Late Onset Optic Neuropathy in Methylmalonic and Propionic Acidemia

doi:10.1016/j.ajo.2008.12.024

American Journal of Ophthalmology

Volume 147, Issue 5, May 2009, Pages 929-933

https://doi.org/10.1016/j.ajo.2008.12.024 Get rights and content

Purpose

To describe 3 cases of late-onset bilateral optic neuropathy with visual dysfunction in patients with organic acidemia.

Design

Retrospective case series.

Methods

A total of 3 subjects, a 16-year-old male with methylmalonic acidemia (MMA), a 21-year-old male with MMA, and a 20-year-old female with propionic acidemia (PA), are included in this series. Comparison of the patients' clinical course, ophthalmologic exam, and testing are discussed. The outcome measures include visual acuity (VA), fundus appearance, visual fields, brain imaging, and genetic testing.

Results

All 3 subjects had late-onset severe bilateral VA loss with bilateral optic nerve pallor, central or cecocentral scotomas on visual field testing, and negative diagnostic workups for other causes of bilateral optic neuropathy.

Conclusions

Patients with organic acidemia may develop late-onset bilateral optic neuropathy with visual dysfunction despite lifelong propiogenic amino acid restriction and dietary supplementation.

Section snippets

Case 1

A 16-year-old male with MMA was referred for neuro-ophthalmic evaluation of unexplained bilateral vision loss. At the time of initial exam by the referring ophthalmologist, the patient reported a 1-week history of blurred vision in his right eye. His visual acuity (VA) was 20/200 in the right eye and 20/20 in the left eye. His dilated fundus exam was normal and nonorganic visual loss was suspected. There were no prior records for comparison. He was seen in follow-up 1 week later at which time

Discussion

Although the pathophysiology of optic atrophy in MMA and PA is unknown, accumulation of neurotoxic substrates secondary to enzymatic blocks in the metabolic pathway is suspected.1, 5 The presentation is very similar in MMA and PA patients supporting this hypothesis.1, 5 In both MMA and PA, neurotoxic processes have been documented, including impaired energy metabolism, bone marrow function, urea cycle function and kidney, pancreas, heart, and brain function.1, 4

