Hypomyelinating leukodystrophy-8 is an autosomal recessive neurologic disorder characterized by early childhood onset of cerebellar ataxia and mild intellectual disabilities associated with diffuse hypomyelination apparent on brain MRI. Variable features include oligodontia and/or hypogonadotropic hypogonadism (summary by Tetreault ... Hypomyelinating leukodystrophy-8 is an autosomal recessive neurologic disorder characterized by early childhood onset of cerebellar ataxia and mild intellectual disabilities associated with diffuse hypomyelination apparent on brain MRI. Variable features include oligodontia and/or hypogonadotropic hypogonadism (summary by Tetreault et al., 2011). See also HLD7 (607694), which has similar features and is caused by mutation in the POLR3A gene (614258) on chromosome 10q22. The POLR3A and POLR3B genes encode the 2 largest subunits of RNA polymerase III. For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.
Sasaki et al. (2009) reported 3 unrelated Japanese patients who presented with early-childhood onset of a neurologic disorder characterized by unsteady gait, cerebellar ataxia, and mild intellectual retardation. Early motor development was normal in 2 and slightly delayed ... Sasaki et al. (2009) reported 3 unrelated Japanese patients who presented with early-childhood onset of a neurologic disorder characterized by unsteady gait, cerebellar ataxia, and mild intellectual retardation. Early motor development was normal in 2 and slightly delayed in 1. All achieved independent walking, although it was unstable. At age 3 to 4 years, patients presented with ataxia and cerebellar signs, including dysarthria, intention tremor, and dysmetria. All also had mild to moderate spasticity with hyperreflexia. One patient retained the ability to walk at age 11 years, another lost the ability to walk at age 12 years, and the third lost the ability to walk at age 25 years. This last patient also had more significant cognitive decline associated with loss of speech and loss of purposeful movements after age 20. None had hearing or visual loss, hypodontia, or hypogonadism. The disorder was slowly progressive. Brain MRI showed diffuse cerebral hypomyelination of the cerebral white matter on T2-weighted images, moderate cerebellar cortical atrophy, and hypoplasia of the corpus callosum. Saitsu et al. (2011) reported 3 patients from 2 unrelated nonconsanguineous Japanese families with childhood-onset hypomyelinating leukodystrophy. Two sibs had a very similar phenotype, with normal early infantile development and walking at ages 14 and 15 months, respectively. At age 3 years, 1 showed unstable walking and frequent falls and the other became poor at exercise. They had mild intellectual disability but were able to finish high school. As adults, both had cerebellar signs, including ataxic speech, wide-based ataxic gait, dysdiadochokinesis, and dysmetria, hypotonia, and mild hyperreflexia without extensor plantar responses. However, the motor deterioration was not considered to be progressive. Both also showed signs of hypogonadotropic hypogonadism. Other features included myopia, mild horizontal nystagmus, slowing of smooth-pursuit eye movements, and vertical gaze limitation. Brain MRI showed high-intensity areas in the white matter on T2-weighted images, consistent with diffuse cerebral hypomyelination, as well as cerebellar atrophy, and hypoplastic corpus callosum. A third unrelated patient, previously reported by Sasaki et al. (2009), could still walk in her teens, showed cerebellar signs, mild spasticity, slowing of smooth-pursuit eye movements, vertical gaze limitations, and intellectual disability. She did not have hypogonadism. None of the 3 had hypodontia. Tetreault et al. (2011) studied 3 unrelated patients of European descent who had a phenotype consistent with 4H syndrome (HLD7; 607694) but who did not have mutations in the POLR3A gene (614258). All presented in early childhood with mild developmental delays and developed dysarthria as well as progressive motor difficulties, including cerebellar ataxia. Two showed progressive spasticity. Two individuals developed hypogonadotropic hypogonadism, whereas the third was too young to evaluate for endocrine dysfunction. All 3 individuals had teeth abnormalities, such as neonatal upper incisors, delayed eruption of deciduous teeth and permanent teeth, abnormal sequence of eruption, and malposition. Brain MRI showed thin corpus callosum, cerebellar atrophy, and hypomyelination.
Using whole-exome sequencing, Saitsu et al. (2011) identified compound heterozygous mutations in the POLR3B gene (614366.0001-614366.0004) in 3 patients from 2 unrelated Japanese families with hypomyelinating leukodystrophy-8. Two of the patients had hypogonadotropic hypogonadism, but none had hypodontia. ... Using whole-exome sequencing, Saitsu et al. (2011) identified compound heterozygous mutations in the POLR3B gene (614366.0001-614366.0004) in 3 patients from 2 unrelated Japanese families with hypomyelinating leukodystrophy-8. Two of the patients had hypogonadotropic hypogonadism, but none had hypodontia. In 3 unrelated patients of European descent with HLD8, Tetreault et al. (2011) identified compound heterozygous mutations in the POLR3B gene (614366.0005-614366.0008). All had hypodontia and 2 developed hypogonadotropic hypogonadism.