4H leucodystrophy phenotypical variation among two brothers: a case report

Case presentation: Patient 1: V.U.F, male, 14 years old. When he was 3 years old the patient presented with ataxic gait and recurrent falls. Ataxia worsened during the 8 years after the first presentation. He had low school performance and developed myopia. Family history: great-grandmother developed ataxia at the age of 32 and died when she was 59. Patient has a brother with similar clinical condition. The patient presented with adequate height, absence of the lower central incisor teeth, upper and lower limb dysmetria and Tanner G1P1. Dysdiadochokinesis, ataxic and unstable gait with amplitude reduction, without Romberg signal, and tendril dancing were observed. Scale for the Assessment and Rating of Ataxia (SARA) was performed: 17.5. Electroneuromyography showed demyelinating sensory polyneuropathy. CGH array was normal. Magnetic Resonance Imaging (MRI) of the brain showed cerebellar atrophy, particularly of the vermix, diffuse and symmetrical hypomyelination of the cerebral hemispheres, and reduction of the corpus callosum. Spectroscopy was normal. Patient 2: I.U.F, male, 10 years old, brother of patient 1. When he was 4 years old his gait worsened accompanied by mild ataxia. He presented with school difficulties, being unable to read or write, with complaint of academic lack of attention and aggressiveness at home and school. He was not able to mention the name or address of his school. Enamel of the teeth was not well formed. Joint hypermobility, fine tremor, SARA 3, and Tanner G1P1 were observed. Brain MRI showed discrete thinning of the corpus callosum, bilateral diffuse alteration of the white matter signal, without significant change in T1. Exoma was performed in both patients and mutation of the POLR3B gene was found.

Discussion: 4H leucodystrophy is na autonomical recessive disease caused by mutations in POLR3A, POLR3B, and POLR1C, resulting in a triad with hypomyelination, hypodontia, and hypogonadotropic hypogonadism. In the absence of these findings, brain MRI helps with the diagnosis showing diffuse hypomyelination associated to cerebellar atrophy, T2-weighted hypointensity of the ventrolateral thalamus and myelinization of the pyramidal tracts, dentate nuclei and optic radiations.

Final comments: The interesting observation of this case report resides in the fact that we were able to demonstrate different phenotype presentations for the same gene mutation. One of the siblings showed predominantly ataxic manifestations whereas the other presented with neuropsychiatric symptom.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023