ContextFabry disease is a metabolic disorder without a specific treatment,
caused by a deficiency of the lysosomal enzyme α-galactosidase A (α-gal
A). Most patients experience debilitating neuropathic pain and premature mortality
because of renal failure, cardiovascular disease, or cerebrovascular disease.ObjectiveTo evaluate the safety and efficacy of intravenous α-gal A for
Fabry disease.Design and SettingDouble-blind placebo-controlled trial conducted from December 1998 to
August 1999 at the Clinical Research Center of the National Institutes of
Health.PatientsTwenty-six hemizygous male patients, aged 18 years or older, with Fabry
disease that was confirmed by α-gal A assay.InterventionA dosage of 0.2 mg/kg of α-gal A, administered intravenously every
other week (12 doses total).Main Outcome MeasureEffect of therapy on neuropathic pain while without neuropathic pain
medications measured by question 3 of the Brief Pain Inventory (BPI).ResultsMean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46)
to 4.3 (0.73) in patients treated with α-gal A vs no significant change
in the placebo group (P = .02). Pain-related quality
of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving α-gal
A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P = .05).
In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5%
for patients receiving α-gal vs a 16.5% increase for placebo (P = .01). Mean inulin clearance decreased by 6.2 mL/min
for patients receiving α-gal A vs 19.5 mL/min for placebo (P = .19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s)
for patients receiving α-gal A vs a decrease of 16.1 mL/min (0.3 mL/s)
for placebo (P = .02). In patients treated with α-gal
A, there was an approximately 50% reduction in plasma glycosphingolipid levels,
a significant improvement in cardiac conduction, and a significant increase
in body weight.ConclusionIntravenous infusions of α-gal A are safe and have widespread
therapeutic efficacy in Fabry disease.

https://jamanetwork.com/journals/jama/articlepdf/193887/JOC10278.pdf

Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

Background: Reliable serum creatinine measurements in glomerular filtration rate (GFR) estimation are critical to ongoing global public health efforts to increase the diagnosis and treatment of chronic kidney disease (CKD). We present an overview of the commonly used methods for the determination of serum creatinine, method limitations, and method performance in conjunction with the development of analytical performance criteria. Available resources for standardization of serum creatinine measurement are discussed, and recommendations for measurement improvement are given.

Methods: The National Kidney Disease Education Program (NKDEP) Laboratory Working Group reviewed problems related to serum creatinine measurement for estimating GFR and prepared recommendations to standardize and improve creatinine measurement.

Results: The NKDEP Laboratory Working Group, in collaboration with international professional organizations, has developed a plan that enables standardization and improved accuracy (trueness) of serum creatinine measurements in clinical laboratories worldwide that includes the use of the estimating equation for GFR based on serum creatinine concentration that was developed from the Modification of Diet in Renal Disease (MDRD) study.

Conclusions: The current variability in serum creatinine measurements renders all estimating equations for GFR, including the MDRD Study equation, less accurate in the normal and slightly increased range of serum creatinine concentrations [<133 μmol/L (1.5 mg/dL)], which is the relevant range for detecting CKD [<60 mL · min−1 · (1.73 m2)−1]. Many automated routine methods for serum creatinine measurement meet or exceed the required precision; therefore, reduction of analytical bias in creatinine assays is needed. Standardization of calibration does not correct for analytical interferences (nonspecificity bias). The bias and nonspecificity problems associated with some of the routine methods must be addressed.

/pdf/recommendations-for-improving-serum-creatinine-measurement-a-12te8ntjth.pdf

Recommendations for Improving Serum Creatinine Measurement: A Report from the Laboratory Working Group of the National Kidney Disease Education Program

Epidemiology of mucopolysaccharidoses

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.

