Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

Abstract

The C10orf2 gene encodes Twinkle, a protein involved in mitochondrial DNA (mtDNA) replication. Twinkle mutations cause mtDNA deletion or depletion and are associated with a large spectrum of clinical symptoms including dominant progressive external ophthalmoplegia (adPEO), infantile-onset spinocerebellar ataxia (IOSCA), and early-onset encephalopathy. The diagnosis remains difficult because of the wide range of symptoms and lack of association with specific metabolic changes. We report herein a child with early-onset encephalopathy, unusual abnormal movements, deafness, and axonal neuropathy. All laboratory investigations were normal with the exceptions of high alpha-fetoprotein levels and an abnormal glycosylation profile. These abnormal parameters resulted in misdiagnosis as a previously unidentified congenital disorder of glycosylation (CDG) type I syndrome. Whole exome sequencing revealed two point mutations in C10orf2 that were confirmed by Sanger sequencing; neither had been previously reported. This report enlarges the clinical phenotype of Twinkle mutations and suggests that an abnormal glycosylation profile suggestive of CDG type I associated with high blood alpha-fetoprotein levels without obvious cause should prompt Twinkle sequencing.

Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency

“…In contrast, our patient did not show abnormal liver functions until 8 months of age, three months after the first abnormal CDT test was obtained. Our findings follow the report of another patient initially diagnosed with a CDG, but eventually found to have mutations in the mitochondrial DNA helicase Twinkle (Bouchereau et al, 2016). Pregnancy history for this patient was significant for a maternal dengue virus infection during the first trimester.…”

Twinkle-Associated Mitochondrial DNA Depletion

“…In one patient reported by Bouchereau et al, plasma and CSF lactate remained normal and the patient had an abnormal glycosylation profile suggestive of congenital disorder of glycosylation type I. 8 Renal tubulopathy has been reported in four patients, including ours. 6,7 In previously reported patients, MRI findings ranged from normal to cerebellar atrophy.…”

“…Only ten patients have been previously reported with MDS caused by autosomal recessive Twinkle mutations, with survival ranging from three months to 4.5 years (Table). [4][5][6][7][8] Commonly reported clinical features of failure to thrive, severe hypotonia, seizures, and abnormal eye movements were represented in our patient. Dyskinesias 5,8 and ataxia 5 have been reported in a subset of patients.…”

Elevated Alpha-Fetoprotein in Infantile-Onset Niemann-Pick Type C Disease with Liver Involvement

“…Nevertheless, increased AFP levels are well documented in several metabolic conditions, most notably tyrosinemia type-1. Case reports have linked elevated AFP levels to other metabolic diseases such as citrullinemia type-2 [17,20], twinkle variants [21], galactosemia, bile acid synthesis defects and gestational alloimmune liver disease (GALD, formerly termed neonatal hemochromato-sis) [22]. Elevated AFP levels were also documented in another lysosomal storage disorder with hepatic involvement-a type-1 Gaucher patient, who developed a Gaucheroma [23].…”