Neurogenic bladder and neuroendocrine abnormalities in Pol III-related leukodystrophy

The patient was a 32-year-old Caucasian female, the third-born to healthy non-consanguineous parents with negative family history of neurologic disorders. The pregnancy, birth and early psychomotor development were uneventful. At the age of 7 years chronic urinary incontinence commenced and remained the unexplained clinical abnormality for 20 years. Prompt nephrologic, gynecologic, and urologic investigations (also including voiding cystourethrogram, cystoscopy, renal scintigraphy, ultrasonography, biochemical analyses of blood and urine) were normal, and there were no accompanying neurologic signs in the overall clinical status. The persisting urinary disturbance brought the patient to neurologic attention only at 32 years of age when the assessment disclosed a 5-year history of slowly progressive cerebellar ataxia followed by pyramidal signs, and then focal upper extremity dystonia. The neuropsychological evaluation at the age of 32 years documented a mild intellectual disability for the first time (full-scale IQ of 57; Wechsler Adult Intelligence Scale-IV). It was thought to be a decline compared to the patient’s historical level of functioning: the patient had finished the compulsory education (age 7–15 years) with regular psychological assessments, was employed as a factory worker, and was able to live independently. She stopped working at the age of 32 years during the neurologic follow-ups. Magnetic resonance imaging (MRI) of the brain revealed diffuse supratentorial hypomyelination that bilaterally spread along the posterior limb of the internal capsule affecting the pyramidal tracts, the middle and inferior cerebellar peduncles (Figure 1a, b, c). T2-weighted hypointensities were observed in the globi pallidi, the optic radiations and the dentate nuclei (Figure 1b, d). There was a marked atrophy of the cerebellum and corpus callosum, as well as of the pontine and midbrain tegmentum (Figure 1e). The adenohypophysis was small (Figure 1e, f). Multivoxel MR Spectroscopy of the brain detected a markedly decreased choline/creatine ratio in the abnormal white matter (Figure 1g). Diffusion tensor imaging of the brain showed a slightly reduced fractional anisotropy consistent with hypomyelination (Figure 1h). MRI of the brain pointed to Pol III-related leukodystrophy [3]. MRI of the spinal cord was normal (Figure 1i, j). Electromyoneurography was unremarkable. Urodynamic tests (uroflow study, postvoid residual volume, filling-voiding cystometry, abdominal leak-point pressure, external sphincter electromyography-EMG) revealed decreased bladder capacity with preserved sensation, uninhibited detrusor muscle contractions, and detrusor- external sphincter synergy, while sphincter EMG recorded normal amplitudes and duration of muscle potentials. The urodynamic study proved the bladder overactivity due to neurologic, suprapontine lesion [4]. The repeated urologic, nephrologic, and metabolic investigations remained normal. At 26 years of age the patient had no sexual development (Tanner stage 1, primary amenorrhea). Hypogonadotropic hypogonadism, low baseline prolactin level and growth hormone (GH) deficiency were confirmed (Table 1). Her height was below the 3^rd percentile and she was normosmic. The karyotype was normal. The patient received sexual hormone replacement for 3 years. At 32 years of age hypogonadotropic hypogonadism was proven by the absence of luteinizing hormone pulsatility (Table 1). Hypoprolactinemia was confirmed by two stimulatory tests (insulin tolerance test-ITT and thyrotropin-releasing hormone-TRH test), while growth hormone level was normal (Table 1). Other hormonal values were normal (Table 1). Her final adult height was 155 cm (10^th percentile) and Tanner stage was 4, with amenorrhea. Given the accompanied hypoestrogenemia, gynecologic and urogynecologic examinations excluded atrophic vaginitis, vulvar structural anomalies, and decreased strength of the pelvic floor and bladder muscles, as possible estrogen-related causes of the urinary incontinence [5]. Dental examination confirmed hypodontia with the lack of second and third molars. A genetic evaluation was necessitated: sequencing of the key exons and exon-intron boundaries of POLR3A using previously reported methods [6], revealed two already known disease-causing mutations, c.272C > T (p.P91L) in exon 3 and c.3014G > A (p.R1005H) in exon 23 which segregated in the parents and proved the diagnosis of 4H leukodystrophy.