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Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy.

Collison FT, Xie YA, Gambin T, Jhangiani S, Muzny D, Gibbs R, Lupski JR, Fishman GA, Allikmets R - Ophthalmic Genet. (2015)

Bottom Line: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull's eye-appearing macular lesions at 28 years of age.The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation.In summary, a unique case of an adult patient with bull's eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.

View Article: PubMed Central - PubMed

Affiliation: a The Pangere Center for Hereditary Retinal Diseases, The Chicago Lighthouse for People Who Are Blind or Visually Impaired , Chicago , IL , USA .

ABSTRACT

Background: Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms.

Materials and methods: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull's eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull's eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed.

Results: Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation.

Conclusions: In summary, a unique case of an adult patient with bull's eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.

No MeSH data available.


Related in: MedlinePlus

Full-field electroretinogram (Espion E3, Diagnosys LLC, Littleton, MA) of the patient’s right eye at age 35 during a follow-up visit. Boxes represent ranges of 13 visually-normal subjects. The cone isolated amplitudes and implicit times (top), and the rod isolated single flash response (bottom left) are within the normal range. The combined rod and cone single flash response (bottom right) is mildly reduced and delayed compared to normal.
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Figure 4: Full-field electroretinogram (Espion E3, Diagnosys LLC, Littleton, MA) of the patient’s right eye at age 35 during a follow-up visit. Boxes represent ranges of 13 visually-normal subjects. The cone isolated amplitudes and implicit times (top), and the rod isolated single flash response (bottom left) are within the normal range. The combined rod and cone single flash response (bottom right) is mildly reduced and delayed compared to normal.

Mentions: By the most recent visit in 2013 at age 35, the patient was still working at her job as a production planner, although her BCVA had dropped to 10/100−2 OD and 10/80 OS. Fundus photos (Figure 2E and F), and near-infrared autofluorescence (Figure 2G and H) demonstrated bull’s eye macular dystrophy with relative preservation of the retinal pigment epithelium (RPE) at the foveolar region. Spectral-domain optical coherence tomography also showed preservation of the RPE at the fovea in the presence of marked foveal thinning (Figure 3). However, the patient’s eccentric viewing and level of visual acuity evidenced a notable degree of compromised foveal function. A repeat full field ERG (Figure 4) of the right eye at that visit still showed amplitudes and implicit times that were within normal limits under both scotopic rod isolated and photopic cone isolated test conditions, whereas the scotopic rod and cone combined response b-wave was mildly reduced and delayed compared to normal.


Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy.

Collison FT, Xie YA, Gambin T, Jhangiani S, Muzny D, Gibbs R, Lupski JR, Fishman GA, Allikmets R - Ophthalmic Genet. (2015)

Full-field electroretinogram (Espion E3, Diagnosys LLC, Littleton, MA) of the patient’s right eye at age 35 during a follow-up visit. Boxes represent ranges of 13 visually-normal subjects. The cone isolated amplitudes and implicit times (top), and the rod isolated single flash response (bottom left) are within the normal range. The combined rod and cone single flash response (bottom right) is mildly reduced and delayed compared to normal.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539287&req=5

Figure 4: Full-field electroretinogram (Espion E3, Diagnosys LLC, Littleton, MA) of the patient’s right eye at age 35 during a follow-up visit. Boxes represent ranges of 13 visually-normal subjects. The cone isolated amplitudes and implicit times (top), and the rod isolated single flash response (bottom left) are within the normal range. The combined rod and cone single flash response (bottom right) is mildly reduced and delayed compared to normal.
Mentions: By the most recent visit in 2013 at age 35, the patient was still working at her job as a production planner, although her BCVA had dropped to 10/100−2 OD and 10/80 OS. Fundus photos (Figure 2E and F), and near-infrared autofluorescence (Figure 2G and H) demonstrated bull’s eye macular dystrophy with relative preservation of the retinal pigment epithelium (RPE) at the foveolar region. Spectral-domain optical coherence tomography also showed preservation of the RPE at the fovea in the presence of marked foveal thinning (Figure 3). However, the patient’s eccentric viewing and level of visual acuity evidenced a notable degree of compromised foveal function. A repeat full field ERG (Figure 4) of the right eye at that visit still showed amplitudes and implicit times that were within normal limits under both scotopic rod isolated and photopic cone isolated test conditions, whereas the scotopic rod and cone combined response b-wave was mildly reduced and delayed compared to normal.

Bottom Line: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull's eye-appearing macular lesions at 28 years of age.The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation.In summary, a unique case of an adult patient with bull's eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.

View Article: PubMed Central - PubMed

Affiliation: a The Pangere Center for Hereditary Retinal Diseases, The Chicago Lighthouse for People Who Are Blind or Visually Impaired , Chicago , IL , USA .

ABSTRACT

Background: Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms.

Materials and methods: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull's eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull's eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed.

Results: Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation.

Conclusions: In summary, a unique case of an adult patient with bull's eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.

No MeSH data available.


Related in: MedlinePlus