Maculopathy and Retinal Degeneration in Cobalamin C Methylmalonic Aciduria and Homocystinuria

The cobalamin C form of methylmalonic aciduria and homocystinuria (Cc-CMAH) is an inherited deficiency of the 2 coezymatically active vitamin B₁₂ derivatives, methylcobalamin and deoxyadenosylcobalamin (Figure 1). Its heterogeneous clinical manifestations include feeding difficulties, neural dysfunction, and ophthalmic abnormalities.¹ The ophthalmic features are visual impairment, nystagmus, and retinopathy with conspicuous maculopathy.^1,2 The mechanism by which the biochemical abnormalities cause retinal disease has not been defined. We analyzed photoreceptor cell and postreceptoral processes represented by electroretinographic responses in a child with Cc-CMAH.

A 7-month-old infant girl, born at term, was first examined because of crossed eyes after an unremarkable perinatal course. Ophthalmic examination demonstrated esotropia, horizontal nystagmus of small amplitude, mildly attenuated retinal arteries, and maculopathy (Figure 2). Grating acuities measured by preferential looking were near the lower limits of normal for age, and by 4 years of age, her visual acuity with binocular viewing of the Lea symbols was 20/200 OU. Although development was delayed, the patient became ambulatory and verbal. Elevated plasma homocysteine levels, a large peak of urine methylmalonic acid level, and cell complementation studies secured the diagnosis of Cc-CMAH. Hydroxycobalamin injections and betaine and protein restriction were started and maintained, with consequent improvement of biochemical measures, including modest decreases in total homocysteine level and increases in methionine level.

Before and after treatment, processes in rod photoreceptor and postreceptoral cells and cone-mediated responses were investigated. The variables of the activation of rod phototransduction and postreceptoral function were derived from the full-field electroretinogram.³ Rod photoresponse sensitivity and saturated amplitude were calculated from the a-wave. The b-wave sensitivity and saturated amplitude represented postreceptoral activity. Each variable was compared with normal values for age.⁴ The saturated amplitudes were, on average, approximately 50% of the normal means. Except for normal rod cell sensitivity at age 3 years 10 months, when methionine was at the highest level, all photoreceptor and postreceptoral sensitivities were significantly attenuated (Figure 3). Cone-mediated b-wave amplitudes remained at 50% of the normal mean.⁵ Despite improving or stable full-field retinal function, the maculopathy progressed to large, atrophic patches (Figure 2).

The Cc-CMAH is one of the few causes of infantile maculopathy. Treatment did not rescue the macula or postreceptoral retinal responses represented by the b-wave. However, in this patient, normal rod photoreceptor sensitivity was restored in conjunction with increased levels of the essential amino acid methionine. This implies methionine rescue of transduction processes that involve rhodopsin and other transduction cascade proteins in the rod cell membranes. Thus, low methionine level may, indeed, have a role in the pathogenesis of retinopathy in Cc-CMAH.²

Correspondence: Dr Fulton, Department of Ophthalmology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115 (anne.fulton@childrens.harvard.edu).

Financial Disclosure: None.