Leukodystrophy, Hypomyelinating, 7, With Or Without Oligodontia And/or Hypogonadotropic Hypogonadism

A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-7 (HLD7) is caused by homozygous or compound heterozygous mutation in the POLR3A gene (614258) on chromosome 10q22.

Description

Hypomyelinating leukodystrophy-7 is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression. Other features may include hypodontia or oligodontia and hypogonadotropic hypogonadism. There is considerable inter- and intrafamilial variability (summary by Bernard et al., 2011).

See also HLD8 (614381), which has similar features and is caused by mutation in the POLR3B gene (614366) on chromosome 12q23. 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.

Clinical Features

In an inbred Syrian pedigree, Atrouni et al. (2003) described oligodontia in association with a degenerative neurologic condition characterized by progressive ataxia and pyramidal syndrome. Age at onset was about 12 years. Abnormalities in the white matter and cortical atrophy were demonstrated by magnetic resonance imaging. In 1 sibship of 8, 3 girls and a boy were affected; the parents were consanguineous. Atrouni et al. (2003) suggested that this might represent a distinct form of dentoleukoencephalopathy with autosomal recessive inheritance.

Wolf et al. (2005) reported 4 unrelated German or Swiss girls with early onset of progressive ataxia during the second year of life, mild to moderate brain hypomyelination, cerebellar atrophy, and delayed dentition. The first teeth to appear were the deciduous molars. Some patients were missing permanent teeth. All patients also had short stature. Wolf et al. (2005) considered the disorder clinically distinct from that reported by Atrouni et al. (2003) because in the Syrian pedigree the MRI did not show hypomyelination, but demyelination mainly of the pyramidal tracts and of the subcortical matter, the onset of ataxia occurred after the age of 10 years, and the pattern of tooth agenesis was different.

Wolf et al. (2007) reported 4 additional patients, including 3 boys, with ataxia, delayed dentition, and hypomyelination similar to their earlier report. All had delayed motor development with early-onset ataxia, tremor, dysarthria, and hypometric saccades. Pyramidal signs were variable, and most had mild cognitive dysfunction. Two patients had neonatal teeth, and all showed delayed dentition and abnormal order of tooth eruption. MRI showed hypomyelination of the supratentorial white matter, with thin corpus callosum and cerebellar atrophy.

Saitsu et al. (2011) reported a 17-year-old Japanese boy with HLD7 confirmed by genetic analysis (614258.0006 and 614258.0007). He showed normal development until age 4, when mild tremors were noted. He later developed cerebellar signs, including expressive ataxic speech, intention tremor, poor finger-to-nose test, dysdiadochokinesis, dysmetria, and wide-based ataxic gait. He also showed intellectual disability with an IQ of 57. Other features included severe myopia and unilateral sensorineural deafness. The motor deterioration was progressive, and he became wheelchair-bound around age 14 years. Brain MRI showed a hypoplastic corpus callosum, cerebellar atrophy, and white matter lesions in the basal ganglia. He did not have hypodontia or hypogonadism.

Clinical Variability

Timmons et al. (2006) reported 4 unrelated patients with delayed tooth eruption and hypodontia of permanent teeth. Three patients were otherwise normal until age 12 years, when progressive hypomyelination and dysmyelination resulted in ataxia, dysmetria, spasticity, dysarthria, and extensor plantar responses. The fourth patient had onset at age 7. None of the patients had spontaneous puberty due to hypogonadotropic hypogonadism. There were also cognitive deficits. Sural nerve biopsy showed granular debris-lined clefts, expanded abaxonal space, vacuolar disruption, and loss of normal myelin periodicity. Brain MRI showed central hypomyelination and cerebellar atrophy. Timmons et al. (2006) proposed the designation '4H syndrome.'

Bernard et al. (2010) reported 6 living patients and 1 deceased patient from 5 French Canadian families with a similar form of very early childhood-onset hypomyelinating leukodystrophy. Two of the families were consanguineous. The average age at onset was 2.5 years (range 1 to 5) and all presented with motor regression, ataxia, tremor, and spasticity. Other features included dysarthria, hyperreflexia, extensor plantar responses, abnormal bladder function, abnormal saccades, and nystagmus. Most became wheelchair-bound by later childhood. Less common features included dysphagia, drooling, optic atrophy, and complex partial seizures. Cognitive decline was mild, but noticeable. Two of 7 patients had some degree of hypodontia, and 1 had hypogonadotropic hypogonadism. Bernard et al. (2010) recognized the phenotypic overlap with the patients reported by Wolf et al. (2005) and Timmons et al. (2006), but noted that not all the French Canadian patients had hypodontia or hypogonadism, and none had peripheral nerve abnormalities.

