Dr.Sruthi, Dr.Sheela Nampoothiri, Dr.Praveena, Dr.C Jayakumar ,AIMS KOCHI
Five year old female child from Jharkand presented for evaluation of neuroregression and recurrent respiratory infections. She is the 4th child of a non-consanguineous marriage with uneventful antenatal period and born and developing normally.
At two years of age she started having difficulty in swallowing, nasal regurgitation and failure to gain weight. At 2.5 years of age she was noted to have regression of milestones and had lost independent walking along with abnormal movements. At 3 years of age she used to have lower respiratory tract infections.
At presentation, her auxology was both wasting and stunting which were more than-3SD with grade II clubbing. In addition she was dolichocephalic with arched eyebrow, thin upper lip, long eyelashes, squared nasal tip, only five teeth and pectus excavatum. Neurologically she showed drooling, hypertonia, spasticity, power of grade 3/5, brisk tendon reflexes, intentional tremors and titubation. Eye examination ruled out presence of cherry red spot. Per abdomen examination showed no organomegaly.
Cystic fibrosis gene analysis and electromyography were found to be normal. Audiometry showed right peripheral pathway dysfunction. MRI brain showed bilateral symmetrical mild volume loss, partial corpus callosal agenesis and diffuse hypomyelination/dysmyelination. Whole exome sequencing revealed a compound heterozygous mutation in POLR3A gene and was thus diagnosed as POLR3A related leukodystrophy.
POLR3 related leukodystrophy, an autosomal recessive disorder, is a hypomyelinating leukodystrophy with specific features on brain MRI which is characterized varying combinations of 4 major clinical features :
1.Neurologic dysfunction: predominated motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent, extra-pyramidal, pyramidal as well cognitive dysfunction.
2.Abnormal dentition (e.g. hypodontia, oligodontia, delayed teeth eruption and abnormally placed or shaped teeth).
3.Endocrine abnormalities such as short stature with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism.
4.Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe
Brain MRI findings includes :
1. A hypomyelinating leukodystrophy pattern characterized T2 mild hyperintensity of the white matter and T1 hyperintensity, isointensity, or mild hypointensity of the white matter when compared with grey matter structures.
2. Relative preservation of myelination of specific brain structures.
The diagnosis of POLR3-related leukodystrophy is established in a proband with the combination of classic clinical findings, typical brain MRI features, and identification of biallelic pathogenic variants on molecular genetic testing. It’s a life limiting condition .Treatment requires multidisciplinary management with special emphasis on swallowing function, dystonia and recurrent respiratory infections. Genetic counselling is also recommended.
The ability to pick up such rare diseases with the history and clinical findings and then choosing the appropriate investigations to come to a diagnosis is the need of the hour and it emphasizes the importance of not keeping our eyes and ears shut to the new developments in our field of medicine.