Incidental finding of cornea verticillata or lamellar inclusions in kidney biopsy: measurement of lyso-Gb3 in plasma defines between Fabry disease and drug-induced phospholipidosis.

INTRODUCTION: Therapy with cationic amphiphilic drugs (Amiodarone or hydroxychloroquine) may result in biochemically and ultrastructurally similar lipid inclusions in many cells also affected by Fabry disease (FD). In addition, it often results in similar clinical manifestations such as cornea verticillata. This may lead to a FD misdiagnosis, especially when a complete medical history is not available to the ophthalmologist confronted with cornea verticillata or to the pathologist examining a kidney biopsy. When enzymatic/genetic test or pathological studies are not conclusive, a specific biomarker may help clarify this dilemma. The plasma globotriaosylsphingosine (lyso-Gb3) assay has high sensitivity and specificity and is elevated above normal levels in FD. MATERIALS AND METHODS: We measured plasma lyso-Gb3 levels in male patients receiving Amiodarone or hydroxychloroquine and compared it with male patients with classic and late onset variant of FD. RESULTS: In all Fabry patients (classic and late onset variant) α-GalA activity was deficient in dried blood spot and plasma lyso-Gb3 was above normal levels. Patients on treatment with Amiodarone or hydroxychloroquine had normal values for α-GalA activity and lyso-Gb3 in plasma. CONCLUSIONS: Even when Amiodarone or hydroxychloroquine may decrease α-GalA activity in vitro or in cell culture, our results showed that in all patients lyso-Gb3 plasma levels remain normal with no evidence of reduction in α-GalA activity, confirming the specificity of this biomarker for the diagnosis of FD.

Chronic intestinal pseudo-obstruction. Did you search for lysosomal storage diseases?

Chronic intestinal pseudo-obstruction results in clinical manifestations that resemble intestinal obstruction but in the absence of any physical obstructive process. Fabry disease is an X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement. We report the occurrence of chronic intestinal pseudo-obstruction in two unrelated patients with Fabry disease and the possible explanation of a direct relation of these two disorders. In Fabry disease, gastrointestinal symptoms occur in approximately 70% of male patients, but the frequency ranges from 19% to 69% in different series. In some patients, colonic dysmotility due glycolipid deposition in autonomic plexus and ganglia can lead to the pseudo-obstruction syndrome, simulating intestinal necrosis. That is why up to this date colostomy has been performed in some cases, even for children with FD without cardiac, renal or cerebrovascular compromise. Early treatment with enzyme replacement therapy in asymptomatic or mildly symptomatic patients may be justified in order to prevent disease progression. Several studies have demonstrated that enzyme replacement therapy alleviates GI manifestations. Because of the non-specific nature of the gastrointestinal symptoms, diagnosis of Fabry disease is often delayed for several years. Gastrointestinal involvement is often misdiagnosed or under-reported. It is therefore very important to consider Fabry disease in the differential diagnosis of chronic intestinal pseudo-obstruction.

Gastrointestinal involvement in Fabry disease. So important, yet often neglected.

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A which causes accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. Gastrointestinal symptoms are due to intestinal dysmotility as well as impaired autonomic function, vasculopathy and myopathy. Since 2001, enzyme replacement therapy has been a mainstay in treatment of gastrointestinal symptoms of Fabry disease (FD), resulting in reduced gastrointestinal symptoms. Here, we report on four patients with Fabry disease (FD) who manifested early gastrointestinal involvement.

Fabry disease and enzyme replacement therapy in classic patients with same mutation: different formulations--different outcome?

