Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD / Glutaric Acidemia Type IIC) Presenting as Chronic Sensory Ataxic Ganglionopathy, Bilateral Sensorineural Hearing Loss, and Vocal Cord Dysfunction Associated with a Novel ETFDH Variant
B. B. Likhitha *
Department of Neurology and Pharmacy Practice, SSIMS & RC Davangere, Karnataka, India.
Akshata N. Chavadi
Department of Neurology and Pharmacy Practice, SSIMS & RC Davangere, Karnataka, India.
Shashank N. Pastay
Department of Neurology and Pharmacy Practice, SSIMS & RC Davangere, Karnataka, India.
*Author to whom correspondence should be addressed.
Abstract
Background: Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidaemia type II (GA II), is a rare inherited autosomal recessive disorder involving the metabolic pathways of fatty acid and amino acid oxidation. Catastrophic metabolic crises are observed in the typical neonatal presentation of MADD, whereas variable lipid storage myopathy is a common characteristic of late-onset type IIC. Sensory ataxic ganglionopathy, cranial neuropathies and vocal cord paralysis are relatively atypical presentations of late-onset MADD, and diagnosis is often difficult.
Case Presentation: A 39-year-old woman had a 5-year history of insidiously progressive symmetrical paraesthesia, with functionally disabling sensory ataxia requiring ambulatory/mobility aid use, progressively debilitating bilateral hearing loss and dysphonia. On examination, she had diffuse hypotonia, moderate (4/5) proximal lower-limb weakness, atrophy of the distal intrinsic interphalangeal muscles, diffuse hyporeflexia, absent knee and ankle jerks, absent plantar responses bilaterally, a positive Romberg sign, bilateral mixed/sensorineural hearing loss (CN VIII, R>L), and a voice abnormality due to vocal cord paresis with a wide phonatory gap (CN IX/X). Microscopic analysis of the sural nerve biopsy revealed marked loss of myelinated fibres without clusters of regenerating nerve fibres; the histology was definitive for sensory ganglionopathy. Initial serology was positive for anti-beta-2 glycoprotein 1 and anti-cardiolipin IgM, suggesting an immune/antiphospholipid-mediated process. Exome sequencing revealed a novel homozygous missense variant in ETFDH exon 13, c.1826G>A, p.Gly609Glu. Classified as a VUS, this had clinical associations with early-onset GA IIC. Following pulse steroid immunotherapy with the addition of metabolic support (riboflavin, L-carnitine, CoQ10), there was subjective sensory recovery and resolution of voice problems, with regained independence in day-to-day tasks; attribution to individual treatments remains problematic.
Conclusion: This study emphasises the phenotypic variability of MADD presenting with features mimicking autoimmune sensory neuronopathy. Exome sequencing is important in resolving diagnostically confusing cases of adult-onset cranial neuropathies and sensory ataxia. Novel ETFDH variants underscore the need for careful clinical and histopathological correlation, while early treatment with riboflavin and metabolic cofactors may contribute to clinical stabilisation.
Keywords: Glutaric acidemia type IIC, multiple acyl-CoA dehydrogenase deficiency (MADD), ETFDH gene, Sensory ataxic ganglionopathy, vocal cord dysfunction, sensorineural hearing loss, riboflavin-responsive myopathy, exome sequencing