Leber Hereditary Optic Neuropathy and Longitudinally Extensive Transverse Myelitis

Abstract

Leber Hereditary Optic Neuropathy is an inherited optic neuropathy caused by mitochondrial DNA point mutations leading to sudden, painless loss of vision. We report a case of an 8-year-old boy presenting with a radiological phenotype of longitudinally extensive transverse myelitis on a background of severe visual impairment secondary to Leber Hereditary Optic Neuropathy (LHON). He was found to have dual mitochondrial DNA mutations at 14484 (MTND6 gene) and 4160 (MTND1 gene) in a family with a severe form of LHON characterised by not only an unusually high penetrance of optic neuropathy, but also severe extra-ocular neurological complications. The m.14484T>C mutation is a common LHON mutation, but the m.4160T>C mutation is to our knowledge not reported outside this family and appears to drive the neurological manifestations. To our knowledge there have been no previous reports of spinal cord lesions in children with LHON.

Establishing risk of vision loss in Leber hereditary optic neuropathy

“…We identified 96 genetically unrelated LHON pedigrees, including 56 new pedigrees, and updated 40 previously known pedigrees in Australia ( Table 1 ). 4 , 22 , 30 , 31 , 32 , 33 , 34 , 35 Updated assignments of LHON matrilineal pedigrees are shown in Table S4 . Among the pedigrees, 43/96 (44.8%) were sporadic cases, with only one affected person identified thus far, and 53/96 (55.2%) were familial.…”

“…Together, the three primary LHON mutations accounted for 88.2% of total LHON cases. Four additional pedigrees harbored either double LHON mutations (VIC20, m.11778G>A + m.14484T>C; 33 QLD01 m.14484T>C + m.4160T>C 30 ) or rare LHON mutations (NSW08, m.14482C>G; 32 SAU04, m.4171C>A) ( Table 2 ). All pedigrees harbored homoplasmic mutations, except for VIC02, 31 VIC30, and NZ10, who harbored heteroplasmic mutations ( Figure S1 ).…”

“… 15 , 22 , 31 , 34 , 36 At least nine members of the QLD01 pedigree presented with neurological abnormalities characteristic of “LHON plus” syndrome. 30 …”

“…15,22,31,34,36 At least nine members of the QLD01 pedigree presented with neurological abnormalities characteristic of ''LHON plus'' syndrome. 30 Vision loss penetrance among mtDNA haplogroups Mitochondrial haplogroup was determined in 68 out of 96 pedigrees (Table 1), as suitable DNA samples were not available for sequencing in all lineages. This is equivalent to 84.8% of affected individuals (526/620) and 94.5% of asymptomatic carriers (4,675/4,948).…”

Mitochondrial Retinopathies

“…LHON, either with the three primary common mtDNA mutations, but more frequently with rarer mtDNA mutations again affecting the mtDNA-encoded cI subunit genes, may present with a spectrum of clinical manifestations ranging from optic atrophy plus dystonia and basal ganglia bilateral lesions resembling Leigh syndrome to MELAS syndrome [ 29 , 30 ]. Other reported associations may include cerebellar atrophy [ 125 ], myoclonus [ 126 ], myelopathy [ 127 , 128 ] and peripheral neuropathy [ 129 ]. Perhaps the most puzzling and controversial association is the co-occurrence of LHON with multiple sclerosis, for which it is still debated if this must be considered merely a coincidence based on prevalence of both disorders or if one may be triggering the other [ 130 , 131 ].…”