Abstract
Background: Classical homocystinuria due to cystathionine β-synthase (CBS) deficiency (OMIM 236200) is a recessively inherited condition caused by mutations in the CBS gene. The founder mutation p.R336C accounts for almost all CBS deficiency in Qatar, affecting approximately 1 in 1,800 births, making it the most prevalent monogenic disease among the Qatari population. Untreated patients can have severe intellectual disability (ID), devastating multisystem complications and premature death. Current treatment is based on pharmacology therapy and life-long methionine-restricted diet, which is difficult to maintain particularly in late diagnosed individuals. Data on the neurodevelopmental and psychological impact of the disease on outcomes among Qatari patients are generally lacking and have not been studied.
Objectives: To examine the cognitive, educational and psychological outcomes of classical homocystinuria on Qatari patients.
Subjects and Methods: Thirty-two cases with classical homocystinuria and 25 sibling controls were recruited to evaluate the neurodevelopmental and cognitive outcomes. We reviewed the subjects’ medical record and collected pertinent clinical and educational data from parents. Stanford–Binet Intelligence Test (Arabic translation – 4th ed.) was used for cognitive (IQ) testing.
Results: The mean age for the subjects was 11.2 years (range 0.6–29) with 56% males. The majority of cases (93%) carried the mutation (p.R336C), and parental consanguinity was 84%. There were no differences between the two groups in the fine motor, expressive language, behavioural and visual skills. However, cases have much lower total IQ particularly in the domains of short memory, quantitative reasoning and visual–spatial domains. A significant number of adolescents and adult cases had medical co-morbidities as well as behavioural and emotional problems.
Conclusion: Individuals with classical homocystinuria have many developmental and cognitive difficulties with significant number of cases having learning disability and lower IQs (cf. sibling controls) with adolescents and adults more affected. Those diagnosed by newborn screening have better developmental and cognitive outcomes compared to late diagnosed cases. Psychological and psychiatric referrals should be part of the standard of care for those cases
Competing interests: None declared
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References
Abbott MH, Folstein SE, Abbey H, Pyeritz RE (1987) Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B6-responsiveness. Am J Med Genet 26(4):959–969
Al-Essa M, Rashed M, Ozand PT (1998) Saudi experience with classic homocystinuria. Ann Saudi Med 18(3):230–233
Bailey JM, Revelle W (1991) Increased heritability for lower IQ levels? Behav Genet 21(4):397–404
Bonnot O, Klunemann HH, Sedel F, Tordjman S, Cohen D, Walterfang M (2014) Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review. Orphanet J Rare Dis 9:65
Devlin B, Daniels M, Roeder K (1997) The heritability of IQ. Nature 388(6641):468–471
Dickens WT, Flynn JR (2001) Heritability estimates versus large environmental effects: the IQ paradox resolved. Psychol Rev 108(2):346–369
Eldridge R, Denckla MB, Bien E, Myers S, Kaiser-Kupfer MI, Pikus A, Schlesinger SL, Parry DM, Dambrosia JM, Zasloff MA et al (1989) Neurofibromatosis type 1 (Recklinghausen’s disease). Neurologic and cognitive assessment with sibling controls. Am J Dis Child 143(7):833–837
El-Said MF, Badii R, Bessisso MS, Shahbek N, El-Ali MG, El-Marikhie M, El-Zyoid M, Salem MS, Bener A, Hoffmann GF, Zschocke J (2006) A common mutation in the CBS gene explains a high incidence of homocystinuria in the Qatari population. Hum Mutat 27(7):719
Gan-Schreier H, Kebbewar M, Fang-Hoffmann J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Bener A, Al Rifai H, Al Khal AL, Lindner M, Zschocke J, Hoffmann GF (2010) Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr 156(3):427–432
Koch R, Azen C, Friedman EG, Williamson ML (1984) Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age. J Inherit Metab Dis 7(2):86–90
