Oculodentodigital Dysplasia: A Hypomyelinating Leukodystrophy with a Characteristic MRI Pattern of Brain Stem Involvement

Abstract

Oculodentodigital dysplasia, a rare genetic disorder caused by mutations in the gene encoding gap junction protein 1, classically presents with typical facial features, dental and ocular anomalies, and syndactyly. Oligosymptomatic patients are common and difficult to recognize, in particular if syndactyly is absent. Neurologic manifestation occurs in approximately 30% of patients, and leukodystrophy or T2 hypointensity of gray matter structures or both have been noted in individual patients. To investigate MR imaging changes in oculodentodigital dysplasia, we retrospectively and systematically reviewed 12 MRIs from 6 genetically confirmed patients. Diffuse supratentorial hypomyelination, T2-hypointense Rolandic and primary visual cortex, and symmetric involvement of middle cerebellar peduncle, pyramidal tract, and medial lemniscus was present in all, T2-hypointense pallidum and dentate nucleus in 2 patients each. This consistent, characteristic pattern of diffuse supratentorial hypomyelination and brain stem involvement differs from other hypomyelinating and nonhypomyelinating leukodystrophies with brain stem involvement, and its recognition should trigger genetic testing for oculodentodigital dysplasia.

Hypomyelinating leukodystrophies in adults: Clinical and genetic features

“…A 36‐year‐old female, ~16 years after onset. There is a mild, symmetric, and diffuse hyperintensity of the supratentorial WM associated with cerebral atrophy in the posterior regions; the typical involvement of the middle cerebellar peduncle and of the pyramidal tract, lemniscus medialis, and raphe at the level of the pons is also shown in the inset [24]. T1‐weighted images are shown for all patients in Figure S1a–f.…”

“…These findings provide definite evidence that adult-onset HLDs can be caused by mutations in genes associated with childhood hypomyelination as previously reported in a few patients with PLP1 [4,14], GJC2 [12,22], or TUBB4A [13,23] mutations. The first subgroup also includes the patient with a GJA1-related disease characterized by dysmorphic facial appearance, variable involvement of eyes, dentition, and fingers (ODDD), and central hypomyelination [24]. The finding of an adult with ODDD provides further evidence that in this disease, dysmorphic features may be mild and overlooked, and neurological manifestations may appear far later in life [25,26].…”

Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy

“…Alternatively, presentation later in life with a milder clinical picture is also possible. 15,16 The prototype of hypomyelinating leukodystrophies is Pelizaeus-Merzbacher disease (PMD [MIM: 312080]) due to alterations of PLP1 (MIM: 300401), encoding the structural myelin protein, proteolipid protein 1. 17 A series of hypomyelinating disorders have been attributed to genetic variants in genes encoding proteins involved in different cellular processes including mRNA translation (tRNA synthetase proteins and cofactors and RNA polymerase III components) and heat-shock response, as well as in genes encoding transcription factors and plasma and lysosomal membrane proteins (please see van der Knaap et al 6 for a recent comprehensive review).…”

Oculodentodigital Dysplasia

“…A middle-aged patient presented with mild facial dysmorphisms, small teeth with enamel hypoplasia, progressive gait disturbances, memory problems, and history of syndactyly, corrected in early childhood. MRI showed a hypomyelination pattern compatible with oculodentaldigital dysplasia (ODDD) 1,2 (Figure 1). Ophthalmic findings revealed severe bilateral myopia.…”