Alpers- and MNGIE-like disease with disturbed CSF folate transport and an unusual mode of genetic transmission of POLG mutations: a case report

Rudolf Korinthenberg,Janbernd Kirschner,Angela Abicht,Rita Horvath,Robert Steinfeld,Matthias Eckenweiler,Nana Nino Tatishvili,Stephanie Kleinle

doi:10.17724/jicna.2020.216

Abstract

We report about a family with three of five siblings affected by a variable remitting-relapsing disease with epileptic seizures, coma and abdominal crises, and lethal outcome in all. In the youngest son and in one of his deceased brothers we identified two disease causing compound heterozygous POLG mutations. One of these was inherited from the mother, but the other was absent in the father`s blood, saliva, buccal swab and hair bulbs although his paternity was proven genetically. Thus, we assume germline mosaicism for this mutation in the father. Very low 5-methyltetrahydrofolate (5-MTHF) and absence of folate receptor-alpha was repeatedly found in the CSF of the youngest brother indicating a secondary cerebral folate transport deficiency. Folinic acid supplementation over 18 months resulted in some improvement of the neurological condition; however, it did not prevent progression of the systemic disease.

Highlights

The POLG gene codes for the catalytic alpha-subunit of polymerase-gamma, which is involved in mitochondrial DNA replication
Biallelic pathogenic variants in POLG usually result in mtDNAdepletion and autosomal-recessive early-onset diseases such as infantile and early-lethal multisystem myocerebrohepatopathy spectrum (MCHS) disorder or Alpers-Huttenlocher syndrome (AHS)
A milder phenotype has been associated with less severe mitochondrial DNA (mtDNA) changes and later onset of symptoms, such as ataxia, peripheral neuropathy and seizures in adolescents and young adults, and late-onset progressive external ophthalmoplegia (PEO) and ataxia in adults more thn 40 years [4]

Summary

Introduction

The POLG gene codes for the catalytic alpha-subunit of polymerase-gamma, which is involved in mitochondrial DNA (mtDNA) replication. At a final clinical investigation before returning to Georgia (at 10 years and eight months of age), his height had increased by 2 cm and his weight by 0.8 kg His gait was broad-based but no longer ataxic. Sanger sequencing of all coding regions of POLG with exon-intron boundaries in blood DNA of the index patient detected two heterozygous variants, while MLPA analysis was normal One of these NM_002693.2: c.680G > A p.(Arg227Gln) is a missense variant that has recently been described in three infants with mitochondrial depletion syndrome (MDS) and Alpers-Huttenlocher syndrome (AHS) [9, 10, 11]. These data suggest the presence of paternal somatic or, most probably, germline mosaicism for the c.680G > A p.(Arg227Gln) (see discussion)

Findings

Discussion

Conclusion