Axonal Polyneuropathy in 2 Brothers With a Homozygous Missense Variant in the First Catalytic Domain of PCYT2

Clinical Findings

The patients are the only children of healthy, nonconsanguineous parents. There is no family history of neurologic disease. Patient 1 (II:1) is a 41-year-old man (Figure 1A). He first presented with balance problems at age 14 months when he started walking. At 19 months, his gait was unsteady and wide based, and he was diagnosed with spastic paraparesis. At age 12 years, he was diagnosed with epilepsy. His seizures were mostly tonic-clonic and well controlled with carbamazepine. In his teens, he was diagnosed with myopia. He attended mainstream school, finished secondary school, and got a job. At age 25 years, he was retired due to gait instability and inability to walk. He had dysarthria and urinary urge incontinence. At the initial examination at our clinic, at age 25 years, he was dysarthric and had horizontal nystagmus, marked intention tremor, spasticity in the upper and lower limbs, and polykinetic patellar and Achilles reflexes. In addition, he showed signs of neuropathy on lower limbs. He had muscle atrophy and weakness distal to the knees (feet dorsiflexion 3/5; plantar flexion 4/5), high-arched feet, and hammertoes, and he reported poor vibration and position perception in the distal parts of the lower limbs. By age 41 years, his condition deteriorated significantly. He was completely wheelchair dependent and cachectic and had cognitive decline with psychosis. He complained of chronic generalized pain, which was unresponsive to pharmacologic and nonpharmacologic treatment. The pain worsened after some analgesics, such as piritramide, and after food intake, causing him to refuse it. On examination, he was 150 cm tall (−4.1 SD), weighed 38 kg (body mass index 16.89 kg/m²), and had a head circumference of 54.5 cm (−0.7 SD). He had pendular nystagmus in all directions. In the upper limbs, the interosseous muscles were bilaterally hypotrophic and weak, muscle tone was increased, and myotatic reflexes were brisk. In the lower limbs, hip and knee flexion contractures (Figure 1B-C) and minimal movement of the toes were noted in addition to the abnormalities already reported. He wore glasses for myopia but had no additional vision problems. Nerve conduction studies showed evidence of axonal motor and sensory polyneuropathy (Table). Neuropsychological assessment revealed cognitive deficits in the domain of verbal memory, executive functions, and construction skills. The patient's global score was in the impaired range. His construction skills, semantic fluency, and delayed recall of verbal information were impaired, and perseveration errors were noted. List learning was in the lower average range, whereas story memory was borderline impaired. Visuospatial abilities, attention span, and delayed memory were below average, whereas language ability was in the average range. A brain MRI scan showed subtle, nonspecific T2 hyperintense, punctiform, frontoparietal white matter lesions and mild parietal and cerebellar brain atrophy. In the last 2 years, the number of generalized tonic-clonic seizures increased despite treatment with topiramate and lacosamide. His EEG was abnormal with short periods of theta between alpha background activity and with high-amplitude spike wave paroxysms, sometimes with frequencies of 4–5 Hz and paroxysms of polyspikes, frontally or generalized.

• Download figure
• Open in new tab
• Download powerpoint

Figure Genetic and Clinical Findings of the Investigated Individuals

(A) Family tree and electropherograms of the identified PCYT2 variants. (B and C) Clinical photographs of patient 1 at age 41 years. Muscle wasting and hip and knee flexion contractures (B). High-arched feet and hammertoes (C). (D) Schematic representation of the protein isoform PCYT2α and location of variants. PCYT2 protein is predicted to have 2 cytidylyltransferase (CTP) catalytic domains. The homozygous missense variant (in red) identified in this study is located in the first CTP domain. Amino acid sequence alignments across multiple species reveal the well-conserved nature of the affected amino acid residue. All previously reported missense variants (in black) are located in the second CTP domain.

Patient 2 (II:2) is a 53-year-old man, an older brother of patient 1, with milder clinical presentation. He presented with gait instability at age 2 years and began using crutches at age 14 years. At age 15 years, he had his first generalized tonic-clonic seizure. The seizures were well controlled with methylphenobarbital. His condition slowly deteriorated and by age 39 years, he was wheelchair dependent. He did not complain of vision problems. At age 53 years, he had a short stature (150 cm; −4.1 SD) and weighed 50 kg, and his head circumference was 57 cm (+0.7 SD). Neurologic examination showed dysarthria, mild saccadic eye movements, and nystagmus. Spasticity, distal muscle atrophy, and weakness were noted in the upper and lower limbs. Patellar reflexes were brisk, and Achilles reflexes were weak. The feet were high arched, and hammertoes were present. He could not feel vibration even on the crista iliaca; otherwise, sensory impairment was noted distal to the forearms and knees. He could not perform active movements with the lower limbs. Signs of cerebellar dysfunction (intension tremor, dysmetria, dysdiadochokinesia, and mild truncal ataxia) were present. He denied problems with urine retention. Cognitive impairment was similar as in patient 1, although of milder degree. His EMG was also consistent with axonal motor and sensory neuropathy (Table).

Genetic Analyses

Analysis of ES data identified a novel homozygous missense variant in PCYT2 (NM_001184917.2):c.88T>G p.(Cys30Gly) (Figure 1A). No significant homozygosity blocks were identified in the ES data, and we did not detect pathogenic variants in other polyneuropathy-related genes in the exome. Sanger sequencing confirmed the homozygous state of the same PCYT2 variant in the index patient and his affected brother. Both unaffected parents were found to be heterozygous carriers of the variant (Figure 1A). The identified variant was absent in databases (gnomAD and our internal database). The nucleotide and amino acid position are well conserved (Figure 1D), and theoretical predictors of pathogenicity consistently predicted a deleterious effect on protein function for this amino acid substitution. MutationTaster, PolyPhen2, SIFT, and MetaSVM anticipated a likely or probably damaging effect, and CADD and REVEL reported high pathogenicity scores of 27.3 and 0.93, respectively. In addition, the variant substitutes a cysteine residue that can form disulfide bonds and thus may be important for maintaining protein structure. The substitution is located in a highly conserved tyrosine kinase site (RVWCDGCY; 24–31 amino acids) 5 residues N-terminal to the HYGH catalytic motif (35–38 amino acids) in the first cytidylyltransferase (CTP) catalytic domain (Figure 1D).⁹