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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

Pedigree of the family and segregation of the MMACHC mutations with the disease phenotype. The open circle and squares represent the unaffected female and male family members, respectively; the closed circle represents the affected female patient.
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Figure 1: Pedigree of the family and segregation of the MMACHC mutations with the disease phenotype. The open circle and squares represent the unaffected female and male family members, respectively; the closed circle represents the affected female patient.

Mentions: A 28-year-old Hispanic female (Figure 1) presented in 2006 with decreased central vision and mild photo-aversion of approximately two years duration. She reported subjectively normal color vision, night vision and peripheral vision. Her medical history was positive for iron deficiency anemia, occasional urinary tract infections, and recurrent kidney infections in 2002. Best corrected Snellen visual acuities (BCVA) were 20/80 OD and 20/70−2 OS with a low myopic refraction. She correctly read only two out of twelve Ishihara color plates OD, and zero out of twelve OS. Goldmann visual field testing demonstrated a pericentral ring scotoma in each eye (Figure 2A and B). Funduscopy showed bilateral bull’s eye-appearing macular lesions (Figure 2C and D) with no visible fundus flecks, vessel attenuation, optic nerve pallor or peripheral pigmentary changes. A scotopic and photopic full-field electroretinogram (ERG) of the right eye showed normal a- and b-wave amplitudes and implicit times. The patient reported no current or previous use of hydroxychloroquine or any other medication or toxic exposure that could be potentially responsible for the bull’s eye-appearing lesions in her maculae. The patient reported no family history of a retinal dystrophy, and examination of both parents and a brother (Figure 1) showed essentially normal maculae; only a few fine drusen near the fovea were observed in the examinations of both parents.


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)

Pedigree of the family and segregation of the MMACHC mutations with the disease phenotype. The open circle and squares represent the unaffected female and male family members, respectively; the closed circle represents the affected female patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Pedigree of the family and segregation of the MMACHC mutations with the disease phenotype. The open circle and squares represent the unaffected female and male family members, respectively; the closed circle represents the affected female patient.
Mentions: A 28-year-old Hispanic female (Figure 1) presented in 2006 with decreased central vision and mild photo-aversion of approximately two years duration. She reported subjectively normal color vision, night vision and peripheral vision. Her medical history was positive for iron deficiency anemia, occasional urinary tract infections, and recurrent kidney infections in 2002. Best corrected Snellen visual acuities (BCVA) were 20/80 OD and 20/70−2 OS with a low myopic refraction. She correctly read only two out of twelve Ishihara color plates OD, and zero out of twelve OS. Goldmann visual field testing demonstrated a pericentral ring scotoma in each eye (Figure 2A and B). Funduscopy showed bilateral bull’s eye-appearing macular lesions (Figure 2C and D) with no visible fundus flecks, vessel attenuation, optic nerve pallor or peripheral pigmentary changes. A scotopic and photopic full-field electroretinogram (ERG) of the right eye showed normal a- and b-wave amplitudes and implicit times. The patient reported no current or previous use of hydroxychloroquine or any other medication or toxic exposure that could be potentially responsible for the bull’s eye-appearing lesions in her maculae. The patient reported no family history of a retinal dystrophy, and examination of both parents and a brother (Figure 1) showed essentially normal maculae; only a few fine drusen near the fovea were observed in the examinations of both parents.

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