Natural history, with clinical, biochemical, and molecular characterization of classical homocystinuria in the Qatari population

Abstract

Classical homocystinuria (HCU) is the most common inborn error of metabolism in Qatar, with an incidence of 1:1800, and is caused by the Qatari founder p.R336C mutation in the CBS gene. This study describes the natural history and clinical manifestations of HCU in the Qatari population. A single center study was performed between 2016 and 2017 in 126 Qatari patients, from 82 families. Detailed clinical and biochemical data were collected, and Stanford‐Binet intelligence, quality of life and adherence to treatment assessments were conducted prospectively. Patients were assigned to one of three groups, according to the mode of diagnosis: (a) late diagnosis group (LDG), (b) family screening group (FSG), and (c) newborn screening group (NSG). Of the 126 patients, 69 (55%) were in the LDG, 44 (35%) in the NSG, and 13 (10%) in the FSG. The leading factors for diagnosis in the LDG were ocular manifestations (49%), neurological manifestations (45%), thromboembolic events (4%), and hyperactivity and behavioral changes (1%). Both FSG and NSG groups were asymptomatic at time of diagnosis. NSG had significantly higher intelligence quotient, quality of life, and adherence values compared with the LDG. The LDG and FSG had significantly higher methionine levels than the NSG. The LDG also had significantly higher total homocysteine levels than the NSG and FSG. Regression analysis confirmed these results even when adjusting for age at diagnosis, current age, or adherence. These findings increase the understanding of the natural history of HCU and highlight the importance of early diagnosis and treatment. Synopsis A study in 126 Qatari patients with HCU, including biochemical, clinical, and other key assessments, reveals that patients with a late clinical diagnosis have a poorer outcome, hereby highlighting the importance of early diagnosis and treatment.

The Spectrum of Mutations of Homocystinuria in the MENA Region

“…Clinically, patients with classic homocystinuria exhibit numerous manifestations during infancy because homocysteine disrupts the development of many organ systems. These include Marfanoid habitus, pectus exavatum (curved-in sternum), pectus carinatum (protruding sternum), genu valgum, where knees are angled toward each other, and many other skeletal deformities [67,68]. In addition, ectopia lentis (dislocation of the lens) can lead to nearsightedness and blurred vision.…”

“…The early detection of homocystinuria along low protein and methionine restricted diet is the best treatment approach for all types of homocystinuria patients [68]. Referring to the homocystinuria metabolism pathway (Figure 1), the administration of folic acid and pyridoxine is also considered as an effective therapy, especially in pyridoxine-responsive patients, as these supplements have shown to enhance the CBS enzyme residual activity in more than half of the patients [77].…”

Clinical genetics and genomic medicine in Qatar

“…Early analyses (2012–2014) of 149 probands undergoing CES identified a causative explanation in 89 (60%) of the studied probands (Yavarna et al., ). More recent analyses of a larger cohort of >500 patients show a diagnostic yield of >48% (Al‐Dewik et al., ). This still high but slightly lower yield may involve factors such as evolving differences in variant classification techniques and guidelines as well as underlying cohort differences and practices in terms of which patients receive CES and when.…”

Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common?

“…[14] A recent study from Qatar observed that patients early diagnosed by neonatal screening had significantly higher intelligence quotient, quality of life, and adherence to treatment when compared with the late diagnosed patients. [26] In addition to the direct toxicity of Hcy on CNS, recurrent strokes can also impact cognitive skills. [11,22] Seizures occur in nearly 20% of the patients.…”

“…[39] Good metabolic control from the neonatal period and thereafter is capable to prevent the clinical manifestations of HCU. [14,26,57,58] In late diagnosed patients, treatment can also significantly prevents morbidity and mortality. [44] Even when tHcy remained higher than the target values, a major reduction in vascular disease risk is observed in HCU patients.…”