Leukodystrophy, Hypomyelinating, 2

A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-2 (HLD2) is caused by homozygous or compound heterozygous mutation in the GJC2/GJA12 gene (608803) on chromosome 1q42.

For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

Clinical Features

Uhlenberg et al. (2004) described a consanguineous Turkish family in which multiple members showed the characteristic clinical symptoms of Pelizaeus-Merzbacher disease (PMD; 312080), including nystagmus, impaired motor development, ataxia, choreoathetotic movements, dysarthria, and progressive spasticity. Nystagmus and poor head and trunk control were presenting symptoms in early infancy. By the age of 8 to 15 months, impaired motor development became apparent when developmental milestones such as unaided sitting and/or walking were delayed or could not be achieved. Only 1 patient was able to walk a few steps at the age of 5 years. All patients demonstrated facial weakness. In addition to involvement of the central nervous system, Uhlenberg et al. (2004) noted that this form of PMLD seems to be accompanied by a mild peripheral neuropathy. Sensory and motor nerve conduction velocities of the lower limb nerves were reduced or slightly below the age-corrected normal values in most patients. Heterozygous individuals had no neurologic symptoms.

Bugiani et al. (2006) reported 12 patients from 3 kindreds with PMLD confirmed by genetic analysis. The largest family was consanguineous and of Saudi Arabian origin with at least 8 affected members. The clinical phenotype was homogeneous with onset of rotary or pendular nystagmus usually in the first weeks of life. All except 1 child had delayed motor development, and most did not achieve ambulation even with support. Neurologic signs included cerebellar ataxia, intention tremor, dysarthria, and spasticity. None had choreoathetosis, dystonia, peripheral neuropathy, or seizures. Six had joint contractures, and 11 of 12 had mild to moderate mental retardation. The course tended to be slowly progressive. Brain MRI showed diffuse cerebral hypomyelination and partial myelination of the pyramidal tracts.

Wolf et al. (2007) reported 2 sibs with PMLD1, born of consanguineous Pakistani parents, who showed different clinical phenotypes. The older sib developed nystagmus at age 4 months, ataxia at 2 years, and spasticity at 6 years. The spasticity progressed, and she was wheelchair-bound by age 16 years. Her younger brother showed nystagmus at age 4 weeks, moderately impaired psychomotor development, and was never able to walk independently. He also had a severe sensory neuropathy, which may not have been related to the disorder. Both showed mainly dysmyelination in addition to progressive demyelination on brain MRI.

Salviati et al. (2007) reported another Pakistani girl with PMLD1. She developed horizontal and rotary nystagmus at age 3 months. By 1 year, she had truncal hypotonia with hypertonia of the lower limbs, motor impairment, ataxia, and optic atrophy. By 5 years of age, she was unable to walk or stand alone, and she had moderate mental impairment (IQ of 50) with dysarthria. In addition, brainstem auditory evoked responses were markedly altered. Brain MRI showed characteristic diffuse T2-weighted hyperintensities consistent with hypomyelination.

Biancheri et al. (2013) reported a girl, born of consanguineous Sri Lankan parents, with a severe form of HLD2. At birth she was noted to have nystagmus, and she subsequently showed severely delayed psychomotor development. Examination at age 7 months showed axial hypotonia, absent head control, increased muscle tone in the lower limbs, and brisk tendon reflexes. Neurophysiologic studies showed abnormal brainstem auditory evoked and visual evoked potentials. Brain MRI showed diffuse hyperintensity on T2-weighted images of the cerebral and cerebellar white matter, including the middle cerebellar peduncles and almost the entire brainstem. The white matter of the cervical spinal cord was also abnormal. At age 5 years, she had not acquired any motor milestones and was severely disabled with spasticity, mental retardation, and poor speech. Funduscopy showed optic atrophy. Biancheri et al. (2013) noted that the phenotype in this patient was consistent with the connatal form of PMD.

Gotoh et al. (2014) reported 2 unrelated patients with HLD2 confirmed by genetic analysis (608803.0013). Both presented with congenital nystagmus in infancy and showed significant motor delays. Neither achieved independent walking, but both walked with support for some time in childhood. Receptive language was relatively spared, as was cognition, but expressive language was severely limited by dysarthria. Both patients had spasticity, rigidity, and dystonia, and 1 also had ataxia and tremor. Neuroimaging showed signal changes consistent with hypomyelination.

Inheritance

The transmission pattern of a Pelizaeus-Merzbacher disease-like phenotype in the family reported by Uhlenberg et al. (2004) was consistent with autosomal recessive inheritance.

Diagnosis

Differential Diagnosis

In a retrospective study of neurophysiologic results from 10 patients with PMLD1 and 8 with classic PMD, Henneke et al. (2010) found that that brainstem auditory evoked potentials (BAEP) were significantly worse among those with classic PMD. Waves III, IV and V, which are generated in the pons and midbrain, were absent in all patients with PMD, but were clearly recordable in 11 of 13 investigations in patients with PMLD1. Investigations of auditory acuity were not available. Visual and somatosensory evoked potentials showed conductive delay in both groups of patients, without significant differences. Nerve conduction studies were normal in all patients with PMD and indicated mild peripheral neuropathy in only 2 of 10 patients with PMLD1. Henneke et al. (2010) concluded that BAEP is a helpful tool to differentiate between these 2 disorders.

Mapping

By genomewide linkage scanning in a consanguineous Turkish family, Uhlenberg et al. (2004) detected linkage of PMLD1 to single-nucleotide polymorphisms (SNPs) on 1q41-q42.

Molecular Genetics

Uhlenberg et al. (2004) studied 6 families with PMLD. In 1 Turkish consanguineous family and 2 German nonconsanguineous families, they identified 5 different mutations in the GJA12 gene (608803.0001-608803.0005). In the other 3 affected families, they found no GJA12 mutations, suggesting further genetic heterogeneity.

In 2 affected sibs with PMLD1, born of consanguineous Pakistani parents, Wolf et al. (2007) identified a homozygous 34-bp deletion in the GJA12 gene (608803.0006). Salviati et al. (2007) independently identified the same 34-bp deletion in another Pakistani girl with PMLD1.

Henneke et al. (2008) identified 11 mutations (see, e.g., 608803.0007) in the GJA12 gene in affected members of 14 (7.7%) of 182 families with a PMLD-like phenotype. The phenotype was similar to that observed in patients with classic PMD, but patients with GJA12 mutations had better cognition and earlier signs of axonal degeneration. The authors concluded that GJA12 mutations are not a common cause for a PMLD-like disorder.

Biancheri et al. (2013) identified a homozygous mutation in the GJC2 gene (608803.0012) in a Sri Lankan girl with a severe connatal form of HLD2.