Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency.

Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 µmol/L. Nevertheless, we recommend keeping the concentration below 100 µmol/L because levels fluctuate and the complications associated with high levels are so serious.

Is Adherence to Imatinib Mesylate Treatment Among Patients with Chronic Myeloid Leukemia Associated with Better Clinical Outcomes in Qatar?

BACKGROUND: Despite the revolutionary success of introducing tyrosine kinase inhibitors (TKIs), such as imatinib mesylate (IM), for treating chronic myeloid leukemia (CML), a substantial proportion of patients' treatments fail. AIM: This study investigates the correlation between patient adherence and failure of TKIs' treatment in a follow-up study. METHODS: This is a follow-up study of a new cohort of CML patients. Adherence to IM is assessed using the Medication Event Monitoring System (MEMS 6 TrackCap, AARDEX Ltd). The 9-item Morisky Medication Adherence Scale, medication possession ratio (MPR) calculation, and the electronic medical records are used for identifying potential factors that influence adherence. Clinical outcomes are assessed according to the European Leukemia Net 2013 guidelines via reverse transcriptase quantitative polymerase chain reaction measurement of the level of BCR-ABL1 transcripts in peripheral blood. Response is classified at the hematological, cytogenetic, and molecular levels into optimal, suboptimal, or failure. RESULTS: A total of 36 CML patients (5 citizens and 31 noncitizen residents) consented to participate in the study. The overall mean MEMS score was 89. Of the 36 patients, 22 (61%) were classified as adherent (mean: 95) and 14 (39%) were classified as nonadherent (mean: 80.2). Adherent patients were significantly more likely to obtain optimal response (95%) compared to the nonadherent group (14.3%; P < 0.0001). The rate of poor adherence was as high as 39% using MEMS, which correlates with 37% treatment failure rate. The survey results show that 97% of patients increased the IM dose by themselves when they felt unwell and 31% of them took the missing IM dose when they remembered. Other factors known to influence adherence show that half of patients developed one or more side effects, 65% of patients experienced lack of funds, 13% of patients declared unavailability of the drug in the NCCCR pharmacy, and 72% of patients believed that IM would cure the disease. The MPR results reveal that 16% of patients had poor access to treatment through the hospital pharmacy. DISCUSSION AND CONCLUSION: This is the first prospective study to evaluate CML patients' adherence and response to IM in Qatar. The high rate of treatment failure observed in Qatar is explained by poor adherence. An economic factor (unaffordable drug prices) is one of the main causes of nonadherence and efforts should be made locally to improve access to medication for cancer diseases. Other risk factors associated with poor adherence could be improved by close monitoring and dose adjustment. Monitoring risk factors for poor adherence and patient education that include direct communication between the health-care teams, doctors, nurses, pharmacists, and patients are essential components for maximizing the benefits of TKI therapy and could rectify this problem. The preliminary results show that patients' response to treatment may be directly linked to patients' adherence to treatment. However, further in-depth and specific analysis may be necessary in a larger cohort.

Late-onset cobalamin-C disorder: a challenging diagnosis.

Cobalamin-C (cblC) disease is a rare autosomal recessive disorder due to defective intracellular cobalamin metabolism. There are few (13) reported patients of the late-onset presentation of cblC disease with paucity of detailed clinical descriptions. This results in this condition being easily missed. In this report, we describe clinical and biochemical findings of two unrelated patients with late-onset cblC disease who presented with neuropsychiatric symptoms. Serial MRI images are provided for one of these patients. Presumptive diagnosis was made with urine and plasma biochemical markers and confirmed with fibroblast analysis. These patients illustrate the challenging diagnosis of this disease and also report on the rare associated findings of vasculopathy and mitochondrial respiratory chain dysfunction. Mutation analysis of the MMACHC gene showed that both patients were homozygous for 394C --> T which suggests a founder effect.

A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome.

The clinical phenotype of Ligase IV syndrome (LIG4 syndrome), an extremely rare autosomal recessive condition caused by mutations in the LIG4 gene, closely resembles that of Nijmegen breakage syndrome (NBS), and is characterized by microcephaly, characteristic facial features, growth retardation, developmental delay, and immunodeficiency. We report a 4(1/2)-year-old boy who presented with acute T-cell leukemia. The facial gestalt was strongly reminiscent of NBS. The patient died shortly after the onset of treatment for his T-cell leukemia. Subsequent chromosome breakage studies showed a high rate of breakage in a fibroblast culture. Radiosensitivity was assessed by a colony survival assay; the results showed radiosensitivity greater than is typically seen in NBS. Mutation screening of the NBS1 gene was negative. Sequencing of the LIG4 gene revealed a homozygous truncating mutation 2440 C>T (R814X). Although this mutation has been previously noted in LIG4 syndrome, this patient is the first reported homozygote for the mutation. In this study, we review the clinical features of this rare syndrome and provide suggestions for differential diagnosis.