The Spectrum of Mutations of Homocystinuria in the MENA Region

Abstract

Homocystinuria is an inborn error of metabolism due to the deficiency in cystathionine beta-synthase (CBS) enzyme activity. It leads to the elevation of both homocysteine and methionine levels in the blood and urine. Consequently, this build-up could lead to several complications such as nearsightedness, dislocated eye lenses, a variety of psychiatric and behavioral disorders, as well as vascular system complications. The prevalence of homocystinuria is around 1/200,000 births worldwide. However, its prevalence in the Gulf region, notably Qatar, is exceptionally high and reached 1:1800. To date, more than 191 pathogenic CBS mutations have been documented. The majority of these mutations were identified in Caucasians of European ancestry, whereas only a few mutations from African-Americans or Asians were reported. Approximately 87% of all CBS mutations are missense and do not target the CBS catalytic site, but rather result in unstable misfolded proteins lacking the normal biological function, designating them for degradation. The early detection of homocystinuria along with low protein and methionine-restricted diet is the best treatment approach for all types of homocystinuria patients. Yet, less than 50% of affected individuals show a significant reduction in plasma homocysteine levels after treatment. Patients who fail to lower the elevated homocysteine levels, through high protein-restricted diet or by B6 and folic acid supplements, are at higher risk for cardiovascular diseases, neurodegenerative diseases, neural tube defects, and other severe clinical complications. This review aims to examine the mutations spectrum of the CBS gene, the disease management, as well as the current and potential treatment approaches with a greater emphasis on studies reported in the Middle East and North Africa (MENA) region.

Congenital cataract: An ocular manifestation of classical homocystinuria

“…In future chemical chaperons to minimize the accumulation of misfolded protein and enzyme replacement therapy is being considered for homocystinuria treatment and clinical trials are being done on mice strain by administration of PEG‐CBS. The results showed the significant reduction in plasma homocysteine levels in CBS‐deficient mice (Al‐Sadeq & Nasrallah, 2020 ; Majtan et al, 2018 ).…”

“…The affected individuals are healthy at the time of birth but they show developmental delay during first years of life. The reported global incidence of homocystinuria is estimated to be 1 in 200,000 (Al‐Sadeq & Nasrallah, 2020 ).…”

Особенности Концентрации Гомоцистеина В Сыворотке Крови Детей С Вазовагальными Синкопе

“…Гомоцистеїн -це сірковмісна амінокислота, яка є продуктом метаболізму амінокислоти метіоніну, що надходить до організму з продуктами тваринного походження (м'ясом, молоком, яйцями тощо). Зростання концентрації гомоцистеїну у сироватці крові може бути пов'язане як із дефіцитом вітамінів В 6 , В 12 , фолієвої кислоти [1], так і з генетичними дефектами ферментів, що беруть участь у метаболізмі гомоцистеїну [2,3]. Прийнято вважати, що метаболізм гомоцистеїну може бути расово та етнічно залежним [4].…”

Early Diagnosis of Classic Homocystinuria in Kuwait through Newborn Screening: A 6-Year Experience

“…The management of HCU resides mainly in lowering Hcy level to near normal levels via Met restricted diet, betaine, folic acid, and pyridoxine supplementation. However, poor compliance to diet and medications as well as the considerable fraction of pyridoxine nonresponsive individuals noted in the Qatari population [6], has led to further therapies that are currently under investigations, such as enzyme replacement and gene therapies [16].…”