Neuropathologic Features

Wolf et al. (2014) reported the neuropathologic features of a 14-year-old girl with HLD7 who was homozygous for a Q599H mutation in the POLR3A gene. There was diffuse white matter atrophy with thin corpus callosum and enlarged ventricles, and the white matter was nonhomogeneously discolored. There was variable white matter rarefaction, lack of myelin, reduced numbers of oligodendrocytes, and foamy macrophages. Sural nerve from the patient showed mild lack of myelin.

Inheritance

The transmission patterns in the families reported by Atrouni et al. (2003) and Bernard et al. (2010) were consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping of several French Canadian families with a similar form of hypomyelinating leukodystrophy, Bernard et al. (2010) found linkage to a 12.6-Mb region between rs7069982 and rs2071510 on chromosome 10q22.3-q23.31 (maximum lod score of 5.47 at markers D10S201, D10S1777, and D10S1696). Sequencing of candidate genes within the region did not reveal any pathogenic mutations.

By genomewide linkage analysis of the Syrian family reported by Atrouni et al. (2003), Chouery et al. (2011) identified an 8.7-Mb region on chromosome 10q22.1-q23.33 (maximum multipoint lod score of 5.66 between SNPs rs10823772 and rs927452) as harboring the candidate gene. Sequencing of candidate genes within the region did not reveal any pathogenic mutations.

Molecular Genetics

By narrowing the candidate disease locus followed by direct sequencing of the genes in the refined 2.99-Mb interval in several families with hypomyelinating leukodystrophy mapping to chromosome 10q22, Bernard et al. (2011) identified 14 different mutations in the POLR3A gene (see, e.g., 614258.0001-614258.0005). All mutations were in the homozygous or compound heterozygous state, and no patient had 2 truncating mutations. There were 19 patients from 12 families, including those reported by Atrouni et al. (2003), Timmons et al. (2006), and Bernard et al. (2010). The mutations were spread throughout the gene, and there were no obvious genotype/phenotype correlations. Immunoblot analysis showed decreased levels of POLR3A protein in fibroblasts from 4 affected individuals, and decreased levels in the cortex and cerebral white matter of another patient, suggesting that loss of function is responsible for the disorder. Bernard et al. (2011) hypothesized that POLR3A mutations lead to dysregulation of RNA polymerase III and its targets, resulting in decreased expression of certain tRNAs during development and impaired protein synthesis.

Genotype/Phenotype Correlations

Wolf et al. (2014) performed a cross-sectional observational study of 105 patients with 4H syndrome, including 43 with mutations in the POLR3A gene and 62 with mutations in the POLR3B gene. Most patients of French Canadian descent carried the G672E mutation (614258.0001). Except for the French Canadian patients, most patients of European descent carried POLR3B mutations. Among all patients, about half had delayed development, including 19 (17%) who were never able to walk independently (4 with POLR3A mutations and 15 and POLR3B mutations). Ten (10%) of patients presented after age 10 years. All patients except one, who was older at the time of diagnosis, had cerebellar signs, such as severe intention tremor, dysmetria, ataxia, abnormal smooth pursuit, and nystagmus. Deterioration of speech and swallowing occurred later. Only a few patients had extrapyramidal signs, mainly dystonia. Cognition varied widely from normal in a few patients to moderate intellectual disability in most. About 20% of patients had seizures. Neurologic deterioration with infection occurred in about half of patients. Dental abnormalities, such as delayed dentition and hypodontia, were common (in 87%). Delayed puberty, in those old enough to assess, occurred in 81% of patients with POLR3A mutations and in 69% of those with POLR3B mutations. Most (87%) patients had severe and often progressive myopia, and about half had short stature. Growth hormone deficiency was found in 5 of 10 patients tested. Brain imaging showed hypomyelination in all patients and cerebellar atrophy in most. Supratentorial atrophy and thin corpus callosum were seen in older patients, reflecting white matter loss. A T2-weighted hypodense dot in the posterior limb of the internal capsule was seen in 70% of patients with POLR3B mutations, but only 13% of those with POLR3A mutations. In general, patients with POLR3A mutations had a more severe disease than those with POLR3B mutations. Two sibs with a homozygous POLR3B V523E mutation (614366.0005) had an exceptionally mild clinical course. Wolf et al. (2014) concluded that 4H syndrome is an insidiously progressive neurologic disorder with declining motor function of variable severity, but dental abnormalities and hypogonadism are not obligatory for the diagnosis.