Kraus JP, Janosik M, Kozich V, Mandell R, Shih V, Sperandeo MP, Sebastio G, de Franchis R, Andria G, Kluijtmans LA, Blom H, Boers GH, Gordon RB, Kamoun P, Tsai MY, Kruger WD, Koch HG, Ohura T, Gaustadnes M (1999) Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat 13(5):362–375
Lindner M, Abdoh G, Fang-Hoffmann J, Shabeck N, Al-Sayrafi M, Al-Janahi M, Ho S, Abdelrahman MO, Ben-Omran T, Bener A, Schulze A, Al-Rifai H, Al-Thani G, Hoffmann GF (2007) Implementation of extended neonatal screening and a metabolic unit in the State of Qatar: developing and optimizing strategies in cooperation with the Neonatal Screening Center in Heidelberg. J Inherit Metab Dis 30(4):522–529
Mudd SH (1985) Vascular disease and homocysteine metabolism. N Engl J Med 313(12):751–753
Mudd SH, Finkelstein JD, Irreverre F, Laster L (1964) Homocystinuria: an enzymatic defect. Science 143(3613):1443–1445
Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GH, Bromberg IL, Cerone R et al (1985) The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 37(1):1–31
Naughten ER, Yap S, Mayne PD (1998) Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr 157(Suppl 2):S84–S87
Schiff M, Blom HJ (2012) Treatment of inherited homocystinurias. Neuropediatrics 43(6):295–304
Turkheimer E, Haley A, Waldron M, D’Onofrio B, Gottesman II (2003) Socioeconomic status modifies heritability of IQ in young children. Psychol Sci 14(6):623–628
Urreizti R, Asteggiano C, Cozar M, Frank N, Vilaseca MA, Grinberg D, Balcells S (2006) Functional assays testing pathogenicity of 14 cystathionine-beta synthase mutations. Hum Mutat 27(2):211
Weisfeld-Adams JD, Bender HA, Miley-Akerstedt A, Frempong T, Schrager NL, Patel K, Naidich TP, Stein V, Spat J, Towns S, Wasserstein MP, Peter I, Frank Y, Diaz GA (2013) Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonic acidemia and homocystinuria, cobalamin C type. Mol Genet Metab 110(3):241–247
Yap S (2012) Classical homocystinuria: newborn screening with early treatment effectively prevents complications. Hamdan Med J 5(3): 351–362
Yap S, Rushe H, Howard PM, Naughten ER (2001) The intellectual abilities of early-treated individuals with pyridoxine-nonresponsive homocystinuria due to cystathionine beta-synthase deficiency. J Inherit Metab Dis 24(4):437–447
Zschocke J, Kebbewar M, Gan-Schreier H, Fischer C, Fang-Hoffmann J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Lindner M, Al Rifai H, Al Khal AL, Hoffmann GF (2009) Molecular neonatal screening for homocystinuria in the Qatari population. Hum Mutat 30(6):1021–1022
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Communicated by: Brian Fowler, PhD
Appendices
Compliance with Ethics Guidelines
Haitham El Bashir, Lubna Dekair, Yasmeen Mahmoud and Tawfeg Ben-Omran declare that they have no conflict of interest. The study was approved by the Hamad Medical Corporation, Medical Research Center Ethics Committee (# 10263/10).
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Haitham El Bashir: conceived the idea, wrote the study protocol and ethical approval, study design, data analysis, wrote the first draft of manuscript, study guarantor
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Lubna Dekair: study design, recruitment, data collection, developmental assessment, critical review of manuscript
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Yasmeen Mahmoud: study design, recruitment, data collection, cognitive assessment, critical review of manuscript
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Tawfeg Ben-Omran: study design, recruitment of cases, data collection, critical review of manuscript
Funding
The study was funded by a research grant from the Medical Research Center, Hamad Medical Corporation, Doha, Qatar. The funding body had no role in the content of this article.
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El Bashir, H., Dekair, L., Mahmoud, Y., Ben-Omran, T. (2014). Neurodevelopmental and Cognitive Outcomes of Classical Homocystinuria: Experience from Qatar. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 21. JIMD Reports, vol 21. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_394
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DOI: https://doi.org/10.1007/8904_2014_394
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