1. Kristina Lin, Eugene Pak, Linda Pang, OD, FAAO
Western University of Health Sciences, College of Optometry, Pomona, CA
Background
METHYLMALONIC ACIDEMIA: PROTEIN METABOLISM AND ITS EFFECTS ON
OCULAR & SYSTEMIC HEALTH
References
Conclusion
MMA is a protein metabolism disorder that can affect infants to adults and is
characterized by an accumulation of methylmalonic acid. Some long term
complications of MMA are chronic kidney dysfunction, pancreatitis, and intellectual
disabilities. If these issues are not addressed, it can lead to coma or death. It is important
to educate patients, family members, as well as healthcare providers, regarding the signs
of MMA. In addition, optometric management including support programs, community
resources, and vision rehabilitation can address patient’s visual needs and quality of life.
Optometrists need to be aware of ocular pathology associated metabolic disease in order
to recognize and properly manage the condition and optimize quality of life through low
vision rehabilitation.
1. Coulombe JT, Shih VE, Levy HL. Massachusetts metabolic disorders screening program. II. Methylmalonic aciduria. Pediatrics. Jan 1981;67(1):26-31.
2. Gerth C, Morel CF, Feigenbaum A, Levin AV. Ocular phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type. J. AAPOS.
2008; 12(6):591-596.
3. Hamel C. Retinitis pigmentosa. Orphanet J. of Rare Dis. 2006; 1(40):687-693.
4. Levrat V, Forest I, Fouilhoux A, et al. Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia? Orphanet. J. Rare Dis.
2008; 3:2.
5. Ng J, Karr D, Reznick L, Pennesi M. Presentation and progression of the ocular manifestation of methylmalonic acidemia in children. Invest. Ophthalmol. Vis.
Sci. 2013; 54: 1332.
Case Report
Our patient was educated on the effects of Methylmalonic acidemia (MMA) on
functional vision and daily living. No spectacles were prescribed at the time due to lack
of improvement in visual acuity with trial frame refraction. We educated the patient and
his aunt about vision rehabilitation services and resources to maximize visual function.
Our patient was also referred for an electroretinogram (ERG) testing to confirm
diagnosis of retinitis pigmentosa sine pigmento. Subsequent follow-up visits included
prescribing optical devices and appropriate training.
Discussion
Our patient was diagnosed with suspected RP Sine Pigmento secondary to MMA. He
presented with ocular signs of arteriolar attenuation and waxy pallor of the optic disc.
However, because he did not present with bony spicules upon fundus examination, we
referred our patient for an ERG to confirm our diagnosis of suspected RP Sine Pigmento.
Our patient demonstrated several different ocular and systemic complications
characteristic of MMA. This includes loss of contrast sensitivity, progressive field loss,
decrease in vision, intellectual disability, and seizures. Young individuals suspected of
organic academia are recommended to receive a screening and evaluation of multiple
factors, such as pH, glucose, urea, electrolytes, bicarbonate, and ketones. Bone marrow
suppression can also occur, which can cause thrombocytopenia, neutropenia and
pancytopenia, so a complete blood count and differentials are used to aid in diagnosis.
Although there is no known cure for MMA, treatment is available to prevent further
complications. Systemic management consists of a low protein diet, avoiding various
medications, such as broad spectrum antibiotics, vitamins, and carglumic acid, especially
for individuals with ammonia levels exceeding 400 micromol/L in the blood.4 Current
literature shows very limited information regarding cases of MMA associated with
pigmentary retinopathy and optometric management. However, a review evaluating
children with MMA with homocystinuria, cobalamin C type suggested a specific
progression in retinal changes, with bull’s eye maculopathy, optic atrophy, and vascular
changes occurring with an increase in age.5
Methylmalonic acidemia (MMA) is a rare type of organic acidemia, which are disorders
that affect certain enzymes responsible in the breakdown of specific amino acids. MMA
may present ocular findings of nystagmus, reduced vision, and Retinitis Pigmentosa.3
Retinitis Pigmentosa (RP) is characterized by a decrease in visual acuity, progressive
field loss with an abnormal electroretinogram (ERG). RP usually presents with a triage
of arteriolar attenuation, waxy pallor of the optic disc and pigmented bone spicules. If
there are no signs of bone spicules present then the condition is called Retinitis
Pigmentosa Sine Pigmento.
MMA follows autosomal recessive inheritance with variable expression. It has an
estimated incidence of 1:48,000 infants.1 MMA causes a buildup of methylmalonic acid
in the body due to a deficiency of adenosylcobalamin-dependent enzyme
methylmalonyl-CoA mutase or vitamin B12 (also known as cobalamin). MMA is a
result of the mutation of the MMACHC gene causing an autosomal recessive disorder
called Cobalamin C type (cblC).2 CblC is the most common inborn error of Vitamin
B12 metabolism that results in the malformation of B12 cofactors, adenosylcobalamin
and methylcobalamin, directly affecting the visual system. These two cofactors are
essential to the formation of methionine, which is needed for rod and cone
photoreceptors to function appropriately.
Patients with the cblC mutation can either displayed a progressive cone-rod or a
nonprogressive rod-cone retinal dysfunction both presenting with a reduced
photoreceptor response on the ERG, making it look similar to RP.2 In addition to RP,
individuals diagnosed with MMA may experience moderate hepatomegaly, metabolic
acidosis (pH <7.30), ketoaciduria, hypoglycemia, seizures, failure to thrive,
developmental delay, and facial dysmorphism.
In December 2014, a twenty year old Hispanic male was presented to the Eye Care
Center for a vision rehabilitation Examination. The chief concern, brought forth by the
patient’s aunt, was longstanding reduced vision at distance. Medical history revealed he
was diagnosed with MMA at one year of age. When asked previous surgeries or
accidents, his aunt revealed he had a gastrostomy feeding tube insertion, a motor vehicle
accident at the age of six, during which vision changes were first noticed and was
subsequently diagnosed as legally blind. Our patient was positive for a history of heart
surgery in December 2013, and seizures following a liver and kidney transplant in March
2014. In addition, he has impaired cognitive function. Ocular history was positive for
optic nerve atrophy in both eyes with temporal pallor, intermittent exotropia and mild
myopia, which was diagnosed on October 2013 at Children’s Hospital Los Angeles. In
October 2015, he had developed a jerk nystagmus to the right. Our patient has an allergy
to Benadryl and protein
OD OS
VAs
dVA: 2/25M (20/250) dVA: 2/400ft (20/4000)
nVA OU: 0.4/4M (20/200)
Pupils PERRL (-) APD PERRL (-) APD
EOMs Full and jerky, (+) nystagmus Full and jerky, (+) nystagmus
CF Restricted in all quadrants
Restricted in all quadrants
OS>> OD
Tonometry 19 mmHg 19 mmHg
Optic Nerve Grade 3-4 temporal pallor Grade 3-4 temporal pallor
Retina- Vascular Low A/V Low A/V and attenuation
MARS Contrast Profound degree of loss Profound degree of loss
Amsler Grid
(+) metamorphosia in superior
and superior temporal fields
(+) metamorphosia in the
superior field
OD OS
Figure 1. Fundus photos right eye (left) and left eye (right). Fundus demonstrates arteriolar attenuation as well as optic
nerve pallor.