Alternative titles; symbols
ORPHA: 85186, 88637; DO: 0060797;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q23.3 | Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism | 614381 | Autosomal recessive | 3 | POLR3B | 614366 |
A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-8 (HLD8) is caused by compound heterozygous mutation in the POLR3B gene (614366) on chromosome 12q23.
Hypomyelinating leukodystrophy-8 (HLD8) 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.
Cerebellar hypoplasia with endosteal sclerosis appears to have been described first by Stoll et al. (1986). The parents in this case were consanguineous.
Charrow et al. (1991) described a brother and sister and an unrelated boy with congenital cerebellar hypoplasia and endosteal sclerosis. All 3 children presented with ataxia and developmental delay and were found to have microcephaly, short stature, oligodontia, strabismus, nystagmus, and congenital hip dislocation.
Ozgen et al. (2005) described 11-year follow-up of an affected girl whose major clinical symptoms were cerebellar hypoplasia causing ataxia, hypotonia, mild to moderate developmental delay, growth retardation, endosteal sclerosis, tooth eruption disturbances, and hip dislocations. The endosteal sclerosis remained stationary over time, as did the clinical neurologic symptoms, but neuroradiologic manifestations slowly progressed. Ozgen et al. (2005) concluded that the disorder is probably autosomal recessive.
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 mildly impaired intellectual development 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 as patient 1 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.
Daoud et al. (2013) reported 7 patients with HLN8. Onset of disease ranged from less than 1 year to 15 years of age. Six of the patients had dental anomalies. Four of the patients had hypogonadotrophic hypogonadism. Upper motor neuron signs were found in 5 of 6 patients for whom this information was available. All of the patients had cerebellar signs. Impaired intellectual development was reported in 4 of 5 patients for whom this information was available. One patient required a wheelchair for mobility.
Ghoumid et al. (2017) reported a patient with severe cognitive impairment who developed worsening tremor and dysmetria in the first year of life. He had 5 teeth at birth, and when his primary teeth erupted, he was missing 4 superior molars and 2 inferior molars. Radiographs at age 2 years showed vertebral, pelvic, and femoral endosteal sclerosis. At age 15 years, he had growth delay, hypotonia, pyramidal signs, dystonia, optic atrophy, and hypogonadotropic hypogonadism. Brain MRI showed diffuse hypomyelination and severe cerebellar atrophy.
Verberne et al. (2020) reported a 21-year-old woman who presented at 14 years of age for evaluation of a history of developmental delay and hypoplasia of the cerebellar vermis. She had cerebellar ataxia, impaired intellectual development, dysarthria, intention tremor, hypodontia, myopia, and gaze-evoked nystagmus. Brain MRI at age 17 years demonstrated diffuse hyperintensity of white matter, supratentorial atrophy, and severe cerebellar atrophy.
The transmission pattern of HLD8 in the families reported by Saitsu et al. (2011) was consistent with autosomal recessive inheritance.
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. One of the patients had previously been reported as patient 1 by Sasaki et al. (2009).
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.
In a cohort of 565 patients with isolated hypogonadotropic hypogonadism, with or without anosmia, Richards et al. (2017) performed whole-exome sequencing and identified 4 patients from 3 unrelated families who were compound heterozygous for rare variants in the POLR3B gene and did not have variants in 7 other ataxia-associated genes. An M415T polymorphism (rs199504211) of unclear pathologic significance was carried by 2 of the patients in addition to another variant in POLR3B; no segregation information was reported in those families. In 2 affected sibs, the V523E variant (614366.0005; rs138249161) and an F400S missense variant in POLR3B were identified, each inherited from an unaffected heterozygous parent. None of the 4 patients were reported to have frank neurologic symptoms at their most recent evaluations in their early 30s, and 1 had a brain MRI at age 23 years that was reported as normal. The authors suggested that a possible reason for the lack of neurodegenerative symptoms might be that the variants identified are less harmful to protein function than those identified in patients with HLD8, and noted that computational programs yielded mixed predictions regarding pathogenicity of the variants. No in vivo or in vitro functional analysis of the variants was reported.
Daoud et al. (2013) identified compound heterozygous mutations in the POLR3B gene in 7 patients with HLD8. Of the 8 mutations identified, 7 were novel (see, e.g., 614366.0016-614366.0018). Six patients carried the previously identified V523E mutation (614366.0005), which was located on a shared common haplotype in all 6.
In a 15-year-old boy with HLD8, Ghoumid et al. (2017) identified compound heterozygous mutations in the POLR3B gene: the recurrent V523E mutation and a missense mutation (P925Q; 614366.0015).
In a 21-year-old woman with HLD8, Verberne et al. (2020) identified homozygosity for the recurrent V523E mutation in the POLR3B gene.
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. Except for the French Canadian patients, who carried a common POLR3A mutation (G672E; 614258.0001), 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.
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Daoud, H., Tetreault, M., Gibson, W., Guerrero, K., Cohen, A., Gburek-Augustat, J., Synofzik, M., Brais, B., Stevens, C. A., Sanchez-Carpintero, R., Goizet, C., Naidu, S., Vanderver, A., Bernard, G. Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism. J. Med. Genet. 50: 194-197, 2013. [PubMed: 23355746] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101357]
Ghoumid, J., Petit, F., Boute-Benejean, O., Frenois, F., Cartigny, M., Vanlerberghe, C., Smol, T., Caumes, R., de Roux, N., Manouvrier-Hanu, S. Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder. Europ. J. Hum. Genet. 25: 1011-1014, 2017. [PubMed: 28589944] [Full Text: https://doi.org/10.1038/ejhg.2017.73]
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Verberne, E. A., Dalen Meurs, L., Wolf, N. I., 4H leukodystrophy caused by a homozygous POLR3B mutation. further delineation of the phenotype. Am. J. Med. Genet. 182A: 1776-1779, 2020. [PubMed: 32319736] [Full Text: https://doi.org/10.1002/ajmg.a.61600]
Wolf, N. I., Vanderver, A., van Spaendonk, R. M. L., Schiffmann, R., Brais, B., Bugiani, M., Sistermans, E., Catsman-Berrevoets, C., Kros, J. M., Soares Pinto, P., Pohl, D., Tirupathi, S., and 10 others. Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. Neurology 83: 1898-1905, 2014. [PubMed: 25339210] [Full Text: https://doi.org/10.1212/WNL.0000000000001002]