Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonic acidemia

Ku, Cristy A.; Ng, Jacqueline K.; Karr, Daniel J.; Reznick, Leah G.; Harding, Cary O.; Weleber, Richard G.; Pennesi, Mark E.

doi:10.3109/13816810.2015.1121500

Cited by 13 publications

(11 citation statements)

References 42 publications

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“…Hcy (mediated by vascular damage) and MMA (in analogy to the optic neuropathy seen in MUT‐associated disease) toxicities cannot explain the typical maculopathy, retinopathy, nystagmus, and abnormal visual acuity in remethylation disorders. Eye disease in CBS deficiency with highly elevated Hcy is fundamentally different (ectopia lentis) and MMA‐associated optic atrophy is a long‐term complication in a mitochondrial disease with significantly higher MMA concentrations.…”

Section: Pathophysiological Considerations and Open Questionsmentioning

confidence: 99%

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

Huemer

Baumgartner

2019

J of Inher Metab Disea

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This review gives an overview of clinical characteristics, treatment and outcome of nutritional and acquired cobalamin (Cbl; synonym: vitamin B12) deficiencies, inborn errors of Cbl absorption and intracellular trafficking, as well as methylenetetrahydrofolate dehydrogenase (MTHFD1) and methylene tetrahydrofolate reductase (MTHFR) deficiencies, which impair Cbl‐dependent remethylation. Acquired and inborn Cbl‐related disorders and MTHFR deficiency cause multisystem, often severe disease. Failure to thrive, neurocognitive or psychiatric symptoms, eye disease, bone marrow alterations, microangiopathy and thromboembolic events are characteristic. The recently identified MTHFD1 defect additionally presents with severe immune deficiency. Deficient Cbl‐dependent enzymes cause reduced methylation capacity and metabolite toxicity. Further net‐effects of perturbed Cbl function or reduced Cbl supply causing oxidative stress, altered cytokine regulation or immune functions are discussed.

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Section: Pathophysiological Considerations and Open Questionsmentioning

confidence: 99%

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

Huemer

Baumgartner

2019

J of Inher Metab Disea

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“…The late-onset cblC disease is characterized by involvement of both the central nervous system and peripheral nerve system. The patients showed commonly cognitive and psychiatric disturbances (2,3,(5)(6)(7)(8), epilepsy (3)(4)(5)(6)(7)(8)(9), spastic paraplegia (3,7,8,10,11), with optic atrophy (3,12). Some patients showed typical subacute combined degeneration (7,13).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?

et al. 2020

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Background: Cobalamin C (cblC) has a fundamental role in both central and peripheral nervous system function at any age. Neurologic manifestations may be the earliest and often the only manifestation of hereditary or acquired cblC defect. Peripheral neuropathy remains a classical but underdiagnosed complication of cblC defect, especially in late-onset cblC disease caused by mutations in the methylmalonic aciduria type C and homocysteinemia (MMACHC) gene. So the clinical, electrophysiological, and pathological characteristics of late-onset cblC disease are not well-known.Methods: A retrospective study of patients with late-onset cblC disease was conducted at our hospital on a 3-year period. The neuropathy was confirmed by the nerve conduction study. Sural biopsies were performed in 2 patients.Results: Eight patients were identified, with a mean onset age of 16.25 ± 6.07 years. All patients had methylmalonic aciduria, homocysteinemia, compound heterozygous MMACHC gene mutations were detected in all patients, and 7/8 patients with c.482G>A mutation. One patient concomitant with homozygote c.665C>T mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. All patients showed limb weakness and cognitive impairment. Five patients had possible sensorimotor axonal polyneuropathy predominantly in the distal lower limbs. Sural biopsies showed loss of myelinated and unmyelinated fibers. Electro microscopy revealed crystalline-like inclusions bodies in Schwann cells and axonal degeneration.Conclusion: Late-onset cblC disease had possible heterogeneous group of distal axonal neuropathy. c.482G>A mutation is a hot spot mutation in late-onset cblC disease.

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“…variant inherited from the mother was predicted to delete the canonical splice site of exon 2. 29 Being at risk, before P-OHCbl-DI, to develop later mild optic neuropathy and/or CRD, because of previous uMMA levels above the approximate threshold of 2000 μmol/mmol/creatinine, 12,13 the cblA patient 4 had normal visual and renal function on early follow up. The cblX patient responded biochemically and clinically only after slowly increasing the P-OHCbl dose and eventually achieved better seizure control.…”

Section: Discussionmentioning

confidence: 99%

“…In cblA defect, caused by a pathogenic MMAA variant, 10 chronic renal disease (CRD) may constitute long-term sequelae, despite OHCbl therapy 11,12 and rarely, mild optic nerve atrophy. 13 Therapy involves OHCbl. 14 cblX defect, an X-linked ICM disorder, with methylmalonic acidemia and homocysteinemia, is caused by a pathogenic HCFC1 variant, resulting in transcriptional dysregulation involving many genes.…”

Section: Introductionmentioning

confidence: 99%

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Parenteral hydroxocobalamin dose intensification in five patients with different types of early onset intracellular cobalamin defects: Clinical and biochemical responses

et al. 2019

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Intracellular cobalamin metabolism (ICM) defects can be present as autosomal recessive or X‐linked disorders. Parenteral hydroxocobalamin (P‐OHCbl) is the mainstay of therapy, but the optimal dose has not been determined. Despite early treatment, long‐term complications may develop. We have analyzed the biochemical and clinical responses in five patients with early onset of different types of ICM defects (cblC: patients 1‐3; cblA: patient 4; cblX: patient 5) following daily P‐OHCbl dose intensification (DI). In patient 4, P‐OHCbl was started at age 10 years and in patient 5 at age 5 years. OHCbl was formulated at either, 5, 25, or 50 mg/mL. P‐OHCbl was intravenously or subcutaneously (SQ) delivered, subsequently by placement of a SQ injection port except in patient 4. In all patients, homocysteine and methylmalonic acid levels, demonstrated an excellent response to various P‐OHCbl doses. After age 36 months, patients 1‐3 had a close to normal neurological examination with lower range developmental quotient. In patient 3, moderate visual impairment was present. Patient 4, at age 10 years, had normal renal, visual and cognitive function. In cblX patient 5, epilepsy was better controlled. In conclusion, P‐OHCbl‐DI caused an excellent control of metabolites in all patients. In the three cblC patients, comparison with patients, usually harboring identical genotype and similar metabolic profile, was suggestive of a positive effect, in favor of clinical efficacy. With P‐OHCbl‐DI, CblA patient has been placed into a lower risk to develop renal and optic impairment. In cblX patient, lower P‐OHCbl doses were administrated to improve tolerability.

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Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonic acidemia

Cited by 13 publications

References 42 publications

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?

Parenteral hydroxocobalamin dose intensification in five patients with different types of early onset intracellular cobalamin defects: Clinical and biochemical responses

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