Arrhythmia and Clinical Cardiac Findings in Children With Anderson-Fabry Disease.

Anderson-Fabry Disease (AFD) is a lysosomal storage disorder that results in progressive cardiovascular hypertrophy, scarring, and arrhythmia burden; yet, the early cardiac phenotype of AFD is still poorly defined. To further characterize early cardiac features in AFD, we evaluated electrocardiographic and clinical findings contained in a local cohort of pediatric AFD patients and arrhythmia data in children enrolled in the Fabry Registry. Twenty-six local patients aged <18 years were identified (average age 9.7 ± 3.8 years, n = 12 males). Sinus bradycardia was the most frequent rhythm abnormality (23%), followed by ectopic atrial rhythm (12%) and premature atrial contractions (8%). No PR, QRS, or QTc intervals were prolonged. First-degree atrioventricular block developed in 1 female during follow-up. Chest pain (35%) and palpitations (23%) were highly prevalent complaints in clinical follow-up and did not differ significantly between genders. Structural findings included aortic root dilation in 3 patients and concurrent aortic insufficiency in 1. Among 593 patients aged < 18 years with electrocardiographic data identified in the Fabry Registry, sinus bradycardia, defined as heart rate <60 beats per minute per registry guidelines, was the most common arrhythmia (12.3%). In conclusion, clinical findings and subtle abnormalities of conduction, rhythm, and structure point toward a heterogeneous inception of Fabry cardiomyopathy. Bradycardia, common in adults, is frequent even among children with AFD. Given the potential for early initiation of enzyme replacement therapy to reduce cardiovascular morbidity, continued work to develop paradigms of therapy and longitudinal cardiovascular surveillance is warranted.

Acute progression of neuromuscular findings in infantile Pompe disease.

A 2-year-old girl with Pompe disease developed an acute worsening of muscle weakness during a hospitalization, and required intubation for an upper respiratory infection. Electromyography and nerve conduction studies produced results consistent with a severe chronic motor axonal peripheral polyneuropathy, with no evidence of reinnervation. Magnetic resonance imaging of the brain demonstrated generalized hypomyelination and parenchymal volume loss, whereas magnetic resonance spectroscopy suggested neuronal injury and hypomyelination. This case provides compelling evidence for a slowly progressive neurodegenerative process in patients with infantile Pompe disease, affecting the motor neurons. Routine electromyography, nerve conduction studies, and cranial magnetic resonance imaging should be considered to delineate the presence of a neurodegenerative process in infantile-onset Pompe disease.

Comparison of health-related quality of life between heterozygous women with Fabry disease, a healthy control population, and patients with other chronic disease.

PURPOSE: Fabry disease is an X-linked lysosomal disorder due to mutations in the GLA gene. Manifestations of the disease are documented in hemizygous males. Recent studies have indicated that women with GLA mutations may report symptoms. The impact on their health-related quality of life is unclear. This study compares the quality of life of obligate heterozygotes to a historical healthy control population and to populations with multiple sclerosis and rheumatoid arthritis. METHODS: The RAND-36 and Fabry-disease specific questions were administered to study participants. Study subjects were obligate heterozygotes for mutations in GLA. Mean scores in each of the subscales from the RAND-36 were compared between study subjects and previously published data from the Women's Health Initiative and studies on multiple sclerosis and rheumatoid arthritis. RESULTS: Comparisons between 202 study participants and the Women's Health Initiative indicated that all eight subscale scores of the RAND-36 were significantly lower for women with Fabry disease (P < 0.0001). The mean scores of the study participants more closely resembled the mean scores of the participants in the multiple sclerosis and rheumatoid arthritis studies. CONCLUSION: Study participants reported clinically important effects on health-related quality of life. It is critical to develop management protocols for this population.

Enzyme therapy of gaucher disease: clinical and biochemical changes during production of and tolerization for neutralizing antibodies.

The clinical impact of neutralizing antibodies directed against the therapeutic enzyme was investigated in patients with Gaucher disease. Two patients with Gaucher disease type 1 were followed for their clinical progression during antibody development and clinical changes during tolerization. Patient 1 developed neutralizing antibodies to imiglucerase (GCase) at the 10th month of enzyme therapy. Tolerization was achieved within a 42-month period with a short course of cyclophosphamide and then higher dose enzyme (60 IU/kg/week) alone. Patient 1 continues to improve up to 100 months of enzyme therapy despite the presence of low level in vitro neutralizing antibodies. Patient 2 developed neutralizing antibodies to GCase at the 29th month of enzyme therapy that correlated with clinical deterioration. Clinical stabilization has been observed with increased enzyme therapy (60 IU/kg/week) even in the presence of the neutralizing antibodies. Patient 2 is the first to develop neutralizing antibodies after 12 months of enzyme therapy. Plasma chitotriosidase activities were not well correlated with the clinical course in either patient. The presence of neutralizing antibodies should be suspected in Gaucher disease patients on enzyme therapy who experience diminished response or deterioration. The persistence of minimal amounts of in vitro neutralizing antibodies does not interfere with the therapeutic effectiveness. Chitotriosidase is not a sensitive marker for the severity of disease or disease progression.

Gaucher disease: in vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes.

Gaucher disease, a common lysosomal storage disorder, is associated with mutations at the acid beta-glucosidase (GCase) locus. Two affected individuals are described to share a common mutant allele, but manifest different clinical categorical phenotypes. A 57-year-old female, with Gaucher disease type 1 and Cherokee ancestry, was homozygous for a rare mutant allele encoding Lys79Asn (K79N). A 2-year-old Caucasian male, with Gaucher disease type 3 and Cherokee ancestry, was a heteroallelic homozygote for this same allele (K79N) and a novel complex mutation (null allele). The shared alleles were identical as determined by complete gene sequencing, suggesting a founder effect. The discrepant phenotypes (types 1 and 3) in these two patients provide support for a threshold of residual activity necessary to "protect" the central nervous system (CNS) from the pathogenic effects of Gaucher disease, indicating an allele dose-effect. Designation of genotype associations with specific phenotypes must be assessed with this perspective.