 19 children with non-NF-1 OPT who were identified retrospectively by a review of medical records. RESULTS: Precocious puberty was a common initial sign in the children with NF-1 OPT (5/17), and was not found in any patients without NF-1. In contrast, children with non-NF-1 OPT had symptoms attributable to increased intracranial pressure (12/19 and nystagmus (5/19); these symptoms were not found in any patient with NF-1. Decreased visual acuity at the time of diagnosis was common in both groups. There was no significant difference between the children with NF-1 OPT and those with non-NF-1 OPT as to age at diagnosis or sex distribution. Optic nerve involvement was more common in NF-1 (p < 0.001). Both isolated and bilateral optic nerve tumors were found exclusively in children with NF-1, whereas chiasmal (p = 0.016) and optic tract involvement (p = 0.001) were more common in those with non-NF-1 OPT. Radiographic evidence of hydrocephalus was found in none of the children with NF-1 OPT compared with 79% of the non-NF-1 OPT group. Progressive disease was seen in 12% of patients with NF-1 OPT compared with 63% of those with non-NF-1 OPT. CONCLUSIONS: Differences exist between NF-1 OPT and non-NF-1 OPT both at the time of diagnosis and during follow-up. Optic pathway tumors caused by NF-1 and non-NF-1 OPT have different biologic properties that distinguish both their initial clinical manifestations and their natural history.