We describe the results of the multidisciplinary evaluation in patients with Fabry disease and the same genetic mutation and their outcomes using different approved enzyme replacement therapy (ERT). We measured baseline data and serial results of neuropathic pain assessment and renal, cardiac and cerebrovascular functioning. Pain scale showed improvement in all male cases treated with agalsidasa beta. A mild improvement was detected in agalsidasa alfa-treated patients after 1 year with posterior increase. During the agalsidase beta shortage, two male patients were switched to agalsidasa alfa, after 1 year both cases presented an increase in scale values. Renal evolution showed a tendency toward a decrease in proteinuria in patients using agalsidase beta and worsening with agalsidase alfa. We found improvement in two females using agalsidase beta and no changes in the other cases regarding cardiac functioning. Brain magnetic resonance imaging (MRI) showed increase of white matter lesions in four patients. Improvement and stabilization in neuropathic pain, renal and cardiac functioning and brain MRI were found mainly in patients treated with agalsidase beta. Following the reported recommendations on reintroduction of agalsidase beta after the enzyme shortage, we decided to switch all patients to agalsidase beta.

Multiple acyl-CoA-dehydrogenase deficiency (MADD): use of acylcarnitines and fatty acids to monitor the response to dietary treatment.

The treatment of multiple acyl-CoA-dehydrogenase deficiency (MADD) includes a low-fat, low-protein, high-carbohydrate diet, avoiding long fasting periods. However, there is no useful biochemical marker to determine the response to different diets or fasting periods. The aims of this study are to report a patient with MADD, diagnosed through a newborn screening program using tandem mass spectrometry, to assess her response to different feedings, and to evaluate the usefulness of acylcarnitines and FFA to monitor the response to dietary changes. The patient was diagnosed at 6 d. Family history revealed three dead siblings. Five tests were performed, one with breast milk and the subsequent four after giving the patient a bottle of a low-fat, low-protein formula (F), F with glucose polymers (GP), F+GP plus uncooked corn starch (CS), or F+GP+CS preceded by amylase. The results showed that acylcarnitines, FFA, and total nonesterified fatty acids levels were greatly improved at 2 and 4 h on F+GP compared with breast milk. At 6 mo of age, the test with F+CS was repeated to assess the response to a longer fast. The results were similar at 2 and 4 h, but showed a marked increase of acylcarnitines, FFA, and total nonesterified fatty acids at 6 h. The increase of these metabolites could not be avoided by the use of F+GP+CS, but was prevented when amylase was used simultaneously. The patient is currently 3.9 y old and has normal growth and development. We conclude that diagnosis of MADD through a newborn screening program using tandem mass spectrometry is suitable; acylcarnitines and FFA are useful to monitor the response to treatment; and exogenous amylase allows the use of CS in small children with MADD. This therapeutic approach may be an alternative to the use of continuous overnight feedings used for young children with severe fatty acid oxidation defects. Early diagnosis and treatment may change the natural history of MADD.

Diagnosis of isovaleric acidaemia by tandem mass spectrometry: false positive result due to pivaloylcarnitine in a newborn screening programme.

Tandem mass spectrometric analysis of acylcarnitines and amino acids has been applied in newborn screening programmes for the detection of several inborn errors of metabolism. We report a false positive result for isovaleric acidaemia in a newborn screening programme using this method. The newborn screening sample showed a very prominent signal corresponding to the mass of isovalerylcarnitine. Repeat samples (age 6 days) of blood and urine showed similar results. However, urine organic acids were normal. Acylcarnitine analysis in blood, breast milk and urine of the mother also showed a prominent signal of the same mass. Gas chromatography-mass spectrometry of the methyl esters demonstrated that the signal in the patient's urine was due to the presence of pivaloylcarnitine, which is isomeric with isovalerylcarnitine. The patient's mother was receiving an antibiotic containing a derivative of pivalic acid to treat a urinary tract infection. Follow-up samples in the patient and the mother confirmed a decrease in the levels of pivaloylcarnitine, concomitant with the discontinuation of the treatment. We conclude that pivaloylcarnitine can give a false positive result for isovaleric acidaemia in newborns whose mothers are on treatment with pivoxilsulbactam-containing antibiotics.