A growing number of studies

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Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), which is responsible for converting propionyl-CoA to methylmalonyl-CoA for further metabolism in the tricarboxylic acid cycle. When this process is disrupted, propionyl-CoA and its metabolites accumulate, leading to a variety of complications including life-threatening cardiac diseases and other metabolic strokes. While the clinical symptoms and diagnosis of PA are well established, the underlying pathophysiological mechanisms of PA-induced diseases are not fully understood. As a result, there are currently few effective therapies for PA beyond dietary restriction. This review focuses on the pathophysiological mechanisms of the various complications associated with PA, drawing on extensive research and clinical reports. Most research suggests that propionyl-CoA and its metabolites can impair mitochondrial energy metabolism and cause cellular damage by inducing oxidative stress. However, direct evidence from in vivo studies is still lacking. Additionally, elevated levels of ammonia can be toxic, although not all PA patients develop hyperammonemia. The discovery of pathophysiological mechanisms underlying various complications associated with PA can aid in the development of more effective therapeutic treatments. The consequences of elevated odd-chain fatty acids in lipid metabolism and potential gene expression changes mediated by histone propionylation also warrant further investigation.
Challenges and strategies for clinical trials in propionic and methylmalonic acidemias
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Clinical trial development in rare diseases poses significant study design and methodology challenges, such as disease heterogeneity and appropriate patient selection, identification and selection of key endpoints, decisions on study duration, choice of control groups, selection of appropriate statistical analyses, and patient recruitment. Therapeutic development in organic acidemias (OAs) shares many challenges with other inborn errors of metabolism, such as incomplete understanding of natural history, heterogenous disease presentations, requirement for sensitive outcome measures and difficulties recruiting a small sample of participants. Here, we review strategies for the successful development of a clinical trial to evaluate treatment response in propionic and methylmalonic acidemias. Specifically, we discuss crucial decisions that may significantly impact success of the study, including patient selection, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families.
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Ocular disease in the cobalamin C defect: A review of the literature and a suggested framework for clinical surveillance
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Citation Excerpt :
It is likely that the prevalence of optic neuropathy is cumulative with advancing age in cblC. Optic atrophy without maculopathy has also been reported in isolated methylmalonic acidemia from methylmalonyl-CoA mutase deficiency [54,55] and in the cblG defect [56]. Like retinal and macular disease, optic atrophy in cblC does not appear to be completely preventable even with early implementation of therapy [23].
The association between combined methylmalonic acidemia and homocystinuria of cblC type (cobalamin C defect, cblC) and ocular disease is now well recognized, and is a significant component of morbidity and disability associated with the condition. In this review, through collation of historically reported cases of early- and late-onset cblC and previously unreported cases, we have attempted to characterize the epidemiology, clinical features, and pathomechanisms of individual ocular features of cblC. These data suggest that maculopathy and nystagmus with abnormal vision are extremely common and affect the majority of children with early-onset cblC, usually before school age; strabismus and optic atrophy are also seen at relatively high frequency. The timing of progression of macular disease may coincide with a critical period of postnatal foveal development. Maculopathy and retinal disease may be subclinical and show only partial correlation with the extent of visual deficits, and visual deterioration may be relentlessly progressive in spite of aggressive treatment of biochemical abnormalities. In later-onset forms of the disease, visual loss and ocular complications appear to be infrequent. Finally, we discuss investigational strategies in diagnosing and characterizing eye disease in individuals with cblC, explore possible therapeutic avenues that may attenuate progression and severity of eye disease, and propose a clinical surveillance guideline for monitoring progression of ocular disease in children and adults with cblC.
Congenital genetic inborn errors of metabolism presenting as an adult or persisting into adulthood: Neuroimaging in the more common or recognizable disorders
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Propionic acidemia is an organic acidemia, being the most common cause of primary lactic acidosis, and most commonly presenting in the neonatal period or early infancy with severe metabolic acidemia and hyperammonemia due to a genetic deficiency in the enzyme propionyl-CoA carboxylase.138 However, owing to mass screening of newborns, several cases have been described that have higher propionyl-CoA carboxylase activity, allowing such patients to present in later childhood or adulthood with atypical symptoms such as adult-onset chorea, dementia, optic neuropathy, or seizures.139,140 Therefore, the findings on MRI may vary, where the early-childhood forms could reflect findings of hyperammonemia with a spectrum of partially reversible diffusion abnormalities that may affect the cortices and basal ganglia (see section Urea Cycle Disorders); the later-onset adult form is more ambiguous and less described, so it is not covered in detail here.
Numerous congenital-genetic inborn errors of metabolism (CIEMs) have been identified and characterized in detail within recent decades, with promising therapeutic options. Neuroimaging is becoming increasingly utilized in earlier stages of CIEMs, and even in asymptomatic relatives of patients with a CIEM, so as to monitor disease progress and treatment response. This review attempts to summarize in a concise fashion the neuroimaging findings of various CIEMs that may present in adulthood, as well as those that may persist into adulthood, whether because of beneficial therapy or a delay in diagnosis. Notably, some of these disorders have neuroimaging findings that differ from their classic infantile or earlychildhood forms, whereas others are identical to their early pediatric forms. The focus of this review is their appearance on routine magnetic resonance imaging sequences, with some basic attention to the findings of such CIEMs on specialized neuroimaging, based on recent or preliminary research. The general classes of disorders covered in this complex review are: peroxisomal disorders (adrenoleukodystrophy), lysosomal storage disorders (including metachromatic leukodystrophy, Krabbe or globoid cell leukodystrophy, Fabry, Niemann-Pick, GM1, GM2, Gaucher, mucopolysaccharidoses, and Salla diseases), mitochondrial disorders (including mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes, myoclonic epilepsy with ragged red fibers, Leigh disease, and Kearns-Sayre syndrome), urea cycle disorders, several organic acidemias (including phenylketonuria, maple syrup urine disease, 3-hydroxy-3-methylglutaryl colyase deficiency, glutaric acidurias, methylmalonic academia, proprionic academia, 3-methylglucatonic aciduria, and 2-hydroxyglutaric acidurias), cytoskeletal or transporter molecule defects (including Alexander or fibrinoid leukodystrophy, proteolipid protein-1 defect or Pelizaeus Merzbacher, Wilson, and Huntington diseases), and several neurodegenerative disorders of brain iron accumulation. Additionally, an arbitrary “miscellaneous” category of 5 recognizable disorders that may present in or persist into adulthood is summarized, which include megalencephalic leukoencephalopathy with subcortical cysts (megancephalic leukoencephalopathy with subcortical cysts or van der Knaap disease), polymerase-III gene defect (“4H syndrome”), childhood ataxia with central nervous system hypomyelination (“vanishing white matter disease”), striopallidodentate calcinosis (“Fahr disease”), and Cockayne syndrome.
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Original articleLate Onset Optic Neuropathy in Methylmalonic and Propionic Acidemia

Purpose

Design

Methods

Results

Conclusions

Section snippets

Case 1

Discussion

Ophthalmology

Brain Res Dev Brain Res

J Pediatrics

Mol Genet Metab

Methylmalonic and propionic aciduria

Am J Med Genet Part C Semin Med Genet

Disorders of propionate and methylmalonate metabolism

Principles of nutrition II: micronutrients

Original article
Late Onset Optic Neuropathy in Methylmalonic and Propionic Acidemia