/pdf/niemann-pick-disease-type-c-1pks03ik9f.pdf

Niemann-Pick disease type C

The classic phenotype of Fabry disease, X-linked alpha -galactosidase A (alpha -Gal A) deficiency, has an estimated incidence of approximately 1 in 50,000 males. The recent recognition of later-onset variants suggested that this treatable lysosomal disease is more frequent. To determine the disease incidence, we undertook newborn screening by assaying the alpha-Gal A activity in blood spots from 37,104 consecutive Italian male neonates. Enzyme-deficient infants were retested, and "doubly screened-positive" infants and their relatives were diagnostically confirmed by enzyme and mutation analyses. Twelve (0.03%) neonates had deficient alpha-Gal A activities and specific mutations, including four novel missense mutations (M51I, E66G, A73V, and R118C), three missense mutations (F113L, A143T, and N215S) identified previously in later-onset patients, and one splicing defect (IVS5(+1G-->T)) reported in a patient with the classic phenotype. Molecular modeling and in vitro overexpression of the missense mutations demonstrated structures and residual activities, which were rescued/enhanced by an alpha-Gal A-specific pharmacologic chaperone, consistent with mutations that cause the later-onset phenotype. Family studies revealed undiagnosed Fabry disease in affected individuals. In this population, the incidence of alpha-Gal A deficiency was 1 in approximately 3,100, with an 11 : 1 ratio of patients with the later-onset : classic phenotypes. If only known disease-causing mutations were included, the incidence would be 1 in approximately 4,600, with a 7 : 1 ratio of patients with the later-onset : classic phenotypes. These results suggest that the later-onset phenotype of Fabry disease is underdiagnosed among males with cardiac, cerebrovascular, and/or renal disease. Recognition of these patients would permit family screening and earlier therapeutic intervention. However, the higher incidence of the later-onset phenotype in patients raises ethical issues related to when screening should be performed--in the neonatal period or at early maturity, perhaps in conjunction with screening for other treatable adult-onset disorders.

High Incidence of Later-Onset Fabry Disease Revealed by Newborn Screening*

ContextLysosomal storage disorders represent a group of at
least 41 genetically distinct, biochemically related, inherited
diseases. Individually, these disorders are considered rare, although
high prevalence values have been reported in some populations. These
disorders are devastating for individuals and their families and result
in considerable use of resources from health care systems; however, the
magnitude of the problem is not well defined. To date, no comprehensive
study has been performed on the prevalence of these disorders as a
group.ObjectiveTo determine the prevalence of lysosomal storage
disorders individually and as a group in the Australian population.DesignRetrospective case studies.SettingAustralia, from January 1, 1980, through December 31,
1996.Main Outcome MeasureEnzymatic diagnosis of a lysosomal storage
disorder.ResultsTwenty-seven different lysosomal storage disorders were
diagnosed in 545 individuals. The prevalence ranged from 1 per
57,000 live births for Gaucher disease to 1 per 4.2 million live
births for sialidosis. Eighteen of 27 disorders had more than 10
diagnosed cases. As a group of disorders, the combined prevalence was 1
per 7700 live births. There was no significant increase in the rate of
either clinical diagnoses or prenatal diagnoses of lysosomal storage
disorders during the study period.ConclusionsIndividually, lysosomal storage disorders are rare
genetic diseases. However, as a group, they are relatively common and
represent an important health problem in Australia.

https://jamanetwork.com/journals/jama/articlepdf/188380/JOC80368.pdf

Prevalence of lysosomal storage disorders.

Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage.

John J. Chen, MD, PhD; Richard C. Allen, MD, PhD Chief complaint: Progressive ptosis History of Present Illness: A 58-year-old female presents with a gradual progressive worsening of bilateral blepharoptosis. She underwent blepharoplasty to both upper eyelids seven years prior to presentation to our clinic. She also has mild dysphagia and proximal muscle weakness. Past Ocular History: Blepharoplasty in 2003 Past Medical History: Non-contributory Medications: Adderall (dextroamphetamine and amphetamine), aspirin, bupropion, vitamins, trazodone Allergies: none Family History: She has a brother with bilateral ptosis, dysphagia, and profound muscle weakness. Social History: Non-smoker Review of systems: Pertinent findings are within the HPI

Oculopharyngeal muscular dystrophy

Neonatal biochemical screening for disease.

Objectives:To determine whether glycolate, a toxic metabolite of ethylene glycol that is chemically similar to lactate, can cause artifactual elevation of measured L-lactate concentrations.Design:Prospective in vitro study.Setting:Intensive care unit and chemical pathology laboratory in a university

A. Clague

Papers

Prevalence of lysosomal storage disorders.

Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage.

Oculopharyngeal muscular dystrophy

Neonatal biochemical screening for disease.

Artifactual elevation of measured plasma L-lactate concentration in the presence of glycolate.