Secondary Logo

Journal Logo

Letters to the Editor

Varied phenotype of Homocystinuria

Possible diagnostic error

Yap, Sufin

Author Information
Indian Journal of Ophthalmology: July 2014 - Volume 62 - Issue 7 - p 835
doi: 10.4103/0301-4738.138637
  • Open

Dear Sir,

There are several crucial points to be made regarding the diagnostic criteria for the diagnosis of homocystinuria (HCU) due to cystathionine β-synthase (CβS) in a recent article.[1]

The authors have provided a comprehensive ophthalmological examination on the two siblings described. However, the diagnosis of HCU seemed to be based mainly on mildly elevated homocysteine levels (16.02 and 18μmol/L) and the ocular findings in the 2 cases, without concurrent levels of methionine, cystine, or other confirmatory tests.

The presence of typical clinical signs may lead to a suspicion of CβS deficiency, but definitive diagnosis depends on a severely raised total homocysteine (tHcy; >100-400μmol/L) with low methionine and cystine levels. The confirmation of diagnosis is by CβS enzymology in cultured skin fibroblast and/or molecular analysis.[2] Plasma B12 and folate are routinely checked for nutritional deficiencies which can cause mildly elevated tHcy similar to the levels reported. Upon diagnosis, a trial of pyridoxine (B6) is given to ascertain clinical B6 responsiveness, as there is no correlation between in vitro and in vivo responsiveness.[3]

Intellectual abilities as reported on sibling 1 as having developmental delay is at odds with a further statement which makes the assumption of probable “B6 responsive type” in the siblings based on the “mild systemic involvement and normal intelligence.“ The authors further conclude that having developed ectopia lentis by 8 years as yet another factor for diagnosing HCU based on Mulvihill et al.[4] As a co-author of the quoted article, the conclusion drawn by the authors on our study having shown that “ectopia lentis in homocystinuria develops after 1 year and maximum by 8 years” is incorrect. Instead, Mulvihill et al. documented that a diagnosis of HCU was made at a median age of 4 years (range: 1.2-8) in 10 out of 14 cases in the late detected group. A further four cases had a median age of diagnosis for HCU of 12.8 years (range: 4-23). All 14 cases had lens subuxation/dislocation at a median age of HCU diagnosis of 6 years (range: 1.25-28 years).[4] Our study only documented the age at which time a diagnosis of HCU was made and did not determine when exactly ectopia lentis had occur.[4] Timing of ectopia lentis is not a diagnostic criteria.

The authors correctly surmised that superonasal subluxation is atypical of HCU, however, the diagnosis of HCU in the reported cases has yet to be confirmed correctly. In view of the abdominal hernias and ectopia lentis, it would be usual to rule out other causes such as Marfan syndrome and to properly confirm the diagnosis of HCU. Vitamin deficiencies should be looked for as a cause of mild hyperhomocysteinemia. In the presence of second degree consanguinity, it may be useful to look for other causes of developmental delay, if indeed present in Sibling 1.

In summary, the diagnosis of HCU must be confirmed and not simply based on mild hyperhomocysteinemia and some clinical features. Ascribing atypical features to HCU is premature especially when there is no evidence of the diagnosis being confirmed in a recognized manner.

1. Kaliaperumal S, Kumar KP. Bhuvaneshwari. Varied phenotypic presentations of Homocystinuria in two siblings Indian J Ophthalmol. 2014;62:93–4
2. Mudd SH, Levy HL, Kraus JPScriver CR, Baeudet AL, Sly WS, Valle D, Childs B, Kinzler KW, et al Disorders of transsulfuration The Metabolic and Molecular Bases of Inherited Disease. 20018th ed New York McGraw-Hill:2007–54
3. Yap S, Naughten E. Homocystinuria due to cystathionine β-synthase deficiency in Ireland: 25 years’ experience of a newborn screened and treated population with reference to clinical outcome and biochemical control J Inher Metab Dis. 1998Last accessed on 2014 Mar 04;21:738–47 Available from:
4. Mulvihill A, Yap S, O’Keefe M, Howard PM, Naughten ER. Ocular findings among patients with late-diagnosed or poorly controlled homocystinuria compared with a screened, well controlled population J AAPOS. 2001;5:311–5
© 2014 Indian Journal of Ophthalmology | Published by Wolters Kluwer – Medknow